Pharmaceutical compounds having activity as wee1 inhibitors

Abstract

The invention provides compounds having the formula (1) or being a salt or tautomer thereof; wherein: R1 is a C1-6 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O or N atom, wherein the hydrocarbyl group is optionally substituted with one or more substituents selected from fluorine, methoxy, cyano, amino, methylamino, dimethylamino and hydroxyl; n is 1, 2 or 3; each R2 is independently selected from halogen, hydroxyl, cyano, C1-4 hydrocarbyl and O-C1-4 hydrocarbyl; R3 is hydrogen or a group Q-R4; Q is absent or a C1-3 hydrocarbyl linker (e.g. CH2 or CH2CH2); and R4 is a C1-4 hydrocarbyl group or a 4-7 membered non-aromatic heterocyclic ring containing one or two heteroatom ring members selected from N, O, S and SO2, wherein the hydrocarbyl group or non-aromatic heterocyclic ring is optionally substituted with one or more substituents R5. The invention also provides pharmaceutical compositions comprising the compounds and medical uses of the compounds, for example as Wee1 inhibitors for the treatment of cancer.

Description

[0001] PHARMACEUTICAL COMPOUNDS HAVING ACTIVITY AS WEE1 INHIBITORS

[0002] This invention relates to compounds that inhibit or modulate the activity of Wee1 kinase, pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds.

[0003] Background of the Invention

[0004] The cell cycle is a highly controlled process and there are numerous cell-cycle checkpoints that prevent or delay mitosis in the event of detected DNA damage. This provides the cell with time to repair the damaged DNA before proliferating via mitosis.

[0005] The G2-M DNA damage checkpoint ensures that cells do not initiate mitosis until damaged or incompletely repaired DNA is sufficiently repaired following replication. Entry into mitosis from the G2-M checkpoint is controlled by phosphorylation of Cdk1 and its association with cyclin B.

[0006] Cyclic-dependent kinases (Cdk) are a family of serine / threonine protein kinases that are involved in the G2-M checkpoint, which controls the entry of the cell into mitosis.

[0007] In normal cells, Cdk1 complexes with Cyclin B in order to induce mitosis. The Cdk1 / cyclin B complex is activated by dephosphorylation of its Tyr15 residue by phosphatase, Cdc25c and the resulting activated complex causes the cell to enter mitosis.

[0008] The Wee1 enzyme is a nuclear kinase belonging to the Tyrosine family of protein kinases, which is capable of deactivating the Cdk1 / Cyclin B complex by phosphorylation. The Wee1 family also includes PKMYT1 and WEE1 B.

[0009] DNA damage is detected by the ataxia-telangiectasia-related (ATR) protein kinase pathway and results in phosphorylation and activation of Chk1 kinase. The Chk1 kinase subsequently phosphorylates Wee1 .

[0010] At high levels of phosphorylation, Wee1 phosphorylates Cdk1 at its Tyr15 residue to maintain it in its inactive state in association with cyclin B and prevent the damaged cell from entering mitosis. Wee1 is therefore a key negative regulator of cell cycle progression.

[0011] Once the DNA damage has been repaired, Wee1 activity decreases and therefore inhibitory phosphorylation of Cdk1 is lost and the cell enters mitosis. Wee1 also plays a role in S phase where it acts on Cdk2 to stabilize the replication machinery and regulates histone synthesis.

[0012] Wee1 is highly expressed in numerous types of cancers, particularly those that have a deficient G1 / S checkpoint and therefore rely on the G2-M checkpoint for survival. These cancers rely on the G2-M checkpoint in order to prevent excessive DNA damage and to prevent apoptosis resulting from mitotic catastrophe. Aberrations in the G1 / S checkpoint are frequently caused by mutations in TP53, RB and / or imbalance in cyclins, CDKs and their inhibitors.

[0013] Copy number alterations are a frequent event in cancers with the Wee1 gene being predominantly involved in copy number loss. Cancer types showing high recurrence of copy number alterations include ovarian serous cystadenocarcinoma, lung squamous cell carcinoma, uterine carcinosarcoma and sarcoma. Wee1 is also over-expressed in solid tumours including hepatocellular carcinoma, colon cancer, glioblastoma, non-small cell lung cancer, neuroblastoma and gastric cancers. Hematological malignancies with high expression of Wee1 kinase include acute lymphoblastic leukemia, multiple myeloid leukemia, chronic myeloid leukemia and chronic lymphocyte leukemia (see Ghellil Luserna di Rora et al., “A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target”, J Hematol Oncol. 2020; 13 (1)).

[0014] Inhibition of Wee1 is therefore seen as an attractive target for these cancers in order to abrogate the G2-M checkpoint leading to unscheduled mitosis and cell death by mitotic catastrophe.

[0015] A wide range of cancers have been reported to be sensitive to Wee1 inhibitors, both as a monotherapy (in particular in cancer types with elevated replicative stress), and in combination with DNA damaging agents that can induce replicative stress (such as Gemcitabine or ionising radiation).

[0016] Causes of replication stress include: mutation in RAS, c-Myc and cyclin E; inactivation of key tumour suppressors such as TP53, RB1 and CDKN2A. Deficits in DNA damage response such as BRCA1 / 2, Chk1 , FANC-family and other homologous recombination genes also result in excessive replication stress.

[0017] One type of cancer reported to be susceptible to treatment with Wee1 inhibitors is medulloblastoma. Medulloblastoma is a common primary brain cancer in children. The cancer typically originates towards the back and the bottom of the brain, on the floor of the skull and / or in the cerebellum or posterior fossa. Medulloblastomas are invasive and rapidly growing tumours. Unlike many brain tumours, medulloblastomas can spread through the cerebrospinal fluid and therefore commonly metastasise to other surfaces of the brain and to the spinal cord. It has been found that small molecule inhibition of Wee1 suppresses medulloblastoma growth (Harris et al, Mol Cancer. 2014; 13: 72).

[0018] A number of other types of cancer have been reported to be sensitive to Wee1 inhibition, including:

[0019] Diffuse Intrinsic Pontine Glioma (DIPG) (see Caretti et al., “WEE1 kinase inhibition enhances the radiation response of diffuse intrinsic pontine gliomas”, Mol Cancer Ther., 2013, 12(2), 141-50);

[0020] Glioblastoma (see Mir et al.. “In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma”, Cancer Cell. 2010,18(3), 244-57 and Sarcar et al., “Targeting Radiation-Induced G2 Checkpoint Activation with the Wee-1 Inhibitor MK-1775 in Glioblastoma Cell Lines”, Mol Cancer Then, 2011, 10(12), 2405-14);

[0021] Ependymoma (see Kool et al., “Therapeutic Targeting of Ependymoma as Informed by Oncogenic Enhancer Profiling”, Nature. 2018 January 04; 553(7686): 101-105. doi: 10.1038 / nature25169);

[0022] Acute myeloid leukemia (see Porter et al., “Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and a novel therapeutic target in acute myeloid leukemia”, Leukemia, 2012, 26, 1266-1276);

[0023] Cervical cancer (see Hirai et al., “Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumour cells to DNA-damaging agents”, Mol Cancer Then, 2009, 8(11), 2992-3000);

[0024] Colorectal cancer (see Hirai et al., “Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumour cells to DNA-damaging agents”, Mol Cancer Then, 2009, 8(11), 2992-3000);

[0025] Head and neck squamous cell carcinoma (see Diab et al., “Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition”, Mol Cancer Res, 2019, 17(5), 1115-1128); Malignant melanoma (see Magnuseen et al., “High expression of Wee1 is associated with poor disease-free survival in malignant melanoma: potential for targeted therapy”, PLoS One., 2012;7(6):e38254);

[0026] Ovarian cancer (see Zhang et al., “WEE1 inhibition by MK1775 as a single-agent therapy inhibits ovarian cancer viability”, Oncol Lett., 2017, 14(3), 3580-3586);

[0027] Pancreatic cancer (see Cuneo et al., “Dose Escalation Trial of the Wee1 Inhibitor Adavosertib (AZD1775) in Combination With Gemcitabine and Radiation for Patients With Locally Advanced Pancreatic Cancer”, J Clin Oncol. 2019 Aug 9: JCO1900730 and Rajeshkumar et al., “MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumour regressions, selectively in p53-deficient pancreatic cancer xenografts”, Clin Cancer Res., 2011 , 17(9), 2799-806);

[0028] Sarcoma (see Kreahling et al., “MK1775, a selective Wee1 inhibitor, shows single-agent antitumour activity against sarcoma cells”, Mol Cancer Ther., 2012, 11 (1), 174-82);

[0029] Small cell lung cancer (see Richer et al., “WEE1 Kinase Inhibitor AZD1775 Has Preclinical Efficacy in LKB1 -Deficient Non-Small Cell Lung Cancer”, Cancer Res., 2017, 77(17), 4663-72 and Lallo et al., “The Combination of the PARP Inhibitor Olaparib and the WEE1 Inhibitor AZD1775 as a New Therapeutic Option for Small Cell Lung Cancer”, Clin Cancer Res, 2018, 24(20), 5153-5164); and

[0030] Triple-negative breast cancer (see Chen et al., “Cyclin E Overexpression Sensitizes Triple-Negative Breast Cancer to Wee1 Kinase Inhibition”, Clin Cancer Res., 2018, 24(24), 6594-6610); and

[0031] Uterine Serous Carcinoma (USC) or Uterine Carcinosarcoma (see Liu et al., “Phase II Study of the WEE1 Inhibitor Adavosertib in Recurrent Uterine Serous Carcinoma”. J Clin Oncol. 2021 May 10;39(14):1531-1539. doi: 10.1200 / JC0.20.03167. Epub 2021 Mar 11. PMID: 33705205 and “ADAGIO: a phase lib international study of the Wee1 inhibitor adavosertib in women with recurrent or persistent uterine serous carcinoma”.

[0032] International Journal of Gynecologic Cancer Published Online First: 29 October 2021. doi: 10.1136 / ijgc-2021-003144.

[0033] A small molecule inhibitor of Wee1 , AZD1775 (also referred to as Adavosertib or MK1775):

[0034] (AZD1775) has been developed and shows good inhibitory activity against Wee1 in cell-based assays (~80nM) and also in vivo when used as a sole therapeutic agent or in combination with a further chemotherapeutic agent (e.g. gemcitabine or carboplatin). However, data have been published suggesting that AZD1775 has sub-optimal ADME (Absorption, Distribution, Metabolism, Excretion) properties. It is highly effluxed from the brain when dosed orally (see Tellingen et al., 2018, Investigational New Drugs, ATP-binding cassette transporters limit the brain penetration of Wee1 inhibitors). It is anticipated that this would limit clinical efficacy of the compound against brain malignancies. Furthermore, data from US patent application with publication number US 2019 / 0084985 show that, following a 20 mg / kg single oral dose of AZD1775 to mice bearing dorsal flank tumour xenografts, only trace amounts of AZD1775 penetrated the brain. In addition, it was reported that when AZD1775 was dosed in a Phase I trial it was found to have an apparent oral clearance of 2.67 L / hour which is high considering that it exceeds human liver blood flow (see Do et al., 2015, Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors).

[0035] It would therefore be beneficial to develop further compounds that have the ability to inhibit Wee1 kinase.

[0036] The Invention

[0037] The present invention provides a class of novel compounds as inhibitors of Wee1 kinase.

[0038] In a first embodiment (Embodiment 1.1) of the invention, there is provided a compound having the formula (1): or being a salt or tautomer thereof; wherein:

[0039] R1is a C1-6 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O or N atom, wherein the hydrocarbyl group is optionally substituted with one or more substituents selected from fluorine, methoxy, cyano, amino, methylamino, dimethylamino and hydroxyl; n is 1 , 2 or 3; each R2is independently selected from halogen, hydroxyl, cyano, C1-4 hydrocarbyl and O-C1-4 hydrocarbyl;

[0040] R3is hydrogen or a group Q-R4;

[0041] Q is absent or a C1-3 hydrocarbyl linker (e.g. CH2 or CH2CH2);

[0042] R4is a C1-4 hydrocarbyl group or a 4-7 membered non-aromatic heterocyclic ring containing one or two heteroatom ring members selected from N, O, S and SO2, wherein the hydrocarbyl group or non-aromatic heterocyclic ring is optionally substituted with one or more substituents R5,

[0043] R5is selected from halogen, hydroxyl, methoxy, amino, mono-Ci-2-alkylamino, di- Ci-2-alkylamino, acetyl, cyano, C1-3 hydrocarbyl, hydroxy-Ci-3-hydrocarbyl, methoxy-Ci-3- hydrocarbyl and a 4-8 membered non-aromatic carbocyclic or heterocyclic ring containing one or two heteroatom ring members selected from N and O, and wherein when two R5substituents are present on the same atom, these may join to form a C3-6 carbocyclic or heterocyclic non-aromatic ring; and wherein, in each substituent consisting of or containing a hydrocarbyl group, the hydrocarbyl group is selected from alkyl, alkenyl, alkynyl and cycloalkyl groups and combinations thereof.

[0044] In a second embodiment (Embodiment 1.1 A) of the invention, there is provided a compound having the formula (1): or being a salt or tautomer thereof; wherein:

[0045] R1is a C1-6 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O or N atom, wherein the hydrocarbyl group is optionally substituted with fluorine or hydroxyl; n is 1 , 2 or 3; each R2is independently selected from halogen, hydroxyl, cyano, C1-4 hydrocarbyl and O-C1-4 hydrocarbyl;

[0046] R3is hydrogen or a group Q-R4;

[0047] Q is absent or a C1-3 hydrocarbyl linker (e.g. CH2 or CH2CH2);

[0048] R4is a C1-4 hydrocarbyl group or a 4-7 membered non-aromatic heterocyclic ring containing one or two heteroatom ring members selected from N, O, S and SO2, wherein the hydrocarbyl group or non-aromatic heterocyclic ring is optionally substituted with one or more substituents R5,

[0049] R5is selected from halogen, hydroxyl, methoxy, amino, mono-Ci-2-alkylamino, di- Ci-2-alkylamino, acetyl, cyano, C1-3 hydrocarbyl, hydroxy-Ci-3-hydrocarbyl, methoxy-Ci-3- hydrocarbyl and a 4-8 membered non-aromatic carbocyclic or heterocyclic ring containing one or two heteroatom ring members selected from N and O, and wherein when two R5substituents are present on the same atom, these may join to form a C3-6 carbocyclic or heterocyclic non-aromatic ring; and wherein, in each substituent consisting of or containing a hydrocarbyl group, the hydrocarbyl group is selected from alkyl, alkenyl, alkynyl and cycloalkyl groups and combinations thereof.

[0050] Particular and preferred compounds of the formula (1) are as defined in Embodiments 1.1 B to 1.100 below.

[0051] 1.1 B A compound according to Embodiment 1.1 wherein R1is a C1-6 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O or N atom and wherein the hydrocarbyl group is optionally substituted with one or more (e.g. one or two) substituents selected from fluorine, methoxy, cyano, amino and hydroxyl.

[0052] 1.1C A compound according to Embodiment 1.1 wherein R1is a C1-4 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O or N atom and wherein the hydrocarbyl group is optionally substituted with one or more (e.g. one or two) substituents selected from fluorine, methoxy, cyano, amino and hydroxyl.

[0053] 1.1 D A compound according to Embodiment 1.1 wherein R1is a C1-6 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O or N atom and wherein the hydrocarbyl group is optionally substituted with one or more (e.g. one or two) substituents selected from fluorine, methoxy and hydroxyl.

[0054] 1.1 E A compound according to Embodiment 1.1 wherein R1is a C1-4 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O or N atom and wherein the hydrocarbyl group is optionally substituted with one or more (e.g. one or two) substituents selected from fluorine, methoxy and hydroxyl.

[0055] 1.2 A compound according to Embodiment 1.1 or 1.1 A wherein R1is a C1-4 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O or N atom and wherein the hydrocarbyl group is optionally substituted with fluorine or hydroxyl. 1.2A A compound according to any one of Embodiments 1.1 or 1.1 B to 1.1 E wherein R1is a C2-4 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O or N atom and wherein the hydrocarbyl group is optionally substituted with one or more (e.g. one or two) substituents selected from fluorine, methoxy and hydroxyl.

[0056] 1.3 A compound according to any one of Embodiment 1.1 , 1.1 A or Embodiment 1.2A wherein R1is a C2-4 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O or N atom and wherein the hydrocarbyl group is optionally substituted with fluorine or hydroxyl.

[0057] 1.3A A compound according to Embodiments 1.1 to 1.1 E or 1.2A wherein R1is a C1-4 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O atom and wherein the hydrocarbyl group is optionally substituted with one or more (e.g. one or two) substituents selected from fluorine, methoxy and hydroxyl.

[0058] 1.4 A compound according to any one of Embodiments 1.1 to 1.2 wherein R1is a C1-4 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O atom and wherein the hydrocarbyl group is optionally substituted with fluorine or hydroxyl.

[0059] 1 ,4A A compound according to Embodiment 1 ,2A wherein R1is a C2-4 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O atom and wherein the hydrocarbyl group is optionally substituted with one or more (e.g. one or two) substituents selected from fluorine, methoxy and hydroxyl.

[0060] 1.5 A compound according to Embodiment 1.3wherein R1is a C2-4 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O atom and wherein the hydrocarbyl group is optionally substituted with fluorine or hydroxyl.

[0061] 1.6 A compound according to Embodiment 1.5 wherein the C2-4 hydrocarbyl group is an alkyl group or a cycloalkyl group.

[0062] 1 ,6A A compound according to Embodiment 1.1 wherein R1selected from: a) an C1-3 alkyl group (e.g. methyl, ethyl, propyl or / so-propyl) optionally substituted with one or more (e.g. one) substituents selected from hydroxyl, methoxy or fluorine; b) a cyclopropyl, cyclopropylmethyl or cyclobutyl group optionally substituted with one or more (e.g. one) substituents selected from methyl, hydroxyl or fluorine; or c) an oxetane group optionally substituted with one or more (e.g. one) fluorine substituents.

[0063] 1.7 A compound according to any one of Embodiments 1 .1 to 1 ,6A wherein R1selected from: a) an ethyl group optionally substituted with one or more (e.g. one) substituents selected from hydroxyl, methoxy or fluorine; b) a cyclopropyl or cyclobutyl group optionally substituted with one or more (e.g. one) substituents selected from hydroxyl or fluorine; or c) an oxetane group optionally substituted with one or more (e.g. one) fluorine substituents.

[0064] 1 .7 A A compound according to Embodiment 1 .7 wherein R1is selected from cyclopropyl, cyclobutyl, 3-hydroxycyclobutyl, 1-methoxypropan-2-yl, 2-hydroxyethyl and 2-methyoxyethyl.

[0065] 1.8 A compound according to Embodiment 1 .7 A wherein R1is selected from cyclopropyl, cyclobutyl, 3-hydroxycyclobutyl, 2-hydroxyethyl and 2-methyoxyethyl.

[0066] 1.9 A compound according to Embodiment 1 .8 wherein R1is cyclopropyl.

[0067] 1.10 A compound according to Embodiment 1.8 wherein R1is cyclobutyl.

[0068] 1.11 A compound according to Embodiment 1.8 wherein R1is 3-hydroxycyclobutyl.

[0069] 1.11 A A compound according to Embodiment 1.7A wherein R1is 1-methoxypropan-2-yl.

[0070] 1.11 B A compound according to Embodiment 1.7A wherein R1is: where the asterisk marks the position of attachment to the oxygen atom in formula (1).

[0071] 1.11C A compound according to Embodiment 1.7A wherein R1is where the asterisk marks the position of attachment to the oxygen atom in formula (1).

[0072] 1.11 D A compound according to Embodiment 1.8 wherein R1is 3-fluorocyclobutyl.

[0073] 1.11E A compound according to Embodiment 1.8 wherein R1is isopropyl. 1.12 A compound according to Embodiment 1.8 wherein R1is selected from 2- hydroxyethyl and 2-methyoxyethyl.

[0074] 1.13 A compound according to any one of Embodiments 1.1 to 1.12 wherein n is 1.

[0075] 1.14 A compound according to any one of Embodiments 1.1 to 1.12 wherein n is 2.

[0076] 1.15 A compound according to any one of Embodiments 1.1 to 1.12 wherein n is 3. 1.16 A compound according to any one of Embodiments 1.1 to 1.12 wherein n is 1 or 2.

[0077] 1.17 A compound according to any one of Embodiments 1.1 to 1.12 wherein n is 2 or 3.

[0078] 1.18 A compound according to any one of Embodiments 1.1 to 1.17 wherein each R2is independently selected from halogen, hydroxyl and cyano.

[0079] 1.19 A compound according to any one of Embodiments 1.1 to 1.18 wherein each R2is independently selected from halogen and hydroxyl.

[0080] 1.20 A compound according to Embodiment 1.19 wherein each R2is a halogen (e.g. chlorine).

[0081] 1.21 A compound according to any one of Embodiments 1.1 to 1.12 wherein the compound has the formula (2): or is a salt or tautomer thereof; wherein R1and R3are as defined in any one of Embodiments 1.1 to 1.12, m is 0 or 1 ; and

[0082] R2A, R2Band R2Care independently selected from hydrogen, halogen, hydroxyl, cyano, C1-4 hydrocarbyl and O-C1-4 hydrocarbyl, provided that one of R2Aand R2Bis other than hydrogen.

[0083] 1.22 A compound according to Embodiment 1.21 wherein R2A, R2Band R2Care independently selected from hydrogen, halogen, hydroxyl and C1-4 hydrocarbyl.

[0084] 1 .23 A compound according to Embodiment 1.21 or Embodiment 1 .22 wherein R2Ais selected from halogen and hydroxyl.

[0085] 1 .24 A compound according to Embodiment 1.23 wherein R2Ais a halogen (e.g. chlorine).

[0086] 1 .25 A compound according to any one of Embodiments 1.21 to 1.24 wherein R2Bis selected from hydrogen, halogen and hydroxyl.

[0087] 1 .26 A compound according to Embodiment 1.25 wherein R2Bis hydrogen or halogen.

[0088] 1 .27 A compound according to Embodiment 1.26 wherein R2Bis hydrogen, chlorine or fluorine.

[0089] 1 .28 A compound according to Embodiment 1.27 wherein R2Bis chlorine.

[0090] 1 .29 A compound according to Embodiment 1.27 wherein R2Bis fluorine.

[0091] 1 .30 A compound according to Embodiment 1.27 wherein R2Bis hydrogen. 1 .31 A compound according to any one of Embodiments 1 .21 to 1 .30 wherein m is 0.

[0092] 1 .32 A compound according to any one of Embodiments 1 .21 to 1 .30 wherein m is 1.

[0093] 1 .33 A compound according to Embodiment 1.32 wherein R2Cis selected from a halogen and hydroxyl.

[0094] 1 .34 A compound according to Embodiment 1.33 wherein R2Cis a halogen.

[0095] 1 .35 A compound according to Embodiment 1.34 wherein R2Cis chlorine.

[0096] 1 .36 A compound according to Embodiment 1.34 wherein R2Cis fluorine.

[0097] 1.36A A compound according to Embodiment 1.33 wherein R2Cis selected from hydroxyl.

[0098] 1 .37 A compound according to any one of Embodiments 1 .21 to 1.36 wherein the compound is of the formula (3): wherein R1, R2A, R2B, R2Cand R3are as defined in any one of Embodiments 1.1 to 1.36.

[0099] 1 .39 A compound according to Embodiment 1.38 wherein:

[0100] R2Ais chlorine;

[0101] R2Bis chlorine; and

[0102] R2Cis hydrogen.

[0103] 1 .40 A compound according to Embodiment 1.38 wherein:

[0104] R2Ais chlorine;

[0105] R2Bis chlorine; and

[0106] R2Cis fluorine. 1.40A A compound according to Embodiment 1.38 wherein:

[0107] R2Ais chlorine;

[0108] R2Bis chlorine; and

[0109] R2Cis hydroxyl.

[0110] 1.41 A compound according to Embodiment 1.38 wherein:

[0111] R2Ais chlorine;

[0112] R2Bis fluorine; and

[0113] R2Cis fluorine.

[0114] 1.42 A compound according to Embodiment 1.38 wherein:

[0115] R2Ais chlorine;

[0116] R2Bis fluorine; and

[0117] R2Cis hydrogen.

[0118] 1.43 A compound according to Embodiment 1.38 wherein:

[0119] R2Ais chlorine;

[0120] R2Bis hydrogen; and

[0121] R2Cis chlorine.

[0122] 1.44 A compound according to any one of Embodiments 1.1 to 1.43 wherein R3is hydrogen.

[0123] 1.45 A compound according to any one of Embodiments 1.1 to 1.43 wherein R3is a group Q-R4.

[0124] 1.46 A compound according to Embodiment 1.45 wherein Q is absent or a C1-2 hydrocarbyl linker (e.g. CH2 or CH2CH2).

[0125] 1.47 A compound according to Embodiment 1.45 wherein Q is absent or a methylene (CH2) linker.

[0126] 1.48 A compound according to Embodiment 1.46 wherein Q is absent.

[0127] 1.49 A compound according to Embodiment 1.46 wherein Q is CH2.

[0128] 1.50 A compound according to Embodiment 1.46 wherein Q is CH2CH2. 1.51 A compound according to any one of Embodiments 1.1 to 1.50 wherein R4is a Ci- 4 hydrocarbyl group or a 4-7 membered non-aromatic heterocyclic ring containing one or two heteroatom ring members selected from N and O, wherein the hydrocarbyl group or non-aromatic heterocyclic ring is optionally substituted with one or more substituents R5.

[0129] 1.52 A compound according to any one of Embodiments 1.1 to 1.50 wherein R4is a Ci- 4 hydrocarbyl group or a 4-6 membered non-aromatic heterocyclic ring containing one or two heteroatom ring members selected from N, O, S and SO2, wherein the hydrocarbyl group or non-aromatic heterocyclic ring is optionally substituted with one or more substituents R5.

[0130] 1.53 A compound according to Embodiment 1.52 wherein R4is a C1-4 hydrocarbyl group or a 4-6 membered non-aromatic heterocyclic ring containing one or two heteroatom ring members selected from N and O, wherein the hydrocarbyl group or non- aromatic heterocyclic ring is optionally substituted with one or more substituents R5.

[0131] 1.54 A compound according to any one of Embodiments 1.1 to 1.53 wherein when R4is a C1-4 hydrocarbyl group, the hydrocarbyl group is saturated.

[0132] 1.55 A compound according to any one of Embodiments 1.1 to 1.54 wherein when R4is a C1-4 hydrocarbyl group, the hydrocarbyl group is a C1-4 alkyl group.

[0133] 1.55 A compound according to any one of Embodiments 1.1 to 1.54 wherein when R4is a C1-4 hydrocarbyl group, the hydrocarbyl group is a cyclopropyl or cyclobutyl group.

[0134] 1.56 A compound according to any one of Embodiments 1.1 to 1.53 wherein when R4is a non-aromatic heterocyclic ring it contains one heteroatom ring member selected from N and O (as the only heteroatom ring member).

[0135] 1.57 A compound according to Embodiment 1.53 wherein when R4is a non-aromatic heterocyclic ring it contains one nitrogen and one oxygen heteroatom ring member (as the only heteroatom ring members).

[0136] 1.58 A compound according to any one of Embodiment 1.1 to 1.53 and 1.56 to 1.57 wherein when R4is a non-aromatic heterocyclic ring it is a 4-membered or a 6-membered non-aromatic heterocyclic ring.

[0137] 1.59 A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is selected from methyl, ethyl, propyl, 2-methylpropyl, cyclobutyl, piperidyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, oxetanyl, azetidinyl, 2-azabicyclo[2.2.1]heptyl and 2- azaspiro[3.3]heptyl, each optionally substituted with one or more substituents R5.

[0138] 1.60 A compound according to Embodiment 1.59 wherein R4is selected from methyl, ethyl, propyl, 2-methylpropyl, cyclobutyl, piperidyl, pyrrolidinyl, tetrahydropyranyl, morpholiny and oxetanyl, each optionally substituted with one or more substituents R5.

[0139] 1.61 A compound according to Embodiment 1.60 wherein R4is methyl substituted with one or more substituents R5.

[0140] 1.62 A compound according to Embodiment 1.60 wherein R4is ethyl substituted with one or more substituents R5.

[0141] 1.63 A compound according to Embodiment 1.60 wherein R4is propyl substituted with one or more substituents R5.

[0142] 1.63A A compound according to Embodiment 1.60 wherein R4is cyclobutyl substituted with one or more substituents R5.

[0143] 1.64 A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is a piperidyl group optionally substituted with one or more substituents R5.

[0144] 1.65 A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is a 4- piperidyl group optionally substituted with one or more substituents R5.

[0145] 1.66 A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is a 3- piperidyl group optionally substituted with one or more substituents R5.

[0146] 1.67 A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is a 1- piperidyl group optionally substituted with one or more substituents R5.

[0147] 1.68 A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is a tetrahydropyranyl group optionally substituted with one or more substituents R5.

[0148] 1.69 A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is a 4- tetrahydropyranyl group optionally substituted with one or more substituents R5.

[0149] 1.70 A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is an oxetanyl group optionally substituted with one or more substituents R5. 1.71 A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is a 4- oxetanyl group optionally substituted with one or more substituents R5.

[0150] 1.72 A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is a morpholinyl group optionally substituted with one or more substituents R5.

[0151] 1.73 A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is a 2- morpholinyl group optionally substituted with one or more substituents R5.

[0152] 1.73A A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is a piperazinyl group optionally substituted with one or more substituents R5.

[0153] 1.73B A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is a 1- piperazinyl group optionally substituted with one or more substituents R5.

[0154] 1.73C A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is a 4- morpholinyl group optionally substituted with one or more substituents R5.

[0155] 1.73D A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is an azetidinyl group (e.g. a 2-azetidinyl group) optionally substituted with one or more substituents R5.

[0156] 1.74E A compound according to any one of Embodiments 1.1 to 1.51 wherein R4is a pyrrolidinyl group (e.g. a 3-pyrrolidinyl group) optionally substituted with one or more substituents R5.

[0157] 1.74 A compound according to any one of Embodiments 1.1 to 1.73B wherein R4is unsubstituted or substituted with one or two substituents R5.

[0158] 1 .75 A compound according to any one of Embodiments 1 .1 to 1.74 wherein R4is unsubstituted or substituted with one substituent R5.

[0159] 1 .76 A compound according to Embodiment 1.75 wherein R4is substituted with one substituent R5.

[0160] 1.77 A compound according to Embodiment 1.75 wherein R4is unsubstituted.

[0161] 1 .78 A compound according to any one of Embodiment 1 .1 to 1.76 wherein R5is selected from fluorine, chlorine, hydroxyl, methoxy, amino, mono-Ci-2-alkylamino, di-Ci-2- alkylamino, acetyl, cyano, C1-3 hydrocarbyl, hydroxy-Ci-3-hydrocarbyl, methoxy-Ci-3- hydrocarbyl and a 4-6 membered non-aromatic carbocyclic or heterocyclic ring containing one or two heteroatom ring members selected from N and O, and wherein when two R5substituents are present on the same atom, these may join to form a C3-5 carbocyclic or heterocyclic non-aromatic ring.

[0162] 1.79 A compound according to Embodiment 1.78 wherein R5is selected from fluorine, chlorine, hydroxyl, methoxy, amino, acetyl, cyano, C1-3 hydrocarbyl (e.g. saturated C1-3 hydrocarbyl), and a 4-6 membered non-aromatic carbocyclic or heterocyclic ring containing one or two heteroatom ring members selected from N and O, and wherein when two R5substituents are present on the same atom, these may join to form a C3-5 carbocyclic or heterocyclic non-aromatic ring.

[0163] 1.80 A compound according to Embodiment 1.79 wherein R5is selected from fluorine, chlorine, hydroxyl, methoxy, amino, acetyl, cyano, methyl, ethyl and a 4 membered non- aromatic carbocyclic or heterocyclic ring containing one heteroatom ring member selected from N and O, and wherein when two R5substituents are present on the same atom, these may join to form a C3-4 carbocyclic or heterocyclic non-aromatic ring.

[0164] 1.80A A compound according to Embodiment 1.78 wherein R5is selected from fluorine, hydroxyl, hydroxymethyl, methoxy, amino, acetyl, cyano, methyl, ethyl, cyclopropyl and an oxetanyl group (e.g. a 4-oxetanyl group).

[0165] 1.81 A compound according to Embodiment 1.80 wherein R5is selected from fluorine, hydroxyl, methoxy, amino, acetyl, cyano, methyl, ethyl and an oxetanyl group (e.g. a 4- oxetanyl group).

[0166] 1.82 A compound according to Embodiment 1.81 wherein R5is methyl or ethyl.

[0167] 1.83 A compound according to Embodiment 1.81 wherein R5is methyl.

[0168] 1.84 A compound according to Embodiment 1.81 wherein R5is ethyl.

[0169] 1.85 A compound according to Embodiment 1.81 wherein R5is fluorine.

[0170] 1.86 A compound according to Embodiment 1.81 wherein R5is hydroxyl.

[0171] 1.87 A compound according to Embodiment 1.81 wherein R5is methoxy.

[0172] 1.88 A compound according to Embodiment 1.81 wherein R5is amino. 1.89 A compound according to Embodiment 1.81 wherein R5is acetyl.

[0173] 1.90 A compound according to Embodiment 1.81 wherein R5is cyano.

[0174] 1.91 A compound according to Embodiment 1.81 wherein R5is a 4-oxetanyl group.

[0175] 1.92 A compound selected from the title compounds of Examples 1 to 45 herein.

[0176] 1.92A A compound selected from the title compounds of Examples 1 to 87 herein.

[0177] 1.92B A compound selected from the title compounds of Examples 1 to 86 herein.

[0178] 1.93 A compound selected from the title compounds of Examples 1 to 32 and 34 herein.

[0179] 1.93A A compound selected from the title compounds of Examples 46 to 87.

[0180] 1.93B A compound selected from the title compounds of Examples 1 , 23, 28, 35 and 57.

[0181] 1.94 A compound which is 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-{[1 -(1 - methylpiperidin-4-yl)-1 H-pyrazol-4-yl]amino}pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof.

[0182] 1.94A A compound which is 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-[(1-{[(2S)-4- methylmorpholin-2-yl]methyl}-1 H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof.

[0183] 1.94B A compound which is 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1-[(2R)-1- hydroxypropan-2-yl]-1 H-pyrazol-4-yl}amino)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof.

[0184] 1.94C A compound which is N-(2,6-dichlorophenyl)-4-(2-methoxyethoxy)-2-{[1-(1- methylpiperidin-4-yl)-1 H-pyrazol-4-yl]amino}pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof.

[0185] 1.94D A compound which is N-(2,6-dichlorophenyl)-4-(2-methoxyethoxy)-2-{[1-(1- methylazetidin-3-yl)-1 H-pyrazol-4-yl]amino}pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof. 1.95 A compound according to any one of Embodiments 1.1 to 1.94D which is in the form of a salt.

[0186] 1.96 A compound according to Embodiment 1.95 wherein the salt is an acid addition salt.

[0187] 1.97 A compound according to Embodiment 1.95 or Embodiment 1.96 wherein the salt is a pharmaceutically acceptable salt.

[0188] 1.98 A compound according to any one of Embodiments 1.1 to 1.94D which is in the form of a non-salt (e.g. free base).

[0189] 1.99 A compound according to any one of Embodiments 1.1 to 1.98 which is in the form of a solvate.

[0190] 1.100 A compound according to Embodiment 1.99 wherein the solvate is a hydrate.

[0191] Definitions

[0192] References to the formula (1) herein include references to the formulae (2) and (3) and subformulae thereof, unless the context indicates otherwise.

[0193] References to “carbocyclic” and “heterocyclic” groups as used herein shall, unless the context indicates otherwise, include both aromatic and non-aromatic ring systems. Thus, for example, the term “carbocyclic and heterocyclic groups” includes within its scope aromatic, non-aromatic, unsaturated, partially saturated and fully saturated carbocyclic and heterocyclic ring systems.

[0194] The carbocyclic or heterocyclic groups can be aryl or heteroaryl groups. The aryl or heteroaryl groups can be monocyclic or bicyclic groups, as defined herein. The term “aryl” as used herein refers to a carbocyclic group having aromatic character and the term “heteroaryl” is used herein to denote a heterocyclic group having aromatic character. Where the context permits, the terms “aryl” and “heteroaryl” may embrace bicyclic ring systems wherein both rings are aromatic or one ring is non-aromatic and the other is aromatic. In such bicyclic systems containing one aromatic and one non-aromatic group, the group may be attached by the aromatic ring, or by the non-aromatic ring. The term “non-aromatic group” refers to unsaturated ring systems without aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. This includes monocyclic, bicyclic, bridged and spiro ring systems.

[0195] The terms “unsaturated” and “partially saturated” refer to rings wherein the ring structure(s) contains atoms sharing more than one valence bond e.g. the ring contains at least one multiple bond e.g. a C=C N=C bond. The term “saturated” refers to rings where there are no multiple bonds between ring atoms. Saturated carbocyclic groups include the cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Partially saturated carbocyclic groups include the cycloalkenyl groups such as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Non-aromatic heterocyclic groups include azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, thiomorpholine S-oxide and S,S-dioxide, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran, imidazoline, imidazolidinone, oxazoline, thiazoline, pyrazoline and pyrazolidine.

[0196] The term “hydrocarbyl” as used herein refers to aliphatic, alicyclic and aromatic groups having an all-carbon backbone and consisting of carbon and hydrogen atoms, except where otherwise stated. Examples of hydrocarbyl groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl and aralkynyl groups. Such groups can be unsubstituted or, where stated, substituted by one or more substituents as defined herein. In certain cases, as defined herein, one or more, but not all, of the carbon atoms of the hydrocarbyl group may be replaced by another atom or group of atoms.

[0197] Where a carbon atom of a hydrocarbyl group is replaced by another atom or group of atoms, the replacement will generally be such that it does not give rise to unstable groups such as peroxides and hemiacetals. In some embodiments, where a carbon atom is replaced by a heteroatom, there is at least one, preferably at least two carbon atoms between two heteroatoms, unless the content specifically indicates otherwise. For example, when a carbon atom in the group OR1is replaced by an oxygen atom, the replacement is typically such that it does to give rise to a 0-0 moiety or an O-C-OH moiety. In addition, for a Ci hydrocarbyl group, no heteroatom replacement can occur.

[0198] The term “alkylene” (e.g. as in C1-4 straight chain or branched chain alkylene) as used herein refers to an alkanediyl group, i.e. a divalent saturated acyclic straight chain or branched chain hydrocarbon group. Examples of straight chain alkanediyl groups include methylene (CH2), ethylene (CH2CH2) and propylene ((CH2CH2CH2). Examples of branched chain alkanediyl groups include CH(CH3), CH2CH(CH3)CH2 and CH2(CH3)CH2CH2.

[0199] The term “haloalkyl” as used herein refers to alkyl group substituted with one or more halogen atom substituents, and in particular fluorine substituents. Particular examples of haloalkyl groups are trifluoromethyl and difluoromethyl.

[0200] Salts

[0201] The compounds of the invention as defined in Embodiments 1.1 to 1.94 may be presented in the form of salts. Unless indicated otherwise, the term “salts” as used herein encompasses inner / internal salts (also referred to as zwitterions).

[0202] The salts referred to above (and also defined in Embodiments 1.95, 1.96 and 1.97) are typically acid addition salts.

[0203] The salts can be synthesized from the parent compound by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free base form of the compound with the acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

[0204] Acid addition salts (as defined in Embodiment 1.96) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4- acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1 S)-camphor-10- sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2- disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a- oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, (+)-L- lactic, (±)-DL-lactic, lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic, naphthalene-1 ,5-disulfonic, 1-hydroxy-2- naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L- pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L- tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.

[0205] The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

[0206] N-Oxides

[0207] Many compounds of the Embodiments 1.1 to 1.100 may form N-oxides. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.

[0208] N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

[0209] Further examples of conditions for forming N-oxides are disclosed in our earlier application WO 2008 / 139152.

[0210] Geometric isomers and tautomers

[0211] The compounds of the invention may exist in a number of different geometric isomeric (including rotational isomers), and tautomeric forms and references to the compounds of the formula (1) as defined in Embodiments 1.1 to 1.100 include all such forms. For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced by formula (1) or subgroups, subsets, preferences and examples thereof.

[0212] Optical Isomers

[0213] Where compounds of the formula contain one or more chiral centres, and can exist in the form of two or more optical isomers, references to the compounds include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise.

[0214] The optical isomers may be characterised and identified by their optical activity (i.e. as + and - isomers, or d and I isomers) or they may be characterised in terms of their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 6thEdition, John Wiley & Sons, New York, 2007, pages 155-158, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.

[0215] Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art.

[0216] As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic, separating the diastereoisomers by preferential crystallisation, and then dissociating the salts to give the individual enantiomer of the free base.

[0217] Where compounds of the invention exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a plurality of diastereoisomers. Accordingly, the invention provides compositions containing a compound having one or more chiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of the formula (1) is present as a single optical isomer (e.g. enantiomer or diastereoisomer). In one general embodiment, 99% or more (e.g. substantially all) of the total amount of the compound of the formula (1) may be present as a single optical isomer (e.g. enantiomer or diastereoisomer).

[0218] The purity of a single enantiomer may be defined by its percent enantiomeric excess, which can be calculated by multiplying the absolute difference between the mole fraction of each enantiomer by 100 (see the IIIPAC Gold Book definition for the term “enantiomeric excess”)

[0219] Isotopes

[0220] The compounds of the invention as defined in any one of Embodiments 1.1 to 1.100 may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope1H,2H (D), and3H (T). Similarly, references to carbon, nitrogen, oxygen and fluorine include within their scope respectively11C,12C,13C and14C;13N and14N;15O,16O and18O; and18F and19F.

[0221] The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the compounds contain no radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment, however, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.

[0222] In some embodiments, the compounds of Embodiments 1.1 to 1.100 contain isotopes in their natural abundance.

[0223] When the compounds of Embodiments 1.1 to 1.100 are deuterated, the percentage of the total hydrogen atoms in the compounds of the invention that are deuterium atoms is less than 2%, more typically less than 1%, more usually less than 0.1 %, preferably less than 0.05% and most preferably no more than 0.02%.

[0224] Solvates

[0225] Compounds of the formula (1) as defined in any one of Embodiments 1.1 to 1.100 may form solvates.

[0226] Preferred solvates are solvates formed by the incorporation into the solid-state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulfoxide. Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray crystallography.

[0227] The solvates can be stoichiometric or non-stoichiometric solvates.

[0228] Particularly preferred solvates are hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates.

[0229] For a more detailed discussion of solvates and the methods used to make and characterise them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0230] Prodrugs

[0231] The compounds of the formula (1) as defined in any one of Embodiments 1.1 to 1.100 may be presented in the form of a pro-drug.

[0232] By “prodrugs” is meant for example any compound that is converted in vivo into a biologically active compound of the formula (1), as defined in any one of Embodiments 1.1 to 1.100. Prodrugs typically comprise a biologically active compound with a biologically labile functional group that can be removed in vivo to form the biologically active compound.

[0233] For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug, either by hydrolysis in acidic or basic aqueous conditions or by esterase enzymes. Such esters may be formed by esterification, for example, of any hydroxyl groups present in the parent compound with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.

[0234] Carbonates and carbamates of active compounds can also be used as prodrugs.

[0235] Similarly to esters, carbonates / carbamates can be hydrolysed in acidic / basic conditions or by esterases to form the active compound in vivo. Other examples of prodrugs are phosphonates or phosphates of the active compound.

[0236] Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

[0237] Further examples of prodrugs are described in Prodrugs Challenges and Rewards, Stella et al, 1st Edition, 2007, Springer-Verlag New York.

[0238] Conjugates and Complexes

[0239] The invention also provides conjugates comprising a compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.100. The conjugates comprise the compound of the formula (1) and another therapeutic agent or binding moiety covalently attached by a chemical linker. Wherein the conjugate comprises another therapeutic agent, the therapeutic agent may be, for example, a small-molecule protein inhibitor or an antibody and may be selected from the additional therapeutic agents described herein. The binding moiety may be a small-molecule motif that binds to a protein of interest or an antibody. Examples of suitable conjugates include antibody drug conjugates (ADCs) and proteolysis targeting chimeras (PROTACs).

[0240] The compounds of the formula (1) or subgroups, subsets, preferences and examples thereof may also be provided as complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds.

[0241] PROTACs

[0242] As noted above, the compounds of the invention may form part of a PROTAC (Proteolysis Targeting Chimera). PROTACs are bifunctional molecules typically formed from two active components and a linker and are used to promote the degradation of selected proteins. Whereas a conventional kinase inhibitor typically blocks the active site of the kinase in order to prevent it from carrying out its catalytic role, PROTACs induce selective intracellular proteolysis. As noted above, PROTACs comprise two proteinbinding molecules covalently bonded via a linker. One of the protein-binding molecules is capable of interacting with an E3 ubiguitin ligase, while the other binds to a target protein to be degraded. Recruitment of the E3 ligase to the target protein results in ubiquitination and subsequent degradation of the target protein via the proteasome.

[0243] Accordingly, the invention also provides PROTACs having the formula (4):

[0244] M-L-E (4) or being salts or tautomers thereof, wherein:

[0245] M is a compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.100, wherein a hydrogen atom of the compound M is replaced by the moiety L-E;

[0246] L is a covalent bond or a linker group; and

[0247] E is an E3 ligase engager.

[0248] Although L may be a covalent bond (in which case the Wee1 inhibitor is bonded directly to the E3 ligase engager), L is generally covalently bonded to M at a location remote from a Wee1-binding site on M, so as not to interfere with the binding of compound M to Wee1 kinase. Typically, therefore, L is covalently bonded to a heteroatom (e.g. O, N or S) present in R3or R4.

[0249] More typically, L is covalently bonded to M through a nitrogen atom present in R3or R4of the compounds of the formula (1).

[0250] For example, when R4is or comprises a 4-7 membered aromatic heterocyclic ring containing at least one heteroatom selected from N, the PROTACs can be of the formula (5): wherein R1, R2, n, Q, L and E are as defined herein and T is a 4-7 membered nonaromatic heterocyclic ring containing one or two heteroatom ring members selected from N, O, S and SO2 optionally substituted with one or more substituents R5, as defined herein, for example in Embodiment 1.1 to 1.100.

[0251] By way of an example, when R4is a piperidine group, the PROTACs can be of the formula (6): wherein R1, R2, n, Q, L and E are as defined herein.

[0252] It will be appreciated that when R4is or comprises another heterocyclic ring containing at least one nitrogen atom (e.g. piperazine, morpholine, or other nitrogen-containing heterocylic rings as defined above in relation to R4), the linker, L, can be attached to attached to any nitrogen atom in R4.

[0253] E3 ligase engagers are known to those skilled in the art (see for example, Bricelj et al., “E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points”, Front. Chem., 2021 , 9 and Sun et al., “PROTACs: great opportunities for academia and industry”, Sig Transduct Target Ther 4, 64 (2019) ), the contents of each of which are incorporated by reference herein.

[0254] The E3 ligase engager can be a ligand for the E3 ligase Cerebron (CBRN), a 442-amino acid protein that forms a Cullin-4-RING E3 ubiquitin ligase. To date, CRBN has been successfully used as the E3 ligase in PROTAC targeting of more than 30 different proteins, including those involved in various cancers (see Sun et al. ibid) and Bassi et al., ((2018). Modulating PCAF / GCN5 Immune Cell Function through a PROTAC Approach. ACS Chem. Biol. 13, 2862-2867. doi:10.1021 / acschembio.8b00705).

[0255] Many known PROTACS contain E3 ligase ligands formed from derivatives of pomalidomide, 4-hydroxythalidomide, alkyl-connected thalidomide derivatives or lenalidomide derivatives. Such structural motifs may be used in the PROTACS of the formula M-L-E according to the present invention. In the biological examples below, the PROTAC compound of Example 87, a pomalidomide derivative, has been shown to degrade Wee1 protein in colon adenocarcinoma cells, and it is believed that the degradation of the Wee1 protein is a consequence of the compound M-L-E binding to Wee1 and to an E3 ligase.

[0256] Accordingly, in one general embodiment, the L-E moieties in the PROTACS of the present invention may have the formula (7): wherein G is CH2 or C(=O); m is 1 or 2 such that ring A is a 5- or 6-membered ring fused to one or two aromatic rings.

[0257] In one embodiment, the ring A is a 5-membered ring which is fused to a single aromatic ring. In one subgroup of compounds within this embodiment, G is C(=O). In another subgroup of compounds within this embodiment, G is CH2.

[0258] In another embodiment, the ring A is a 6-membered ring which is fused to two aromatic rings. In this embodiment, G is typically a C(=O) group.

[0259] The aromatic ring(s) to which the ring A is fused will typically be a benzene ring(s), although isosteres such as pyridine, thiophene and furan may also be employed provided that they do not detract from the T3 ligase binding ability of the group E.

[0260] The aromatic ring(s) (e.g. benzene ring(s) are typically unsubstituted, except for the linker group L or any heteroatom or functional group through which the linker group L is attached to the ring A, although small substituents such as alkyl groups may be present provided that they do not interfere with the T3 ligase binding ability of the molecule.

[0261] In a further embodiment, L-E moieties are selected from those listed in the table below, wherein L, R or LINKER indicates the point of attachment to the linker:

[0262]

[0263]

[0264] Alternatively, it is possible to incorporate the VHL ligand into the PROTAC, rather than CRBN ligand, in order to recruit the E3 Ligase von Hippel-Lindau (VHL) protein. In accordance with the PROTAC formula above (i.e. M-L-E), the L-E unit for VHL is as follows:

[0265] Linkers to conjugate small molecule protein inhibitors with E3 ligase engagers in PROTACs are well-known to those skilled in the art (see for example, Troup et al., “Current strategies for the design of PROTAC linkers: a critical review”, Explor Target Antitumor Ther. 2020; 1 (5): 273-312).

[0266] For example, L may be an optionally substituted cyclic or acyclic linker group (or a linker group comprising cyclic groups, but not entirely cyclic) having a chain length between M and E of 2 to 12 carbon atoms wherein one or more of the carbon atoms may optionally be replaced with a heteroatom selected from O, N, S and oxidized forms thereof. The term “chain length” as used herein refers to the number of atoms (e.g. carbon atoms) extending in a line between two specified points (e.g. between X1and X2), excluding any atoms branching from the chain. Thus, for example, a group -(CH2)3-C(CH3)2-CH2- has a chain length of 5 carbon atoms.

[0267] When the chain includes a ring structure, the chain length is based on the smallest number of carbon atoms (or other atoms) needed to traverse the ring. For example, in the linker group: the chain length consists of the two carbon atoms in the methylene groups plus four intervening carbon atoms in the cyclohexane ring, giving a total chain length of 6 carbon atoms.

[0268] In one embodiment, L can be a hydrocarbyl chain (linear or branched), for example a C2- C10 hydrocarbyl chain. In a preferred embodiment, L is a C2-C4 hydrocarbyl linker, such as an ethylene (i.e. CH2CH2) or propylene (i.e. CH2CH2CH2).

[0269] Alternatively, L can additionally comprise one or more oxygen atoms and thus be polyether, polyoxyalkylene or polyglycol chain, such as polyethyleneglycol.

[0270] The use of PROTACs comprising Wee1 inhibitors to degrade Wee1 proteins is known from for example, Alli et al. , “Synthetic and Medicinal Chemistry Approaches Toward WEE1 Kinase Inhibitors and Its Degraders”, ACS Omega, 2023, 8(23), pp. 20196-20233 and Zhu et al., “Design, synthesis, and biological evaluation of Wee1 kinase degraders”, Eur. J. Med. Chem., 2022, 243, pp.114786 In addition, Example 87 as described herein is a Protac comprising a Wee1 inhibitor of the invention, which has been shown to degrade Wee1 protein (see Example A(c) below).

[0271] Biological Activity

[0272] Compounds of the formula (1) as defined in any one of Embodiments 1.1 to 1.100 have activity as inhibitors of Wee1 kinase. As such, they may be useful in preventing or treating disease states and conditions in which Wee1 kinase or mutant forms thereof play an active part. Therefore, it is envisaged that the compounds of Embodiments 1.1 to 1.100 will be useful in treating a range of diseases or conditions, for example proliferative disorders such as cancers.

[0273] Accordingly, in further embodiments (Embodiments 2.1 to 2.9), the invention provides:

[0274] 2.1 A compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.100 for use in medicine or therapy.

[0275] 2.2 A compound of the formula (1) as defined in any one of Embodiments 1.1 to

[0276] 1.100 for use in preventing or treating disease states and conditions mediated by Wee1 kinase or mutant forms thereof.

[0277] 2.3 A compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.100 for use in preventing or treating disease states and conditions characterised by abnormal expression of Wee1 kinase (e.g. over-expression or expression of a mutant form of Wee1 kinase).

[0278] 2.4 A compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.100 for use as an anti-cancer agent.

[0279] 2.5 The use of a compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.100 for the manufacture of a medicament for the treatment of cancer.

[0280] 2.6 A method of treating a cancer, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.100, optionally together with another anticancer agent or radiation therapy.

[0281] 2.7 A compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.100 for use in enhancing a therapeutic effect of radiation therapy or chemotherapy in the treatment of a proliferative disease such as cancer.

[0282] 2.8 The use of a compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.100 for the manufacture of a medicament for enhancing a therapeutic effect of radiation therapy or chemotherapy in the treatment of a proliferative disease such as cancer. 2.9 A method for the prophylaxis or treatment of a proliferative disease such as cancer, which method comprises administering to a patient in combination with radiotherapy or chemotherapy a compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.100.

[0283] Examples of proliferative disorders (e.g. cancers) as defined in Embodiments 2.4 to 2.9 include, but are not limited to carcinomas, for example carcinomas of the bladder, breast, colon, kidney, epidermis, liver, lung, oesophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, gastrointestinal system, or skin, hematopoietic tumours such as leukaemia, B-cell lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, hairy cell lymphoma, or Burkett's lymphoma; hematopoietic tumours of myeloid lineage, for example acute and chronic myelogenous leukaemias, myelodysplastic syndrome, or promyelocytic leukaemia; thyroid follicular cancer; tumours of mesenchymal origin, for example fibrosarcoma or rhabdomyosarcoma ; tumours of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

[0284] Further examples of proliferative disorders (e.g. cancers) as defined in Embodiments 2.4 to 2.9 are carcinoma of the uterus, glioblastoma (GBM); medulloblastoma and ependymoma.

[0285] One particular subset of cancers against which the compounds of Embodiments 1.1 to 1.100 should prove particularly active are cancers which are characterised by Wee1 overexpression or elevated expression of Wee1 or elevated activation (phosphorylation).

[0286] The ability of the compounds of the invention to inhibit Wee1 kinase can be determined by means of the protocols set out in the Examples section below.

[0287] As described above, several types of cancer have been reported to be sensitive to Wee1 inhibition. Accordingly, further particular examples of cancers against which the compounds of Embodiments 1.1 to 1.100 should prove particularly active are:

[0288] • Medulloblastoma;

[0289] • Diffuse Intrinsic Pontine Glioma (DIPG);

[0290] • Glioblastoma;

[0291] • Acute myeloid leukemia;

[0292] • Cervical cancer; • Colorectal cancer;

[0293] • Head and neck squamous cell carcinoma;

[0294] • Malignant melanoma;

[0295] • Ovarian cancer;

[0296] • Pancreatic cancer;

[0297] • Sarcoma;

[0298] • Small cell lung cancer;

[0299] • Triple-negative breast cancer;

[0300] • Uterine Serous Carcinoma (USC) or Uterine Carcinosarcoma; and

[0301] • Ependymoma

[0302] • Endometrial cancer

[0303] • Osteosarcoma

[0304] • Ewing’s sarcoma

[0305] • Esophageal and gastroesophageal

[0306] • Prostate

[0307] • Non Small Cell Lung Carcinoma (NSCLC)

[0308] • Breast cancer including hormone receptor-positive tumours / HER2+ tumours

[0309] • Pediatric cancers including Neuroblastoma, rhabdomyosarcoma, medulloblastoma, and other CNS embryonal tumours

[0310] • Non-Hodgkin lymphomas including but not limited to diffuse large B cell lymphomas, mantle cell lymphoma and Burkitt lymphoma

[0311] • Multiple Myeloma

[0312] • Neuroblastoma

[0313] A further sub-set of cancers against which the compounds of Embodiments 1.1 to 1.100 should prove particularly active includes cancers of the brain such as:

[0314] • Medulloblastoma

[0315] • Diffuse Intrinsic Pontine Glioma (DIPG)

[0316] • Glioblastoma; and

[0317] • Ependymoma.

[0318] It has also been shown that Wee1 inhibitors can sensitize p53 deficient cancer cells to other DNA-damaging chemotherapeutic agents (see Hirai et al., ibid). Accordingly, it is envisaged that the compounds of the present invention can be used in the treatment of p53 deficient or mutated cancers. Furthermore, it has been determined that tumours with BRCA1 mutations are especially sensitive to Wee1 inhibition due to the inability of the cancer to repair double-strand DNA breaks (see Do et al, 2015, Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors). Tumours that have become resistant to PARP inhibitors have also been determined to overcome PARPi resistance using Wee1 inhibitors (see Serra et al “Identification of a molecularly-defined subset of breast and ovarian cancer models that respond to Wee1 or ATR inhibition, overcoming PARP inhibitor resistance”, 2022).

[0319] Other markers of sensitivity to Wee1 inhibition include, but are not limited to:

[0320] • a mutation in RAS or KRAS (an oncogene), (see Seligmann et al., Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring. J. Clin Oncol 2021, 39 (33), 3705-3715.

[0321] • a mutation in LKB1 (a tumour suppressor)

[0322] • a co-mutation in KRAS and LKB1 (See Whitsett et al., 2017, WEE1 Kinase Inhibitor AZD1775 Has Preclinical Efficacy in LKB1 -Deficient Non-Small Cell Lung Cancer)

[0323] • a mutation in SETD2 (see Pfister et al, 2015 Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation)

[0324] • a mutation in ATRX (see Liang, 2019. Genome-wide CRISPR-Cas9 screen reveals selective vulnerability of ATRX-mutant cancers to Wee1 inhibition)

[0325] • CCNE1 alterations (see Xu 2021 , “CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models”)

[0326] • EGFR (Epidermal Growth Factor Receptor) mutants (see Cetin et al., G2 Checkpoint Targeting via Wee1 Inhibition Radiosensitizes EGFRvlll-Positive Glioblastoma Cells. Radiat Oncol 2023, 18 (1), 19.

[0327] In addition, tumours with high levels of replication stress (RS) caused by inactivation of a tumour suppressor e.g. RB1 or those harbouring a DNA Damage Response (DDR) defect can be sensitive (see review by Fu et al., 2018, Strategic development of AZD1775, a Wee1 kinase inhibitor, for cancer therapy). Furthermore, RS in certain tumours such as medulloblastoma, diffuse large B cell lymphoma, small-cell lung cancer and neuroblastoma, can be driven by the transcription factor MYC and such tumours are sensitive to small molecule Wee1 inhibition (see Moreira et al., 2020, Targeting MYC-driven replication stress in medulloblastoma with AZD1775 and gemcitabine and Restelli et al., 2018, “Inhibition of CHK1 and WEE1 as a new therapeutic approach in diffuse large B cell lymphomas with MYC deregulation”).

[0328] It is also known that Wee1 inhibition sensitizes cancer cells to immunotherapy such as a PD-1 monoclonal antibody (mAb) checkpoint inhibitor (Allen et al., 2018, WEE1 kinase inhibition reverses G2 / M cell cycle checkpoint activation to sensitize cancer cells to immunotherapy).

[0329] It is also known that copy number alterations are a frequent event in cancers with the Wee1 gene being predominantly involved in copy number loss. Cancer types showing high recurrence of copy number alterations include ovarian serous cystadenocarcinoma, lung squamous cell carcinoma, uterine carcinosarcoma and sarcoma.

[0330] Accordingly, in further Embodiments 2.10 to 2.33, the invention also provides

[0331] 2.10 A compound according to any one of Embodiments 1.1 to 1.100, optionally in combination with a further therapeutic agent (e.g. a further therapeutic agent described herein), for use in the treatment of a cancer which is characterised by mutant or deficient tumour protein p53.

[0332] 2.11 A method for the treatment of a subject (e.g. a human patient) suffering from a cancer characterised by mutant or deficient tumour protein p53, which method comprises administering to the subject and effective therapeutic amount of a compound of any one of Embodiments 1.1 to 1.100, optionally in combination with a further therapeutic agent (e.g. a further therapeutic agent described herein).

[0333] 2.12 The use of a compound of any one of Embodiments 1.1 to 1.100, optionally in combination with a further therapeutic agent (e.g. a further therapeutic agent described herein), for the manufacture of a medicament for the treatment of a subject (e.g. a human patient) suffering from a cancer characterised by mutant or deficient tumour protein p53.

[0334] 2.13 A compound as defined in any one of Embodiments 1.1 to 1.100 for use in the treatment of a cancer in a patient who has been screened and has been determined as suffering from a cancer which is characterised by mutant or deficient tumour protein p53. 2.14 The use of a compound as defined in any one of Embodiments 1.1 to 1.100 for the manufacture of a medicament for the treatment of a cancer in a patient who has been screened and has been determined as suffering from a cancer which is characterised by mutant or deficient tumour protein p53.

[0335] 2.15 A method for the diagnosis and treatment of a cancer which is characterised by mutant or deficient tumour protein p53, which method comprises (i) screening a patient to determine whether a cancer from which the patient is suffering is one which is characterised by mutant or deficient tumour protein p53; and (ii) where it is indicated that the cancer is one which is characterised by mutant or deficient tumour protein p53, thereafter administering to the patient a therapeutically effective amount of a compound as defined in any one of Embodiments 1.1 to 1.100.

[0336] 2.16 A compound of the formula (1) as defined in any one of Embodiments 1.1 to

[0337] 1.100 for use in preventing or treating cancers which are sensitive to Wee1 kinase inhibition.

[0338] 2.17 A compound for use according to Embodiment 2.18 wherein the cancer which is sensitive to Wee1 kinase inhibition is a cancer which contains one or more mutations selected from mutations of BRCA1, KRAS and LKB1.

[0339] 2.18 A compound of the formula (1) as defined in any one of Embodiments 1.1 to

[0340] 1.100 for use in treating a cancer in a patient who has been screened and has been determined as suffering from a cancer which is sensitive to Wee1 kinase inhibition.

[0341] 2.19 A compound of the formula (1) as defined in any one of Embodiments 1.1 to

[0342] 1.100 for use in treating a cancer in a patient who has been screened and has been determined as suffering from a cancer which is sensitive to Wee1 kinase inhibition and contains one or more mutations selected from mutations of BRCA1 , KRAS and LKB1.

[0343] 2.20 The use of a compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.100 for the manufacture of a medicament for a use as defined in any one of Embodiments 2.9 to 2.21.

[0344] 2.21 A method of treating a subject suffering from a cancer which is sensitive to Wee1 inhibition, which method comprises administering to the subject an effective amount of a compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.100. 2.22 A method of treating a subject who has been diagnosed and has been found to be suffering from a cancer which is sensitive to Wee1 kinase inhibition, which method comprises administering to the subject an effective amount of a compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.100.

[0345] 2.23 A method of treating a subject who has been diagnosed and has been found to be suffering from a cancer which is sensitive to Wee1 kinase inhibition and contains one or more mutations selected from mutations of BRCA1 , KRAS and LKB1 , which method comprises administering to the subject an effective amount of a compound of the formula (1) as defined in any one of Embodiments 1.1 to 1.100.

[0346] 2.24 A method for the diagnosis and treatment of a disease state or condition mediated by Wee1 kinase which method comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against Wee1 kinase; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient a compound as defined in any one of Embodiments 1.1 to 1.100.

[0347] 2.25 The use of a compound as defined in any one of Embodiments 1.1 to 1.100 for the manufacture of a medicament for the treatment or prophylaxis of a disease state or condition in a patient who has been screened and has been determined as suffering from, or being at risk of suffering from, a disease or condition which would be susceptible to treatment with a compound having activity against Wee1 kinase.

[0348] 2.26 A compound as defined in any one of Embodiments 1.1 to 1.100 for use in the treatment or prophylaxis of a disease state or condition in a patient who has been screened and has been determined as suffering from, or being at risk of suffering from, a disease or condition which would be susceptible to treatment with a compound having activity against Wee1 kinase.

[0349] 2.27 A method for the diagnosis and treatment of a disease state or condition characterised by up-regulation of Wee1 kinase or the presence of a mutated form of Wee1 kinase, which method comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against Wee1 kinase; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient a compound as defined in any one of Embodiments 1.1 to 1.100.

[0350] 2.28 A method for the treatment of a disease state or condition characterised by upregulation of Wee1 kinase or the presence of a mutated form of Wee1 , which method comprises administering a therapeutically effective amount of a compound as defined in any one of Embodiments 1.1 to 1.100 to a patient who has been screened and has been determined as suffering from, or being at risk of suffering from, a disease or condition which would be susceptible to treatment with a compound having activity against Wee1 kinase.

[0351] 2.29 The use of a compound as defined in any one of Embodiments 1.1 to 1.100 for the manufacture of a medicament for the treatment or prophylaxis of a disease, condition or disorder as defined in any one of Embodiments 2.1 to 2.28 in a patient who has been screened and has been determined as suffering from, or being at risk of suffering, from a said disease, condition or disorder which would be susceptible to treatment with a compound having activity against Wee1 kinase.

[0352] 2.30 A compound as defined in any one of Embodiments 1.1 to 1.100 for use in the treatment or prophylaxis of a disease or condition or disorder in a patient who has been screened and has been determined as suffering from, or being at risk of suffering from, a disease, condition or disorder as defined in any one of Embodiments 2.1 to 2.31 which would be susceptible to treatment with a compound having activity against Wee1 kinase.

[0353] 2.31 A compound as defined in any one of Embodiments 1.1 to 1.100 for use in the treatment or prophylaxis of a cancer showing high recurrence of copy number alterations (e.g. a high recurrence of copy number losses).

[0354] 2.32 The use of a compound as defined in any one of Embodiments 1.1 to 1.100 for the manufacture of a medicament for the treatment or prophylaxis of a cancer showing high recurrence of copy number alterations (e.g. a high recurrence of copy number losses).

[0355] 2.33 A method for the treatment of a showing high recurrence of copy number alterations (e.g. a high recurrence of copy number losses), which method comprises administering a therapeutically effective amount of a compound as defined in any one of Embodiments 1.1 to 1.100 to a patient. The diagnostic methods used to determine whether a particular cancer is susceptible to treatment with the compounds of the invention can be as described below in the section headed “Methods of Diagnosis”.

[0356] Determination of Biological Properties

[0357] The ability of the compounds of Embodiments 1.1 to 1.100 to inhibit cell proliferation can also be determined using the protocols set out in the Examples section below.

[0358] Preferred compounds of Embodiments 1.1 to 1.100 are those having an IC50 against Wee1 kinase of less than 100 nM, or less than 50nM and preferably less than 10 nM.

[0359] Accordingly, in further embodiments (Embodiments 2.34 to 2.37), the invention provides:

[0360] 2.34 A compound according to any one of Embodiments 1.1 to 1.100 having an IC50 against Wee1 kinase of less than 100 nM.

[0361] 2.35 A compound according to any one of Embodiments 1.1 to 1.100 having an IC50 against Wee1 kinase of or less than 50 nM.

[0362] 2.36 A compound according to any one of Embodiments 1.1 to 1.100 having an IC50 against Wee1 kinase of less than 10 nM.

[0363] 2.37 A compound according to any one of Embodiments 2.34 to 2.36 for use in a therapy, treatment, method or use according to any one of Embodiments 2.1 to 2.33.

[0364] Methods for the Preparation of Compounds of the Invention

[0365] The invention also provides methods for the preparation of a compound of the formula (1).

[0366] Accordingly, in another embodiment (Embodiment 3.1), the invention provides a method for preparing a compound as defined in any one of Embodiments 1.1 to 1.100 which method comprises the reaction of a compound of the formula (10): or a protected form thereof, wherein X is a leaving group, such as -SOCH3, -SO2CH3, halogen or a sulfonate (e.g. mesylate or tosylate), with a compound of the formula (11): or a protected form thereof; and thereafter optionally: a) removing any protecting group(s) present; and / or b) interconverting a compound of the formula (1) or a protected derivative thereof to a further compound of the formula (1) or a protected derivative thereof and optionally removing any protecting group present.

[0367] In one embodiment, X is -SOCH3 or -SO2CH3. The reaction between the compounds of formulae (10) and (11) may be carried out in the presence of an acid, such as trifluoroacetic acid. The reaction is typically carried out in a polar, protic solvent (such as iso-propyl alcohol). The reaction may be conducted at a temperature of 30°C or greater, typically 40°C or greater, for example at a temperature of around 50°C. The reaction may be carried out for a time period of greater than 4 hours, for example a time period of greater than 12 hours.

[0368] Compounds of formula (10) in which X is -S(O)CH3 or -SO2CH3 can be prepared by oxidation of the corresponding compound in which X is -S-CHswith an oxidizing agent. Examples of suitable oxidizing agents include peroxides, such as hydrogen peroxide and meta-chloroperoxybenzoic acid (mCPBA). The oxidation reaction may be carried out in a polar, aprotic solvent, such as dichloromethane. Compounds of the formula (10) can be prepared by reacting a compound of the formula (12): or a protected derivative thereof, with a compound of the formula (13): wherein Y is a leaving group, such as OH or an activated form thereof, an alkoxy group (e.g. methoxy or ethoxy) or a halogen (such as chlorine) and X’ is X as defined above or a precursor to X (such as -SCH3).

[0369] The reaction of the compound of the formula (12) with a compound of the formula (13) may be conducted in the presence of an alkyl-aluminium compound, such as trimethyl aluminium. Alternatively, the reaction can be conducted in the presence of an amide- coupling agent / catalyst, such benzotriazolyl salts (including Hexafluorophosphate Benzotriazole Tetramethyl Uronium [HBTLI], Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium [HATU], 2-(1 H-Benzotriazole-1-yl)-1 ,1 ,3,3-tetramethylaminium tetrafluoroborate [TBTU] and derivatives or analogues thereof) or carbodiimides (including N,N'-Dicyclohexylcarbodiimide [DCC], N,N'-Diisopropylcarbodiimide [DIC], 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide [EDC] and derivatives or analogues thereof). The reaction can take place in a polar, aprotic solvent, such as dichloromethane or tetrahydrofuran.

[0370] The compound of the formula (12) can be formed by reacting a compound of the formula (14): wherein X’ and Y are as defined above and Z is a suitable leaving group, such as a halogen (e.g. chlorine), with an alcohol of the formula HO-R1.

[0371] The reaction of the compound of the formula (14) with the alcohol HO-R1, typically takes place in the presence of a strong lithium ion or sodium ion base, such as sodium bis(trimethylsilyl)amide (NaHMDS) and may take place in the presence of a polar, aprotic solvent, such as tetra hydrofuran.

[0372] Also provided are compounds of the formulae (10), (11), (12), (13) and (14) wherein R1, R2, R3, n, X, X’, Y and Z are as defined herein, for example in Embodiments 1.1 to 1.100.

[0373] Once formed, one compound of the formula (1), or a protected derivative thereof, can be converted into another compound of the formula (1) by methods well known to the skilled person. Examples of synthetic procedures for converting one functional group into another functional group are set out in standard texts such as Advanced Organic Chemistry, by Jerry March, 4thedition, 119, Wiley Interscience, New York; Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2); and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8)).

[0374] In many of the reactions described above, it may be necessary to protect one or more groups to prevent reaction from taking place at an undesirable location on the molecule. Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4thEdition; John Wiley and Sons, 2006).

[0375] Compounds made by the foregoing methods may be isolated and purified by any of a variety of methods well known to those skilled in the art and examples of such methods include recrystallisation and chromatographic techniques such as column chromatography (e.g. flash chromatography) and HPLC. Pharmaceutical Formulations

[0376] The compounds of the invention are typically administered to patients in the form of a pharmaceutical composition. Accordingly, in another Embodiment of the invention (Embodiment 4.1), the invention provides a pharmaceutical composition comprising a compound according to any one of Embodiments 1.1 to 1.100 and a pharmaceutically acceptable excipient.

[0377] In further embodiments, there are provided:

[0378] 4.2 A pharmaceutical composition according to Embodiment 4.1 which comprises from approximately 1% (w / w) to approximately 95% (w / w) of a compound of any one of Embodiments 1.1 to 1.100 and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient or combination of excipients and optionally one or more further therapeutically active ingredients.

[0379] 4.3 A pharmaceutical composition according to Embodiment 4.2 which comprises from approximately 5% (w / w) to approximately 90% (w / w) of a compound of any one of Embodiments 1.1 to 1.100 and from 95% (w / w) to 10% of a pharmaceutically excipient or combination of excipients and optionally one or more further therapeutically active ingredients.

[0380] 4.4 A pharmaceutical composition according to Embodiment 4.3 which comprises from approximately 10% (w / w) to approximately 90% (w / w) of a compound of any one of Embodiments 1.1 to 1.100 and from 90% (w / w) to 10% of a pharmaceutically excipient or combination of excipients.

[0381] 4.5 A pharmaceutical composition according to Embodiment 4.4 which comprises from approximately 20% (w / w) to approximately 90% (w / w) of a compound of any one of Embodiments 1.1 to 1.100 and from 80% (w / w) to 10% of a pharmaceutically excipient or combination of excipients.

[0382] 4.6 A pharmaceutical composition according to Embodiment 4.5 which comprises from approximately 25% (w / w) to approximately 80% (w / w) of a compound of any one of Embodiments 1.1 to 1.100 and from 75% (w / w) to 20% of a pharmaceutically excipient or combination of excipients. The pharmaceutical compositions of the invention can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery.

[0383] Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, sprays, powders, granules, elixirs and suspensions, sublingual tablets, sprays, wafers or patches and buccal patches.

[0384] Accordingly, in further embodiments, the invention provides:

[0385] 4.7 A pharmaceutical composition according to any one of Embodiments 4.1 to 4.6 which is suitable for oral administration.

[0386] 4.8 A pharmaceutical composition according to Embodiment 4.7 which is selected from tablets, capsules, caplets, pills, lozenges, syrups, solutions, sprays, powders, granules, elixirs and suspensions, sublingual tablets, sprays, wafers or patches and buccal patches.

[0387] 4.9 A pharmaceutical composition according to Embodiment 4.8 which is selected from tablets and capsules.

[0388] 4.10 A pharmaceutical composition according to any one of Embodiments 4.1 to 4.6 which is suitable for parenteral administration.

[0389] 4.11 A pharmaceutical composition according to Embodiment 4.10 which is formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery.

[0390] 4.12 A pharmaceutical composition according to Embodiment 4.11 which is a solution or suspension for injection or infusion.

[0391] Pharmaceutical compositions (e.g. as defined in any one of Embodiments 4.1 to 4.12) containing a compound according to Embodiments 1.1 to 1.100 of the invention can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. Thus, tablet compositions (as in Embodiment 4.9) can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, e.g.; lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, talc, calcium carbonate, or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.

[0392] Capsule formulations (as in Embodiment 4.9) may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant-derived equivalents thereof.

[0393] The solid dosage forms (e.g.; tablets, capsules etc.) can be coated or un-coated, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a release controlling coating. The coating (e.g. a Eudragit ™ type polymer) can be designed to release the active component at a desired location within the gastro-intestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum or duodenum.

[0394] Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract.

[0395] Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods. Compositions for parenteral administration (as in Embodiments 4.10 to 4.12) are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection.

[0396] Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped mouldable or waxy material containing the active compound.

[0397] Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.

[0398] The compounds of the inventions will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, according to any one of Embodiments 4.1 to 4.9), a composition intended for oral administration may contain from 2 milligrams to 200 milligrams of active ingredient, more usually from 10 milligrams to 100 milligrams, for example, 12.5 milligrams, 25 milligrams and 50 milligrams.

[0399] Combination Therapy

[0400] It is envisaged that the compounds of Embodiments 1.1 to 1.100 will be useful either as sole chemotherapeutic agents or, more usually, in combination therapy with chemotherapeutic agents or radiation therapy in the prophylaxis or treatment of a range of proliferative disease states or conditions. Examples of such disease states and conditions are set out above.

[0401] Particular examples of chemotherapeutic agents that may be co-administered with the compounds of Embodiments 1.1 to 1.100 include:

[0402] • Topoisomerase I inhibitors e.g. Topotecan, Irinotecan

[0403] • Antimetabolites e.g. 5-fluoro uracil (5-Fll)

[0404] • Tubulin targeting agents

[0405] • Topoisomerase II inhibitors e.g. etoposide • EGFR inhibitors (e.g. Gefitinib - see Biochemical Pharmacology 78 2009460-468 or Osimertinib)

[0406] • mTOR inhibitors (e.g. Everolimus)

[0407] • PI3K pathway inhibitors (e.g. PI3K, PDK1)

[0408] • Akt inhibitors

[0409] • Alkylating Agents (e.g. temozolomide, cyclophosphamide)

[0410] • Monoclonal Antibodies (e.g. antibodies targeting CTLA-4, PD-1 , PD-L1, 0X40, CD52 or CD20). Examples include nivolumab, pembrolizumab, avelumab, durvalumab, atezolizumab.

[0411] Anti-Hormones

[0412] Signal Transduction Inhibitors

[0413] Proteasome Inhibitors

[0414] DNA methyl transferases

[0415] Cytokines and retinoids

[0416] Hypoxia triggered DNA damaging agents (e.g. Tirapazamine) Aromatase inhibitors

[0417] Anti Her2 antibodies (for example, those described in WO 2007 / 056118)

[0418] Inhibitors of angiogenesis

[0419] HDAC inhibitors

[0420] MEK inhibitors

[0421] B-Raf inhibitors

[0422] ERK inhibitors

[0423] HER2 small molecule inhibitors (e.g. lapatinib)

[0424] Bcr-Abl tyrosine-kinase inhibitors (e.g. imatinib)

[0425] CDK4 / 6 inhibitors e.g. Ibrance (Palbociclib)

[0426] VEGFR inhibitors

[0427] IGFR-1 inhibitors

[0428] Inhibitors of the Hedgehog signalling pathway

[0429] PARP inhibitors e.g. Olaparib

[0430] Immune Checkpoint inhibitors

[0431] Gemcitabine

[0432] Chk1 inhibitors

[0433] PKMYT1 inhibitors

[0434] KRAS inhibitors eg. sotorasib • ATR inhibitors

[0435] • ATM inhibitors

[0436] • HDAC inhibitors

[0437] • cGAS / STING activators

[0438] • Chk1 (Checkpoint 1 kinase) inhibitors

[0439] Further examples of chemotherapeutic agents that may be co-administered with a compound as defined in any one Embodiments 1.1 to 1.100 include:

[0440] • Tore 1 inhibitors

[0441] • Taxanes (e.g. paclitaxel, docetaxel, cabazitaxel)

[0442] • Platinum agents (e.g. cisplatin, carboplatin, oxaliplatin)

[0443] • Anthracyclines (e.g. Doxorubicin)

[0444] • Inhibitors of Bcl-2 family proteins e.g. ABT263 (navitoclax), a Bcl-2 / Bcl-extra large (Bcl-xL) inhibitor

[0445] • Cytarabine

[0446] • Belinostat

[0447] One particular combination comprises a compound according to any one of Embodiments 1.1 to 1.100 together with a PARP inhibitor, such as niraparib, olaparib, rucaparib or talazoparib.

[0448] A further particular combination comprises a compound according to any one of Embodiments 1.1 to 1.100 together with a DNA damaging agent, such as gemcitabine, cisplatin, oxaliplatin, carboplatin, cyclophosphamide, chlorambucil or temozolomide.

[0449] Yet a further particular combination a compound according to any one of Embodiments 1.1 to 1.100 together with an immune checkpoint inhibitor, e.g. a PD-1 or a PD-L1 inhibitor, such as nivolumab, pembrolizumab, avelumab, durvalumab or atezolizumab.

[0450] The compounds may also be administered in conjunction with radiotherapy.

[0451] Posology

[0452] The compounds may be administered over a prolonged term to maintain beneficial therapeutic effects or may be administered for a short period only. Alternatively, they may be administered in a pulsatile or continuous manner. The compounds of the invention will be administered in an effective amount, i.e. an amount which is effective to bring about the desired therapeutic effect. For example, the "effective amount" can be a quantity of compound which, when administered to a subject suffering from cancer, slows tumour growth, ameliorates the symptoms of the disease and / or increases longevity.

[0453] The amount of Wee1 inhibitor compound of the invention administered to the subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. The skilled person will be able to determine appropriate dosages depending on these and other factors.

[0454] The compounds are generally administered to a subject in need of such administration, for example a human or animal subject (patient), preferably a human.

[0455] A typical daily dose of the compound of any of Embodiments 1.1 to 1.100 can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of body weight, and more usually 10 nanograms to 15 milligrams per kilogram of body weight (e.g. 10 nanograms to 10 milligrams, and more typically 1 microgram per kilogram to 20 milligrams per kilogram, for example 1 microgram to 10 milligrams per kilogram) although higher or lower doses may be administered where required. The compound can be administered on a daily basis or on a repeat basis every 2, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21, or 28 days for example.

[0456] In one particular dosing schedule, a patient will be given an infusion of a compound for periods of one hour daily for up to ten days in particular up to five days for one week, and the treatment repeated at a desired interval such as two to four weeks, in particular every three weeks.

[0457] More particularly, a patient may be given an infusion of a compound for periods of one hour daily for 5 days and the treatment repeated every three weeks.

[0458] In another particular dosing schedule, a patient is given an infusion over 30 minutes to 1 hour followed by maintenance infusions of variable duration, for example 1 to 5 hours, e.g. 3 hours. In a further particular dosing schedule, a patient is given a continuous infusion for a period of 12 hours to 5 days, and in particular a continuous infusion of 24 hours to 72 hours.

[0459] Ultimately, however, the quantity of compound administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

[0460] Methods of Diagnosis

[0461] Prior to administration of a compound of any one of Embodiments 1.1 to 1.100, a patient may be screened to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against Wee1 kinase. Such patient can then be treated according to the methods described above.

[0462] For example, a biological sample taken from a patient may be analysed to determine whether a condition or disease, such as cancer, that the patient is or may be suffering from is one which is characterised by a genetic abnormality or abnormal protein expression which leads to up-regulation of Wee1 kinase or to sensitisation of a pathway to normal Wee1 kinase activity or to over-expression of Wee1 kinase. The term upregulation includes elevated expression or over-expression, including gene amplification (i.e. multiple gene copies) and increased expression by a transcriptional effect, and hyperactivity and activation, including activation by mutations. Thus, the patient may be subjected to a diagnostic test to detect a marker characteristic of up-regulation of Wee1 kinase. The term diagnosis includes screening. By marker we include genetic markers including, for example, the measurement of DNA composition to identify mutations of Wee1. The term marker also includes markers which are characteristic of up-regulation of Wee1, including enzyme activity, enzyme levels, enzyme state (e.g. phosphorylated or not) and mRNA levels of the aforementioned proteins.

[0463] Tumours with upregulation of Wee1 kinase may be particularly sensitive to Wee1 inhibitors. Tumours may preferentially be screened for upregulation of Wee1. Thus, the patient may be subjected to a diagnostic test to detect a marker characteristic of upregulation of Wee1. The diagnostic tests are typically conducted on a biological sample selected from tumour biopsy samples, blood samples (isolation and enrichment of shed tumour cells), stool biopsies, sputum, chromosome analysis, pleural fluid, peritoneal fluid, Methods of identification and analysis of mutations and up-regulation of proteins are known to a person skilled in the art. Screening methods could include, but are not limited to, standard methods such as reverse-transcriptase polymerase chain reaction (RT-PCR) or in-situ hybridisation.

[0464] In screening by RT-PCR, the level of mRNA in the tumour is assessed by creating a cDNA copy of the mRNA followed by amplification of the cDNA by PCR. Methods of PCR amplification, the selection of primers, and conditions for amplification, are known to a person skilled in the art. Nucleic acid manipulations and PCR are carried out by standard methods, as described for example in Ausubel, F.M. et al., eds. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc., or Innis, M.A. et al., eds. PCR Protocols: a guide to methods and applications, 1990, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al., 2001 , 3rdEd, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively a commercially available kit for RT-PCR (for example Roche Molecular Biochemicals) may be used, or methodology as set forth in United States patents 4,666,828; 4,683,202; 4,801 ,531 ; 5,192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated herein by reference.

[0465] An example of an in-situ hybridisation technique for assessing mRNA expression would be fluorescence in-situ hybridisation (FISH) (see Angerer, 1987 Meth. Enzymol., 152: 649).

[0466] Generally, in situ hybridisation comprises the following major steps: (1) fixation of tissue to be analyzed; (2) pre-hybridisation treatment of the sample to increase accessibility of target nucleic acid, and to reduce nonspecific binding; (3) hybridisation of the mixture of nucleic acids to the nucleic acid in the biological structure or tissue; (4) post-hybridisation washes to remove nucleic acid fragments not bound in the hybridisation, and (5) detection of the hybridized nucleic acid fragments. The probes used in such applications are typically labelled, for example, with radioisotopes or fluorescent reporters. Preferred probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to enable specific hybridisation with the target nucleic acid(s) under stringent conditions. Standard methods for carrying out FISH are described in Ausubel, F.M. et al., eds. Current Protocols in Molecular Biology, 2004, John Wiley & Sons Inc and Fluorescence In Situ Hybridisation: Technical Overview by John M. S. Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1- 59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine.

[0467] Alternatively, the protein products expressed from the mRNAs may be assayed by immunohistochemistry of tumour samples, solid phase immunoassay with microtiter plates, Western blotting, 2-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and other methods known in the art for detection of specific proteins. Detection methods would include the use of site-specific antibodies. The skilled person will recognize that all such well-known techniques for detection of up-regulation of Wee1 kinase could be applicable in the present case. Brief Description of the Drawings

[0468] Figures 1 and 2 illustrate western blot analysis of Wee1 levels in HT29 cells following treatment with Examples 87 and Z, as described in Example A(c) below. Figure 1 illustrates the effect at 6 h. Figure 2 illustrates the effect at 24 h.

[0469] EXAMPLES EXAMPLES 1 TO 87

[0470] The compounds of Examples 1 to 87 in Table 1 below are illustrative of the invention.

[0471]

[0472] Abbreviations

[0473] In the examples, the following abbreviations are used. aq. aqueous

[0474] DCM dichloromethane

[0475] DIAD diisopropyl azodicarboxylate

[0476] DIPEA / V, / V-diisopropylethylamine

[0477] DMF dimethylformamide DMSO dimethylsulfoxide ee enantiomeric excess

[0478] Et20 diethyl ether

[0479] EtOAc ethyl acetate

[0480] EtOH ethanol h hour(s)

[0481] HCI hydrogen chloride

[0482] HPLC high performance liquid chromatography

[0483] I PA isopropanol

[0484] LC liquid chromatography LCMS liquid chromatography-mass spectrometry mCPBA m-chloroperoxybenzoic acid

[0485] MeCN acetonitrile

[0486] MeOH methanol min minute(s)

[0487] NaHCOs sodium hydrogen carbonate

[0488] Na2SC>4 sodium sulfate

[0489] NMR nuclear magnetic resonance

[0490] PDA photodiode-array detection

[0491] SFC supercritical fluid chromatography

[0492] TFA trifluoroacetic acid

[0493] THF tetra hydrofuran

[0494] TMA trimethyl aluminium

[0495] UPLC Ultra Performance Liquid Chromatography

[0496] VT Variable temperature

[0497] Analytical Data and Experimental Conditions

[0498] Nomenclature

[0499] Unless otherwise indicated, the nomenclature of structures was determined using the 'Convert Structure to Name' to function of Marvin Sketch 22.5 (ChemAxon) to generate the preferred IUPAC name.

[0500] NMR

[0501] Proton magnetic resonance (1H NMR) spectra were recorded on a Bruker 400 instrument operating at 400 MHz, in DMSO-d6 or MeOH-d4 (as indicated) at 27°C, unless otherwise stated and are reported as follows: chemical shift 5 / ppm (multiplicity where s=singlet, d=doublet, dd= double doublet, dt - double triplet, t=triplet, q=quartet, m=multiplet, br=broad, number of protons). The residual protic solvent was used as the internal reference. In several cases, high-temperature NMR (70 °C 1348 K) was required to resolve peaks for conformational rotamers. This is noted as variable temperature NMR (VT) in the analytical data.

[0502] LCMS Methods Liquid chromatography and mass spectroscopy analyses were carried out using the system and operating conditions set out below. Where atoms with different isotopes are present and a single mass quoted, the mass quoted for the compound is the monoisotopic mass (i.e. 35CI; 79Br etc.)

[0503] LCMS Method 1

[0504] LCMS was carried out on a LIPLC Acquity with PDA detector and QDa mass detector. The column used was X-BRIDGE BEH C18 (2.1 mm x 50 mm, 2.5 pm). Column flow ranged from 0.8 to 1.2 mL / min. Mobile phases used were: (A) 0.1% Formic acid in water (B) 0.1% Formic acid in water: MeCN (10:90). The injection volume was 1-10 pL. Samples were prepared in water: MeCN, waterMeOH, MeCN or other appropriate solvent to achieve an approximate concentration of 250 ppm. The following gradient was used for the elution:

[0505] LCMS Method 2

[0506] LCMS was carried out on UPLC Acquity with PDA detector and QDa mass detector. The column used was X-BRIDGE BEH C18 (2.1 mm x 50 mm, 2.5 pm). Column flow was 0.55 mL / min. Mobile phases used were: (A) 2 mM ammonium acetate with 0.1 % formic acid in water (B) 0.1 % formic acid in water: acetonitrile (10:90). The injection volume was 1-10 pL. Samples were prepared in water: MeCN, waterMeOH, MeCN or other appropriate solvent to achieve an approximate concentration of 250 ppm. The following gradient was used for the elution:

[0507] LCMS Method 3 LCMS was carried out on LIPLC ACQUITY with PDA photodiode array detector and QDa mass detector. The column used was X-BRIDGE BEH C18 (2.1 mm x 50 mm, 2.5pm). Column flow was 0.55 mL / min and mobile phase used was: (A) 5 mM ammonium bicarbonate in water (B) 100% MeCN. The injection volume was 1-10 pL. Samples were prepared in water: MeCN, waterMeOH, MeCN or other appropriate solvent to achieve an approximate concentration of 250 ppm. The following gradient was used for the elution:

[0508] LCMS Method 4

[0509] As described for LCMS Method 3, except the column used was XTIMATE C18 (50 mm x 4.6 mm, 5 pm).

[0510] LCMS Method 5

[0511] As described for LCMS Method 3, except for mobile phase (A) 2 mM ammonium bicarbonate in water.

[0512] Preparative HPLC Methods Preparative HPLC Method 1

[0513] Purification was carried out using (A) 5 mM ammonium carbonate in water and (B) MeCN as the mobile phase, using a Waters X-Bridge Prep C8 (250 mm x 19 mm, 5 pm) column with a flow rate of 16 mL / min and the following gradient:

[0514] Preparative HPLC Method 2

[0515] Purification was carried out using (A) water and (B) MeCN as the mobile phase, using a Shim-Pack GIST C18 (250 mm x 20 mm, 5pm) column with a flow rate of 22 mL / min and the following gradient:

[0516] Preparative HPLC Method 3

[0517] Purification was carried out using (A) water and (B) MeCN as the mobile phase, using a

[0518] Shim-Pack GIST C18 (250 mm x 20 mm, 5 pm) column with a flow rate of 22 mL / min and the following gradient:

[0519] Preparative HPLC Method 4

[0520] Purification was carried out using (A) 5 mM ammonium carbonate in water and (B) MeCN as the mobile phase, using a YMC Triart C18 (250 mm x 20 mm, 5pm) column with a flow rate of 16 mL / min and the following gradient:

[0521] Preparative HPLC Method 5

[0522] Purification was carried out using (A) 5 mM ammonium carbonate in water and (B) MeCN as the mobile phase, using a Waters X-Bridge C8 OBD (250 mm x 19 mm, 5pm) column with a flow rate of 15 mL / min and the following gradient:

[0523] Preparative HPLC Method 6

[0524] Purification was carried out using (A) 0.5% HCI in water and (B) MeCN : water : THF (70:20:10) as the mobile phase, using a Shim-Pack GIST C18 (250 mm x 20 mm, 5pm) column with a flow rate of 22 mL / min and the following gradient: Preparative HPLC Method 7

[0525] Purification was carried out using (A) 5 mM ammonium bicarbonate in water with 0.05% ammonium hydroxide (B) MeCN: water : THF (70:20:10) as the mobile phase, using a Waters X-Bridge Prep C8 (250 mm x 19 mm, 5 pm) column with a flow rate of 14 mL / min and the following gradient:

[0526] Preparative HPLC Method 8

[0527] Purification was carried out using (A) 5 mM ammonium bicarbonate in water with 0.05% ammonia (B) 100% MeCN as the mobile phase, using a Waters X-Bridge Prep C8 (250 mm x 19 mm, 5 pm) column with a flow rate of 14 mL / min and the following gradient:

[0528] Preparative HPLC Method 9

[0529] Purification was carried out using (A) 0.05% formic acid in water (B) MeCN : THF (80:20) as the mobile phase, using a Waters Sunfire C18 OBD (250 mm x 19 mm, 5 pm) column with a flow rate of 15 mL / min and the following gradient:

[0530] Preparative HPLC Method 10

[0531] Purification was carried out using (A) 5 mM ammonium bicarbonate in water with 0.05% ammonia (B) 100% MeCN as the mobile phase, using a YMC Triart C18 (250 mm x 20 mm, 5pm) column with a flow rate of 20 mL / min and the following gradient:

[0532] Preparative HPLC Method 11

[0533] Purification was carried out using (A) 5 mM ammonium bicarbonate in water, (B) 100% MeCN as the mobile phase, using an X-Bridge C8 OBD (250 mm x 19 mm, 5 mm) column with a flow rate of 11 mL / min and the following gradient:

[0534] Preparative HPLC Method 12 Purification was carried out using (A) 5 mM ammonium bicarbonate and 0.05% ammonia in water, (B) MeCN : MeOH, 50:50 as the mobile phase, using an YMC Triart C18 (250 mm x 20 mm, 5 pm) column with a flow rate of 17 mL / min and the following gradient: Preparative HPLC Method 13

[0535] Purification was carried out using (A) 5 mM ammonium bicarbonate in water with 0.05% ammonia (B) MeCN : water : THF; 80:20:20 as the mobile phase, using a YMC Triart C18 (250 mm x 20 mm, 5pm) column with a flow rate of 18 mL / min and the following gradient: Preparative HPLC Method 14

[0536] As for preparative HPLC Method 12 with a flow rate of 20 mL / min and the following gradient:

[0537] Preparative HPLC Method 15

[0538] Purification was carried out using (A) 5 mM ammonium carbonate in water and (B)

[0539] MeCN: water; 80:20 as the mobile phase, using a Waters X-Bridge Prep C8 (250 mm x 19 mm, 5 pm) column with a flow rate of 10 mL / min and the following gradient:

[0540] Preparative HPLC Method 16

[0541] As for preparative HPLC Method 11 but with using an X-Bridge Prep C18 (250 mm x 19 mm, 5 pm) column with a flow rate of 6 mL / min. Preparative HPLC Method 17

[0542] Purification was carried out using (A) 5 mM ammonium bicarbonate in water with 0.05% ammonia (B) MeCN as the mobile phase, using an X-Bridge C18 (250 mm x 20 mm, 5 pm) column with a flow rate of 10 mL / min and the following gradient: Preparative HPLC Method 18

[0543] As for preparative HPLC method 17 except using an X-Bridge C18 (250 mm x 19 mm, 5 pm) column with a flow rate of 12 mL / min and the following gradient:

[0544] Preparative HPLC Method 19

[0545] Purification was carried out using (A) 5 mM ammonium bicarbonate in water with 0.05% ammonia (B) MeCN : water : THF (80:20:10) as the mobile phase, using an X-Bridge C18 (250 mm x 20 mm, 5 pm) column with a flow rate of 11 mL / min and the following gradient:

[0546] Preparative HPLC Method 20

[0547] As for Preparative HPLC Method 18 with the following gradient:

[0548] Preparative HPLC Method 21

[0549] Purification was carried out using (A) 5 mM ammonium bicarbonate in water, (B) 100%

[0550] MeCN as the mobile phase, using an X-Bridge C18 (250 mm x 19 mm, 5 pm) column with a flow rate of 7 mL / min and the following gradient:

[0551] Preparative HPLC Method 22

[0552] As for Preparative HPLC Method 15 with the following gradient. Preparative HPLC Method 23

[0553] As for preparative HPLC method 21 except with a flow rate of 11 mL / min and the following gradient:

[0554] Chiral Methods

[0555] Chiral HPLC Analytical Method 1

[0556] HPLC was carried out using Shimadzu LC-20 AD system with DAD detector using a Chiral IG-3 (100 mm x 3 mm, 3 pm) column. The mobile phase was: (A) liquid carbon dioxide; and (B) 0.1% methanolic ammonia in MeOH: MeCN (50: 50). The compounds were eluted with an isocratic method (50% A, 50% B), a flow rate of 4.0 mL / min and analysis time of 5 min.

[0557] Chiral HPLC Analytical Method 2

[0558] HPLC was carried out using Waters SFC Investigator system with 2998 PDA detector using a CHIRAL ICT (250 mm x 4.6 mm, 5 pm) column. The mobile phase was: (A) liquid carbon dioxide; and (B) 0.1% diethylamine in I PA: MeCN (70: 30). The compounds were eluted with an isocratic method (50% A, 50% B), a flow rate of 4.0 mL / min and run time of 15 min.

[0559] Chiral HPLC Analytical Method 3

[0560] HPLC was carried out using Shimadzu LC-20 AD system with DAD detector using a Chiralpak IG (250 mm x 4.6 mm, 5pm) column. The mobile phase was: (A) 0.1% methanolic ammonia in n-heptane; and (B) 0.1% methanolic ammonia in IPA: MeCN (70:30). The flow rate was 1 mL / min, oven temperature 60°C and run time 30 min with the following gradient:

[0561] Chiral HPLC Analytical Method 4

[0562] HPLC was carried out using a Waters SFC Investigator with PDA detector using a Chiralpak IG (250 mm x 4.6 mm, 5pm) column. The mobile phase was: (A) Liquid carbon dioxide and (B) 0.1% diethylamine in MeOH: MeCN (50:50). The compounds were eluted with an isocratic method (50% A, 50% B), a flow rate of 4.0 mL / min and run time of 10 min.

[0563] Chiral HPLC Analytical Method 5

[0564] HPLC was carried out using Waters SFC Investigator system with DAD detector using a Chiralpak IG (100mm x 3mm, 3 pm) column. The mobile phase was: (A) liquid carbon dioxide; and (B) 0.1% methanolic ammonia in MeOH: MeCN (50: 50). The compounds were eluted with an isocratic method (50% A, 50% B), a flow rate of 4.0 mL / min and analysis time of 5 min.

[0565] Chiral HPLC Analytical Method 6

[0566] HPLC was carried out using Waters SFC Investigator system with PDA detector using a Chiral Pak IB-N (250 mm x 4.6 mm, 3 pm) column. The mobile phase was: (A) liquid carbon dioxide; and (B) 0.1% methanolic ammonia in MeOH: MeCN (50: 50). The compounds were eluted with an isocratic method (50% A, 50% B), a flow rate of 4.0 mL / min and analysis time of 10 min.

[0567] Chiral HPLC Analytical Method 7

[0568] HPLC was carried out using Waters SFC Investigator system with PDA detector using a Chiralpak IG (250 mm x 4.6 mm, 5 pm) column. The mobile phase was: (A) liquid carbon dioxide; and (B) 0.1% methanolic ammonia in MeOH: TBME (50: 50). The compounds were eluted with an isocratic method (95% A, 5% B), a flow rate of 4.0 mL / min and analysis time of 16 min.

[0569] Chiral HPLC Analytical Method 8

[0570] HPLC was carried out using Shimadzu LC-20 AD system with DAD detector using a Chiralpak IG (100 mm x 3 mm, 3 pm) column. The mobile phase was: (A) liquid carbon dioxide; and (B) 0.1% methanolic ammonia in MeOH: MeCN (50: 50). The compounds were eluted with an isocratic method (50% A, 50% B), a flow rate of 2.0 mL / min and analysis time of 5 min.

[0571] Chiral HPLC Analytical Method 9

[0572] HPLC was carried out using a Waters SFC Investigator with PDA detector using a Chiralpak IG (250 mm x 4.6 mm, 5 pm) column. The mobile phase was: (A) Liquid carbon dioxide and (B) 0.1% diethylamine in IPA: MeCN (70:30). The compounds were eluted with an isocratic method (60% A, 40% B), a flow rate of 4.0 mL / min and run time of 12 min.

[0573] Chiral HPLC Analytical Method 10

[0574] As for chiral HPLC analytical method 1 but with a flow rate of 2.0 mL / min, a run time of 5 min and the following gradient:

[0575] Chiral HPLC Analytical Method 11

[0576] HPLC was carried out using Waters Acquity UPC2 detector using a Chiral IG-3 (100 mm x 3mm, 3 pm) column. The mobile phase was: (A) liquid carbon dioxide; and (B) 0.1% methanolic ammonia in MeOH: MeCN (50: 50). The compounds were eluted with an isocratic method (50% A, 50% B), a flow rate of 2.0 mL / min and analysis time of 5 min.

[0577] Chiral HPLC Analytical Method 12

[0578] As for Method 5 but using a chiralpak IG (250 mm x 4.6 mm, 5pm) column.

[0579] Chiral Preparative HPLC Method 1

[0580] Purification was carried out using (A) 0.1% methanolic ammonia in heptane and (B) 0.1% methanolic ammonia in IPA : MeCN (70:30) as the mobile phase, using a YMC Cellulose SC (250 mm x 19 mm, 5pm) column. The compounds were eluted with an isocratic method (90% A, 10% B), a flow rate of 30 mL / min and run time of 40 min. Chiral Preparative HPLC Method 2

[0581] Purification was carried out using (A) 0.1% methanolic ammonia in heptane and (B) 0.1% methanolic ammonia in IPA : MeCN (70:30) as the mobile phase, using a Chiralpak IG (250 mm x 50 mm, 5pm) column. The compounds were eluted with an isocratic method (70% A, 30% B), a flow rate of 40 mL / min and run time of 44 min.

[0582] Chiral Preparative HPLC Method 3

[0583] Purification was carried out on a Waters SFC 350 with 2489 UV Detector with (A) Liquid carbon dioxide and (B) 0.1% methanolic ammonia in MeOH : MeCN (50:50) as the mobile phases, using a Chiralpak IG (250 mm x 50 mm, 5 pm) column. The compounds were eluted with an isocratic method (55% A, 45% B), a flow rate of 150 mL / min and a run time of 44 min.

[0584] Chiral Preparative HPLC Method 4

[0585] As Chiral Preparative HPLC Method 3 with the following exception:

[0586] The compounds were eluted with an isocratic method (50% A, 50% B) and a run time of 32 min.

[0587] Chiral Preparative HPLC Method 5

[0588] Purification was carried out on a PHP-04-Agilent 1260 Series Infinity-I I with UV Detector with (A) 0.1% methanolic ammonia in MeOH as the mobile phase, using a Hypersil Chiral-ICT (250 mm x 50 mm, 5pm) column. The compounds were eluted with an isocratic method (100% A), a flow rate of 40 mL / min and a run time of 32 min.

[0589] Chiral Preparative HPLC Method 6

[0590] Purification was carried out using (A) 0.1% methanolic ammonia in heptane and (B) 0.1% methanolic ammonia in IPA:MeCN (70:30) as the mobile phase, using a Chiral ART cellulose-SC (250 mm x 20 mm, 5 pm) column. The compounds were eluted with an isocratic method (65% A, 35% B), a flow rate of 25 mL / min and run time of 25 min.

[0591] Chiral Preparative HPLC Method 7

[0592] Purification was carried out using (A) 0.1% methanolic ammonia in heptane and (B) 0.1% methanolic ammonia in IPA : MeOH (50:50) as the mobile phase, using a Chiralpak IG (250 mm x 50 mm, 5 pm) column. The compounds were eluted with an isocratic method (60% A, 30% B), a flow rate of 40 mL / min and run time of 50 min. Chiral Preparative HPLC Method 8

[0593] Purification was carried out using (A) liquid CO2 and (B) 0.1 % methanolic ammonia in MeOH : MeCN (50:50) as the mobile phase, using a Chiralpak IG (250 mm x 50 mm x 5 pm) column. The compounds were eluted with an isocratic method (50% A, 50% B), a flow rate of 150 mL / min and run time of 50 min.

[0594] Chiral Preparative HPLC Method 9

[0595] Purification was carried out using (A) 0.1 % methanolic ammonia in heptane and (B) 0.1 % methanolic ammonia in IPA : MeOH : MeCN (50:25:25) as the mobile phase, using a Chiral ART cellulose-SC (250 mm x 20 mm, 5pm) column. The compounds were eluted with an isocratic method (60% A, 40% B), a flow rate of 20 mL / min and run time of 25 min.

[0596] Chiral Preparative HPLC Method 10

[0597] Purification was carried out using 0.1 % methanolic ammonia in heptane: I PA (50:50) as the mobile phase, using a using a Chiralpak IG (250 mm x 50 mm, 5pm) column. The compounds were eluted with a flow rate of 43 mL / min and a run time of 75 min.

[0598] Preparation of Intermediates lnt-1 and lnt-2 were prepared following Scheme 1 below.

[0599] Scheme 1

[0600] Step 1 : Ethyl 4-cyclopropoxy-2-(methylsulfanyl)pyrimidine-5-carboxylate (lnt-1)

[0601] To stirred suspension of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (CAS 5909- 24-0) (0.5 g, 2.15 mmol) and cyclopropanol (1.25 mL, 21.49 mmol) was added sodium bis(trimethylsilyl)amide (1 M in THF, 2.1 mL, 2.14 mmol) at 0°C. The reaction mixture was stirred at 0°C for 15 min. The reaction mixture was quenched with aq. ammonium chloride solution (20 mL) and extracted into EtOAc (2 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (silica, eluting with 3% EtOAc in Hexane) afforded the title compound (1.1 g, 67%).

[0602] 1 H NMR (DMSO-d6) 5 8.76 (s, 1 H), 4.48-4.52 (m, 1 H), 4.23 (1, 2H), 2.58 (s, 3H), 1.26 (t, 3H), 0.86-0.78 (m, 4H).

[0603] Step-2: 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-(methylsulfanyl)pyrimidine-5- carboxamide (lnt-2)

[0604] To a stirred solution of 2,6-dichloroaniline (1.90 g, 11.79 mmol) in DCM (15 mL) was added trimethyl aluminium (2M in toluene, 7.80 mL, 15.79 mmol) dropwise at 0°C. The reaction mixture was stirred at 0°C for 10 min followed by addition of ethyl 4- cyclopropoxy-2-(methylsulfanyl)pyrimidine-5-carboxylate (lnt-1) (1.00 g, 3.93 mmol) in DCM (5.0 mL). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ammonium chloride solution (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. Trituration with n-pentane (20 mL) afforded the title compound as a white solid (1.1 g, 79%).

[0605] 1 H NMR (DMSO-d6) 5 9.77 (s, 1 H), 8.69 (s, 1H), 7.58 (d, 2H), 7.39 (t, 1 H), 4.57-4.54 (m, 1 H), 2.63 (s, 3H), 0.91-0.81 (m, 4H). lnt-3 was prepared from lnt-1 according to the scheme below.

[0606] Step 1 : 4-cyclopropoxy-N-(2,6-dichloro-3-fluorophenyl)-2-(methylsulfanyl)pyrimidine-5- carboxamide (lnt-3) To a stirred solution of 2,6-dichloro-3-fluoroaniline (CAS # 1692388-75-2) (0.43 g, 2.36 mmol) in toluene (5 mL) was added trimethylalumininum (2M in toluene) (3.53 mL, 7.08 mmol) at 0°C temperature. The reaction mixture was stirred at 0°C temperature for 20 min and lnt-1 (0.3 g, 1.18 mmol) in toluene (1 mL) was added drop wise. The resulting reaction mixture was allowed to stir at 70°C temperature for 3 h. The reaction mixture was quenched with aq. ammonium chloride solution (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was triturated with n-pentane (20 mL) to afford the title product as off- white solid (0.23 g, 50%).

[0607] 1 H NMR (DMSO-d6) 5 9.88 (s, 1 H), 8.70 (s, 1 H), 7.66 (dd, 1 H), 7.52 (t, 1 H), 4.56 (br s, 1 H), 2.60 (s, 3H), 0.92-0.82 (m, 4H). lnt-4: (6-chloro-2,3-difluorophenyl)-4-cyclopropoxy-2-(methylsulfanyl)pyrimidine-5- carboxamide

[0608] The title compound was prepared following a similar method to that used for lnt-3 with the following exceptions:

[0609] The reaction mixture was heated to 100°C for 3 h. Purification by column chromatography (silica, eluting with 6% EtOAc in Hexane) afforded the title product as a white solid (0.17 g, 17%).

[0610] 1 H NMR (DMSO-d6) 5 9.73 (s, 1 H), 8.73 (s, 1 H), 7.57-7.47 (m, 2H), 4.55 (br s, 1 H), 2.68 (s, 3H), 0.92-0.83 (m, 4H). lnt-5: 4-cyclopropoxy-N-(2,5-dichlorophenyl)-2-(methylsulfanyl)pyrimidine-5-carboxamide

[0611] The title compound was prepared following a similar method to that used for lnt-3 with the following exceptions:

[0612] The reaction mixture was heated to 100°C for 3 h. Purification by column chromatography (silica, eluting with 8% EtOAc in Hexane) afforded the title product as a white solid (0.17 g, 33%).

[0613] 1 H NMR (DMSO-d6) 5 9.71 (s, 1 H), 8.89 (s, 1 H), 8.45 (d, 1 H), 7.62 (d, 1H), 7.29 (dd, 1H), 4.61-4.58 (m, 1 H), 2.62 (s, 3H). lnt-6: N-(2-chloro-6-fluorophenyl)-4-cyclopropoxy-2-(methylsulfanyl)pyrimidine-5- carboxamide lnt-6 was prepared according to the following scheme.

[0614] To a stirred solution of lnt-1 (0.6 g, 2.36 mmol) in DCM (6.0 mL) was added trimethyl aluminium (2 M in toluene) (4.12 mL, 8.26 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at 0°C temperature for 30 min followed by addition of 2- chloro-6-fluoroaniline (CAS # 363-51-9) (0.41 g, 2.83 mmol) in DCM (2 mL). The resulting reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was poured into saturated ammonium chloride solution (30 mL) and extracted with DCM (50 mL). The combined organic layers were dried (Na2SO4) and concentrated.

[0615] Purification by column chromatography (silica, eluting with 3% EtOAc in Hexane) afforded the title product as a brown solid (0.45 g, 54%).

[0616] 1 H NMR (DMSO-d6) 5 9.60 (s, 1 H), 8.71 (s, 1 H), 7.46-7.33 (m, 3H), 4.55 (br s, 1 H), 2.60 (s, 3H), 0.92-0.82 (m, 4H).

[0617] I nt- 7 was prepared according to the scheme below.

[0618] Step 1 : Ethyl 4-(2-methoxyethoxy)-2-(methylsulfanyl)pyrimidine-5-carboxylate

[0619] The title compound was prepared following a similar method to that used for lnt-1 (Scheme 1) with the following exceptions: 2-methoxyethan-1-ol (6.54 g, 85.95 mmol) was used instead of cyclopropanol.

[0620] Purification by column chromatography (silica, eluting with 12% EtOAc in hexane) afforded the title compound as a yellow liquid (0.32 g, 14%).

[0621] LCMS (Method 2) RT 2.00 min, m / z 273.1 (MIT).

[0622] Step 2: N-(2,6-Dichlorophenyl)-4-(2-methoxyethoxy)-2-(methylsulfanyl)pyrimidine-5- carboxamide (lnt-7)

[0623] The title compound was prepared following a similar method to that used for lnt-2 (Scheme 1) with the following exceptions:

[0624] Ethyl 4-(2-methoxyethoxy)-2-(methylsulfanyl)pyrimidine-5-carboxylate (0.32 g, 1.18 mmol) was used. Purification by column chromatography (silica, eluting with 12% EtOAc in hexane) afforded the title compound as a white solid (0.30 g, 66%).

[0625] 1 H NMR (DMSO-d6) 0.98 (s, 1 H), 8.75 (s, 1 H), 7.62-7.59 (m, 2H), 7.43-7.39 (m, 1 H), 4.67-4.65 (m, 2H), 3.77-3.75 (m, 2H), 3.28 (s, 3H), 2.59 (s, 3H). lnt-8 was prepared according to the following scheme.

[0626] Step-1 : Ethyl 4-cyclobutoxy-2-(methylsulfanyl)pyrimidine-5-carboxylate

[0627] To a slurry of ethyl 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylate (2.0 g, 8.59 mmol) and cyclobutanol (6.19 g, 85.9 mmol) was added sodium bis(trimethylsilyl)amide (1M in THF) (8.59 mL) at 0°C. The reaction mixture was stirred at 0°C for 10 min. The reaction mixture was quenched with aq. NH4CI (100 mL) and extracted into EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 3% EtOAc in hexane) afforded the title compound (0.75 g, 33%). LCMS (Method 1) RT 2.26 min, m / z 268.7 (M+H)+.

[0628] Step 2: 4-Cyclobutoxy- / V-(2,6-dichlorophenyl)-2-(methylsulfanyl)pyrimidine-5- carboxamide (lnt-8)

[0629] To a stirred solution of 2,6-dichloroaniline (1.21 g, 7.49 mmol) in DCM (20 mL) was added trimethyl aluminium (2M in toluene) (4.98 mL, 9.96 mmol) drop wise at 0°C. The reaction mixture was stirred 0°C for 20 min. Ethyl 4-cyclobutoxy-2-(methylsulfanyl)pyrimidine-5- carboxylate (0.670 g, 2.49 mmol) in DCM (6.8 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ammonium chloride solution (100 mL) and extracted into DCM (2 x 100mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Trituration with n-pentane (20 mL) afforded the title compound (0.6 g, 63%).

[0630] LCMS (Method 1) RT 2.4 min, m / z 383.8 (M+H)+. lnt-9: 4-cyclopropoxy-N-(2,6-dichloro-3-hydroxyphenyl)-2-(methylsulfanyl)pyrimidine-5- carboxamide lnt-9 was prepared according to the following scheme. lnt-1 lnt-9

[0631] The title compound was prepared following a similar method to that used for lnt-3 with the following exceptions:

[0632] The amine used was 3-amino-2,4-dichlorophenol-hydrochloride and the reaction mixture was heated at 80°C for 12 h. Purification by column chromatography (silica, eluting with 25% EtOAc in hexane) afforded the title compound as an off-white solid (0.6 g, 66%).

[0633] 1 H NMR (DMSO-d6) 5 10.61 (s, 1 H), 9.68 (s, 1 H), 8.67 (s, 1 H), 7.36-7.33 (m, 1 H), 6.68 (d, 1 H), 4.60-4.53 (m, 1 H), 2.60 (s, 3H), 0.90-0.81 (m, 4H). lnt-10: N-(2,6-dichlorophenyl)-4-{f(2R)-1-methoxypropan-2-yl1oxy}-2-

[0634] (methylsulfanyl)pyrimidine-5-carboxamide lnt-10 was prepared according to the following scheme: lnt-10

[0635] The title compound was prepared following a similar method to that used for lnt-2 (Scheme 1) with the following exceptions:

[0636] In step 1 , (R)-1-methoxypropan-2-ol (CAS # 4984-22-9) (1.16 g, 12.89 mmol) was used.

[0637] In step 2 the reaction was heated at 60°C for 1 h and for the work-up the reaction mixture was quenched with sodium bicarbonate solution (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2SC>4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 15% EtOAc in hexane) afforded the title compound as a light yellow oil (0.54 g, 96%).

[0638] 1 H NMR (DMSO-d6) 5 9.70 (s, 1 H), 8.75 (s, 1 H), 7.60 (d, 2H), 7.41 (t, 1 H), 5.61-5.60 (m, 1 H), 3.71-3.67 (m, 1 H), 3.57-3.54 (m, 1 H), 3.27 (s, 3H), 2.58 (s, 3H), 1.39 (d, 3H). lnt-11 : N-(2,6-dichlorophenyl)-4-{f(2S)-1-methoxypropan-2-yl1oxy}-2-

[0639] (methylsulfanyl)pyrimidine-5-carboxamide lnt-11 was prepared as described for lnt-10 with the following exceptions:

[0640] In step 1 , (S)-1-methoxypropan-2-ol (CAS # 26550-55-0) (0.58 g, 6.44 mmol) was used.

[0641] In step 2 the reaction was heated at 80°C for 1 h.

[0642] 1 H NMR (DMSO-d6) 8 9.71 (s, 1 H), 8.75 (s, 1 H), 7.60 (d, 2H), 7.41 (t, 1 H), 5.61-5.60 (m, 1 H), 3.71-3.67 (m, 1 H), 3.57-3.54 (m, 1 H), 3.27 (s, 3H), 2.58 (s, 3H), 1.39 (d, 3H). lnt-12: N-(2,6-dichlorophenyl)-4-(1-methylcyclopropoxy)-2-(methylsulfanyl)pyrimidine-5- carboxamide lnt-12 was prepared according to the following scheme. lnt-12 lnt-12 was prepared as described for lnt-2 (Scheme 1) with the following exceptions:

[0643] In step 1 , 1-methylcyclopropan-1-ol was used. In step 2, purification by column chromatography (silica, eluting with 11% EtOAc in hexane) afforded the title compound as a white solid (0.34 g, 59%).

[0644] 1 H NMR (DMSO-d6) 8 9.76 (s, 1 H), 8.67 (s, 1 H), 7.58 (d, 2H), 7.40 (t, 1 H), 2.60 (s, 3H), 1.70 (s, 3H), 1.08-1.09 (m, 2H), 0.82-0.79 (m, 2H). lnt-13: N-(2,6-dichlorophenyl)-2-(methylsulfanyl)-4-(propan-2-yloxy)pyrimidine-5- carboxamide lnt-13 was prepared according to the following scheme.

[0645] Step 2 lnt-13

[0646] Step-1 : 4-lsopropoxy-2-(methylthio)pyrimidine-5-carboxylic acid

[0647] A solution of NaH (60%) (1.11 g, 77.36 mmol) in IPA (40 mL) was stirred at rt for 18 h. Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (CAS 5909-24-0) (4.0 g, 17.19 mmol) was added at rt and the reaction mixture was stirred for 18 h. The reaction mixture was concentrated in vacuo, acidified with dilute HCI to pH ~3-4 (30 mL) and extracted into EtOAc (3 x 50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Trituration with Et20 (20 mL) afforded the title compound (4.1 g, quantitative).

[0648] LCMS (Method 1) RT 1.56 min, m / z 228.8 (M+H)+. Step-2: N-(2,6-Dichlorophenyl)-4-isopropoxy-2-(methylthio)pyrimidine-5-carboxamide (Int- 13)

[0649] To a cooled, stirred solution of 4-isopropoxy-2-(methylthio)pyrimidine-5-carboxylic acid (2.0 g, 8.76 mmol) in DCM (20 mL) was added 2,6-dichloroaniline (1.6 g, 9.64 mmol) and pyridine (6.93 g, 87.61 mmol). Phosphorus oxychloride (9.40 g, 61.33 mmol) was added drop-wise and stirred at rt for 18 h. The reaction mixture was quenched with ice-water (100 mL) and extracted into EtOAc (3 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (silica, eluting with 2.7% MeOH in DCM) afforded the title compound (1.73 g, 53%).

[0650] LCMS (Method 1) RT 2.33 min, m / z 371.8 (M+H)+. lnt-14: N-(2,6-dichlorophenyl)-4-methoxy-2-(methylsulfanyl)pyrimidine-5-carboxamide lnt-14 was prepared according to the following scheme.

[0651] Step 1 : methyl 4-methoxy-2-(methylsulfanyl)pyrimidine-5-carboxylate

[0652] To a stirred solution of ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate (CAS # 5909-24-0) (3.0 g, 12.89 mmol) in THF (90 mL, 30 vol) was added sodium methoxide (25% in MeOH) (5.56 g, 25.79 mmol) dropwise at 0°C under nitrogen. The resulting reaction mixture was stirred at 0°C for 1 h. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 18% EtOAc in hexane) afforded the title compound as a white solid (0.7 g, 25%).

[0653] 1H NMR (CDCh) 6 8.34 (s, 1H), 4.12 (s, 3H), 3.91 (s, 3H), 2.61 (s, 3H).

[0654] Step 2: N-(2,6-dichlorophenyl)-4-methoxy-2-methylsulfanyl)pyrimidine-5-carboxamide (lnt-14) To a stirred solution of 2,6-dichloroaniline (0.68 g, 4.20 mmol) in toluene (15 mL, 50 vol) was added trimethyl aluminium (2M in toluene) (2.8 mL, 5.60 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was allowed to stir at 0°C for 30 min and methyl 4- methoxy-2-(methylsulfanyl)pyrimidine-5-carboxylate (0.3 g, 1.40 mmol) was added dropwise. The resulting reaction was allowed to stir at 80°C for 2 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (250 mL) and filtered through Celite®, washing with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 16% EtOAc in hexane) afforded the title compound as a white solid (0.85 g, 88%).

[0655] 1 H NMR (DMSO-d6) 5 9.27 (s, 1 H), 8.77 (s, 1 H), 7.59 (d, 2H), 7.40 (t, 1 H), 4.09 (s, 1 H), 2.59 (s, 3H), lnt-15: N-(2,6-dichlorophenyl)-4-ethoxy-2-(methylsulfanyl)pyrimidine-5-carboxamide lnt-15 was prepared according to the following scheme. lnt-15 lnt-15 was prepared as described for lnt-2, scheme 1 with the following exceptions. In step 1 , ethanol was used. In step 2, purification by column chromatography (silica, eluting with 10% EtOAc in hexane) afforded the title compound as an off-white solid (1.4 g, 47%).

[0656] 1 H NMR (DMSO-d6) 5 9.87 (s, 1H), 8.73 (s, 1H), 7.59 (d, 2H), 7.40 (t, 1H), 4.58 (q, 2H), 2.58 (s, 3H), 1.41 (t, 3H). lnt-16 and lnt-17 were prepared according to the following scheme.

[0657] Step 1 : 4-chloro-N-(2,6-dichlorophenyl)-2-(methylsulfanyl)pyrimidine-5-carboxamide (Int- 16)

[0658] To a stirred solution of 4-chloro-2-(methylthio) pyrimidine-5-carbonyl chloride (CAS # 55084-66-7) (2.0 g, 8.96 mmol) and 2,6-dichloroaniline (1.45 g, 8.96 mmol) in DCM (40 mL) was added pyridine (0.85 g, 10.76 mmol) dropwise at 0°C. The reaction mixture was allowed to stir at room temperature for 24 h. The resulting reaction mixture was poured into water (200 mL), extracted with DCM (3 X 200 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 20% EtOAc in hexane) afforded the title compound as yellow solid (0.46 g, 15%).

[0659] Step 2: 4-(cyclopropylmethoxy)-N-(2,6-dichlorophenyl)-2-(methylsulfanyl)pyrimidine-5- carboxamide (lnt-17)

[0660] To stirred suspension of ethyl 4-chloro-N-(2,6-dichlorophenyl)-2-(methylthio) pyrimidine-5- carboxamide (0.3 g, 0.86 mmol) and cyclopropyl methanol (CAS # 2516-33-8) (0.62 g, 8.60 mmol) in a THF (6 mL, 20 vol) was added sodium bis(trimethylsilyl)amide (1M in THF) (1.29 mL, 1.29 mmol) at 0°C. The resulting reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was quenched with aqueous sodium bicarbonate solution (100 mL) and extracted with EtOAc (2 X 80mL). Purification by flash column chromatography (silica, eluting with 10% EtOAc in hexane) afforded the title compound as a white solid (0.16 g, 48%).

[0661] 1 H NMR (DMSO-d6) 5 9.88 (s, 1 H), 8.75 (s, 1 H), 7.60 (d, 2H), 7.41 (t, 2H), 4.39 (d, 2H), 2.58 (s, 3H), 1.37-1.35 (m, 1 H), 0.57-0.42 (m, 2H). lnt-18: N-(2,6-dichlorophenyl)-4-(2,2-difluoroethoxy)-2-(methylsulfanyl)pyrimidine-5- carboxamide lnt-18 was prepared according to the following scheme. lnt-18 was prepared as described for lnt-2 (Scheme 1) with the following exceptions. In step 1, 2,2-difluoroethan-1-ol was used. In step 2, purification by column chromatography (silica, eluting with 8% EtOAc in hexane) afforded the title compound as a light yellow liquid (0.3 g, 84%).

[0662] 1 H NMR (DMS0-d6) 5 8.82 (s, 1 H), 6.42 (tt, 1 H), 4.75 (td, 2H), 4.27 (q, 2H), 2.57 (s, 3H), 1.29 (t, 3H). lnt-19 was prepared according to the following scheme.

[0663] Int-16 lnt-19

[0664] Step 1 : N-(2,6-dichlorophenyl)-4-(3-methoxycyclobutoxy)-2-(methylsulfanyl)pyrimidine-5- carboxamide (lnt-19)

[0665] To a stirred solution of Int-16 (0.5 g, 1.43 mmol) and 3-methoxycyclobutan-1-ol (CAS # 1432680-25-5) (0.439 g, 4.30 mmol) in THF (10 mL, 20 vol) was added sodium bis trimethylsilyl amide (1M in THF) (1.72 mL, 1.72 mmol) dropwise at 0°C. The resulting reaction mixture was stirred at room temperature for 30 min. After completion of reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (100 mL) and extracted with DCM (2 x 60 mL). The combined organic layers were dried (Na2SC>4) and concentrated in vacuo. Purification by column chromatography (silica, eluting with 22% EtOAc in hexane) afforded the title compound as a white solid (0.06 g, 10%).

[0666] 1 H NMR (DMS0-d6) 5 9.87 (s, 1H), 8.68 (2, 1 H), 7.59 (d, 2H), 7.40 (t, 1 H), 5.04 (pentet, 1 H), 3.67 (pentet, 1H), 3.15 (s, 3H), 2.87-2.80 (m, 2H), 2.56 (2, 3H), 2.23-2.16 (m, 2H). lnt-20: N-(2,6- carboxamide lnt-20 was prepared according to the scheme below. lnt-20 lnt-20 was prepared as described for lnt-2 (Scheme 1) with the following exceptions. In step 1 , (R)-2-methoxypropan-1-ol (1.0 g, 4.30 mmol) was used. In step 2, purification by column chromatography (silica, eluting with 15% EtOAc in hexane) afforded the title compound as a yellow solid (0.5 g, 71 %).

[0667] LCMS (Method 2) RT 2.39 min, m / z 402.2 (MH+) lnt-21 : N-(2,6-dichlorophenyl)-4-f(2S)-2-methoxypropoxy1-2-(methylsulfanyl)pyrimidine-5- carboxamide lnt-21 was prepared as described for lnt-20 with the following exceptions. In step 1 , (S)- 2-methoxypropan-1-ol (CAS 116422-39-0) (1.0 g, 4.30 mmol) was used. In step 2, purification by column chromatography (silica, eluting with 15% EtOAc in hexane) afforded the title compound as a yellow solid (1.0 g, 89%).

[0668] LCMS (Method 1) RT 2.35 min, m / z 402.2 (MH+) lnt-22: N- 6-di carboxamide lnt-22 was prepared according to the following scheme. lnt-22 was prepared as described for lnt-2 (Scheme 1) with the following exceptions. In step 1 , 3-methoxypropan-1-ol as used. In step 2, purification by trituration with 20% Et20 in pentane afforded the title compound as an off-white solid (0.8 g, 95%).

[0669] LCMS (Method 2) RT 2.37 min, m / z 402.2 (MH+) lnt-23: 4-(2-cyclopropoxyethoxy)-N-(2,6-dichlorophenyl)-2-(methylsulfanyl)pyrimidine-5- carboxamide lnt-23 was prepared according to the following scheme. lnt-16 lnt-23

[0670] To a stirred solution of 2-cyclopropoxyethan-1-ol (0.03 g, 0.32 mmol) in THF (3 mL, 20 vol) was added sodium hydride (60% in mineral oil) (0.025 g, 0.60 mmol) portion wise at 0°C temperature under nitrogen. The resulting reaction mixture was stirred at 0°C for 30 min and a solution of 4-chloro-N-(2,6-dichlorophenyl)-2-(methylthio) pyrimidine-5- carboxamide (0.14 g, 0.40 mmol) in THF (1 mL, 10 vol) was added dropwise. The resulting reaction was stirred at 60°C for 6 h. The reaction was poured into ice cold water (30 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried (Na2SC>4) and concentrated. Purification by flash column chromatography (silica, eluting with 12% EtOAc in hexane) afforded the title compound as off-white solid (0.06 g, 36%).

[0671] LCMS (Method 2) RT 2.42 min, m / z 414.2 (MH+). lnt-24: 4-(1-cyanoethoxy)-N-(2,6-dichlorophenyl)-2-(methylsulfanyl)pynmidine-5- carboxamide lnt-24 was prepared according to the following scheme. lnt-16 lnt-24

[0672] The title compound was prepared from lnt-16 following a similar method to that used for lnt-19 with the following exceptions:

[0673] 2-Hydroxypropanenitrile was used to afford the title product as light-yellow solid (0.35 g, 32%).

[0674] 1 H NMR (DMSO-d6) 8 10.06 (s, 1 H), 8.77 (s, 1 H), 7.60 (d, 2H), 7.42 (t, 1 H), 5.94 (q, 1 H), 2.65 (s, 3H), 1.78 (d, 3H).

[0675] Amine synthesis

[0676] A-1 was prepared according to the following scheme:

[0677] Step 1 : 1-(2-(4-nitro-1 H-pyrazol-1-yl) ethyl) piperidine

[0678] To a stirred solution of 4-nitro-1 H-pyrazole (1.0 g, 8.84 mmol) and 1-(2-chloroethyl) piperidine-hydrochloride (1.79 g, 9.73 mmol) in MeCN (20 mL) was added potassium carbonate (6.11 g, 44.22 mmol). The reaction mixture was allowed to stir at 80°C for 18 h. The reaction mixture was concentrated in vacuo and the resulting suspension was diluted with water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (silica, eluting with 58% EtOAc in hexane) afforded the title compound as an off-white solid (1.2 g, 30%).

[0679] Step 2: 1-(2-(piperidin-1-yl) ethyl)-1 H-pyrazol-4-amine (A-1)

[0680] To a stirred solution of 1-(2-(4-nitro-1 H-pyrazol-1-yl) ethyl) piperidine (1.10 g, 4.90 mmol) in MeOH (22 mL) was added Pd-C (50% wet basis, 0.55 g) at room temperature. The reaction mixture was stirred under hydrogen for 4 h. The reaction mixture was filtered through Celite® and washed with MeOH (3 x 50 mL). The combined filtrates were dried (Na2SO4) and concentrated in vacuo to afford the title product as a light brown solid (0.85 g, 89%).

[0681] A-2 was prepared according to the following scheme:

[0682] Step 1 Step 2 A-2

[0683] Step 1 : tert-butyl (3-(4-nitro-1 H-pyrazol-1-yl) propyl) carbamate

[0684] To a stirred solution of 4-nitro-1 H-pyrazole (3.0 g, 26.53 mmol) and tert-butyl (3-(4-nitro- 1 H-pyrazol-1-yl) propyl) carbamate (7.58 g, 31.84 mmol) in MeCN (90 mL) was added potassium carbonate (5.13 g, 37.14 mmol) at room temperature. The reaction mixture was allowed to stir at 80°C temperature for 16 h. The resulting mixture was allowed to cool to room temperature, poured into water (150 mL) and extracted with EtOAc (2 x 250 mL). The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was triturated with n-pentane (40 mL) and dried to afford the title product as a white solid (6.5 g, 91 %).

[0685] Step 2: tert-butyl (3-(4-amino-1 H-pyrazol-1-yl) propyl) carbamate (A-2)

[0686] To a stirred solution of tert-butyl (3-(4-nitro-1 H-pyrazol-1-yl) propyl) carbamate (1.5 g, 5.55 mmol) in MeOH (45 mL) was added 10 % Pd / C (wetted with ca. 55% water) (0.75 g, 50% w / w). The reaction mixture was stirred under hydrogen gas for 4 h. The reaction mixture was filtered through Celite® and washed with MeOH (2 x 30 mL). The combined filtrates were dried (Na2SC>4) and concentrated in vacuo to afford the title product as a brown liquid (1.2 g, 90%).

[0687] A-3 was prepared according to the following scheme. Step 1 : 1 -methyl- 1 H-pyrazol-4-amine (A-3)

[0688] To a solution of 1-methyl-4-nitro-1 H-pyrazol (CAS # 3994-50-1) (0.3 g, 2.36 mmol) in MeOH (10 mL) was added palladium on carbon (10 % w / w 50% wet basis, 0.1 g). The resulting reaction mixture was stirred under hydrogen gas at room temperature for 2 h. The reaction mixture was filtered through Celite® washed with MeOH (3 x 150 mL). The combined filtrates were dried (Na2SO4) and concentrated. The resulting residue was triturated with Et2O:n-pentane, 2:8 (10 mL) to afford the title compound as a pink gum (0.2 g, 87%).

[0689] 1 H NMR (DMSO-d6) 5 6.97 (d, 1 H), 6.86 (d, 1 H), 3.79 (br s, 2H), 3.64 (s, 3H).

[0690] A-4 was prepared according to the following scheme.

[0691] HCHO, acetic acid,

[0692] NaCN(NH3)4, Pd / C, Hydrogen, MeOH

[0693] Step 3 Step 4

[0694] Step 1 : tert-butyl 3-(4-nitro-1 H-pyrazol-1-yl)azetidine-1 -carboxylate To a stirred solution of tert-butyl 3-iodoazetidine-1 -carboxylate (CAS # 254454-54-1) (4.0 g, 14.13 mmol) and 4-nitro-1 H-pyrazole (CAS # 2075-46-9) (1.59 g, 14.13 mmol) in DMF (40 mL, 10 vol) was added potassium carbonate (5.84 g, 41.30 mmol) at room temperature. The reaction mixture was allowed to stir at 80°C for 16 h. After completion of reaction, the resulting reaction mixture was poured into cold water (60 mL). The precipitated solid was filtered and dried in vacuo to afford the title product as white solid (3.5 g, 37%).

[0695] Step 2: 1-(azetidin-3-yl)-4-nitro-1 H-pyrazole

[0696] To a stirred solution of (tert-butyl 3-(4-nitro-1 H-pyrazol-1-yl)azetidine-1 -carboxylate (1.0 g, 3.73 mmol) in DCM (20 mL, 20 vol) was added 4M HCI in 1,4 dioxane (10 mL, 10 vol) at 0°C. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The resulting solid was triturated with Et20 (10 mL) to afford the title product as grey solid (0.9 g, 67%).

[0697] Step 3: 1-(1-methylazetidin-3-yl)-4-nitro-1 H-pyrazole

[0698] To a solution of 1-(azetidin-3-yl)-4-nitro-1 H-pyrazole (0.79 g, 3.86 mmol) in MeOH (4 mL) was added formaldehyde (37% in MeOH) (0.313 g, 3.86 mmol) and acetic acid (0.079 mL, 0.1 vol). The reaction mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (0.218 g, 3.47 mmol) was added at 0°C and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated in vacuo and the obtained suspension poured into water (60 mL) and added aq. sodium bicarbonate solution (3 mL) was added until pH ~7. The aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was purified by column chromatography (silica, eluting with 7% MeOH in DCM) to afford the title product as white solid (0.1 g, 14%).

[0699] Step 4: 1-(1-methylazetidin-3-yl)-1 H-pyrazol-4-amine (A-4)

[0700] To a stirred solution of 1-(1-methylazetidin-3-yl)-4-nitro-1 H-pyrazole (0.1 g, 0.55 mmol) in MeOH (2 mL) was added 10 % Pd / C (wetted with ca. 55% water) (0.05 g, 50% w / w) at room temperature. The reaction mixture was stirred under hydrogen gas at room temperature for 3 h. The reaction mixture was filtered through Celite® washing with MeOH (2 x 50 mL). The combined filtrates were dried (Na2SO4) and concentrated. The resulting residue was triturated with Et20 (10 mL) and dried to afford the title product as a brown solid (0.08 g, 96%).

[0701] 1 H NMR (DMSO-d6) 5 7.15 (s, 1 H), 6.95 (s, 1 H), 4.71 (q, 1 H), 3.62 (t, 2H), 3.42 (br s, 2H), 3.23 (t, 2H), 2.28 (s, 3H).

[0702] A-5 was prepared according to the following scheme.

[0703] Step 1 : 4-nitro-1-(oxetan-3-yl)-1 H-pyrazole

[0704] To a stirred solution of 4-nitro-1 H-pyrazole (CAS # 2075-46-9) (1.0 g, 8.84 mmol) and oxetan-3-ol (CAS # 7748-6-9) (0.66 g, 8.84 mmol) in THF (10 mL, 10 vol) was added triphenylphosphine (3.48 g, 13.26 mmol) and diisopropyl azodicarboxylate (DIAD) (2.86 g, 14.15 mmol) dropwise at 0°C. The reaction mixture was stirred at room temperature for 5 h. The resulting mixture was poured into water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was purified by column chromatography (silica, eluting with 20% EtOAc in hexane) to afford the title product as off-white solid (0.4 g, 27%).

[0705] 1 H NMR (DMSO-d6) 5 9.03 (s, 1 H), 8.42 (s, 1 H), 5.64-5.61 (m, 1 H), 4.94-4.87 (m, 4H).

[0706] Step 2: 1-(oxetan-3-yl)-1 H-pyrazol-4-amine (A-5)

[0707] To a stirred solution of 4-nitro-1-(oxetan-3-yl)-1 H-pyrazole (0.4 g, 2.36 mmol) in MeOH (10 mL) was added 10 % Pd / C (wetted with ca. 55% water) (0.2 g, 50% w / w). The reaction mixture was stirred under hydrogen gas purging at room temperature for 2 h. The reaction mixture was filtered through Celite® washing with MeOH (3 x 50 mL). The combined filtrates were dried (Na2SO4) and concentrated. The resulting residue was triturated using Et20 (20 mL) to afford the title product as a brown solid (0.30 g, 91%). 1 H NMR (DMSO-d6) 5 7.17 (s, 1 H), 7.04 (s, 1 H), 5.38-5.33 (m, 1 H), 4.86-4.79 (m, 4H), 3.91 (br s, 2H).

[0708] A-6 was prepared according to Scheme 2.

[0709] A-6

[0710] Scheme 2

[0711] Step 1 : [(2R)-4-methylmorpholin-2-yl]methyl methanesulfonate

[0712] To a stirred solution of (R)-(4-methylmorpholin-2-yl) methanol (CAS # 1159598-35-2) (1.0 g, 7.62 mmol) in DCM (10 mL, 10 vol) were added DIPEA (2.96 g, 22.87 mmol) and methanesulfonyl chloride (1.75 g, 15.25 mmol) dropwise at 0°C. The reaction mixture was allowed to stir at ambient temperature for 16 h. The reaction mixture was poured into ice cold water (150 mL), extracted with DCM (3 x 150 mL). The combined organic layers were dried (Na2SO4) and concentrated to afford the title compound as a brown gum (1.5 g, 94%).

[0713] Step 2: (2R)-4-methyl-2-[(4-nitro-1 H-pyrazol-1-yl)methyl]morpholine

[0714] To a stirred solution of [(2R)-4-methylmorpholin-2-yl]methyl methanesulfonate (1.50 g, 7.17 mmol) and 4-nitro-1 H-pyrazole (0.81 g, 7.17 mmol) in DMF (15 mL, 10 vol) was added cesium carbonate (5.84 g, 17.92 mmol) at room temperature. The resulting reaction mixture was allowed to stir at 55°C for 16 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was purified by column chromatography (silica, eluting with 3% MeOH in DCM) to afford the title product as white solid (0.4 g, 25%). Step 3: 1-{[(2R)-4-methylmorpholin-2-yl]methyl}-1 H-pyrazol-4-amine (A-6)

[0715] To a stirred solution of (2R)-4-methyl-2-[(4-nitro-1 H-pyrazol-1-yl)methyl]morpholine (0.4 g, 1.77 mmol) in MeOH (20 mL) was added 10 % Pd / C (wetted with ca. 55% water) (0.2 g, 50% w / w). The reaction mixture was stirred with hydrogen gas purging at room temperature for 2 h. The reaction mixture was filtered through Celite® and washed with MeOH (3 x 50 mL). The combined filtrates were dried (Na2SO4) and concentrated. The resulting residue was triturated with Et20: n-pentane (3:7) to afford the title product as brown solid (0.3 g, 86%).

[0716] 1 H NMR (DMSO-d6) 5 6.99 (d, 1 H), 6.89 (d, 1 H), 3.99-3.93 (m, 2H), 3.80 (br s, 2H), 3.78- 3.74 (m, 1 H), 3.69-3.65 (m, 1 H), 3.47-3.41 (m, 1 H), 2.56-2.50 (m, 2H), 2.13 (s, 3H), 1.96- 1.89 (m, 1 H), 1.67-1.62 (m, 1 H).

[0717] LCMS (Method 2) RT 0.23 min, m / z 197.0 (MH+).

[0718] A-7:1-{f(2S)-4-methylmorpholin-2-yl1methyl}-1 H-pyrazol-4-amine

[0719] A-7 was prepared as described for A-6 following Scheme 2 with the following exceptions:

[0720] In step 1 , (S)-(4-methylmorpholin-2-yl) methanol (CAS # 1159598-33-0) was used. In step 2, potassium carbonate was used as base and the reaction was stirred at 70°C for 6 h. In step 3 the residue was triturated with n-pentane to afford the title product as a brown solid (1.0 g, 82%).

[0721] LCMS (Method 3) RT 0.64 min, m / z 197.3 (MH+).

[0722] A-8 was prepared according to the Scheme 3 below.

[0723] A-8

[0724] Scheme 3

[0725] Step 1 : (3R)-4-methyl-3-[(4-nitro-1 H-pyrazol-1-yl)methyl]morpholine To a stirred solution of (R)-(4-methylmorpholin-3-yl) methanol (CAS # 1620510-51-1) (0.7 g, 5.34 mmol) and 4-nitro-1 H-pyrazole (0.6 g, 5.34 mmol) in THF (10 mL, 15 vol) were added triphenylphosphine (2.10 g, 8.00 mmol) and diethyl azodicarboxylate (DEAD) (1.49 g, 8.54 mmol) at 0°C in a dropwise manner. The reaction mixture was allowed to stir at room temperature for 3 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was purified by column chromatography (silica, eluting with 60-65% EtOAc in hexane) to afford the title product as a yellow solid (0.35 g, quantitative).

[0726] Step 2: 1-{[(3R)-4-methylmorpholin-3-yl]methyl}-1 H-pyrazol-4-amine (A-8)

[0727] To a stirred solution of ((3R)-4-methyl-3-[(4-nitro-1 H-pyrazol-1-yl)methyl]morpholine (0.3 g, 1.33 mmol) in MeOH (15 mL) was added 10 % Pd / C (wetted with ca. 55% water) (0.15 g, 50 w / w). The reaction mixture was stirred under hydrogen gas purging at room temperature for 2 h. The reaction mixture was filtered through Celite® washing with MeOH (2 x 50 mL). The combined filtrates were dried (Na2SO4) and concentrated to afford the title product as a brown solid (0.25 g, 96%).

[0728] LCMS (Method 3) RT 0.49 min, m / z 197.3 (MH+).

[0729] A-9: 1-{f(3S)-4-methylmorpholin-3-yl1methyl}-1 H-pyrazol-4-amine

[0730] A-9 was prepared as described for A-8 following Scheme 3 with the following exceptions:

[0731] In step 1 , (S)-(4-methylmorpholin-3-yl)methanol was used. In step 2, the resulting residue was triturated with Et20 (10 mL) to afford the title product as a brown solid (0.25 g, 96%).

[0732] LCMS (Method 3) RT 0.48 min, m / z 197.3 (MH+).

[0733] A-10 was prepared according to the scheme below.

[0734] Step 1 : 1-methyl-3-(4-nitro-1 H-pyrazol-1-yl)piperidine

[0735] To a stirred solution of 1-methypiperidin-3-ol (CAS # 3554-74-3) (0.5 g, 4.34 mmol) and 4- nitro-1 H-pyrazole (CAS # 2075-46-9) (0.59 g, 5.21 mmol) in THF (10 mL, 20 vol) was added triphenylphosphine (1.14 g, 4.34 mmol) and diisopropyl azodicarboxylate (DIAD) (1.4 g, 6.95 mmol) dropwise at 0°C. The reaction mixture was stirred at room temperature for 5 h. The resulting mixture was poured into water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers dried (Na2SO4) and concentrated. The resulting residue was purified by column chromatography (silica, eluting with 30% EtOAc in hexane) to afford the title product as a yellow solid (0.4 g, 44%).

[0736] Step 2: 1-(1-methylpiperidin-3-yl)-1 H-pyrazol-4-amine (A-10)

[0737] To a stirred solution of 1-methyl-3-(4-nitro-1 H-pyrazol-1-yl)piperidine (0.4 g, 1.90 mmol) in MeOH (20 mL) was added 10 % Pd / C (wetted with ca. 55% water) (0.20 g, 50% w / w). The reaction mixture was stirred under hydrogen gas purging at room temperature for 4 h. The reaction mixture was filtered through a Celite® bed. The Celite® bed was washed with MeOH (3 x 50 mL). The combined filtrates were dried (Na2SO4) and concentrated. The resulting residue was triturated with Et20 : n-pentane, 7:3 (50 mL) to afford the title product as off-white solid (0.3 g, 87%).

[0738] LCMS (Method 2) RT 0.85 min, m / z 181.3 (MH+).

[0739] A-11 was prepared according to the scheme below. Step 1 : Methyl 2-(4-nitro-1 H-pyrazol-1-yl)propanoate

[0740] Method as described for A-10 step 1 , except the alcohol used was (+)-methyl D-lactate. The reaction mixture was stirred for 5 h and purified by flash column chromatography (silica, eluting with 22% EtOAc in hexane) to afford the title product as light-yellow liquid (0.5 g, 57%) as a racemic mixture.

[0741] Step 2: Methyl 2-(4-amino-1 H-pyrazol-1-yl)propanoate (A-11)

[0742] Method as described for A-10 step 2 to afford the title product as brown solid (0.15 g, 88%).

[0743] LCMS (Method 3) RT 0.66 min, m / z 170.2 (MH+).

[0744] A-11 R: methyl (2R)-2-(4-amino-1 H-pyrazol-1-yl)propanoate

[0745] A-11 R was prepared according to the scheme below:

[0746] A-11 R

[0747] Step 1 : methyl (2R)-2-(4-nitro-1 H-pyrazol-1-yl)propanoate

[0748] To a stirred solution of 4-nitro-1 H-pyrazole (1.0 g, 8.84 mmol) and methyl (S)-2- hydroxypropanoate (1.01 g, 9.73 mmol) in THF (20 mL) were added triphenyl phosphine (2.78 g, 10.61 mmol) and DIAD (2.15 g, 10.61 mmol) under nitrogen at 0°C. The resulting reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 20% EtOAc in hexane) afforded the title compound as a light-yellow oil (0.6 g, 34%).

[0749] 1 H NMR (DMSO-d6) 5 9.04 (s, 1 H), 8.32 (s, 1 H), 5.43 (q, 1 H), 3.69 (s, 3H), 1.72 (d, 3H).

[0750] Step 2: methyl (2R)-2-(4-amino-1 H-pyrazol-1-yl)propanoate (A-11 R)

[0751] Method as described for A-10 step 2 to afford the title compound as a brown solid (0.6 g, quantitative). 1 H NMR (DMSO-d6) 5 7.08 (s, 1 H), 6.94 (s, 1 H), 5.02 (q, 1 H), 3.87 (brs, 2H), 3.62 (s, 3H), 1.56 (d, 3H).

[0752] A-11S: methyl (2S)-2-(4-amino-1 H-pyrazol-1-yl)propanoate

[0753] A-11S

[0754] A-11 S was prepared as for A-11 R except that in step 1 methyl (R)-2-hydroxypropanoate was used.

[0755] A-12 was prepared according to the scheme below.

[0756] Step 1 : tert-butyl N-[2-(4-nitro-1 H-pyrazol-1-yl)ethyl]carbamate

[0757] To a stirred solution of 4-nitro-1 H-pyrazole (1.5 g, 13.26 mmol) and tert-butyl (2- hydroxyethyl) carbamate (2.14 g, 13.26 mmol) in THF (15 mL, 10 vol) was added triphenylphosphine (5.22 g, 19.90 mmol) and diisopropyl azodicarboxylate (DIAD) (4.29 g, 21 .22 mmol) dropwise at 0°C temperature. The reaction mixture was allowed to stir at room temperature for 12 h. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was purified by column chromatography (silica, eluting with 20% EtOAc in hexane) to afford the title compound as an off-white solid (1.2 g, 35%).

[0758] Step 2: tert-butyl N-[2-(4-amino-1 H-pyrazol-1-yl)ethyl]carbamate (A-12)

[0759] To a stirred solution of tert-butyl (2-(4-nitro-1 H-pyrazol-1-yl) ethyl) carbamate (Example 21- Al) (0.6 g, 2.34 mmol) in methanol (10 mL, 25 vol) was added 10 % Pd / C (wetted with ca. 55% water) (0.3 g, 50% w / w). The reaction mixture was stirred under hydrogen gas at room temperature for 2 h. The reaction mixture was filtered through Celite® washing with MeOH (3 x 30 mL). The combined filtrates were dried (Na2SO4) and concentrated. The resulting residue was triturated with Et20 (50 mL) and dried to afford the title compound as a brown gum (0.40 g, 75%).

[0760] LCMS (Method 4) RT 1.49 min, m / z 227.3 (MIT).

[0761] A-13 was prepared according to the scheme below.

[0762] A-13

[0763] Step 1 : tert-Butyl 3-hydroxy-4-(4-nitro-1 H-pyrazol-1-yl)piperidine-1 -carboxylate

[0764] To a stirred solution of 4-nitro-1 H-pyrazole (2.0 g, 17.68 mmol) and tert-butyl 7-oxa-3- azabicyclo [4.1.0] heptane-3-carboxylate (CAS # 161157-50-2) (3.52 g, 17.68 mmol) in DMF (20 mL, 10 vol) was added caesium carbonate (17.28 g, 53.05 mmol) at room temperature. The reaction mixture was allowed to stir at 100°C for 12 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, eluting with 20% EtOAc in hexane) to afford the title compound (1 .9 g, 34%).

[0765] LCMS (Method 2) RT 1.96 min, m / z 313.5 (MT). Step 2: 4-(4-nitro-1 H-pyrazol-1-yl)piperidin-3-ol

[0766] To a stirred solution of tert-butyl 3-hydroxy-4-(4-nitro-1 H-pyrazol-1-yl)piperidine-1- carboxylate (1.9 g, 6.08 mmol) in DCM (19 mL, 10 vol) was added 4M HCI in 1 ,4 dioxane (3.8 mL, 2 vol) at 0°C. The reaction mixture was allowed to stir at room temperature for 4 h. The reaction mixture was concentrated in vacuo, azeotroped with Et20 and triturated Et20 (3 x 15 mL). The resulting solid material was diluted with sat. aq. sodium bicarbonate solution (70 mL) and extracted with DCM (3 x 70 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by reverse phase column chromatography (C18 silica, eluting with 5% MeCN in water) to afford the title compound (0.66 g, 35%).

[0767] LCMS (Method 3) RT 1.14 min, m / z 213.3 (MIT).

[0768] Step 3: 1-methyl-4-(4-nitro-1 H-pyrazol-1-yl)piperidin-3-ol

[0769] To a stirred solution of 4-(4-nitro-1 H-pyrazol-1-yl)piperidin-3-ol (0.65 g, 3.06 mmol) in MeOH (13 mL, 20 vol) were added acetic acid (0.32 mL, catalytic) and formaldehyde (0.09 g, 37%) at 0°C. The reaction mixture was stirred for 1 h followed by addition of sodium cyanoborohydride (0.17 g, 2.76 mmol) at 0°C temperature. The resulting reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was concentrated in vacuo, diluted with water (70 mL) and extracted with EtOAc (3 x 70 mL). The aqueous layer further extracted with 20% MeOH in DCM (3 x 50 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting material was purified by reverse phase column chromatography (C18 silica, eluting with 30% MeCN in water) to afford the title product as brown gum (0.3 g, 43%).

[0770] Step 4: 4-(4-amino-1 H-pyrazol-1-yl)-1-methylpiperidin-3-ol (A-13)

[0771] To a stirred solution of 1-methyl-4-(4-nitro-1 H-pyrazol-1-yl)piperidin-3-ol (0.25 g, 1.10 mmol) in MeOH (10 mL, 40 vol) was added 10% w / w Pd / C (wetted with ca. 55% water) (0.12 g, 50%w / w). The reaction mixture was stirred under hydrogen gas in an autoclave under 20 psi pressure and 60°C for 12 h. The reaction mixture was filtered through Celite® washing with MeOH (3 x 50 mL). The combined filtrates were dried (Na2SO4), concentrated in vacuo and triturated with Et20 (50 mL) to afford the title product as a brown gum (0.25 g, quantitative) which was used directly.

[0772] MS 197.3 (MH+) A-14 was prepared according to the scheme below.

[0773] HCHO, NaCHBH3, AcOH, MeOH H2, Pd / C, MeOH

[0774] Step 4 Step 5

[0775] A-14

[0776] Step 1 : tert-butyl 6-(methanesulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate

[0777] To a stirred solution of tert-butyl 6-hydroxy-2-azaspiro [3.3] heptane-2-carboxylate (CAS # 1147557-97-8) (3.0 g, 14.07 mmol) in DCM (60 mL, 20 vol) was added DI PEA (9.09 g, 70.33 mmol). The reaction mixture was stirred at room temperature for 30 min and methane sulfonyl chloride (3.22 g, 28.13 mmol) was added dropwise at 0°C. The reaction mixture was further stirred at room temperature for 16 h. The reaction mixture was poured into water (300 mL) and extracted with DCM (2 x 80 mL). The combined organic layers were dried (Na2SC>4) and concentrated in vacuo. Trituration with n-pentane (30 mL) afforded the title compound as a brown solid (4.0 g, 98%).

[0778] 1 H NMR (DMSO-d6) 5 4.90-4.87 (m, 1 H), 3.84 (br d,4H), 3.14 (s, 3H), 2.66-2.61 (m, 2H), 2.39-2.34 (m, 2H), 1.37 (s, 9H).

[0779] Step 2: tert-butyl 6-(4-nitro-1 H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0780] To a stirred solution of 4-nitro-1 H-pyrazole (CAS # 2075-46-9) (2.32 g, 20.60 mmol) in DMF (80 mL, 20 vol) was added potassium carbonate (5.68 g, 41.20 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min and tert-butyl 6- (methanesulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (4.0 g, 13.73 mmol) was added. The reaction mixture was stirred at 70°C for 16 h. The resulting reaction mixture was poured into cold water (200 mL). The precipitated solid was filtered and dried in vacuo. Purification by column chromatography (silica, eluting with 30% EtOAc in hexane) afforded the title compound as white solid (2.0 g, 47%).

[0781] 1 H NMR (DMSO-d6) 5 8.98 (s, 1 H), 8.30 (s, 1 H), 4.89-4.83 (m, 1 H), 3.95 (s, 2H), 3.85 (s, 2H), 2.74-2.51 (m , 4H), 1.38 (s, 9H).

[0782] Step 3: 6-(4-nitro-1 H-pyrazol-1-yl)-2-azaspiro[3.3]heptane

[0783] A stirred solution of tert-butyl 6-(4-nitro-1 H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2- carboxylate (1.2 g, 3.89 mmol) in formic acid (12 mL, 10 vol) was allowed to stir at 50°C for 1 h. The reaction mixture was concentrated in vacuo and the resulting material was triturated with Et20 (10 mL) to afford the title compound as its formic acid salt as a white solid (1.4 g, quantitative).

[0784] LCMS (Method 3) RT 1.02 min, m / z 209.3 (MH+).

[0785] Step 4: 2-methyl-6-(4-nitro-1 H-pyrazol-1-yl)-2-azaspiro[3.3]heptane

[0786] To a solution of 6-(4-nitro-1 H-pyrazol-1-yl)-2-azaspiro[3.3]heptane formate salt (1.90 g, 7.50 mmol) in MeOH (38 mL) were added formaldehyde (37% in MeOH) (0.69 g, 7.50 mmol) and acetic acid (0.19 mL, 0.1 vol). The reaction mixture was stirred at room temperature for 1 h and sodium cyanoborohydride (0.42 g, 6.75 mmol) was added at 0°C temperature. The reaction mixture was further stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo. The resulting suspension was poured into water (200 mL) extracted with DCM (2 x 200 mL). The combined organic layers were dried (Na2SC>4) and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, eluting with 6% MeOH in DCM with ammonia as modifier) to afford the title compound as a yellow solid (0.85 g, 51 %).

[0787] LCMS (Method 2) RT 0.87 min, m / z 222.8 (MH+).

[0788] Step 5: 1-{2-methyl-2-azaspiro[3.3]heptan-6-yl}-1 H-pyrazol-4-amine (A-14)

[0789] To a stirred solution of 2-methyl-6-(4-nitro-1 H-pyrazol-1-yl)-2-azaspiro[3.3]heptane (0.2 g, 0.90 mmol) in MeOH (4 mL) was added 10 % Pd / C (wetted with ca. 55% water) (0.1 g, 50% w / w) at room temperature. The reaction mixture was stirred under hydrogen gas at room temperature for 2 h. The reaction mixture was filtered through Celite® washing with MeOH (3 x 60 mL). The combined filtrates were dried (Na2SO4) and concentrated in vacuo. The resulting residue was triturated with Et20 (10 mL) to afford the title compound as a brown solid (0.15 g, 87%).

[0790] 1 H NMR (DMSO-d6) 5 7.04 (s, 1 H), 6.91 (s, 1 H), 4.51-4.47 (m, 1 H), 3.79 (s, 2H), 3.16 (s, 2H), 3.06 (s, 2H), 2.51-2.39 (m, 4H), 2.15 (s, 3H).

[0791] A-15

[0792] A-15 was prepared according to the scheme below:

[0793] A-15

[0794] Step 1 : tert-butyl 3-fluoro-4-(methanesulfonyloxy)piperidine-1 -carboxylate

[0795] To a stirred solution of tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (1.5 g, 6.84 mmol) in DCM (15 mL, 10 vol) was added TEA (2.76 g, 27.36 mmol) and methane sulfonyl chloride (1.41 g, 12.31 mmol) dropwise at 0°C. The reaction mixture was allowed to stir at room temperature for 3 h. The resulting reaction mixture was poured into aqueous sodium bicarbonate solution (150 mL) and extracted with DCM (2 x 60 mL). The combined organic layers were dried (Na2SO4). The resulting residue was triturated with Et20 (20 mL) to afford the title compound (1.8 g, 88%) as white solid.

[0796] Step 2: tert-butyl 3-fluoro-4-(4-nitro-1 H-pyrazol-1-yl)piperidine-1 -carboxylate

[0797] To a stirred solution of tert-butyl 3-fluoro-4-(methanesulfonyloxy)piperidine-1-carboxylate (0.6 g, 2.02 mmol) and 4-nitro-1 H-pyrazole (0.23 g, 2.02 mmol) in DMF (12 mL, 20 vol) was added K2CO3 (0.56 g, 4.03 mmol) at room temperature. The resulting reaction mixture was allowed to stir at 110°C for 16 h. The reaction mixture was poured into ice- cold water (300 mL) and extracted with DCM (2 x 150 mL). The combined organic layers were washed with water (2 x 60 mL), dried (Na2SO4) and concentrated. Purification by flash column chromatography (silica, eluting with 15% EtOAc in hexane) afforded the title compound (0.78 g, 41%) as a white solid.

[0798] LCMS (Method 2) RT 2.25 min, m / z 315.0 (MIT).

[0799] Step 3: 3-fluoro-4-(4-nitro-1 H-pyrazol-1-yl)piperidine

[0800] To a stirred solution of tert-butyl 3-fluoro-4-(4-nitro-1 H-pyrazol-1-yl)piperidine-1- carboxylate (0.78 g, 2.48 mmol) in DCM (15.6 mL, 20 vol) was added 4 M HCI in 1 ,4 dioxane (6.24 mL, 8 vol) at 0°C. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was concentrated. The resulting suspension was triturated using Et20 (10 mL) to afford the hydrochloride salt of the title compound (0.46 g, 74%) as a white solid.

[0801] LCMS (Method 3) RT 1.42 min, m / z 215.1 (MT).

[0802] Step 4: 3-fluoro-1-methyl-4-(4-nitro-1 H-pyrazol-1-yl)piperidine

[0803] To a stirred solution of 3-fluoro-4-(4-nitro-1 H-pyrazol-1-yl) piperidine hydrochloride salt (0.46 g, 1.83 mmol) in MeOH (9.2 mL, 20 vol) were added AcOH (0.05 mL, catalytic) and formaldehyde, 37% in MeOH (0.149 g 1.83 mmol) at 0°C. The reaction mixture was stirred for 1 h followed by addition of sodium cyanoborohydride (0.103 g, 1.65 mmol) at 0°C. The resulting reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated and the resulting residue poured into aqueous sodium bicarbonate solution (100 mL) and extracted with DCM (2 x 60 mL). The combined organic layers were dried (Na2SO4) and concentrated to afford the title compound as colourless liquid (0.4 g, 96%).

[0804] LCMS (Method 2) RT 0.85 min, m / z 229.2 (MH+).

[0805] Step 5: 1-(3-fluoro-1-methylpiperidin-4-yl)-1 H-pyrazol-4-amine (A-15)

[0806] To a stirred solution of 3-fluoro-1-methyl-4-(4-nitro-1 H-pyrazol-1-yl)piperidine (0.2 g, 0.87 mmol) in MeOH (4 mL, 20 vol) was added 10% w / w palladium on carbon (50% wet basis) (0.10 g, 50%w / w). The reaction mixture was stirred with hydrogen gas purging at room temperature for 2 h. The reaction mixture was filtered through Celite® and washed with MeOH (2 x 60 mL). The combined filtrates were dried (Na2SO4) and concentrated in vacuo. Trituration with n-pentane (10 mL) afforded the title compound as a brown solid (0.15 g, 87%). LCMS (Method 3) RT 1.22 min, m / z 199.2 (MIT).

[0807] A-16: 4-r(4-amino-1 H-pyrazol-1-yl)methyl1-1-ethylpiperidin-4-ol

[0808] A-16 was prepared according to the scheme below:

[0809] Step 1 : tert-Butyl 4-hydroxy-4-[(4-nitro-1 H-pyrazol-1-yl)methyl]piperidine-1 -carboxylate To a stirred solution of 4-nitro-1 H-pyrazole (3.17 g, 28.13 mmol) and tert-butyl 1-oxa-6- azaspiro [2.5] octane-6-carboxylate (5.0 g, 23.43 mmol) in DMF (100 mL, 20 vol) was added K2CO3 (9.70 g, 70.30 mmol) at room temperature. The reaction mixture was allowed to stir at 80°C for 3 h. The reaction mixture was poured into ice cold water (300 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers dried (Na2SO4) and concentrated in vacuo. The material was triturated using Et20 (50 mL) to afford the title compound as off-white solid. (5.4 g, 71 %).

[0810] LCMS (Method 2) RT 1.85 min, m / z 227.2 (M-100)+

[0811] Steps 2-4 follow similar methods as described for A-15 (steps 3-5).

[0812] In step 5, trituration with Et2O (10 mL) afforded the title compound as a brown solid.

[0813] LCMS (Method 3) RT 0.40 min, m / z 211.4 (MH)+

[0814] A-17

[0815] A-17 was prepared according to the scheme below:

[0816] A-17

[0817] Step 1 : 2-(4-nitro-1 H-pyrazol-1-yl)cyclobutan-1-one

[0818] To a stirred solution of 4-nitro-1 H-pyrazole (0.1 g, 0.88 mmol) and 2-bromocyclobutan-1- one (0.657 g, 4.41 mmol) in MeCN (2 mL, 20 vol) was added potassium carbonate (0.365 g, 2.65 mmol). The resulting reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was poured into water (80 mL) and extracted with DCM (2 x 60 mL). The combined organic layers were dried (Na2SC>4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 65% DCM in hexane) afforded the title compound as white solid (0.08 g, 50%).

[0819] Step 2: 2-(4-nitro-1 H-pyrazol-1-yl)cyclobutan-1-ol

[0820] To a stirred solution of 2-(4-nitro-1 H-pyrazol-1-yl)cyclobutan-1-one (0.23 g, 1.27 mmol) in MeOH (4.6 mL) was added sodium borohydride (0.096 g, 2.54 mmol) portion wise at 0°C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and the resulting suspension was diluted with aqueous saturated sodium bicarbonate solution (60 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried (Na2SO4) and concentrated to afford the title compound as a colourless solid (0.21 g, 90%).

[0821] Step 3: 2-(4-amino-1 H-pyrazol-1-yl)cyclobutan-1-ol (A-17)

[0822] To a stirred solution 2-(4-nitro-1 H-pyrazol-1-yl)cyclobutan-1-ol (0.21 g, 1.15 mmol) in MeOH (4.2 mL, 20 vol) was added 10 % Pd / C (50 % wet basis) (0.105 g, 50% w / w) at room temperature. The reaction mixture was stirred with hydrogen gas purging at room temperature for 1 h. The reaction mixture was filtered through Celite® washing with MeOH (2 x 70 mL). The combined filtrates were dried (Na2SO4) and concentrated in vacuo. The resulting residue was triturated with Et20 (10 mL) to afford the title compound as a brown solid (0.2 g, quantitative) as a mixture of 4 diastereomers.

[0823] A-18

[0824] A-18 was prepared according to the scheme below:

[0825] A-18

[0826] Step 1 : 3-(benzyloxy)cyclobutan-1-ol

[0827] To a stirred solution of 3-(benzyloxy) cyclobutan-1-one (1.50 g, 8.51 mmol) in MeOH (20 mL) was added sodium borohydride (1.0 g, 25.54 mmol) at 0°C. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into cold water (100 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 25% EtOAc in hexane) afforded the title compound as colourless oil (1.30 g, 86%).

[0828] 1 H NMR (DMSO-d6): 5 7.36-7.26 (m, 5H), 5.06-5.02 (m, 1 H), 4.38 (s, 2H), 3.72-3.64 (m, 1 H), 3.57-3.50 (m, 1 H), 2.56-2.51 (m, 2H), 1.76-1.72 (m, 2H).

[0829] Step 2: 3-(benzyloxy)cyclobutyl methanesulfonate

[0830] To a stirred solution of 3-(benzyloxy) cyclobutan-1-ol (1.30 g, 7.29 mmol) in DCM (15 mL, 15 vol) were added DIPEA (2.85 g, 21.88 mmol) and methanesulfonyl chloride (2.10 g, 18.23 mmol) dropwise at 0°C. The reaction mixture was allowed to stir at ambient temperature for 2 h. The reaction mixture was poured into ice cold water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford the title compound as a brown gum (1.5 g, 80%). The material was used directly without further purification. Step 3: 1-[3-(benzyloxy)cyclobutyl]-4-nitro-1 H-pyrazole

[0831] To a stirred solution of 3-(benzyloxy)cyclobutyl methanesulfonate (1.50 g, 5.85 mmol) and 4-nitro-1 H-pyrazole (0.66 g, 5.85 mmol) in DMF (15 mL, 15 vol) was added potassium carbonate (2.42 g, 17.56 mmol). The reaction mixture was allowed to stir at 70°C for 12 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 10% EtOAc in hexane) afforded the title compound as an off-white solid (0.9 g, 56%).

[0832] 1 H NMR (DMSO-d6): 5 8.99 (s, 1 H), 8.34 (s, 1 H), 7.39-7.29 (m, 5H), 5.10-5.06 (m, 1 H), 4.43 (s, 2H), 4.38-4.35 (m, 2H), 2.72-2.65 (m, 2H), 2.58-2.51 (m, 2H).

[0833] Step 4: 1-[3-(benzyloxy)cyclobutyl]-1 H-pyrazol-4-amine (A-18) To a stirred solution of 1-[3-(benzyloxy)cyclobutyl]-4-nitro-1 H-pyrazole (0.2 g, 0.73 mmol) in MeOH (10 mL, 50 vol) was added 10 % Pd / C (50 % wet basis) (0.10 g, 50% w / w) at room temperature. The reaction mixture was stirred with hydrogen gas purging at room temperature for 2 h. The reaction mixture was filtered through Celite® washing with MeOH (2 x 50 mL). The combined filtrates were dried (Na2SO4) and concentrated in vacuo. Trituration with Et2O:n-pentane, 1 :1 (10 mL) afforded the title compound as an off- white solid (0.15 g, 84%).

[0834] LCMS (Method 2) RT 1.69 min, m / z 244.2 (MH+). A-19 was prepared according to the scheme below:

[0835] Step 1 : tert-butyl (2R)-2-[(4-nitro-1 H-pyrazol-1-yl)methyl]morpholine-4-carboxylate

[0836] To a stirred solution of tert-butyl (R)-2-(hydroxymethyl) morpholine-4-carboxylate (1.0 g, 4.60 mmol) and 4-nitro-1 H-pyrazole (0.52 g, 4.60 mmol) in THF (20 mL, 20 vol) was added triphenylphosphine (1.70 g, 6.44 mmol) and diisopropyl azodicarboxylate (1.40 g, 6.90 mmol) dropwise at 0°C. The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was poured into water (150 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 20% EtOAc in hexane) afforded the title compound as off-white solid (1.2 g, 83%).

[0837] Step 2: tert-butyl (2R)-2-[(4-amino-1 H-pyrazol-1-l)methyl]morpholine-4-carboxylate (A-19) To a stirred solution of tert-butyl (2R)-2-[(4-nitro-1 H-pyrazol-1-yl)methyl]morpholine-4- carboxylate (0.5 g, 1.60 mmol) in MeOH (25 mL) was added 10% Pd / C (50% wet basis) (0.25 g, 50% w / w). The reaction mixture was stirred under hydrogen gas purging at room temperature for 2 h. The reaction mixture was filtered through Celite® washing with MeOH (2 x 50 mL). The combined filtrates were dried (Na2SO4) and concentrated in vacuo. Trituration with Et20 (15 mL) afforded the title compound as a brown solid (0.4 g, 89%).

[0838] LCMS (Method 3) RT 1.57 min, m / z 288.2 (MH+).

[0839] A-20: tert-butyl (2S)-2-f(4-amino-1 H-pyrazol-1-yl)methyl1morpholine-4-carboxylate

[0840] A-20 was prepared as described for A-19 with the following exceptions:

[0841] In step 1 , tert-butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate was used. In step 2, trituration using Et20 (15 mL) afforded the title compound as a light brown solid (0.30 g, 55%).

[0842] LCMS (Method 3) RT 1.58 min, m / z 288.3 (MH+).

[0843] A-21 : 1-f2-(morpholin-4-yl)ethyl1-1 H-pyrazol-4-amine A-21 was prepared as described for A-8 following Scheme 3 with the following exceptions:

[0844] In step 1, 2-(morpholin-4-yl)ethan-1-ol (1.0 g, 7.62 mmol) and diethyl azodicarboxylate (1.59 g, 9.14 mmol) were used.

[0845] Following step 2, the title compound was isolated as brown solid (0.35 g, 81%).

[0846] 1 H NMR (DMSO-d6) 7.05 (s, 1H), 6.87 (s, 1 H), 4.02 (t, 2H), 3.79 (brs, 2H), 3.54 (t, 4H), 2.61 (t, 2H), 2.36 (t, 4H).

[0847] A-22 was prepared according to the following scheme.

[0848] Step 1 : tert-butyl (3R)-3-(4-nitro-1 H-pyrazol-1-yl)pyrrolidine-1 -carboxylate

[0849] To a stirred solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (1.0 g, 5.34 mmol) and 4-nitro-1 H-pyrazole (0.60 g, 5.34 mmol) in THF (20 mL, 20 vol) were added triphenylphosphine (2.11 g, 8.01 mmol) and DIAD (1.61 g, 8.01 mmol) at O°C. The reaction mixture was allowed to stir at room temperature for 12 h. The resulting reaction mixture was poured into water (100 mL), extracted with EtOAc (2 x 80 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 25% EtOAc in hexane) afforded the title compound as a colourless oil (1.20 g, 80%).

[0850] Step 2: 4-nitro-1-[(3R)-pyrrolidin-3-yl]-1 H-pyrazole

[0851] To a stirred solution of tert-butyl (3R)-3-(4-nitro-1 H-pyrazol-1-yl)pyrrolidine-1 -carboxylate (1.0 g, 3.54 mmol) in DCM (10 mL, 10 vol) was added 4M HCI in 1 ,4 dioxane (5 mL, 5 vol) at 0°C. The reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated in vacuo and triturated with Et20 (10 mL) to afford the title compound as an off-white solid (0.45 g, 70%).

[0852] Step 3: 1-[(3R)-1-methylpyrrolidin-3-yl]-4-nitro-1 H-pyrazole

[0853] To a stirred solution of 4-nitro-1-[(3R)-pyrrolidin-3-yl]-1 H-pyrazole hydrochloride salt (0.40 g, 1.82 mmol) in MeOH (10 mL, 20 vol) was added acetic acid (0.5 mL, catalytic) and formaldehyde (37%, 0.150 g, 1.82 mmol) at 0°C. The reaction mixture was stirred for 1 h followed by addition of sodium cyanoborohydride (0.10 g, 1.65 mmol). The resulting reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated in vacuo. Aqueous sodium bicarbonate solution (70 mL) was added the solution was extracted with DCM (3 x 50 mL). The combined organic layers were dried (Na2SC>4) and concentrated in vacuo. Trituration was Et20 (10 mL) afforded the title compound as a white solid. (0.4 g, quantitative).

[0854] Step 4: 1-[(3R)-1-methylpyrrolidin-3-yl]-1 H-pyrazol-4-mine (A-22)

[0855] To a stirred solution of 1-[(3R)-1-methylpyrrolidin-3-yl]-4-nitro-1 H-pyrazole (0.40 g, 1.74 mmol) in MeOH (10 mL, 20 vol) was added 10% w / w palladium on carbon (50% wet basis) (0.20 g, 50%w / w). The reaction mixture was stirred with hydrogen gas purging at room temperature for 3 h. The reaction mixture was filtered through Celite® washing with MeOH (2 x 20 mL). The combined filtrates were dried (Na2SO4) and concentrated in vacuo. Trituration with Et20 afforded the title compound as a brown solid (0.30 g, 89%).

[0856] 1 H NMR (DMSO-d6) 7.08 (s, 1 H), 6.87 (s, 1H), 4.70-4.64 (m, 1H), 3.82 (brs, 2H), 2.75- 2.65 (m, 2H), 2.61-2.58 (m, 1H), 2.44-2.39 (m, 1H), 2.30-2.21 (m, 4H), 1.98-1.91 (m, 1 H).

[0857] A-23: 1-f(3S)-1-methylpyrrolidin-3-yl1-1 H-pyrazol-4-amine

[0858] A-23 was prepared as described for A-22 with the following exceptions:

[0859] In step 1, tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (1.0g, 5.34 mmol) was used.

[0860] Following step 4, the title compound was isolated as a brown solid (0.25 g, 84%).

[0861] 1 H NMR (DMSO-d6) 7.08 (s, 1 H), 6.87 (s, 1 H), 4.70-4.64 (m, 1H), 3.82 (brs, 2H), 2.75- 2.65 (m, 2H), 2.61-2.59 (m, 1H), 2.44-2.39 (m, 1H), 2.29-2.21 (m, 4H), 1.98-1.91 (m, 1 H). A-24: 1-r(4-fluoro-1-methylpiperidin-4-yl)methyl1-1H-pyrazol-4-amine

[0862] A-24 was prepared according to the following scheme:

[0863] Step 1 : tert-butyl 4-fluoro-4-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate

[0864] To a stirred solution of tert-butyl 4-fluoro-4-(hydroxymethyl) piperidine-1 -carboxylate (1.0 g, 4.29 mmol) in DCM (20 mL, 20 vol) was added TEA (1.74 g, 17.15 mmol) at 0°C. The reaction mixture was allowed to stir at 0°C for 10 min and methanesulfonyl chloride (0.88 g, 7.72 mmol) was added dropwise at 0°C. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (200 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford the title compound as an off-white solid (1.0 g, 75%).

[0865] Step 2: tert-butyl 4-fluoro-4-[(4-nitro-1 H-pyrazol-1-yl)methyl]piperidine-1 -carboxylate To a stirred solution of tert-butyl 4-fluoro-4-[(methanesulfonyloxy)methyl]piperidine-1- carboxylate (0.9 g, 2.89 mmol) and 4-nitro-1 H-pyrazole (0.33 g, 2.89 mmol) in DMF (18 mL, 20 vol) was added potassium carbonate (0.8 g, 5.78 mmol) at room temperature. The resulting reaction mixture was allowed to stir at 110°C for 48 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with ice-cold water (2 x 100 mL), dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 22% EtOAc in hexane) afforded the title compound as a white solid (0.67 g, 71%). Steps 3-5 are as described for A-22, steps 2-4, with the following exceptions:

[0866] In step 4, the reaction mixture was concentration in vacuo, diluted with water (50 mL) and lyophilised. The material was used directly in step 5 without further purification to afford the title compound as a brown solid (0.3 g, 76%).

[0867] LCMS (Method 3) RT 1.19 min, m / z 213.2 (MH+).

[0868] A-25: 1-{r(2S)-4-ethylmorpholin-2-yl1methyl}-1 H-pyrazol-4-amine

[0869] A-25 was prepared according to the following scheme:

[0870] K2CO3, Etl, DMF Pd / C, H2, MeOH

[0871] Step 3 Step 4

[0872] Step 1 is as described for A-19 step 1 except tert-butyl (2S)-2- (hydroxymethyl)morpholine-4-carboxylate was used.

[0873] Step 2 is as described for A-22 step 2.

[0874] Step 3: (2S)-4-ethyl-2-[(4-nitro-1 H-pyrazol-1-yl)methyl]morpholine

[0875] To a stirred solution of (S)-2-((4-nitro-1 H-pyrazol-1-yl) methyl) morpholine hydrochloride salt (0.8 g, 3.22 mmol) in DMF (16 mL, 20 vol) were added potassium carbonate (1.3 g, 9.65 mmol) and ethyl iodide (0.6 g, 3.86 mmol) at room temperature. The resulting reaction mixture was allowed to stir at 60°C for 12 h. The reaction mixture was poured into ice cold water (200 mL) and extracted with EtOAc (2 x 70 mL). The combined organic layers were washed with cold water (3 x 200 mL) and brine solution (100 mL), dried (Na2SC>4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 20% EtOAc in hexane) afforded the title compound as a light yellow oil (0.7 g, 91%). Step 4: 1-{[(2S)-4-ethylmorpholin-2-yl]methyl}-1 H-pyrazol-4-amine (A-25)

[0876] Step 4 is as described for A-22 step 4 to afford the title compound as a brown oil (0.4 g, 65%).

[0877] LCMS (Method 3) RT 1.25 min, m / z 211.2 (MH+).

[0878] A-26: tert-butyl N-methyl-N-[2-(4-nitro-1 H-pyrazol-1-yl)ethyl1carbamate

[0879] A-26 was prepared according to the following scheme:

[0880] A-26

[0881] Step 1 is as described for A-19 step 1 except tert-butyl N-(2-hydroxyethyl)-N- methylcarbamate was used.

[0882] Step 2 is as described for A-22 step 4 to afford the title compound as brown solid (0.45 g, quantitative).

[0883] LCMS (Method 3) RT 1.18 min, m / z 214.1 (MH+).

[0884] A-27 was prepared according to the following scheme.

[0885] Step 1 : tert-Butyl (1S,4S)-5-(4-nitro-1 H-pyrazol-1-yl)-2-azabicyclo[2.2.1]heptane-2- carboxylate

[0886] To a stirred solution of tert-butyl (1S,4S,5S)-5-hydroxy-2-azabicyclo [2.2.1] heptane-2- carboxylate (0.3 g, 1.41 mmol) and 4-nitro-1 H-pyrazole (0.24 g, 2.11 mmol) in THF (15 mL, 50 vol) were added triphenylphosphine (0.74 g, 2.81 mmol) and DIAD (0.43 g, 2.11 mmol) at 0°C for 30 min. The reaction mixture was stirred at 60°C for 21 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (silica, eluting with 20% EtOAc in hexane) afforded the title compound as a yellow oil as a racemic mixture (0.5 g, quantitative).

[0887] LCMS (Method 2) RT 2.2 min, m / z 258.2 (M-56)+

[0888] Step 2: tert-Butyl (1S,4S)-5-(4-amino-1 H-pyrazol-1-yl)-2-azabicyclo[2.2.1]heptane-2- carboxylate (A-27)

[0889] To a stirred solution of tert-butyl (1S,4S)-5-(4-nitro-1 H-pyrazol-1-yl)-2-azabicyclo [2.2.1] heptane-2-carboxylate (0.50 g, 1.62 mmol) in MeOH (25 mL, 50 vol) was added 10% w / w Pd / C (50%, 0.25 g). The reaction mixture was stirred under hydrogen at rt for 2 h. The reaction mixture was filtered through Celite® and washed with MeOH (3 x 50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a brown gum (0.50 g, quantitative).

[0890] LCMS (Method 3) RT 1.59 min, m / z 279.2 (MH+)

[0891] A-28: 1-[(1-methylpiperidin-4-yl)methyl1-1 H-pyrazol-4-amine

[0892] A-28 was prepared according to the following scheme.

[0893] Step 1 : tert-butyl 4-{[(4-methylbenzenesulfonyl)oxy]methyl}piperidine-1-arboxylate

[0894] To a stirred solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (CAS 123855- 51-6, 5.0 g, 23.22 mmol) in DCM (100 mL, 20 vol) were added TEA (9.80 mL, 69.67 mmol) and p-toluene sulfonyl chloride (6.64 g, 37.84 mmol) at 0°C. The reaction mixture was stirred at rt for 12 h. After completion of reaction, the reaction mixture was poured into ice cold water (200 mL) and extracted with DCM (2 x 150 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (silica, eluting with 25% EtOAc in hexane) afforded the title compound as a colourless gum (9.1 g, quantitative).

[0895] LCMS (Method 2) RT 2.50 min, m / z 314.2 (M-56)+

[0896] Steps 3-5 are as described for A-24 to afford A-28 as a brown liquid (0.5 g, 96%).

[0897] LCMS (Method 3) RT 0.53 min, m / z 195.2 (MH+)

[0898] A-29: 1-{[(3R)-1-Methylpiperidin-3-yl1methyl}-1 H-pyrazol-4-amine

[0899] A-29 was prepared according to the following scheme.

[0900] Step 1 and 2 are as described for A-28, step 3 is as described for A-22 step 4 to afford the title compound as brown liquid (0.15 g, 87%).

[0901] LCMS (Method 5) RT 0.71 min, m / z 195.2 (MH+).

[0902] A-30: 1-{f(3S)-1-methylpiperidin-3-yl1methyl}-1 H-pyrazol-4-amine

[0903] The title compound was prepared as described for A-29 with the following exceptions: In step 1 , [(3S)-1-methylpiperidin-3-yl]methanol was used. In step 2, the product was purified using flash column chromatography (silica gel, eluting with 9% MeOH in DCM). Following step 3, the title compound was isolated as a brown liquid (0.15 g, 79%).

[0904] LCMS (Method 5) RT 0.76 min, m / z 195.2 (MH+)

[0905] A-31 : 1-{r(2S)-4-cyclopropylmorpholin-2-yl1methyl}-1 H-pyrazol-4-amine

[0906] A-31 was prepared according to the following scheme.

[0907] Step-1 : (2S)-4-Cyclopropyl-2-[(4-nitro-1 H-pyrazol-1-yl)methyl]morpholine

[0908] To a stirred solution of (2S)-2-[(4-nitro-1 H-pyrazol-1-yl)methyl]morpholine hydrochloride (0.70 g, 2.81 mmol) in 1 ,4-dioxane (15 mL) was added cyclopropyl bromide (CAS 4333- 56-6, 0.41 g, 3.38 mmol) and K2CO3 (0.58 g, 2.81 mmol). The reaction mixture was stirred under nitrogen at rt for 20 min. Cui (0.54 g, 2.81 mmol) and DMEDA (0.25 g, 2.81 mmol) were added. The reaction mixture was stirred at 100°C for 3 h. The reaction mixture was poured into water (80 mL) and extracted into EtOAc (3 x 60 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 30% EtOAc in hexane) afforded the title compound as a red oil (0.50 g, 70%).

[0909] LCMS (Method 3) RT 1.37 min, m / z 252.9 (MH+)

[0910] Step-2: (S)-1-((4-Cyclopropylmorpholin-2-yl) methyl)-1 H-pyrazol-4-amine

[0911] To a stirred solution of (2S)-4-cyclopropyl-2-[(4-nitro-1 H-pyrazol-1-yl)methyl]morpholine (0.25 g, 0.99 mmol) in 1-4 dioxane (4.8 mL, 15 vol) and water (0.25 mL, 1.0 vol) was added ammonium chloride (0.13 g, 2.48 mmol), acetic acid (0.15 g, 2.48 mmol) and zinc dust (0.16 g, 2.48 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 min. The reaction mixture was filtered through Celite® and washed with EtOAc (2 x 30 mL). The combined filtrates were dried (Na2SO4) and concentrated in vacuo to afford the title compound as a brown gum (0.20 g, 91 %).

[0912] LCMS (Method 3) RT 1.04 min, m / z 223.3 (MH+)

[0913] A-32: {2-r(tert-butyldiphenylsilyl)oxy1-3-(4-nitro-1 H-pyrazol-1-yl)propyl}dimethylamine

[0914] A-32 was prepared according to the following scheme.

[0915] A-32

[0916] Step 1 : 4-nitro-1-[(oxiran-2-yl)methyl]-1 H-pyrazole

[0917] To a stirred solution of ethyl 4-nitro-1 H-pyrazole (0.2 g, 8.84 mmol) and potassium carbonate (2.46 g, 17.82 mmol) in 2-(bromomethyl)oxirane (CAS # 3132-64-7) (2.5 mL, 2.5 vol) was added tetrabutylammonium bromide (0.122 g, 0.38 mmol). The resulting reaction mixture was allowed to stir at 100°C for 1 h. Five reactions were run in parallel, cooled to RT and combined, diluted with water (500 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 25% EtOAc in hexane) afforded the title compound as off-white solid (1.0 g, 13%).

[0918] 1 H NMR (DMSO-d6) 8.87 (s, 1 H), 8.32 (s, 1 H), 4.54 (dd, 1 H), 4.24 (dd, 1 H), 3.42-3.38 (m, 1H), 2.84 (dd, 1 H), 2.60 (dd, 1 H).

[0919] Step 2: 1-(dimethylamino)-3-(4-nitro-1 H-pyrazol-1-yl)propan-2-ol

[0920] A solution of 4-nitro-1-(oxiran-2-ylmethyl)-1 H-pyrazole (1.6 g, 9.46 mmol) in dimethylamine (11% in EtOH, 32.72 mL, 80.03 mmol) was allowed to stir at room temperature for 5 h. The reaction mixture was concentrated in vacuo and triturated with Et20 (20 mL) to afford the title product as light yellow solid (1.5 g, 74%).

[0921] 1 H NMR (DMSO-d6) 8.77 (s, 1 H), 8.26 (s, 1 H), 5.04 (br d, 1 H), 4.29 (dd, 1 H), 4.07-4.02 (m, 1 H), 3.96 (br s, 1H), 2.31-2.21 (m, 2H), 2.19 (s, 6H).

[0922] Step 3: {2-[(tert-butyldiphenylsilyl)oxy]-3-(4-nitro-1H-pyrazol-1-yl)propyl}dimethylamine

[0923] To a stirred solution of 1-(dimethylamino)-3-(4-nitro-1 H-pyrazol-1-yl) propan-2-ol (1.0 g, 4.67 mmol) in MeCN (25 mL) were added imidazole (1.59 g, 23.34 mmol) and tert-butyl chloro diphenylsilane (3.21 g, 11.67 mmol) at room temperature. The resulting reaction mixture was allowed to stir at 80°C for 5 h. The reaction mixture was concentrated in vacuo, diluted with water (250 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 95% EtOAc in hexane) afforded the title compound as off-white solid (1.9 g, 90%).

[0924] LCMS (Method 2) RT 2.19 min, m / z 453.3 (MH+).

[0925] Step 4: 1-{2-[(tert-butyldiphenylsilyl)oxy]-3-(dimethylamino)propyl}-1 H-pyrazol-4-amine

[0926] Step 4 is as described for A-22 step 4 to afford the title compound as brown liquid (0.9g, 96%).

[0927] LCMS (Method 3) RT 2.11 min, m / z 423.2 (MH+).

[0928] A-33: 1-n-(propan-2-yl)azetidin-3-yl1-1 H-pyrazol-4-amine

[0929] A-33 was prepared according to the following scheme.

[0930] Step 1 is as described for A-4 step 3 except that acetone was used instead of formaldehyde.

[0931] Step 2 is as described for A-4 step 4 to afford the title compound as light brown solid (0.14 g, 96%).

[0932] 1 H NMR (DMSO-d6) 5 7.14 (d, 1 H), 6.95 (d, 1 H), 4.67 (quintet, 1H), 3.85 (brs, 2H), 3.59- 3.56 (m, 2H), 3.21-3.17 (m, 2H), 2.34 (septet, 1H), 0.87 (d, 6H).

[0933] Examples 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2- (1-methylpiperidin-4-yl)-1 H-pyrazol-4- yl1amino}pyrimidine-5-carboxamide

[0934] The title compound was prepared by General Method 1 from lnt-2 as outlined in Scheme 4.

[0935] Scheme 4

[0936] Step 1 : 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-methanesulfinylpyrimidine-5- carboxamide and 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-methanesulfonylpyrimidine-5- carboxamide

[0937] To a solution of lnt-2 (0.30 g, 0.81 mmol) in DCM (3 mL) was added mCPBA (0.27 g, 1.21 mmol) at 0°C. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was poured into aq. NaHCCh solution (5 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried (Na2SO4) and concentrated. Trituration with Et20 afforded the title compounds as a mixture (0.25 g, 80%).

[0938] Step 2: 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-{[1-(1-methylpiperidin-4-yl)-1 H-pyrazol-4- yl]amino}pyrimidine-5-carboxamide

[0939] To a solution of 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-methanesulfinylpyrimidine-5- carboxamide and 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-methanesulfonylpyrimidine-5- carboxamide (0.150 g, 0.388 mmol) in I PA (7.5 mL) was added 1-(1-methylpiperidin-4-yl)- 1 H-pyrazol-4-amine (CAS # 1201935-36-5) (0.084 g, 0.465 mmol) and TFA (0.05 mL). The resulting reaction mixture was stirred at 50°C for 16 h. The reaction mixture was diluted with aq. NaHCCh (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried (Na2SO4) and concentrated. Purification by flash column chromatography (silica, eluting with 10% MeOH in DCM) afforded the title compound as a white solid (0.14 g, 72%).

[0940] 1 H NMR (DMSO-d6) 5 9.85 (br s, 1 H), 9.10 (s, 1 H), 8.69 (s, 1 H), 7.99 (s, 1 H), 7.68 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.61 - 4.57 (m, 1 H), 4.13 - 4.06 (m, 1 H), 2.86 (d, 2H), 2.23 (s, 3H), 2.13 - 2.07 (m, 2H), 2.03 - 1.93 (m, 4H), 1.01 - 0.88 (m, 4H).

[0941] Example 2

[0942] 4-cyclopropoxy-N-(2,6-dichloro-3-fluorophenyl)-2- (1-methylpiperidin-4-yl)-1 H-pyrazol- 4-yl1amino}pyrimidine-5-carboxamide

[0943] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions.

[0944] Step 1 used lnt-3 and trituration was with n-pentane. In step 2, the reaction mixture was heated under microwave irradiation at 80°C for 2 h.

[0945] Purification by flash column chromatography (silica, eluting with 7% MeOH in DCM), followed by trituration with Et20 (10 mL) afforded the title compound as an off-white solid (0.095 g, 73%).

[0946] 1 H NMR (VT, DMSO-d6) 5 9.90 (br s, 1 H), 9.20 (s, 1 H), 8.69 (s, 1 H), 8.0 (s, 1 H), 7.68 (s, 1 H), 7.62 - 7.58 (m, 1 H), 7.44 (t, 1 H), 4.61 - 4.57 (m, 1 H), 4.14 - 4.06 (m, 1 H), 2.87 (br d, 2H), 2.24 (s, 3H), 2.15 - 2.08 (m, 2H), 2.03 - 1.94 (m, 4H), 1.00 - 0.87 (m, 4H).

[0947] Example 3

[0948] N-(6-chloro-2,3-difluorophenyl)-4-cyclopropoxy-2- (1-methylpiperidin-4-yl)-1 H-pyrazol- 4-yl1amino}pyrimidine-5-carboxamide

[0949] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions.

[0950] Step 1 used lnt-4 and the reaction mixture was stirred for 30 min before work-up. In step 2, the reaction mixture was heated under microwave irradiation at 120°C for 1 h. Purification by flash column chromatography (silica, eluting with 15% MeOH in DCM) afforded the title compound as a white solid (0.065 g, 39%).

[0951] 1 H NMR (VT, DMSO-d6) 5 9.95 (br s, 1 H), 9.09 (s, 1 H), 8.71 (s, 1 H), 8.00 (s, 1 H), 7.68 (s, 1 H), 7.46 - 7.43 (m, 2H), 4.61 - 4.58 (m, 1 H), 4.14 - 4.08 (m, 1 H), 2.88 (d, 2H), 2.55 (s, 3H), 2.14 (t, 2H), 2.01 - 1.95 (m, 4H), 1.00 - 0.89 (m, 4H).

[0952] 4-cyclopropoxy-N-(2,5-dichlorophenyl)-2-{[1-(1-methylpiperidin-4-yl)-1 H-pyrazol-4- yl]amino}pyrimidine-5-carboxamide

[0953] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions.

[0954] Step 1 used I nt- 5 and the reaction mixture was stirred for 30 min before work-up. In step 2, the reaction mixture was heated under microwave irradiation at 120°C for 1 h. Purification by flash column chromatography (silica, eluting with 7% MeOH in DCM) afforded the title compound as a white solid (0.10 g, 51 %).

[0955] 1 H NMR (VT, DMSO-d6) 5 10.03 (br s, 1 H), 9.51 (s, 1 H), 8.85 (s, 1 H), 8.55 (d, 1 H), 8.00 (s, 1H), 7.70 (br s, 1 H), 7.57 (d, 1 H), 7.21 (dd, 1 H), 4.65 - 4.61 (m, 1 H), 4.14 - 4.09 (m, 1 H), 2.87 (d, 2H), 2.25 (s, 3H), 2.16 - 2.12 (m, 2H), 2.10 - 1.95 (m, 4H), 1.04 - 0.94 (m, 4H).

[0956] Example 5

[0957] N-(2-chloro-6-fluorophenyl)-4-cyclopropoxy-2-{[1-(1-methylpiperidin-4-yl)-1 H-pyrazol-4- yl]amino}pyrimidine-5-carboxamide

[0958] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions.

[0959] Step 1 used lnt-6 and the reaction mixture was stirred for 30 min before work-up. In step 2, the reaction mixture was heated under microwave irradiation at 120°C for 1 h. Purification by flash column chromatography (silica, eluting with 7% MeOH in DCM) afforded the title compound as a white solid (0.07 g, 63%). 1 H NMR (VT, DMSO-d6) 5 9.88 (s, 1 H), 8.96 (s, 1 H), 8.70 (s, 1 H), 7.99 (s, 1 H), 7.68 (s, 1 H), 7.42 - 7.29 (m, 3H), 4.60 - 4.57 (m, 1 H), 4.13 - 4.08 (m, 1 H), 2.88 (d, 2H), 2.25 (s, 3H), 2.13 (t, 2H), 2.01 - 1.94 (m, 4H), 0.99 - 0.89 (m, 4H).

[0960] The title compound was prepared from Example 18 according to the scheme below:

[0961] To a solution of Example 18 hydrochloride salt (0.1 g, 0.19 mmol) in MeOH (5 mL) was added oxetan-3-one (0.027 g, 0.38 mmol) and zinc chloride (0.051 g, 0.38 mmol). The reaction mixture was stirred at 0°C temperature for 10 min followed by addition of sodium cyanoborohydride (0.024 g, 0.38 mmol). The reaction mixture was allowed to stir at 70°C for 12 h. The reaction mixture was concentrated in vacuo. The resulting suspension was diluted with aqueous sodium bicarbonate solution (200 mL) and extracted with DCM (2 x 150 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (silica, eluting with 4% MeOH in DCM) afforded the title compound as a white solid (0.058 g, 56%).

[0962] 1 H NMR (VT, DMSO-d6) 5 9.90 (br s, 1 H), 9.11 (s, 1 H), 8.68 (s, 1 H), 8.00 (s, 1 H), 7.69 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.59 - 4.49 (m, 5H), 4.18 (br s, 1 H), 3.53 (br s, 1 H), 2.83 (br s, 2H), 2.07 - 2.04 (m, 6H), 0.99 - 0.88 (m, 4H).

[0963] Example 7

[0964] -2-{[1-(1-ethylpiperidin-4-yl)-1 H-pyrazol-4-

[0965] The title compound was prepared from Example 18 according to the scheme below:

[0966] To a solution of Example 18 hydrochloride salt (0.10 g, 0.19 mmol) in THF (5 mL) was added DI PEA (0.05 g, 0.38 mmol) at 0°C. The reaction mixture was stirred at 0°C for 10 min followed by addition of iodoethane (0.06 g, 0.38 mmol). The reaction was stirred at 50°C for 4 h. The reaction was concentrated in vacuo, diluted with water (80 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (silica, eluting with 5% MeOH in DCM) afforded the title compound as an off-white solid (0.039 g, 40%).

[0967] 1 H NMR (VT, DMSO-d6) 5 9.87 (br s, 1 H), 9.10 (s, 1 H), 8.68 (s, 1 H), 7.99 (s, 1 H), 7.68 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4,61-4.57 (m, 1 H), 4.13 (br s, 1 H), 3.00-2.99 (m, 2H), 2.51- 2.50 (m, 2H), 2.15-1.92 (m, 6H), 1.06 (t, 3H), 1.02-0.90 (m, 4H).

[0968] Example 8

[0969] 2- (1-acetylpiperidin-4-yl)-1 H-pyrazol-4-yl1amino}-4-cyclopropoxy-N-(2,6- dichlorophenyl)pyrimidine-5-carboxamide

[0970] The title compound was prepared from Example 18 according to the scheme below:

[0971] To a solution of Example 18 hydrochloride salt (0.10 g, 0.19 mmol) in THF (5 mL) was added 4-dimethylaminopyridine (0.005 g, 0.04 mmol). The reaction mixture was stirred at room temperature for 10 min followed by addition of acetic anhydride (0.06 g, 0.57 mmol). The reaction mixture was allowed to stir at 50°C for 12 h. The reaction mixture was concentrated in vacuo and the suspension was diluted with water (80 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (silica, eluting with 6% MeOH in DCM) afforded the title compound as an off-white solid (0.026 g, 26%). 1 H NMR (VT, DMS0-d6) 5 9.89 (br s, 1 H), 9.11 (s, 1 H), 8.68 (s, 1 H), 8.01 (s, 1 H), 7.69 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.60 - 4.57 (m, 1 H), 4.43 - 4.38 (m, 2H), 3.91 (br s, 1 H), 3.24 (br s, 1 H), 2.78 (br s, 1 H), 2.04 (br s, 4H), 1 .83 (br s, 3H), 0.99 - 0.84 (m, 4H).

[0972] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[0973] In step 2, the amine used was 2-(4-amino-1 H-pyrazol-1-yl)acetonitrile.

[0974] Purification by column chromatography (silica, eluting with 4% MeOH in DCM) afforded the title compound as a white solid (0.035 g, 15%).

[0975] 1 H NMR (VT, DMSO-d6) 5 10.01 (s, 1 H), 9.15 (s, 1 H), 8.70 (s, 1 H), 8.16 (s, 1 H), 7.78 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1 H), 5.45 (s, 2H), 4.59 (t, 1 H), 0.98 - 0.93 (m, 4H).

[0976] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1-[2-(piperidin-1-yl)ethyl]-1 H-pyrazol-4- yl}amino)pyrimidine-5-carboxamide

[0977] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[0978] In step 2, A-1 was used.

[0979] Purification by column chromatography (silica, eluting with 5% MeOH in DCM) followed by preparative HPLC (method 1) afforded the title compound as a white solid (0.080 g, 39%).

[0980] 1 H NMR DMSO-d6 5 10.21 (s, 1 H), 9.23 (s, 1 H), 8.65 (s, 1 H), 8.03 (s, 1 H), 7.64 (s, 1 H), 7.56 (d, 2H), 7.37 (t, 1 H), 4.56 (br s, 1 H), 4.18 (t, 2H), 2.65 (t, 2H), 2.36 (br s, 4H), 1.46 (br s, 4H), 1.37 (br d, 2H), 1.00 - 0.89 (m, 4H).

[0981] Example 11 2-{[1-(3-aminopropyl)-1 H-pyrazol-4-yl]amino}-4-cyclopropoxy-N-(2,6-

[0982] H5-carboxamide

[0983] The title compound was prepared according to the following scheme.

[0984] Steps 1 and 2 follow General Method 1 with the exception that A-2 is used in step 2 and the reaction is heated under microwave irradiation at 80°C for 80 min.

[0985] Step 3: 2-{[1-(3-aminopropyl)-1 H-pyrazol-4-yl]amino}-4-cyclopropoxy-N-(2,6- dichlorophenyl)pyrimidine-5-carboxamide

[0986] To a stirred solution of tert-butyl (3-(4-((4-cyclopropoxy-5-((2,6-dichlorophenyl)carbamoyl) pyrimidin-2-yl)amino)-1 H-pyrazol-1-yl) propyl)carbamate (0.1 g, 0.18 mmol) in DCM (2 mL) was added 4 M HCI in 1,4 dioxane (0.5 mL). The resulting reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was concentrated in vacuo. The resulting residue was triturated with Et20 (20 mL) and lyophilized to afford the hydrochloride salt of the title product as a light-yellow solid (0.08 g, 90%)

[0987] 1 H NMR (DMSO-d6) (VT-NMR) 5 9.94 (br s, 1H), 9.12 (s, 1 H), 8.69 (s, 1 H), 8.02 - 7.95 (m, 4H), 7.70 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1H), 4.61 - 4.60 (m, 1H), 4.23 (t, 2H), 2.85 - 2.80 (m, 2H), 2.15 - 2.08 (m, 2H), 0.98 - 0.91 (m, 4H).

[0988] Example 12

[0989] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-{[1-(2-methoxyethyl)-1 H-pyrazol-4- yllamino}pyrimidine-5-carboxamide The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[0990] In step 2, 1-(2-methoxyethyl)-1 H-pyrazol-4-amine (CAS # 948570-74-9) was used and the reaction mixture was heated under microwave irradiation at 90 °C for 2 h. Purification by column chromatography (silica, eluting with 2% MeOH in DCM) followed by preparative HPLC (method 2) afforded the title compound as a white solid (0.06 g, 17%).

[0991] 1 H NMR (VT, DMSO-d6) 5 9.89 (s, 1 H), 9.10 (s, 1 H), 8.67 (s, 1 H), 8.02 (s, 1 H), 7.65 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.59 - 4.56 (m, 1 H), 4.25 (t, 2H), 3.70 (t, 2H), 3.26 (s, 3H), 1.00 - 0.91 (m, 4H).

[0992] Example 13

[0993] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-[(1 H-pyrazol-4-yl)amino]pyrimidine-5- carboxamide

[0994] The title compound was prepared according to the following scheme.

[0995] Steps 1 and 2 follow General Method 1 (Scheme 4) with the exception that the amine used in step 2 was tert-butyl 4-amino-1 H-pyrazole-1 -carboxylate and the reaction is heated under microwave irradiation at 80°C for 80 min. Step 3 is as described for Example 11 step 3 to afford the title compound as its hydrochloride salt as an off-white solid (0.034 g, 65%).

[0996] 1 H NMR (VT, DMSO-d6) 5 9.89 (br s, 1 H), 9.11 (s, 1 H), 8.69 (s, 1 H), 7.87 (s, 2H), 7.54 (d, 2H), 7.36 (t, 1 H), 5.55 (br s, 2H), 4.60 - 4.57 (m, 1 H), 1.01 - 0.93 (m, 4H). Example 14

[0997] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-r(1-methyl-1 H-pyrazol-4-yl)aminolpyrimidine-5- carboxamide

[0998] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[0999] In step 2, the amine used was A-3 and the reaction mixture was heated at 80 °C for 12 h. Purification by column chromatography (silica, eluting with 4% MeOH in DCM) afforded the title compound as a white solid (0.062 g, 14%).

[1000] 1 H NMR (VT, DMSO-d6) 5 9.86 (br s, 1 H), 9.10 (s, 1 H), 8.69 (s, 1 H), 7.95 (s, 1 H), 7.62 (s, 1 H), 7.54 (d, 3H), 7.36 (t, 1 H), 4.60 - 4.57 (m, 1 H), 3.83 (s, 3H), 0.98 - 0.89 (m, 4H).

[1001] Example 15

[1002] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2- (2-hydroxyethyl)-1 H-pyrazol-4- yl1amino}pyrimidine-5-carboxamide

[1003] The title compound was prepared from Example 12 according to Scheme 5 below.

[1004] Scheme 5

[1005] To a stirred solution of Example 12 (0.2 g, 0.43 mmol) in DCM (4.0 mL, 20 vol) was added boron tribromide (1M in DCM) (2.15 mL, 2.15 mmol) at 0°C. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was quenched into 10% aq. sodium hydroxide solution (40 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was purified (silica, eluting with 3% MeOH in DCM) followed by reverse phase preparative HPLC (method 3) to afford the title product as a white solid (0.07 g, 36%). 1 H NMR (VT, DMSO-d6) 6 9.87 (br s, 1 H), 9.09 (br s, 1 H), 8.68 (s, 1 H), 8.05 (s, 1 H), 7.64 (s, 1H), 7.53 (d, 2H), 7.34 (t, 1 H), 4.69 (br s, 1H), 4.61 - 4.57 (m, 1 H), 4.14 (t, 2H), 3.75 (t, 2H), 0.99 - 0.91 (m, 4H).

[1006] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-{[1-(oxan-4-yl)-1 H-pyrazol-4- yl]amino}pyrimidine-5-carboxamide

[1007] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1008] In step 2, the amine used was 1-(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-4-amine. Purification by column chromatography (silica, eluting with 68% EtOAc in hexane) afforded the title compound as a white solid (0.06 g, 13%).

[1009] 1 H NMR (VT, DMSO-d6) 5 9.87 (s, 1 H), 9.10 (s, 1 H), 8.69 (s, 1 H), 8.02 (s, 1H), 7.70 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.60 - 4.57 (m, 1 H), 4.41 - 4.36 (m, 1 H), 3.97 (d, 2H), 3.53

[1010] - 3.46 (m, 2H), 2.02 - 1.91 (m, 4H), 0.99 - 0.89 (m, 4H).

[1011] Example 17

[1012] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-{[1-(1-methylazetidin-3-yl)-1 H-pyrazol-4- yl]amino}pyrimidine-5-carboxamide

[1013] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1014] In step 2, the amine used was A-4 and the reaction was heated under microwave irradiation at 80°C for 80 min. Purification by column chromatography (silica, eluting with 7% MeOH in DCM) afforded the title compound as an off-white solid (0.08 g, 43%).

[1015] 1 H NMR (VT, DMSO-d6) 5 9.91 (s, 1H), 9.11 (s, 1H), 8.69 (s, 1H), 8.19 (s, 1H), 7.70 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.94 (q, 1 H), 4.62-4.59 (m, 1H), 3.72 (t, 2H), 3.42 (t, 2H), 2.35 (s, 3H), 0.99-0.92 (m, 4H).

[1016] Example 18 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2- (piperidin-4-yl)-1 H-pyrazol-4- yl1amino}pyrimidine-5-carboxamide

[1017] The title compound was prepared in three steps from lnt-2 as described for Example 11 with the following exceptions.

[1018] In step 2, the amine used was tert-butyl 4-(4-amino-1 H-pyrazol-1-yl)piperidine-1- carboxylate and the reaction mixture was heated at 80°C for 8 h. In step 3, 1 ,4-dioxane was used as solvent instead of DCM and the reaction was stirred for 5 h. The resulting residue was triturated with Et20 (50 mL) and dried in vacuo to afford the title product as its hydrochloride salt as off-white solid (0.3 g, quantitative).

[1019] 1 H NMR (VT, DMSO-d6) 5 9.95 (br s, 1 H), 9.12 (br s, 3H), 8.69 (s, 1 H), 8.03 (s, 1 H), 7.71 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.59-4.57 (m, 1 H), 4.54-4.47 (m, 1 H), 3.43 - 3.38 (m, 2H), 3.08 (br s, 2H), 2.34 - 2.20 (m, 4H), 1.01 - 0.93 (m, 4H).

[1020] Example 19

[1021] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-{n-(2-hydroxy-2-methylpropyl)-1 H-pyrazol-4- yl1amino}pyrimidine-5-carboxamide

[1022] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1023] In step 2, the amine used was 1-(4-amino-1 H-pyrazol-1-yl)-2-methylpropan-2-ol. Purification by column chromatography (silica, eluting with 70% EtOAc in hexane) followed by preparative HPLC (method 4) afforded the title compound as a white solid (0.083 g, 67%).

[1024] 1 H NMR (VT, DMSO-d6) 5 9.87 (s, 1 H), 9.09 (s, 1 H), 8.69 (s, 1 H), 8.07 (s, 1 H), 7.63 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.61-4.57 (m, 1 H), 4.45 (s, 1 H), 4.01 (s, 2H), 1.10 (s, 6H), 0.96-0.92 (m, 4H).

[1025] Example 20

[1026] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2- (oxetan-3-yl)-1 H-pyrazol-4- yl1amino}pyrimidine-5-carboxamide The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1027] In step 2, the amine used was A-5 and the reaction was heated at 80°C for 12 h. Purification by column chromatography (silica, eluting with 3% MeOH in DCM) followed by preparative HPLC (method 5) afforded the title compound as a white solid (0.044 g, 37%).

[1028] 1 H NMR (VT, DMSO-d6) 5 9.93 (bs, 1 H), 9.11 (s, 1 H), 8.69 (s, 1 H), 8.16 (s, 1 H), 7.79 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 5.59-5.52 (m, 1 H), 4.97-4.87 (m, 4H), 4.62-4.58 (m, 1 H), 1.00-0.88 (m, 4H).

[1029] Example 21

[1030] 2- (2-aminoethyl)-1 H-pyrazol-4-yl1amino}-4-cyclopropoxy-N-(2,6- dichlorophenyl)pyrimidine-5-carboxamide

[1031] The title compound was prepared following the scheme for Example 13 with the following exceptions:

[1032] In step 2, the amine used was A-12 and the reaction was heated at 80°C for 12 h. Step 3 is as described for Example 11 to afford the title compound as its hydrochloride salt as a white solid (0.056 g, 80%).

[1033] 1 H NMR (DMSO-d6) 5 9.98 (br s, 1H), 9.12 (s, 1H), 8.70 (s, 1H), 8.08 (br s, 3H), 7.77 (s, 1 H), 7.54 (d, 2H), 7.37 (t, 1 H), 4.63 (br s, 1 H), 4.40 (t, 2H), 3.29 (br s, 3H), 0.99-0.95 (m, 4H).

[1034] Example 22

[1035] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-r(1-{r(2R)-4-methylmorpholin-2-yl1methyl}-1 H- pyrazol-4-yl)aminolpyrimidine-5-carboxamide

[1036] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1037] In step 2, the amine used was A-6 and the reaction was heated at 80°C for 12 h.

[1038] Purification by column chromatography (silica, eluting with 7% MeOH in DCM) followed by trituration with Et20 afforded the title compound as a white solid (0.072 g, 54%). 1 H NMR (VT, DMSO-d6) 6 9.89 (s, 1 H), 9.11 (s, 1 H), 8.69 (s, 1 H), 8.02 (s, 1 H), 7.65 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1 H), 4.60 - 4.56 (m, 1 H), 4.17 - 4.15 (m, 2H), 3.83 - 3.77 (m, 2H), 3.54 - 3.48 (m, 1 H), 2.68 - 2.56 (m, 2H), 2.19 (s, 3H), 2.04 - 1.98 (m, 1 H), 1.77 (t, 1 H), 1.02 - 0.91 (m, 4H).

[1039] Chiral HPLC (Method 1) RT 2.99 min, 99.91%.

[1040] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-[(1-{[(2S)-4-methylmorpholin-2-yl]methyl}-1 H- pyrazol-4-yl)amino]pyrimidine-5-carboxamide

[1041] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1042] In step 2, the amine used was A-7 and the reaction was heated at 90°C for 6 h. Purification by column chromatography (silica, eluting with 4% MeOH in DCM) followed by trituration n-pentane: Et20 (7:3) afforded the title compound as a white solid (0.054 g, 40%).

[1043] 1 H NMR (VT, DMSO-d6) 5 9.87 (s, 1 H), 9.09 (s, 1 H), 8.69 (s, 1 H), 8.01 (s, 1 H), 7.64 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.59 - 4.56 (m, 1 H), 4.17 - 4.15 (m, 2H), 3.79 - 3.76 (m, 2H), 3.54 - 3.48 (m, 1 H), 2.68 - 2.56 (m, 2H), 2.18 (s, 3H), 2.04 - 1.97 (m, 1 H), 1.77 (t, 1 H), 0.98 - 0.91 (m, 4H).

[1044] Chiral HPLC (Method 1) RT 2.83 min, 98.62%.

[1045] Example 24

[1046] -3-yllmethyl}-1 H-

[1047] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1048] In step 2, the amine used was A-8 and the reaction was heated under microwave irradiation at 80°C for 80 min. Purification by column chromatography (silica, eluting with 7% MeOH in DCM) followed by trituration n-pentane: Et20 (8:3) afforded the title product as an off-white solid (0.075 g, 37%). 1 H NMR (VT, DMSO-d6) 5 9.89 (bs, 1 H), 9.11 (s, 1 H), 8.69 (s, 1 H), 8.01 (s, 1 H), 7.65 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.62-4.59 (m, 1 H), 4.37-4.32 (m, 1 H), 4.13-4.08 (m, 1 H), 3.67-3.64 (m, 1 H), 3.52-3.49 (m, 2H), 3.23-3.18 (m, 1 H), 2.71-2.67 (m, 1 H), 2.54-2.52 (m, 1 H), 2.32 (s, 3H), 2.28-2.24 (m, 1 H), 1.00-0.90 (m, 4H).

[1049] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-[(1-{[(3S)-4-methylmorpholin-3-yl]methyl}-1 H- pyrazol-4-yl)amino]pyrimidine-5-carboxamide

[1050] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1051] In step 2, the amine used was A-9 and the reaction was heated under microwave irradiation at 80°C for 80 min. Purification by column chromatography (silica, eluting with 6% MeOH in DCM) afforded the title product as an off-white solid (0.1 g, 37%).

[1052] 1 H NMR (VT, DMSO-d6) 5 9.89 (s, 1 H), 9.11 (s, 1 H), 8.69 (s, 1 H), 8.01 (s, 1 H), 7.65 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.62-4.59 (m, 1 H), 4.37-4.32 (m, 1 H), 4.13-4.07 (m, 1 H), 3.67-3.64 (m, 1 H), 3.52-3.49 (m, 2H), 3.10 (t, 1 H), 2.70-2.67 (m, 1 H), 2.53-2.50 (m, 1 H), 2.33 (s, 3H), 2.28-2.24 (m, 1 H), 0.99-0.90 (m, 4H).

[1053] The title compounds were prepared following General Method 1 (Scheme 4) with the following exceptions:

[1054] In step 2, the amine used was A-10 and the reaction was heated at 80°C for 12 h. Purification by column chromatography (silica, eluting with 3% MeOH in DCM) followed by preparative HPLC (Method 6) afforded the title products as a racemic mixture (0.08 g, 31%).

[1055] The individual isomers were isolated by chiral preparative HPLC (Method 1).

[1056] Peak 1 : RT 8.60 min (chiral HPLC Analytical Method 2), 100% ee 1 H NMR (VT, DMS0-d6) 6 9.99 (s, 1 H), 9.14 (s, 1 H), 8.71 (s, 1 H), 8.19 (s, 1 H), 7.78 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1 H), 4.71 - 4.48 (m, 3H), 3.87 - 3.60 (m, 2H), 3.12-3.00 (m, 1 H, obscured by water peak), 2.66 (br s, 3H), 2.20 (br s, 1 H), 2.00 - 1.79 (m, 3H), 0.99 - 0.92 (m, 4H). Peak 1 : RT 9.41 min (chiral HPLC Analytical Method 2), 90.72% ee

[1057] 1 H NMR (VT, DMSO-d6) 5 9.98 (br s, 1 H), 9.13 (s, 1 H), 8.71 (s, 1 H), 8.17 (s, 1 H), 7.78 (s, 1 H), 7.56 (d, 2H), 7.38 (t, 1 H), 4.64 - 4.47 (m, 3H), 3.82 - 3.60 (m, 2H), 3.12-3.00 (m, 1 H, obscured by water peak), 2.67 (br s, 3H), 2.17 - 1.76 (m, 4H), 0.99 - 0.92 (m, 4H).

[1058] Example 28 and Example 29 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1-r(2R)-1-hydroxypropan-2-yl1-1 H-pyrazol-4- yl}amino)pyrimidine-5-carboxamide and 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1- r(2S)-1-hydroxypropan-2-yl1-1 H-pyrazol-4-yl}amino)pyrimidine-5-carboxamide

[1059] The title compounds were prepared following the scheme below: Steps 1 and 2 follow General Method 1 with the following exceptions: In step 2, the amine used was A-11 and the reaction was heated at 120°C for 80 min.

[1060] Step 3: 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-{[1-(1-hydroxypropan-2-yl)-1 H-pyrazol-4- yl]amino}pyrimidine-5-carboxamide To a solution of methyl 2-[4-({4-cyclopropoxy-5-[(2,6-dichlorophenyl)carbamoyl]pyrimidin- 2-yl}amino)-1 H-pyrazol-1-yl]propanoate (0.12 g, 0.24 mmol) in THF (2.4 mL, 20 vol) was added lithium aluminium hydride (1M in THF) (0.48 mL, 0.48 mmol) at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 30 min. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was purified by flash column chromatography (silica, eluting with 100% EtOAc) to afford the title product as an off-white solid (0.05 g, 44%).

[1061] The individual isomers were isolated by chiral preparative HPLC (Method 2).

[1062] Peak 1 : RT 12.50 min (chiral HPLC Analytical Method 3), 98.84% ee

[1063] 1 H NMR (VT, DMSO-d6) 5 9.88 (br s, 1 H), 9.09 (s, 1 H), 8.69 (s, 1 H), 8.04 (s, 1 H), 7.66 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.71-4.58 (m, 2H), 4.36-4.31 (m, 1 H), 3.71-3.61 (m, 2H), 1.41 (d, 3H), 0.98-0.91 (m, 4H).

[1064] Peak 1 : RT 12.53 min (chiral HPLC Analytical Method 3), 94.45% ee

[1065] 1 H NMR (VT, DMSO-d6) 5 9.87 (br s, 1 H), 9.09 (s, 1 H), 8.69 (s, 1 H), 8.04 (s, 1 H), 7.66 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.69 (t, 1 H), 4.61-4.57 (m, 1 H), 4.36-4.31 (m, 1 H), 3.71- 3.61 (m, 2H), 1.41 (d, 3H), 0.99-0.91 (m, 4H).

[1066] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1-n-(2-methoxyethyl)piperidin-4-yl1-1 H- pyrazol-4-yl}amino)pyrimidine-5-carboxamide

[1067] The title compound was prepared from Example 18 according to the scheme below.

[1068] To a stirred solution of Example 18 hydrochloride salt (0.2 g, 0.38 mmol) in DMF (4 mL, 20 vol) was added potassium carbonate (0.26 g, 1.90 mmol) at room temperature. The reaction mixture was stirred for 30 min at room temperature. 1-bromo-2-methoxyethane (0.063 g, 0.46 mmol) was added and the reaction stirred at 60°C for 12 h. The reaction mixture was poured into ice cold water (100 mL) and extracted with DCM (2 x 60 mL).

[1069] The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, eluting with 7% MeOH in DCM) to afford the title compound as a white solid (0.055 g, 26%).

[1070] 1 H NMR (VT, DMSO-d6) 5 9.85 (s, 1 H), 9.09 (s, 1 H), 8.69 (s, 1 H), 7.99 (s, 1 H), 7.68 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.61-4.58 (m, 1 H), 4.11-4.09 (m, 1 H), 3.48 (m, 2H), 3.08 (s, 3H), 3.01-2.91 (m, 2H), 2.56-2.51 (m, 2H), 2.25-2.22 (m, 2H), 2.00-1.95 (m, 4H), 0.99- 0.88 (m, 4H).

[1071] Example 31

[1072] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1-n-(2-hydroxyethyl)piperidin-4-yl1-1 H-pyrazol- 4-yl}amino)pyrimidine-5-carboxamide

[1073] The title compound was prepared from Example 18 hydrochloride salt as described for Example 30 with the exception that 2-bromoethanol was used. The resulting residue was purified by reverse phase preparative HPLC (Method 7) to afford the title product as a white solid (0.039 g, 32%).

[1074] 1 H NMR (DMSO-d6) 5 10.22 (s, 1 H), 9.24 (s, 1 H), 8.69 (s, 1 H), 8.02 (s, 1H), 7.69 (s, 1H), 7.57 (d, 2H), 7.38 (t, 1 H), 4.57 (br s, 1H), 4.42 (t, 1 H), 4.13-4.08 (m, 1 H), 3.53-3.48 (m, 1 H), .96 (d, 2H), 2.51-2.40 (m, 2H), 2.15-2.10 (m, 2H), 1.96-1.88 (m, 4H), 1.01-0.82 (m, 4H).

[1075] Example 32

[1076] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2- (3-hydroxy-1-methylpiperidin-4-yl)-1 H- pyrazol-4-yl1amino}pyrimidine-5-carboxamide

[1077] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1078] In step 2, the amine used was A-13 and the reaction was heated under microwave irradiation at 120°C for 1.5 h. The material was purified by column chromatography (silica, eluting with 5% MeOH in DCM with 0.005% ammonia modifier), followed by reverse phase preparative HPLC purification (Method 8) to afford the title product as a white solid (0.052 g, 19%). 1H NMR (DMSO-d6) 510.21 (s, 1 H), 9.23 (s, 1 H), 8.66 (s, 1 H), 8.03 (s, 1 H), 7.71 (s, 1 H), 7.57 (d, 2H), 7.37 (t, 1 H), 4.98 (s, 1 H), 4.56 (br s, 1 H), 3.83-3.73 (m, 2H), 2.95-2.93 (m, 1 H), 2.79 (d, 1 H), 2.21 (s, 3H), 2.05-1.80 (m, 4H), 0.98-0.83 (m, 4H).

[1079] The individual isomers from Example 32 were isolated by chiral preparative HPLC (Method 6).

[1080] Peak 1: RT 12.83 min (chiral HPLC Analytical Method), 100% ee

[1081] 1H NMR (DMSO-d6) 510.22 (s, 1H), 9.23 (s, 1H), 8.69-8.65 (m, 1H), 8.03-7.99 (m, 1H), 7.71 (s, 1H), 7.57 (d, 2H), 7.38 (t, 1H), 4.99 (d, 1H), 4.56 (s, 1H), 3.80-3.74 (m, 2H), 2.93 (d, 1H), 2.79 (d, 1H), 2.21 (s, 3H), 2.04-1.93 (m, 2H), 1.85-1.80 (m, 2H), 0.99-0.82 (m, 4H).

[1082] Peak 2: RT 13.86 min (chiral HPLC Analytical Method), 95.4% ee

[1083] 1H NMR (DMSO-d6) 510.22 (s, 1H), 9.23 (s, 1H), 8.65 (s, 1H), 8.03-7.99 (m, 1H), 7.71 (s, 1H), 7.58 (d, 2H), 7.38 (t, 1H), 4.99 (d, 1H), 4.56 (s, 1H), 3.80-3.74 (m, 2H), 2.93 (d, 1H), 2.79 (d, 1H), 2.21 (s, 3H), 2.04-1.93 (m, 2H), 1.85-1.80 (m, 2H), 0.99-0.82 (m, 4H).

[1084] The title compounds were prepared following General Method 1 (Scheme 4) with the following exceptions: In step 2, the amine used was A-15 and the reaction mixture was heated under microwave irradiation at 80°C for 80 min. Purification by flash column chromatography (silica, eluting with 7% MeOH in DCM) afforded the title compounds as a racemic mixture (0.1 g, 41%).

[1085] The individual isomers were separated by chiral preparative HPLC (Method 3).

[1086] Peak 1 : RT 7.64 min (Chiral HPLC Analytical Method 4), 100% ee

[1087] 1 H NMR (DMSO-d6) 5 10.24 (brs, 1 H), 9.26 (brs, 1 H), 8.66 (s, 1 H), 8.09 (s, 1 H), 7.75 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1H), 4.88-4.72 (m, 1H), 4.61-4.56 (m, 1H), 4.33-4.29 (m, 1H), 3.22-3.20 (m, 1H), 2.83-2.81 (m, 1H), 2.33 (s, 3H), 2.11-1.98 (m, 4H), 0.97-0.89 (m, 4H).

[1088] Peak 2: RT 8.46 min (Chiral HPLC Analytical Method 4), 99.17% ee

[1089] 1 H NMR (DMSO-d6) 5 10.10 (brs, 1 H), 9.23 (brs, 1 H), 8.66 (s, 1 H), 8.09 (s, 1 H), 7.75 (s, 1 H), 7.56 (d, 2H), 7.37 (t, 1H), 4.90-4.74 (m, 1H), 4.61-4.56 (m, 1H), 4.33-4.29 (m, 1H), 3.22-3.20 (m, 1H), 2.83-2.81 (m, 1H), 2.33 (s, 3H), 2.11-1.98 (m, 4H), 0.97-0.84 (m, 4H).

[1090] Example 34

[1091] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-[(1-{2-methyl-2-azaspiro[3.3]heptan-6-yl}-1 H- pyrazol-4-yl)amino]pyrimidine-5-carboxamide

[1092] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1093] In step 2, the amine used was A-14 and the reaction was heated under microwave irradiation for 80 min. Purification by reverse phase preparative HPLC (Method 9) afford the title compound as its formate salt as an off-white solid (0.025g, 13%).

[1094] LCMS (Method 2) RT 1.83 min, m / z 514.3 (MH+).

[1095] Example 35

[1096] N-(2,6-dichlorophenyl)-4-(2-methoxyethoxy)-2-{[1-(1-methylpiperidin-4-yl)-1 H-pyrazol-4-

[1097] -5-carboxamide The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions.

[1098] Step 1 used lnt-7. In step 2 the reaction mixture was heated under microwave irradiation at 80°C for 80 min. Purification by column chromatography (silica, eluting with 12% MeOH in DCM) afforded the title compound as an off-white solid (0.14 g, 57%).

[1099] 1 H NMR (VT, DMSO-d6) 5 9.82 (brs, 1 H), 9.28 (s, 1 H), 8.75 (s, 1 H), 7.93 (s, 1 H), 7.62 (s, 1 H), 7.65 (d, 2H), 7.37 (t, 1 H), 4.72-4.69 (m, 2H), 4.14-4.07 (m, 1 H), 3.81 (t, 2H), 3.31 (s, 3H), 2.87 (d, 2H), 2.24 (s, 3H), 2.15-2.09 (m, 2H), 2.01-1.95 (m, 4H).

[1100] Example 36

[1101] N-(2,6-dichlorophenyl)-4-(2-hydroxyethoxy)-2-{n-(1-methylpiperidin-4-yl)-1 H-pyrazol-4- yl1amino}pyrimidine-5-carboxamide

[1102] The title compound was prepared from Example 35 according to the scheme below:

[1103] To a stirred solution of Example 35 (0.08 g, 0.15 mmol) in DCM (4.0 mL) was added boron tribromide (1M in DCM, 0.31 mL) at 0°C. The resulting reaction mixture was allowed to stir at RT for 4 h. The reaction mixture was poured into aqueous sodium bicarbonate solution (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was purified by flash column chromatography (silica, eluting with 5% MeOH in DCM) followed by trituration with n-pentane (10 mL) to afford the title compound as an off-white solid (0.052 g, 67%).

[1104] 1 H NMR (VT, DMSO-d6) 5 9.82 (brs, 1 H), 9.29 (s, 1 H), 8.75 (s, 1 H), 7.93 (s, 1 H), 7.63 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1 H), 4.81 (s, 1 H), 4.62-4.60 (m, 2H), 4.16-4.11 (m, 1 H), 3.87- 3.86 (m, 2H), 2.92 (d, 2H), 2.33 (s, 3H), 2.21-2.19 (m, 2H), 2.04-1.92 (m, 4H). Example 37

[1105] N-(2,6-dichlorophenyl)-4-(3-hydroxycyclobutoxy)-2-{n-(Tmethylpiperidin-4-yl)-1 H- pyrazol-4-yl1amino}pyrimidine-5-carboxamide

[1106] The title compound was prepared according to the following scheme.

[1107] Step 1 : 4-chloro-N-(2,6-dichlorophenyl)-2-(methylsulfanyl)pyrimidine-5-carboxamide To a stirred solution of 4-chloro-2-(methylthio) pyrimidine-5-carbonyl chloride ( (2.0 g, 8.96 mmol) and 2,6-dichloroaniline (1.45 g, 8.96 mmol) in DCM (40 mL) was added pyridine (0.85 g, 10.76 mmol) drop wise at 0°C. The reaction mixture was allowed to stir at room temperature for 24 h. The resulting reaction mixture was poured into water (200 mL), extracted with DCM (3 x 200 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica, eluting with 20% EtOAc in hexane) to afford the title compound as yellow solid (0.46 g, 15%).

[1108] LCMS (Method 1) RT 1.88 min, m / z 347.7 (MIT). Step 2: 4-[3-(benzyloxy)cyclobutoxy]-N-(2,6-dichlorophenyl)-2-(methylsulfanyl)pyrimidine- 5-carboxamide

[1109] To stirred suspension of ethyl 4-chloro-N-(2,6-dichlorophenyl)-2-(methylthio) pyrimidine-5- carboxamide (0.5 g, 1.43 mmol) and 3-(benzyloxy) cyclobutan-1-ol (1.27 g, 7.17 mmol) in THF (10 mL, 20 vol) was added sodium bis(trimethylsilyl)amide (1 M in THF, 2.15 mL, 2.15 mmol) at 0°C. The resulting reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was quenched with aqueous ammonium chloride solution (60 mL) and extracted with EtOAc (2 x 70 mL). The combined organic layers were dried (Na2SC>4), filtered and concentrated. The residue was purified by flash column chromatography (silica, eluting with 15% EtOAc in hexane) to afford the title compound as a white solid (0.79 g, 16%).

[1110] LCMS (Method 2) RT 2.71 min, m / z 490.1 (MIT).

[1111] Step 3: 4-[3-(benzyloxy)cyclobutoxy]-N-(2,6-dichlorophenyl)-2-methanesulfinylpyrimidine- 5-carboxamide and 4-[3-(benzyloxy)cyclobutoxy]-N-(2,6-dichlorophenyl)-2- methanesulfonylpyrimidine-5-carboxamide

[1112] To a stirred solution of 4-[3-(benzyloxy)cyclobutoxy]-N-(2,6-dichlorophenyl)-2- (methylsulfanyl)pyrimidine-5-carboxamide (0.79 g, 1.61 mmol) in DCM (15.8 mL, 20 vol) was added meta-chloroperoxybenzoic acid (0.595 g, 2.42 mmol) at 0°C. The reaction mixture was allowed to stir at room temperature for 30 min. The reaction mixture was poured into aqueous sodium bicarbonate solution (200 mL) and extracted with DCM (150 mL). The combined organic layers were washed with aqueous sodium bicarbonate solution (2 x 150 mL), dried (Na2SO4) and concentrated. The resulting residue was triturated with Et20 (20 mL) to afford the title compound as a white solid (0.65 g, 77%).

[1113] Step 4: 4-[3-(benzyloxy)cyclobutoxy]-N-(2,6-dichlorophenyl)-2-{[1 -(1 -methylpiperidin-4-yl)- 1 H-pyrazol-4-yl]amino}pyrimidine-5-carboxamide

[1114] To a solution of 4-[3-(benzyloxy)cyclobutoxy]-N-(2,6-dichlorophenyl)-2- methanesulfinylpyrimidine-5-carboxamide and 4-[3-(benzyloxy)cyclobutoxy]-N-(2,6- dichlorophenyl)-2-methanesulfonylpyrimidine-5-carboxamide (0.5 g, 0.99 mmol) in I PA (10 mL) were added 1-(1-methylpiperidin-4-yl)-1 H-pyrazol-4-amine (0.213 g, 1.18 mmol) and TFA (4 to 6 drops, catalytic). The resulting reaction mixture was stirred under microwave irradiation at 80°C for 80 min. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (70 mL) and extracted with DCM (2 x 80 mL). The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was purified by column chromatography (silica, eluting with 10% MeOH in DCM) to afford the title compound as off-white solid (0.22 g, 98%).

[1115] LCMS (Method 2) RT 2.25 min, m / z 622.3 (MIT).

[1116] Step 5: N-(2,6-dichlorophenyl)-4-(3-hydroxycyclobutoxy)-2-{[1-(1-methylpiperidin-4-yl)-1 H- pyrazol-4-yl]amino}pyrimidine-5-carboxamide

[1117] To a stirred solution of 4-[3-(benzyloxy)cyclobutoxy]-N-(2,6-dichlorophenyl)-2-{[1-(1- methylpiperidin-4-yl)-1 H-pyrazol-4-yl]amino}pyrimidine-5-carboxamide (0.12 g, 0.19 mmol) in DCM (2.4 mL) was added boron tribromide (1 M in DCM, 0.6 mL, 20 vol) at 0°C. The resulting reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (60 mL) and extracted with DCM (2 x 40 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by reverse phase chromatography (C18 silica, eluting with 14% MeCN in water) followed by reverse phase preparative HPLC (Preparative HPLC Method 10) to afford the title compound as off-white solid (0.005 g, 5%).

[1118] 1 H NMR (VT, DMSO-d6, D2O shake) 5 8.68 (s, 1 H), 7.93 (s, 1 H), 7.63 (s, 1 H), 7.54 (d, 2H), 7.39 (t, 1 H), 5.02 (t, 1 H), 4.28 (brs, 1 H), 3.92 (t, 1 H), 3.17 (brs, 2H), 2.85-2.84 (m, 2H), 2.73-2.67 (m, 2H), 2.50 (s, 3H, obscured by DMSO peak), 2.16-2.00 (m, 6H).

[1119] Example 38

[1120] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1-r(4-hydroxy-1-methylpiperidin-4-yl)methyl1- 1 H-pyrazol-4-yl}amino)pyrimidine-5-carboxamide

[1121] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions. In step 2, A-16 was used and the reaction mixture was heated under microwave irradiation at 80°C for 80 min. Purification by column chromatography (silica, eluting with 20% MeOH in DCM with 0.005% ammonia solution as modifier) followed by reverse phase preparative HPLC (Preparative HPLC method 11) afforded the title compound as an off-white solid (0.015 g, 5%).

[1122] 1 H NMR (VT, DMSO-d6) 5 9.89 (s, 1 H), 9.09 (s, 1 H), 8.68 (s, 1 H), 8.06 (s, 1 H), 7.63 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.61-4.57 (m, 1 H), 4.31 (s, 1 H), 4.05 (s, 2H), 2.42-2.24 (m, 4H), 2.16 (s, 3H), 1.55-1.27 (m, 4H), 0.99-0.93 (m, 4H).

[1123] Examples 39A, 39B, 40A & 40B

[1124] 4-(cyclopropoxy)-N-(2,6-dichlorophenyl)-2-[[1-[(1S,2R)-2-hydroxycyclobutyl]pyrazol-4- yl]amino]pyrimidine-5-carboxamide (Example 39A) 4-(cyclopropoxy)-N-(2,6-dichlorophenyl)-2-[[1-[(1 R,2S)-2-hydroxycyclobutyl]pyrazol-4- yl]amino]pyrimidine-5-carboxamide (Example 39B) 4-(cyclopropoxy)-N-(2,6-dichlorophenyl)-2-[[1-[(1S,2S)-2-hydroxycyclobutyl]pyrazol-4- yl]amino]pyrimidine-5-carboxamide (Example 40A) 4-(cyclopropoxy)-N-(2,6-dichlorophenyl)-2-[[1-[(1R,2R)-2-hydroxycyclobutyl]pyrazol-4- yl]amino]pyrimidine-5-carboxamide (Example 40B),

[1125] The title compounds were prepared following General Method 1 (Scheme 4) with the following exceptions.

[1126] Step 2 uses A-17 and the reaction mixture was heated under microwave irradiation at 120°C for 80 min. Purification by column chromatography (silica, eluting with 3% MeOH in DCM) afforded the title compounds as a mixture of diastereomers. Separation by prep HPLC (Preparative HPLC Method 12) afforded two fractions, each a mixture of diastereomers.

[1127] Fraction 1 : RT 2.67 min, 48% and 2.88 min, 48% (Chiral HPLC Method 5). Fraction 2: RT 4.68 min, 48% and 6.47 min, 49% (Chiral HPLC Method 4).

[1128] Fraction 1 was further separated by chiral HPLC (Chiral Preparative HPLC Method 4) to afford the following diastereomers: Peak 1: RT 2.69 min (Chiral HPLC Method 5), 100% ee

[1129] 1H NMR (VT, DMSO-d6) 59.47 (brs, 2H), 8.68 (s, 1H), 8.04 (s, 1H), 7.68 (s, 1H), 7.53 (d, 2H), 7.33 (t, 1H), 5.42 (brs, 1H), 4.58 (brs, 1H), 4.45-4.39 (m, 1H), 4.31-4.25 (m, 1H), 2.16-2.07 (m, 2H), 1.89-1.79 (m, 1H), 1.63-1.53 (m, 1H), 0.98-0.90 (m, 4H).

[1130] Peak 2: RT 2.91 min (Chiral HPLC Method 5), 98.36% ee

[1131] 1H NMR (VT, DMSO-d6) 59.44 (brs, 2H), 8.69 (s, 1H), 8.04 (s, 1H), 7.68 (s, 1H), 7.53 (d, 2H), 7.34 (t, 1H), 5.39 (brs, 1H), 4.58 (s, 1H), 4.46-4.39 (m, 1H), 4.31-4.25 (m, 1H), 2.16- 2.07 (m, 2H), 1.89-1.79 (m, 1H), 1.63-1.53 (m, 1H), 0.98-0.90 (m, 4H).

[1132] Fraction 2 was further separated by chiral HPLC (Chiral Preparative HPLC Method 5) to afford the following diastereomers:

[1133] Peak 1: RT 5.17 min (Chiral HPLC Method 4), 100% ee

[1134] 1H NMR (VT, DMSO-d6) 59.80 (brs, 1H), 9.19 (brs, 1H), 8.68 (s, 1H), 8.15 (s, 1H), 7.67 (s, 1H), 7.52 (d, 2H), 7.31 (t, 1H), 4.96 (brs, 1H), 4.82-4.79 (m, 1H), 4.61 (s, 1H), 4.47- 4.46 (m, 1H), 2.34-2.19 (m, 3H), 1.97-1.94 (m, 1H), 0.98-0.93 (m, 4H).

[1135] Peak 2: RT 7.16 min (Chiral HPLC Method 4), 100% ee

[1136] 1H NMR (VT, DMSO-d6) 59.80 (brs, 1H), 9.21 (brs, 1H), 8.68 (s, 1H), 8.15 (s, 1H), 7.67 (s, 1H), 7.52 (d, 2H), 7.31 (t, 1H), 4.96 (brs, 1H), 4.82-4.79 (m, 1H), 4.61 (s, 1H), 4.47- 4.46 (m, 1H), 2.34-2.19 (m, 3H), 1.97-1.94 (m, 1H), 0.98-0.93 (m, 4H). carboxamide

[1137] The title compounds were prepared according to the following scheme.

[1138] Steps 1 and 2 follow General Method 1 (Scheme 4) with the exception that A-18 is used in step 2 and the reaction is heated at 80°C for 2 h. Step 3 is as described for Example 12, Scheme 5. Purification by column chromatography (silica, eluting with 5% MeOH in DCM) afforded the title compounds as a white solid (0.12 g, 74%).

[1139] 1 H NMR (VT, DMS0-d6) 5 9.87 (brs, 1 H), 9.10 (s, 1 H), 8.68 (s, 1 H), 8.0 (s, 1 H), 7.69 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.92 (brs, 1 H), 4.59-4.45 (m, 2H), 2.63-2.62 (m, 2H), 2.39- 2.37 (m, 2H), 0.99-0.90 (m, 4H).

[1140] 4-cyclobutoxy-N-(2,6-dichlorophenyl)-2- (1-methylpiperidin-4-yl)-1 H-pyrazol-4- yl1amino}pyrimidine-5-carboxamide

[1141] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1142] In step 1 , lnt-8 was used. In step 2, the reaction was heated at 80°C for 4 h.

[1143] Purification by flash column chromatography (silica, eluting with 3% MeOH in DCM) afforded the title compound as a white solid (0.069 g, 36%).

[1144] 1 H NMR (VT, DMSO-d6) 5 9.73 (brs, 1H), 9.27 (s, 1 H), 8.70 (s, 1 H), 7.94 (s, 1 H), 7.59- 7.55 (m, 3H), 7.37 (t, 1H), 5.49-5.45 (m, 1H), 4.14-4.09 (m, 1 H), 2.87 (d, 2H), 2.52-2.49 (m, 2H, obscured by water peak), 2.37-2.28 (m, 2H), 2.25 (s, 3H), 2.14 (t, 2H), 1.99-1.91 (m, 5H), 1.88-1.74 (m, 1 H).

[1145] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1-[2-(dimethylamino)ethyl]-1 H-pyrazol-4- yl}amino)pyrimidine-5-carboxamide

[1146] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1147] In step 2, the amine used was 1-(2-(dimethylamino)ethyl)-1 H-pyrazol-4-amine and the reaction mixture was stirred under microwave irradiation at 80°C for 80 min. Purification by flash column chromatography (silica, eluting with 10% MeOH in DCM) afforded the title compound as a white solid (0.1 g, 41 %).

[1148] 1 H NMR (VT, DMSO d6) 5 9.87 (brs, 1 H), 9.10 (s, 1 H), 8.68 (s, 1 H), 8.02 (s, 1 H), 7.63 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.62-4.58 (m, 1 H), 4.18 (t, 2H), 2.67 (t, 2H), 2.21 (s, 6H), 0.99-0.87 (m, 4H).

[1149] Example 46

[1150] 4-cyclopropoxy-N-(2,6-dichloro-3- i-2-{r 1 -d -methylpiperidin-4-yl)-

[1151] 1 i-5-carboxamide

[1152] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1153] In step 1 , lnt-9 was used. In step 2, the reaction mixture was stirred at 80°C for 2 h. Purification by flash column chromatography (silica, eluting with 8% MeOH in DCM) followed by reverse phase preparative HPLC (Preparative HPLC Method 13) afforded the title compound as a white solid (0.033 g, 21 %).

[1154] 1 H NMR (DMSO-d6) 5 10.54 (brs, 1 H), 10.19 (s, 1 H), 9.14 (s, 1 H), 8.64 (s, 1 H), 8.02 (s, 1 H), 7.68 (s, 1 H), 7.32 (d, 1 H), 6.96 (d, 1 H), 4.55 (brs, 1 H), 4.12 (brs, 1 H), 2.88 (brs, 2H), 2.24 (brs, 3H), 2.10 (brs, 2H), 1.97-1.91 (m, 4H), 0.98-0.89 (m, 4H).

[1155] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-r(1-{[(2R)-morpholin-2-yl1methyl}-1 H-pyrazol-4- yl)aminolpyrimidine-5-carboxamide

[1156] The title compound was prepared according to the following scheme (Scheme 6).

[1157] Scheme 6

[1158] Steps 1 and 2 follow General Method 1 (Scheme 4) with the exception that A-19 is used in step 2 and the reaction is heated at 80°C for 4 h.

[1159] Step 3 is as described for Example 11 , step 3, to afford the title compound as its hydrochloride salt as a yellow solid (0.020 g, quantitative).

[1160] 1 H NMR (VT, DMSO-d6) 5 9.96 (brs, 1 H), 9.53 (brs, 1 H), 9.12 (s, 1 H), 8.69 (s, 1 H), 8.03 (s, 1 H), 7.70 (s, 1 H), 7.55 (d, 2H), 7.36 (t, 1 H), 4.58 (brs, 1 H), 4.28-4.26 (m, 2H), 4.16- 4.14 (m, 1 H), 3.93-3.90 (m, 1 H, obscured by water peak), 3.83-3.77 (m, 1 H), 3.25-3.15 (m, 2H), 2.95 (brs, 2H), 2.77 (brs, 1 H), 0.98-0.93 (m, 4H).

[1161] Example 47B

[1162] -4- The title compound was prepared as described in Scheme 6 for Example 47A with the following exception.

[1163] In step 2, A-20 was used. The title compound was isolated as its hydrochloride salt.

[1164] 1 H NMR (VT, DMSO-d6) 5 9.94 (brs, 1H), 9.30 (brs, 2H), 9.11 (s, 1 H), 8.69 (s, 1H), 8.03 (s, 1 H), 7.69 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.59-4.58 (m, 1 H), 4.28-4.15 (m, 2H), 4.14-4.10 (m, 1 H), 3.99-3.96 (m, 1 H), 3.81-3.74 (m, 1 H), 3.25-3.16 (m, 2H), 2.96 (brs, 1 H), 2.78 (brs, 1 H), 0.98-0.91 (m, 4H).

[1165] 4-cyclobutoxy-N-(2,6-dichlorophenyl)-2-{n-(2-hydroxyethyl)-1 H-pyrazol-4- yl1amino}pyrimidine-5-carboxamide

[1166] The title compound was prepared according to the following scheme.

[1167] Steps 1 and 2 follow General Method 1 (Scheme 4) with the following exceptions:

[1168] In step 1, lnt-8 was used. In step 2, tert-butyl 4-amino-1 H-pyrazole-1 -carboxylate (0.14 g, 0.75 mmol) was used and the reaction was heated at 80°C for 12 h. Step 3 is as described for step 3, Example 11.

[1169] Step 4: 4-cyclobutoxy-N-(2,6-dichlorophenyl)-2-{[1-(2-hydroxyethyl)-1 H-pyrazol-4- yl]amino}pyrimidine-5-carboxamide

[1170] To a stirred solution of 4-cyclobutoxy-N-(2,6-dichlorophenyl)-2-[(1 H- pyrazol-4-yl)amino]pyrimidine-5-carboxamide hydrochloride (0.12 g, 0.26 mmol) in DMF (2.4 mL, 20 vol) was added potassium carbonate (0.22 g, 1.58 mmol) at room temperature. The reaction mixture was allowed to stir for 30 minutes at room temperature and 2-bromoethan-1-ol (0.04 g, 0.32 mmol) was added. The reaction mixture was stirred at 60°C for 16 h. The reaction mixture was poured into ice cold water (50 mL) and extracted with DCM (2 x 40 mL). The combined organic layers were dried (Na2SO4) concentrated in vacuo. Purification by reverse phase preparative HPLC purification (Preparative HPLC Method 14) afforded the title compound as a white solid (0.012 g, 10%).

[1171] 1 H NMR (DMSO-d6) 5 9.33 (brs, 2H), 8.68 (brs, 1 H), 7.98 (s, 1 H), 7.60-7.58 (m, 3H), 7.39 (t, 1H), 5.53-5.35 (m, 2H), 4.98 (brs, 1 H), 4.15-4.11 (m, 2H), 3.74 (brs, 2H), 2.51- 2.34 (m, 4H), 1.85-1.73 (m, 2H).

[1172] Example 49

[1173] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1-[2-(morpholin-4-yl)ethyl]-1 H-pyrazol-4- yl}amino)pyrimidine-5-carboxamide

[1174] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1175] In step 2, A-21 was used and the reaction was heated under microwave irradiation for 1 h. Purification by flash column chromatography (silica, eluting with 10% MeOH in DCM) afforded the title compound as an off-white solid (0.15 g, 75%). 1 H NMR (VT, DMSO-d6) 5 9.87 (brs, 1 H), 9.10 (s, 1 H), 8.69 (s, 1 H), 8.01 (s, 1 H), 7.66 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.61-4.58 (m, 1 H), 4.21 (t, 2H), 3.57 (t, 4H), 2.74 (t, 2H), 2.44-2.42 (m, 4H), 1.01-0.97 (m, 2H), 0.92-0.89 (m, 2H).

[1176] Example 50A

[1177] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1-[(3R)-1-methylpyrrolidin-3-yl]-1 H-pyrazol-4- yl}amino)pyrimidine-5-carboxamide

[1178] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1179] In step 2, A-22 was used and the reaction was heated at 80°C for 2 h.

[1180] Purification by flash column chromatography (silica, eluting with 7% MeOH in DCM) afforded the title compound as a white solid (0.050 g, 40%).

[1181] 1 H NMR (VT, DMSO-d6) 5 9.90 (brs, 1 H), 9.10 (s, 1 H), 8.68 (s, 1H), 8.14 (s, 1H), 7.60 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1H), 4.92-4.86 (m, 1H), 4.60-4.57 (m, 1H), 2.83-2.78 (m, 3H), 2.50-2.35 (m, 2H), 2.32 (s, 3H), 2.07-2.03 (m, 1 H), 0.98-0.92 (m, 4H).

[1182] Chiral HPLC (Method 6) RT 8.70 min, 99%ee

[1183] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1184] In step 2, A-23 was used and the reaction was heated at 80°C for 2 h.

[1185] Purification by flash column chromatography (silica, eluting with 7% MeOH in DCM) afforded the title compound as a white solid (0.060 g, 48%). 1 H NMR (DMSO-d6) 6 10.26 (s, 1 H), 9.23 (s, 1 H), 8.66 (s, 1 H), 8.24 (s, 1 H), 7.58-7.55 (m, 3H), 7.38 (t, 1 H), 4.91-4.89 (m, 1 H), 4.56 (brs, 1 H), 2.82-2.80 (m, 2H), 2.70-2.66 (m, 1 H), 2.41-2.31(m, 2H), 2.26 (s, 3H), 1.99-1.95 (m, 1 H), 0.96-0.84 (m, 4H).

[1186] Chiral HPLC (Method 6) RT 9.02 min, 99%ee

[1187] 4-cyclobutoxy-N-(2,6-dichlorophenyl)-2-{[1-(2-methoxyethyl)-1 H-pyrazol-4- yllamino}pyrimidine-5-carboxamide

[1188] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1189] In step 1 , lnt-8 was used. In step 2, 1-(2-methoxyethyl)-1 H-pyrazol-4-amine (0.11 g, 0.75 mmol) was used and the reaction was heated at 80°C for 12 h. Purification by flash column chromatography (silica, eluting with 3% MeOH in DCM) afforded the title compound as a white solid (0.070 g, 33%).

[1190] 1 H NMR (VT, DMSO-d6) 5 9.74 (brs, 1H), 9.28 (s, 1 H), 8.70 (s, 1 H), 7.92 (s, 1 H), 7.60- 7.55 (m, 3H), 7.37 (t, 1H), 5.51-5.46 (m, 1H), 4.6 (t, 2H), 3.71 (t, 2H), 3.28 (s, 3H), 2.35- 2.28 (m, 2H), 1.93-1.69 (m, 4H).

[1191] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1-[(4-fluoro-1-methylpiperidin-4-yl)methyl]-1 H- pyrazol-4-yl}amino)pyrimidine-5-carboxamide

[1192] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1193] In step 2, A-24 was used and the reaction mixture was heated under microwave irradiation at 100°C for 80 min. Purification by flash column chromatography (silica, eluting with 14% MeOH in DCM) to afforded the title compound as an off-white solid (0.08 g, 29%). 1 H NMR (VT, DMSO-d6) 6 9.92 (brs, 1 H), 9.11 (s, 1 H), 8.69 (s, 1 H), 8.03 (s, 1 H), 7.66 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.65-4.55 (m, 1 H), 4.33 (d, 2H), 2.60-2.51 (m, 2H), 2.21- 2.17 (m, 5H), 1.77-1.73 (m, 1 H), 1.68-1.59 (m, 3H), 0.98-0.89 (m, 4H).

[1194] Example 53

[1195] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-l(1-{r(2S)-4-ethylmorpholin-2-yl1methyl}-1 H- pyrazol-4-yl)aminolpyrimidine-5-carboxamide

[1196] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1197] In step 2, A-25 was used and the reaction mixture was heated under microwave irradiation at 110°C for 2 h. Purification by flash column chromatography (silica, eluting with 2% MeOH in DCM) afforded the title compound as an off-white solid (0.21 g, 76%).

[1198] 1 H NMR (VT, DMSO-d6) 5 9.88 (brs, 1 H), 9.10 (s, 1 H), 8.69 (s, 1 H), 8.02 (s, 1 H), 7.64 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.59-4.56 (m, 1 H), 4.16 (d, 2H), 3.79 (d, 2H), 3.53-3.47 (m, 1 H), 2.73-2.64 (m, 2H), 2.37-2.31 (m, 2H), 2.05-1.99 (m, 1 H), 1.79 (t, 1 H), 1.01-0.91 (m, 7H).

[1199] Chiral HPLC (Method 1) RT 2.84 min, 100%ee

[1200] Example 54

[1201] 2- (azetidin-3-yl)-1 H-pyrazol-4-yl1amino}-4-cyclopropoxy-N-(2,6- dichlorophenyl)pyrimidine-5-carboxamide

[1202] The title compound was prepared as described for Example 11 with the following exceptions.

[1203] In step 2, the amine used was tert-butyl 3-(4-amino-1 H-pyrazol-1-yl) azetidine-1- carboxylate (CAS # 1029413-51-1) (0.110 g, 0.39 mmol) and the reaction mixture was allowed to stir at 90°C for 12 h. In step 3, the reaction was worked up as follows:

[1204] The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (70 mL) and extracted with DCM (3 x 60 mL). The combined organic layers were dried (Na2SC>4) and concentrated in vacuo. The resulting residue was triturated using Et20 (10 mL), followed by purification by reverse phase preparative HPLC (Method 16) to afford the title compound as a white solid (0.049 g, 60%).

[1205] 1 H NMR (DMSO-d6) 5 10.27 (s, 1 H), 9.24 (s, 1 H), 8.65 (s, 1 H), 8.22 (s, 1 H), 7.71 (s, 1 H), 7.59-7.56 (m, 2H), 7.37 (t, 1 H), 5.17 (brs, 1 H), 4.57 (brs, 1 H), 3.83-3.77 (m, 4H), 2.51- 2.50 (m, 1 H), 1.0-0.94 (m, 4 H).

[1206] 4-cyclobutoxy-N-(2,6-dichlorophenyl)-2-[(1-{[(2S)-4-methylmorpholin-2-yl]methyl}-1 H- pyrazol-4-yl)amino]pyrimidine-5-carboxamide

[1207] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1208] In step 1 , lnt-8 was used. In step 2, the amine used was A-7 the reaction was heated under microwave irradiation at 100°C for 1.5 h.

[1209] Purification by flash column chromatography (silica, eluting with 2% MeOH in DCM) afforded the title compound as a light pink solid (0.036 g, 14%).

[1210] 1 H NMR (VT, DMSO-d6) 5 9.76 (brs, 1 H), 9.28 (s, 1 H), 8.70 (s, 1 H), 7.91 (s, 1 H), 7.58- 7.55 (m, 3H), 7.37 (t, 1 H), 5.47 (t, 1 H), 4.18-4.16 (m, 2H), 3.80 (brd, 2H), 3.52 (t, 1 H), 2.68-2.59 (m, 4H), 2.33 (m, 2H), 2.19 (s, 3H), 2.04-1.98 (m, 1 H), 1.94-1.89 (m, 1 H), 1.81- 1.70 (m, 2H).

[1211] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1212] In step 1 , I nt- 7 was used. In step 2, A-7 was used and the reaction was heated at 100°C for 3 h. Purification by flash column chromatography (silica, eluting with 5% MeOH in DCM) followed by reverse phase chromatography (C-18 silica, eluting with 27% MeCN in water) afforded the title compound as an off-white solid (0.05 g, 15%).

[1213] 1 H NMR (VT, DMSO-d6) 5 9.84 (brs, 1 H), 9.28 (s, 1 H), 8.75 (s, 1 H), 7.91 (s, 1 H), 7.60 (s, 1 H), 7.56 (d, 2H), 7.37 (t, 1 H), 4.71-4.69 (m, 2H), 4.17-4.14 (m, 2H), 3.83-3.80 (m, 4H), 3.54-3.49 (m, 1 H), 3.31 (s, 3H), 2.64-2.50 (m, 2H), 2.19 (s, 3H), 2.05-1.99 (m, 1 H), 1.79 (t, 1 H).

[1214] Chiral HPLC (Method 1) RT 2.67 min, 100%ee

[1215] Example 57

[1216] N-(2,6-dichlorophenyl)-4-(2-methoxyethoxy)-2- (1-methylazetidin-3-yl)-1 H-pyrazol-4- yl1amino}pyrimidine-5-carboxamide

[1217] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1218] In step 1 lnt-7 was used. In step 2, the amine used was A-4 and the reaction was heated under microwave irradiation at 80°C for 80 min. Purification by flash column chromatography (silica, eluting with 10% MeOH in DCM) followed by reverse phase chromatography (C-18 silica, eluting with 48% MeCN in water) afforded the title compound as a light brown solid (0.086 g, 24 %).

[1219] 1 H NMR (VT, DMSO-d6) 5 9.88 (brs, 1 H), 9.29 (s, 1 H), 8.76 (s, 1 H), 8.07 (s, 1 H), 7.67 (s, 1 H), 7.56 (d, 2H), 7.38 (t, 1 H), 4.95 (t, 1 H), 4.72 (brs, 2H), 3.82 (brs, 2H), 3.73 (t, 2H), 3.42 (t, 2H), 3.31 (s, 3H), 2.36 (s, 3H).

[1220] Example 58A

[1221] N-(2,6-dichlorophenyl)-4-CT(2R)-1-methoxypropan-2-yl1oxy}-2-CT1-(1-methylpiperidin-4-yl)-

[1222] 1 H-pyrazol-4-yl1amino}pyrimidine-5-carboxamide The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1223] In step 1, lnt-10 was used. In step 2, the reaction was stirred under microwave irradiation at 100°C for 1 h. Purification by flash column chromatography (silica, eluting with 14% MeOH in DCM) followed by trituration with Et20 afforded the title compound as a light brown solid (0.22 g, 43%).

[1224] 1 H NMR (VT, DMSO-d6) 5 9.79 (brs, 1 H), 9.21 (s, 1 H), 8.75 (s, 1 H), 7.91 (s, 1 H), 7.61 (s, 1 H), 7.56 (d, 2H), 7.37 (t, 1 H), 5.61-5.57 (m, 1 H), 4.12-4.05 (m, 1 H), 3.74-3.70 (m, 1 H), 3.64-3.60 (m, 1 H), 3.29 (s, 3H), 2.85 (d, 2H), 2.24 (s, 3H), 2.15-2.09 (m, 2H), 2.01-1.92 (m, 4H), 1.45 (d, 3H).

[1225] Chiral HPLC (Method 7) RT 11.01 min, 98.2%ee

[1226] Example 58B

[1227] N-(2,6-dichlorophenyl)-4-{[(2S)-1-methoxypropan-2-yl]oxy}-2-{[1-(1-methylpiperidin-4-yl)-

[1228] 1 H-pyrazol-4-yllamino}pyrimidine-5-carboxamide

[1229] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1230] In step 1, lnt-11 was used. In step 2, the reaction was stirred under microwave irradiation at 80°C for 80 min. Purification by flash column chromatography (silica, eluting with 10% MeOH in DCM) followed reverse phase chromatography (C18 silica, eluting with 37% MeCN in water) afforded the title compound as a light brown solid (0.14 g, 37%).

[1231] 1 H NMR (VT, DMSO-d6) 5 9.79 (brs, 1 H), 9.21 (s, 1 H), 8.75 (s, 1 H), 7.91 (s, 1H), 7.61 (s, 1 H), 7.56 (d, 2H), 7.37 (t, 1H), 5.61-5.57 (m, 1H), 4.12-4.05 (m, 1H), 3.74-3.70 (m, 1H), 3.64-3.60 (m, 1H), 3.29 (s, 3H), 2.85 (d, 2H), 2.34 (s, 3H), 2.23-1.92 (m, 6H), 1.45 (d, 3H).

[1232] Chiral HPLC (Method 7) RT 11.26 min, 90.73%ee

[1233] N-(2,6-dichlorophenyl)-4-(1-methylcyclopropoxy)-2-{[1-(1-methylpiperidin-4-yl)-1 H- pyrazol-4-yllamino}pyrimidine-5-carboxamide

[1234] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1235] In step 1, lnt-12 was used. In step 2, the reaction was stirred under microwave irradiation at 120°C for 1 h. Purification by flash column chromatography (silica, eluting with 11% MeOH in DCM) followed reverse phase preparative HPLC (Method 17) afforded the title compound as a white solid (0.045 g, 23%).

[1236] 1 H NMR (VT, DMSO-d6) 5 9.80 (brs, 1 H), 9.15 (s, 1 H), 8.69 (s, 1 H), 8.02 (s, 1 H), 7.66 (s, 1 H), 7.55 (d, 2H), 7.36 (t, 1 H), 4.12-4.07 (m, 1 H), 2.86 (brd, 2H), 2.23 (s, 3H), 2.13- 1.92 (m, 6H), 1.77 (s, 3H), 1.17 (brs, 2H), 0.88 (brs, 2H).

[1237] Example 60

[1238] -4-(propan-2-

[1239] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1240] In step 1, lnt-13 was used. In step 2, the reaction was stirred under microwave irradiation at 120°C for 1 h. Purification by flash column chromatography (silica, eluting with 7% MeOH in DCM) afforded the title compound as an off-white solid (0.1 g, 37%).

[1241] 1 H NMR (VT, DMSO-d6) 5 9.75 (brs, 1 H), 9.20 (s, 1 H), 8.73 (s, 1 H), 7.90 (s, 1H), 7.61 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1H), 5.60-5.54 (m, 1H), 4.13-4.07 (m, 1 H), 2.88 (d, 2H), 2.24 (s, 3H), 2.14-2.09 (m, 2H), 2.01-1.94 (m, 4H), 1.49 (d, 6H).

[1242] 61 -1 H-pyrazol-4-

[1243] The title compound was prepared according to the following scheme.

[1244] Steps 1 and 2 follow General Method 1 (Scheme 4) with the following exceptions:

[1245] In step 2, A-26 was used and the reaction was heated under microwave irradiation at 80°C for 1 h.

[1246] Step 3 is as described for step 3, Example 11. Purification by preparative HPLC (Method 15) afforded the title compound as a white solid (0.05 g, 41 %).

[1247] 1 H NMR (DMSO-d6) 5 9.87 (brs, 1 H), 9.10 (brs, 1 H), 8.68 (s, 1 H), 8.02 (s, 1 H), 7.64 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.61-4.58 (m, 1 H), 4.14 (t, 2H), 2.88 (brs, 2H), 2.31 (s, 3H), 0.98-0.90 (m, 4H).

[1248] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions: In step 1, lnt-14 was used. In step 2, the reaction was stirred under microwave irradiation at 120°C for 1 h. Purification by flash column chromatography (silica, eluting with 7% MeOH in DCM) followed by trituration with Et20 afforded the title compound as a light brown solid (0.080 g, 40%).

[1249] 1 H NMR (VT, DMSO-d6) 5 9.81 (brs, 1 H), 9.35 (s, 1 H), 8.73 (s, 1 H), 7.95 (s, 1 H), 7.63 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1 H), 4.14 (s, 3H), 4.13-4.11 (m, 1 H), 2.87 (brd, 2H), 2.24 (s, 3H), 2.12-2.09 (m, 2H), 2.01-1.96 (m, 4H).

[1250] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1251] In step 1, lnt-15 was used. In step 2, the reaction was stirred at 80°C for 2 h. Purification by flash column chromatography (silica, eluting with4% MeOH in DCM) afforded the title compound as a white solid (0.10 g, 38%).

[1252] 1 H NMR (VT, DMSO-d6) 5 9.77 (brs, 1 H), 9.29 (s, 1 H), 8.72 (s, 1 H), 7.91 (s, 1H), 7.62 (s, 1 H), 7.55 (d, 2H), 7.36 (t, 1 H), 4.64 (q, 2H), 4.12-4.07 (m, 1H), 2.86 (br d, 2H), 2.33 (s, 3H), 2.24-1.94 (m, 6H), 1.47 (t, 3H).

[1253] 4-(cyclopropylmethoxy)-N-(2,6-dichlorophenyl)-2-{[1-(1-methylpiperidin-4-yl)-1 H-py

[1254] 4-yl]amino}pyrimidine-5-carboxamide

[1255] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions: In step 1 , lnt-17 was used. In step 2, the reaction was stirred under microwave irradiation at 120 °C for 1 h. Purification by flash column chromatography (silica, eluting with 12% MeOH in DCM) afforded the title compound as a white solid (0.07 g, 36%)

[1256] 1 H NMR (VT, DMSO) 5 9.79 (s, 1 H), 9.34 (s, 1 H), 8.75 (s, 1 H), 7.95 (s, 1 H), 7.60 (s, 1 H), 7.57 (d, 2H), 7.38 (t, 1 H), 4.46-4.37 (m, 2H), 4.09 (br s, 1 H), 2.86 (br d, 2H), 2.19 (s, 3H), 2.08-1.91 (m, 6H), 1 .43 (br s, 1 H), 0.58-0.44 (m, 4H).

[1257] 4-cyclobutoxy-N-(2,6-dichlorophenyl)-2-({1-f(2R)-1-hydroxypropan-2-yl1-1 H-pyrazol-4- yl}amino)pyrimidine-5-carboxamide

[1258] The title compound was prepared according to the following scheme:

[1259] Steps 1 and 2 follow General Method 1 (Scheme 4) with the following exceptions:

[1260] In step 1 , lnt-8 was used.

[1261] In step 2, A-11 R was used and the reaction was heated under microwave irradiation at 120°C for 1 h.

[1262] Step 3: 4-cyclobutoxy-N-(2,6-dichlorophenyl)-2-({1-[(2R)-1-hydroxypropan-2-yl]-1 H- pyrazol-4-yl}amino)pyrimidine-5-carboxamide To a solution of methyl (R)-2-(4-((4-cyclobutoxy-5-((2,6-dichlorophenyl) carbamoyl) pyrimidin-2-yl) amino)-1 H-pyrazol-1-yl) propanoate (0.1 g, 0.20 mmol) in THF (5.0 mL, 50 vol) was added lithium aluminium hydride (1M in THF) (0.40 mL, 0.40 mmol) at 0°C under nitrogen. The resulting reaction mixture was stirred at 0°C for 30 min. The reaction mixture was quenched with aqueous sodium bicarbonate solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 70% EtOAc in hexane) followed by purification by chiral preparative HPLC (Method 7) afforded the title compound as an off-white solid (0.025 g, 26%).

[1263] 1 H NMR (VT, DMSO-d6) 5 9.74 (brs, 1H), 9.27 (s, 1 H), 8.70 (s, 1 H), 7.96 (s, 1 H), 7.59- 7.55 (m, 3H), 7.37 (t, 1H), 5.51-5.47 (m, 1H), 4.73 (s, 1 H), 4.37-4.31 (m, 1H), 3.70-3.67 (m, 2H), 2.51-2.50 (m, 2H, obscured by DMSO signal), 2.37-2.28 (m, 2H), 1.93-1.85 (m, 1 H), 1.79-1.72 (m, 1 H), 1.43 (d, 3H).

[1264] Chiral HPLC (Method 1) RT 2.73 min, 98.7%ee

[1265] Example 65B

[1266] 4-cyclobutoxy-N-(2,6-dichlorophenyl)-2-({1-f(2S)-1-hydroxypropan-2-yl1-1 H-pyrazol-4- yl}amino)pyrimidine-5-carboxamide

[1267] The title compound was prepared as described for Example 65A with the following exceptions:

[1268] In step 2, A-11S was used.

[1269] 1 H NMR (VT, DMSO-d6) 5 9.75 (brs, 1 H), 9.27 (brs, 1 H), 8.70 (s, 1H), 7.96 (s, 1H), 7.59- 7.55 (m, 3H), 7.37 (t, 1H), 5.49 (t, 1 H), 4.73 (brs, 1H), 4.37-4.33 (m, 1H), 3.69-3.67 (m, 2H), 2.51-2.50 (m, 2H, obscured by DMSO signal), 2.35-2.31 (m, 2H), 1.93-1.85 (m, 1 H), 1.76-1.69 (m, 1H), 1.43 (d, 3H).

[1270] Chiral HPLC (Method 1) RT 2.62 min, 100%ee

[1271] Example 66 N-(2,6-dichlorophenyl)-4-ethoxy-2-{[1-(1-methylazetidin-3-yl)-1 H-pyrazol-4- yllamino}pyrimidine-5-carboxamide

[1272] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1273] In step 1, I nt- 15 was used. In step 2, A-4 was used and the reaction was stirred heated at 80°C for 80 min. Purification by flash column chromatography (silica, eluting with 4% MeOH in DCM) followed by reverse phase preparative HPLC (Method 17) afforded the title compound as a white solid (0.04 g, 16%).

[1274] 1 H NMR (VT, DMSO-d6) 5 9.83 (brs, 1 H), 9.31 (s, 1 H), 8.73 (s, 1 H), 8.07 (s, 1 H), 7.66 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1 H), 4.94-4.91 (m, 1 H), 4.68-4.63 (m, 2H), 3.69 (t, 2H), 3.37 (t, 2H), 2,34 (s, 3H), 1.48 (t, 3H).

[1275] Example 67

[1276] N-(2,6-dichlorophenyl)-4-(2,2-difluoroethoxy)-2-{[1-(1-methylpiperidin-4-yl)-1 H-pyrazol-4- yllamino}pyrimidine-5-carboxamide

[1277] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1278] In step 1, lnt-18 was used. In step 2, the reaction was stirred heated at 120°C for 1 h. Purification by flash column chromatography (silica, eluting with 15% MeOH in DCM) followed by trituration with Et20 afforded the title compound as a light brown solid (0.2 g, 52%).

[1279] 1 H NMR (VT, DMSO-d6) 5 9.89 (brs, 1 H), 9.25 (s, 1 H), 8.76 (s, 1 H), 7.93 (s, 1H), 7.62 (s, 1 H), 7.56 (d, 2H), 7.38 (t, 1H), 6.52 (tt, 1 H), 4.88-4.80 (m, 2H), 4.14-4.07 (m, 1H), 2.87 (brd, 2H), 2.24 (s, 3H), 2.14 -1.93 (m, 6H).

[1280] Example 68 N-(2,6-dichlorophenyl)-4-methoxy-2-r(1-{r(2S)-4-methylmorpholin-2-yl1methyl}-1 H-pyrazol-

[1281] 4-yl)aminolpyrimidine-5-carboxamide

[1282] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1283] In step 1 , lnt-14 was used. In step 2, A-7 was used and the reaction was stirred heated under microwave irradiation at 120°C for 1 h. Purification by flash column chromatography (silica, eluting with 8% MeOH in DCM) afforded the title compound as an off-white solid (0.18 g, 66%).

[1284] 1 H NMR (VT, DMSO-d6) 5 9.83 (brs, 1 H), 9.36 (s, 1 H), 8.73 (s, 1 H), 7.95 (s, 1 H), 7.62 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1 H), 4.21-4.14 (m, 5H), 3.80 (brd, 2H), 3.54-3.49 (m, 1 H), 2.67- 2.56 (m, 2H), 2.19 (s, 3H), 2.05-2.01 (m, 1 H), 1.79 (t, 1 H).

[1285] Example 69

[1286] N-(2,6-dichlorophenyl)-4-ethoxy-2-r(1-{r(2S)-4-methylmorpholin-2-yl1methyl}-1 H-pyrazol-4- yl)aminolpyrimidine-5-carboxamide

[1287] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1288] In step 1 , lnt-15 was used. In step 2, A-7 was used and the reaction was stirred heated under microwave irradiation at 120°C for 1 h. Purification by flash column chromatography (silica, eluting with 8% MeOH in DCM) afforded the title compound as a white solid (0.16 g, 59%).

[1289] 1 H NMR (VT, DMSO-d6) 5 9.80 (brs, 1 H), 9.30 (s, 1 H), 8.72 (s, 1 H), 7.91 (s, 1 H), 7.60 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1 H), 4.64 (q, 2H), 4.21-4.11 (m, 2H), 3.81 (brd, 2H), 3.52 (t, 1 H), 2.68-2.59 (m, 2H), 2.19 (s, 3H), 2.02 (t, 1 H), 1.79 (t, 1 H), 1.47 (t, 3H).

[1290] Example 70 4-(cvclopropylmethoxy)-N-(2,6-dichlorophenyl)-2-[(1-{[(2S)-4-methylmorpholin-2- yl1methyl}-1 H-pyrazol-4-yl)aminolpyrimidine-5-carboxamide

[1291] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1292] In step 1, lnt-17 was used. In step 2, A-7 was used and the reaction was stirred heated under microwave irradiation at 120°C for 1 h. Purification by flash column chromatography (silica, eluting with 8% MeOH in DCM) afforded the title compound as a white solid (0.016 g, 12%).

[1293] 1 H NMR (VT, DMSO-d6) 5 9.80 (brs, 1 H), 9.34 (s, 1 H), 8.75 (s, 1 H), 7.91 (s, 1 H), 7.60- 7.55 (m, 3H), 7.38 (t, 1 H), 4.46 (brd, 2H), 4.15 (brs, 2H), 3.81 (brd, 2H), 3.55-3.49 (m, 1 H), 2.64-2.56 (m, 2H), 2.19 (s, 3H), 2.04-1.99 (m, 1 H), 1.78 (t, 1 H), 1.42 (brs, 1 H), 0.61- 0.46 (m, 4H).

[1294] Example 71 A

[1295] N-(2,6-dichlorophenyl)-2-({1-r(2R)-1-hydroxypropan-2-yl1-1 H-pyrazol-4-yl}amino)-4- methoxypyrimidine-5-carboxamide

[1296] The title compound was prepared as described for Example 65A with the following exceptions.

[1297] In step 1, I nt- 14 was used. In step 2, A-11 R was used and the reaction was heated under microwave irradiation at 120°C for 1 h. Purification by flash column chromatography (silica, eluting with 56% EtOAc in hexane) afforded the title compound as a light brown solid (0.28 g, 72%).

[1298] In step 3, purification by flash column chromatography (silica, eluting with 90% EtOAc in hexane) followed by purification by chiral preparative HPLC (Method 8) afforded the title compound as a white solid (0.040 g, 28%). 1 H NMR (VT, DMSO-d6) 5 9.60 (brs, 2H), 8.73 (s, 1 H), 7.96 (s, 1 H), 7.63 (s, 1 H), 7.55 (d, 2H), 7.36 (t, 1 H), 4.70 (brs, 1 H), 4.36-4.32 (m, 1 H), 4.14 (s, 3H), 3.72-3.62 (m, 2H), 1.42 (d, 3H).

[1299] Chiral HPLC (Method 8) RT 3.41 min, 100%ee

[1300] Example 71 B

[1301] N-(2,6-dichlorophenyl)-2-({1-[(2S)-1-hydroxypropan-2-yl]-1 H-pyrazol-4-yl}amino)-4- methoxypyrimidine-5-carboxamide

[1302] The title compound was prepared as described for Example 71A with the following exceptions.

[1303] In step 2, A-11S was used.

[1304] In step 3, purification by flash column chromatography (silica, eluting with 50% EtOAc in hexane) followed by purification by chiral preparative HPLC (Method 9) afforded the title compound as a white solid (0.046 g, 16%).

[1305] 1 H NMR (VT, DMSO-d6) 5 9.81 (brs, 1 H), 9.35 (s, 1 H), 8.73 (s, 1 H), 7.96 (s, 1 H), 7.63 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1 H), 4.69 (t, 1 H), 4.34-4.33 (m, 1 H), 4.14 (s, 3H), 3.70-3.64 (m, 2H), 1.41 (d, 3H).

[1306] Chiral HPLC (Method 8) RT 3.18 min, 93.14%ee

[1307] Examples 72A and 72B

[1308] 2-({1-[(1S,4S,5R)-2-Azabicyclo[2.2.1]heptan-5-yl]-1 H-pyrazol-4-l}amino)-4-cyclopropoxy- N-(2,6-dichlorophenyl)pyrimidine-5-carboxamide (Example 72A) and 2-({1-[(1S,4S,5S)-2- azabicyclo[2.2.1]heptan-5-yl]-1 H-pyrazol-4-yl}amino)-4-cyclopropoxy-N-(2,6- dichlorophenyl)pyrimidine-5-carboxamide (Example 72B)

[1309] Examples 72A and 72B were prepared according to the following scheme.

[1310] Steps 1 and 2 follow General Method 1 (Scheme 4) with the following exceptions:

[1311] In step 2, A-27 was used and the reaction was stirred 80°C for 2 h. Purification by column chromatography (silica, eluting with 40% EtOAc in hexane) afforded the title compound as a white solid (0.20 g, 51%).

[1312] LCMS (Method 1) RT 2.46 min, m / z 600.3 (MH+)

[1313] Step 3a: Chiral Separation

[1314] The boc protected diastereomers were isolated by chiral preparative HPLC (Method 10).

[1315] Fraction 1

[1316] Peak 1 : RT 6.0 min (Chiral HPLC Analytical Method 9), 100% ee

[1317] 1 H NMR (DMSO-d6) 5 10.23 (s, 1 H), 9.23 (s, 1 H), 8.67 (s, 1H), 8.07 (s, 1H), 7.70 (s, 1 H), 7.56 (d, 2H), 7.37 (t, 1 H), 4.58 (br s, 2H), 4.18 (d, 1 H), 3.20-3.07 (m, 2H), 2.63 (br s, 1 H), 2.22-1.98 (m, 3H), 1.60-1.57 (m, 1H), 1.41 (s, 9H), 0.98-0.84 (m, 4H).

[1318] Fraction 2

[1319] Peak 2: RT 6.99 min (Chiral HPLC Analytical Method 9), 96% ee

[1320] 1 H NMR (DMSO-d6) 5 10.23 (s, 1 H), 9.23 (s, 1 H), 8.65 (s, 1H), 8.07 (s, 1H), 7.70 (s, 1 H), 7.56 (d, 2H), 7.37 (t, 1 H), 4.57 (br s, 2H), 4.18 (d, 1 H), 3.21-3.07 (m, 2H), 2.64 (br s, 1 H), 2.19-1.98 (m, 3H), 1.60-1.53 (m, 1H), 1.41 (s, 9H), 1.03-0.84 (m, 4H). Step 3b: 2-({1-[(1S,4S,5R)-2-Azabicyclo[2.2.1]heptan-5-yl]-1 H-pyrazol-4-l}amino)-4- cyclopropoxy-N-(2,6-dichlorophenyl)pyrimidine-5-carboxamide and 2-({1 -[(1 S,4S,5S)-2- azabicyclo[2.2.1]heptan-5-yl]-1 H-pyrazol-4-yl}amino)-4-cyclopropoxy-N-(2,6- dichlorophenyl)pyrimidine-5-carboxamide

[1321] Fraction 1 and 2 were each individually subjected to Step 3b conditions.

[1322] Step 3b is as described for step 3, Example 11 .

[1323] Fraction 1 product:

[1324] Following step 3b fraction 1 afforded the title compound as a white solid (0.030 g, 80%). 1 H NMR (VT, DMSO-d6) 5 9.86 (br s, 1 H), 9.10 (br s, 1 H), 8.69 (s, 1 H), 8.03 (s, 1 H), 7.67 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.59 (brs, 1 H), 4.40 (brs, 1 H), 3.52 (s, 1 H), 2.84 (d, 1 H), 2.66-2.61 (m, 2H), 2.19-2.04 (m, 2H), 1.87 (d, 1 H), 1.47-1.40 (m, 2H), 0.99-0.88 (m, 4H).

[1325] Fraction 2 product:

[1326] Following step 3b fraction 2 afforded the title compound as a white solid (0.030 g, 80%). 1 H NMR (VT, DMSO-d6) 5 9.86 (br s, 1 H), 9.10 (br s, 1 H), 8.68 (s, 1 H), 8.02 (s, 1 H), 7.67 (s, 1 H), 7.55 (d, 2H), 7.36 (t, 1 H), 4.59 (br s, 1 H), 4.39-4.38 (m, 1 H), 3.49 (s, 1 H), 2.83- 2.81 (m, 1 H), 2.67-2.60 (m, 2H), 2.18-2.02 (m, 2H), 1.87-1.85 (m, 1 H), 1.41-1.36 (m, 2H), 0.99-0.88 (m, 4H).

[1327] Example 73

[1328] 4-Cyclopropoxy-N-(2,6-dichlorophenyl)-2-{[1-(1-hydroxy-2-methylpropan-2-yl)-1 H-p

[1329] 4-yl]amino}pyrimidine-5-carboxamide

[1330] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1331] In step 2, 2-(4-amino-1 H-pyrazol-1-yl)-2-methylpropan-1-ol (CAS 1462287-40-6) was used and the reaction was stirred at 80°C for 3 h. Purification by reverse phase prep HPLC (Preparative HPLC Method 19) afforded the title compound as a white solid (0.045 g, 24%). 1 H NMR (VT, DMSO-d6) 6 9.87 (brs, 1 H), 9.16 (br s, 1 H), 8.68 (s, 1 H), 8.09 (s, 1 H), 7.67 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.77 (t, 1 H), 4.62-4.59 (m, 1 H), 3.60 (d, 2H), 1.48 (s, 6H), 0.99-0.90 (m, 4H).

[1332] Example 74

[1333] N-(2,6-Dichlorophenyl)-4-{l(2R)-1-methoxypropan-2-yl1oxy}-2-{n-(1-methylazetidin-3-yl)- 1 H-pyrazol-4-yl1amino}pyrimidine-5-carboxamide

[1334] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1335] In step 1 , lnt-10 was used. In step 2, A-4 was used and the reaction was stirred at 80°C for 2 h. Purification by column chromatography (silica, eluting with 15% MeOH in DCM ) afforded the title compound as a brown solid (0.045 g, 24%).

[1336] 1 H NMR (VT, DMSO-d6) 5 9.88 (brs, 1 H), 9.23 (s, 1 H), 8.76 (s, 1 H), 8.07 (s, 1 H), 7.70 (s, 1 H), 7.57 (d, 2H), 7.40-7.37 (m, 1 H), 5.62 (s, 1 H), 5.04 (s, 1 H), 3.93 (s, 2H), 3.72-3.64 (m, 4H), 3.30 (s, 3H), 2.51 (s, 3H), 1.46 (s, 3H).

[1337] Chiral HPLC (Method 10) RT 2.47 min, 100%ee

[1338] Example 75

[1339] 4-Cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1-f(1-methylpiperidin-4-yl)methyl1-1 H-pyrazol- 4-yl}amino)pyrimidine-5-carboxamide

[1340] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1341] In step 2, A-28 was used and the reaction was stirred at 80°C for 2 h. Purification by column chromatography (silica, eluting with 10% MeOH in DCM) followed by trituration with Et20 (10 mL) afforded the title compound as a white solid (0.070 g, 26%). 1 H NMR (VT, DMSO-d6) 6 9.91 (brs, 1 H), 9.10 (s, 1 H), 8.69 (s, 1 H), 7.99 (s, 1 H), 7.68 (s, 1 H), 7.56 (d, 2H), 7.36 (t, 1 H), 4.59 (t, 1 H), 4.06 (d, 2H), 3.25 (d, 2H), 2.74 (br s, 2H), 2.61 (s, 3H), 2.04 (br s, 1 H), 1.69 (d, 2H), 1.55-1.46 (m, 2H), 0.99-0.89 (m, 4H).

[1342] N-(2,6-Dichlorophenyl)-4-(2-methoxyethoxy)-2-[(1-{[(3R)-1-methylpiperidin-3-yllmethyl}- 1 H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide

[1343] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1344] In step 1 , lnt-7 was used. In step 2, A-29 was used and the reaction was stirred at 100°C for 1 h. Purification by reverse phase column chromatography (C18 silica, eluting with 73% MeCN in water) followed by reverse phase prep HPLC (Preparative HPLC Method 22) afforded the title compound as a white solid (0.095 g, 29%).

[1345] 1 H NMR (VT, DMSO-d6) 5 9.83 (br s, 1 H), 9.28 (s, 1 H), 8.75 (s, 1 H), 7.88 (s, 1 H), 7.60 (s, 1H), 7.56 (d, 2H), 7.38 (t, 1 H), 4.70 (br t, 2H), 4.01 (d, 2H), 3.81 (t, 2H), 3.31 (s, 3H), 2.58-2.55 (m, 2H), 2.14 (s, 3H), 2.08-1.93 (m, 2H), 1.77 (t, 1H), 1.66-1.44 (m, 3H), 1.00- 0.98 (m, 1 H)

[1346] Chiral HPLC (Method 10) RT 3.02 min, 94.6%ee

[1347] N-(2,6-Dichlorophenyl)-4-(2-methoxyethoxy)-2-[(1-{[(3S)-1-methylpiperidin-3-yl]methyl}- 1 H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide

[1348] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1349] In step 1 , lnt-7 was used. In step 2, A-30 was used and the reaction was stirred at 100°C for 1 h. Purification by flash column chromatography (silica, eluting with 12% MeOH in DCM) followed by prep HPLC (Preparative HPLC Method 20) afforded the title compound as a white solid (0.043 g, 16%).

[1350] 1 H NMR (VT, DMSO-d6) 5: 9.82 (br s, 1 H), 9.27 (s, 1 H), 8.75 (s, 1 H), 7.88 (s, 1 H), 7.59- 7.55 (m, 3H), 7.37 (t, 1 H), 4.71 (t, 2H), 4.01 (d, 2H), 3.81 (t, 2H), 3.31 (s, 3H), 2.51-2.49 (m, 2H), 2.09 (s, 3H), 2.08-2.06 (m, 1 H), 1.97-1.92 (m, 1 H), 1.76 (t, 1 H), 1.66-1.45 (m, 3H), 1.01-0.97 (m, 1 H)

[1351] Example 77

[1352] N-(2,6-Dichlorophenyl)-4-{f(2R)-1-methoxypropan-2-yl1oxy}-2-r(1-{r(2S)-4- methylmorpholin-2-yl1methyl}-1 H-pyrazol-4-yl)aminolpyrimidine-5-carboxamide

[1353] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1354] In step 1 , lnt-10 was used. In step 2, A-7 was used and the reaction was stirred at 100°C for 1 h. Purification by column chromatography (silica, eluting with 4% MeOH in DCM) followed by trituration with Et2O:n-pentane (1 :1) afforded the title compound as an off- white solid (0.20 g, 58%).

[1355] 1 H NMR (VT, DMSO-d6) 5 9.81 (br s, 1 H), 9.22 (s, 1 H), 8.75 (s, 1 H), 7.89 (s, 1 H), 7.60 (s, 1 H), 7.56 (d, 2H), 7.37 (t, 1 H), 5.61-5.57 (m, 1 H), 4.17-4.14 (m, 2H), 3.82-3.79 (m, 2H), 3.74-3.70 (m, 1 H), 3.64-3.61 (m, 1 H), 3.54-3.49 (m, 1 H), 3.29 (s, 3H), 2.64-2.59 (m, 2H), 2.18 (s, 3H), 2.04-1.98 (m, 1 H), 1.78 (t, 1 H), 1.45 (d, 3H).

[1356] Chiral HPLC (Method 1) RT 2.45 min, 96.86%ee

[1357] Example 78

[1358] N-(2,6-Dichlorophenyl)-2-r(1-{r(2S)-4-ethylmorpholin-2-yl1methyl}-1 H-pyrazol-4-yl)amino1-

[1359] 4-methoxypyrimidine-5-carboxamide

[1360] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions: In Step 1, lnt-14 was used. In step 2, A-25 was used and the reaction was stirred at 120°C for 1 h. Purification by column chromatography (silica, eluting with 7% MeOH in DCM) afforded the title compound as a white solid (0.12 g, 43%).

[1361] 1 H NMR (VT, DMSO-d6): 5 9.83 (s, 1 H), 9.36 (s, 1 H), 8.73 (s, 1 H), 7.95 (s, 1 H), 7.62 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1 H), 4.17-4.13 (m, 5H), 3.84 (d, 2H), 3.54-3.52 (m, 1 H), 2.69- 2.68 (m, 2H), 2.44- 2.34 (m, 2H), 1.87-1.86 (m, 2H), 1.03 (s, 3H).

[1362] Chiral HPLC (Method 11) RT 3.03 min, >99%ee

[1363] Example 79

[1364] 2-r(1-{r(2S)-4-Cyclopropylmorpholin-2-yl1methyl}-1H-pyrazol-4-yl)amino1-N-(2,6- dichlorophenyl)-4-methoxypyrimidine-5-carboxamide

[1365] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1366] In Step 1, lnt-14 was used. In step 2, A-31 was used and the reaction was stirred at 80°C for 2 h. Purification by column chromatography (silica, eluting with 60% EtOAc in hexane) followed by prep HPLC (Preparative HPLC Method 21) afforded the title compound as a white solid (0.050 g, 17%).

[1367] 1 H NMR (VT, DMSO-d6) 5 9.83 (br s, 1 H), 9.35 (s, 1 H), 8.72 (s, 1 H), 7.94 (s, 1 H), 7.61 (s, 1H), 7.55 (d, 2H), 7.36 (t, 1 H), 5.84-5.77 (m, 1H), 5.21-5.12 (m, 2H), 4.17-4.13 (m, 5H), 3.81 (d, 2H), 3.51 (t, 1 H), 2.95 (d, 2H), 2.73-2.62 (m, 2H), 2.07 (t, 1H), 1.85 (t, 1 H).

[1368] Chiral HPLC (Method 11) RT 3.51 min, >99%ee

[1369] Example 80

[1370] N-(2,6-Dichlorophenyl)-4-(3-methoxycyclobutoxy)-2-{n-(1-methylpiperidin-4-yl)-1 H- pyrazol-4-yl1amino}pyrimidine-5-carboxamide

[1371] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1372] In Step 1 , lnt-19 was used. In step 2, purification by column chromatography (silica, eluting with 16% MeOH in DCM) afforded the title compound as a white solid (0.035 g, 55%).

[1373] 1 H NMR (VT, DMSO-d6) 5 9.73 (brs, 1 H), 9.28 (s, 1 H), 8.69 (s, 1 H), 7.93 (s, 1 H), 7.60 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1 H), 5.2-5.08 (m, 1 H), 4.17-4.16 (m, 1 H), 3.70 (t, 1 H), 3.22 (s, 3H), 2.97-2.88 (m, 4H), 2.33-2.25 (m, 7H), 2.06-2.04 (m, 4H).

[1374] Example 81A

[1375] / V-(2,6-Dichlorophenyl)-4-[(2R)-2-methoxypropoxy]-2-{[1-(1-methylpiperidin-4-yl)- 7 / 7- pyrazol-4-yllamino}pyrimidine-5-carboxamide

[1376] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1377] In Step 1 , lnt-20 was used. In step 2, the reaction was heated at 100°C for 1h.

[1378] Purification by column chromatography (silica, eluting with 12% MeOH in DCM) afforded the title compound as an off-white solid (0.12 g, 63%).

[1379] 1 H NMR (VT, DMSO-d6) 5 9.84 (brs, 1 H), 9.27 (s, 1 H), 8.75 (s, 1 H), 7.95 (s, 1 H), 7.63 (s, 1 H), 7.57 (d, 2H), 7.38 (t, 1 H), 4.54 (d, 2H), 4.17-4.14 (m, 1 H), 3.87-3.83 (m, 1 H), 3.29 (s, 3H), 2.96-2.94 (m, 2H), 2.32-2.26 (m, 5H), 2.05-2.00 (m, 4H), 2.21 (d, 3H).

[1380] Chiral HPLC (Method 12) RT 4.99 min, 97.7%ee

[1381] / V-(2,6-Dichlorophenyl)-4-[(2S)-2-methoxypropoxy]-2-{[1-(1-methylpiperidin-4-yl)- 7 / 7- pyrazol-4-yl]amino}pyrimidine-5-carboxamide

[1382] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions: In Step 1, lnt-21 was used. In step 2, the reaction was heated at 100°C for 16 h.

[1383] Purification by column chromatography (C18 silica, eluting with 34% MeCN in water) afforded the title compound as an off-white solid (0.068 g, 21%).

[1384] 1 H NMR (VT, DMSO-d6) 5 9.81 (brs, 1 H), 9.26 (s, 1 H), 8.75 (s, 1 H), 7.94 (s, 1 H), 7.62 (s, 1 H), 7.57-7.55 (m, 2H), 7.40-7.36 (m, 1 H), 4.55 (d, 2H), 4.12-4.05 (m, 1 H), 3.87-3.83 (m, 1 H), 3.29 (s, 3H), 2.87-2.84 (m, 2H), 2.23 (s, 3H), 2.13-1.95 (m, 6H), 2.22 (d, 3H).

[1385] Chiral HPLC (Method 12) RT 5.92 min, 98.9%ee

[1386] Example 82

[1387] N-(2,6-dichlorophenyl)-4-(3-methoxypropoxy)-2-{[1-(1-methylpiperidin-4-yl)-1 H-pyrazol-4- yllamino}pyrimidine-5-carboxamide

[1388] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1389] In Step 1, lnt-22 was used. In step 2, the reaction was heated at 80°C for 2 h. Purification by column chromatography (C-18 silica, eluting with 55% MeCN in water)) followed by trituration with Et20 afforded the title compound as a light brown solid (0.22 g, 49%).

[1390] 1 H NMR (VT, DMSO-d6) 5 9.79 (s, 1H), 9.35 (s, 1H), 8.74 (s, 1 H), 7.93 (s, 1 H), 7.62 (s, 1 H), 7.55 (d, 2H), 7.37 (t, 1 H), 4.65 (t, 1H), 4.11-4.06 (m, 1H), 3.54 (t, 2H), 3.16 (s, 3H), 2.85 (d, 2H), 2.22 (2, 3H), 2.14-2.06 (m, 4H), 2.03-1.92 (m, 4H).

[1391] Example 83

[1392] 4-(2-cyclopropoxyethoxy)-N-(2,6-dichlorophenyl)-2-[(1-{[(2S)-4-methylmorpholin-2- yl]methyl}-1 H-pyrazol-4-yl)amino]pyrimidine-5-carboxamide

[1393] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions: In Step 1 , lnt-23 was used. In step 2, A-7 was used and the reaction was heated at 80°C for 1 h. Purification by reverse phase preparative HPLC (Preparative HPLC Method 23) afforded the title compound as a white solid (0.08 g, 15%).

[1394] 1 H NMR (VT, DMSO-d6) 5 9.84 (brs, 1 H), 9.22 (s, 1 H), 8.75 (s, 1 H), 7.90 (s, 1 H), 7.60 (s, 1 H), 7.56 (d, 2H), 7.38 (t, 1 H), 4.69 (t, 2H), 4.17-4.14 (m, 2H), 3.91-3.89 (m, 2H), 3.82- 3.78 (m, 2H), 3.54-3.49 (m, 1 H), 3.37-3.35 (m, 1 H), 2.64-2.51 (m, 2H), 2.18 (s, 3H), 2.04- 2.01 (m, 1 H), 1.81-1.76 (m, 1 H), 0.38-0.36 (m, 4H).

[1395] 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1-[3-(dimethylamino)-2-hydroxypropyl1-1 H- pyrazol-4-yl}amino)pyrimidine-5-carboxamide

[1396] The title compound was prepared according to the following scheme:

[1397] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1398] In Step 1 , lnt-2 was used. In step 2, A-32 was used and the reaction was heated at 120°C for 2 h. Purification by column chromatography (silica, eluting with 90% EtOAc in hexane) afforded the title compound as an off-white solid (0.55 g, 57%).

[1399] Step 3: 4-cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1 -[3-(dimethylamino)-2-hydroxypropyl]- 1 H-pyrazol-4-yl}amino)pyrimidine-5-carboxamide To a solution of 2-((1-(2-((tert-butyldiphenylsilyl) oxy)-3-(dimethylamino) propyl)-1 H- pyrazol-4-yl) amino)-4-cyclopropoxy-N-(2,6-dichlorophenyl) pyrimidine-5-carboxamide (0.15 g, 0.2 mmol) in THF (7.5 mL, 50 vol) was added tetra-n-butylammonium fluoride (1 M in THF, 0.4 mL, 0.4 mmol). The resulting reaction mixture was allowed to stir at 60°C for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by reverse phase chromatography (C18 silica, eluting with 50% MeCN in water) afforded the title compound as white solid (0.015 g, 15%).

[1400] 1 H NMR (VT, DMSO-d6) 5 9.89 (brs, 1 H), 9.09 (s, 1 H), 8.68 (s, 1 H), 8.06 (s, 1 H), 7.64 (s, 1 H), 7.54 (d, 2H), 7.36 (t, 1 H), 4.60 (brs, 1 H), 4.60-4.57 (m, 1 H), 4.19 (dd, 1 H), 4.01-3.97 (m, 1 H), 3.93-3.90 (m, 1 H), 2.25 (dd, 2H), 2.20 (s, 6H), 0.97-0.94 (m, 4H).

[1401] Example 85

[1402] N-(2,6-dichlorophenyl)-4-(2-methoxyethoxy)-2-({1-n-(propan-2-yl)azetidin-3-yl1-1 H- pyrazol-4-yl}amino)pyrimidine-5-carboxamide

[1403] The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1404] In Step 1 , I nt- 7 was used. In step 2, A-33 was used and the reaction was heated at 100°C for 2 h. Purification by reverse phase chromatography (C-18 silica, eluting with 50% MeCN in water) followed by column chromatography (silica, eluting with 4% MeOH in DCM) afforded the title compound as a white solid (0.13 g, 32%).

[1405] 1 H NMR (VT, DMSO-d6) 5 9.89 (s, 1 H), 9.29 (s, 1 H), 8.76 (s, 1 H), 8.08 (s, 1 H), 7.68 (s, 1 H), 7.56 (d, 2H), 7.38 (t, 1 H), 4.96-4.93 (m, 1 H), 4.72 (t, 2H), 3.81 (t, 2H), 3.80-3.76 (m, 2H), 3.50-3.45 (m, 2H), 3.31 (s, 3H), 2.57-2.50 (m, 1 H), 0.96 (d, 6H).

[1406] Example 86

[1407] 4-(1-cyanoethoxy)-N-(2,6-dichlorophenyl)-2- (1-methylpiperidin-4-yl)-1 H-pyrazol-4- yl1amino}pyrimidine-5-carboxamide The title compound was prepared following General Method 1 (Scheme 4) with the following exceptions:

[1408] In Step 1 , lnt-24 was used. In step 2, purification by reverse phase chromatography (C18 silica, eluting with 51 % MeCN in water) followed by column chromatography (silica, eluting with 3% MeOH in DCM) and trituration with 20% Et20 in pentane to afford the title compound as an off-white solid (0.14 g, 36%)

[1409] 1 H NMR (DMSO-d6) 8 9.94 (brs, 1 H), 9.38 (s, 1 H), 8.72 (s, 1 H), 7.98 (s, 1 H), 7.64 (s, 1 H), 7.56 (d, 2H), 7.38 (dd, 1 H), 5.93 (q, 1 H), 4.14-4.06 (m, 1 H), 2.88-2.85 (m, 2H), 2.23 (s, 3H), 2.13-1.96 (m, 6H), 1.84 (d, 3H).

[1410] Example 87

[1411] 4- -1 ,3-dioxo-

[1412] 2,3-dihydro-1 H-isoindol-4- -4- -5-carboxamide

[1413] The title compound was prepared according to the following scheme (Scheme 7):

[1414] Scheme 7

[1415] Step-1 : tert-Butyl N-(3-{4-[4-({4-cyclopropoxy-5-[(2,6-dichlorophenyl)carbamoyl]pyrimidin-

[1416] 2-yl}amino)-1 H-pyrazol-1-yl]piperidin-1-yl}propyl)carbamate To a stirred solution of Example 18 hydrochloride salt (0.3 g, 0.57 mmol) and tert-butyl (3- bromopropyl) carbamate (CAS 83948-53-2, 0.19 g, 0.80 mmol) in DMF (6 mL) was added K2CO3 (0.394 g, 2.86 mmol). The reaction mixture was stirred at 80°C for 16 h. The reaction mixture was diluted with ice cold water (100 mL) and extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with ice-cold water (2 x 80 mL), dried (Na2SC>4), filtered and concentrated in vacuo. Purification by flash column chromatography (silica, eluting with 4% MeOH in DCM) afforded the title compound as a white solid (0.5 g, 68%).

[1417] LCMS (Method 1) RT 1.88 min, m / z 645.4 (MH+)

[1418] Step-2: 2-({1 -[1 -(3-Aminopropyl)piperidin-4-yl]-1 H-pyrazol-4-yl}amino)-4-cyclopropoxy-N- (2,6-dichlorophenyl)pyrimidine-5-carboxamide hydrochloride

[1419] To a stirred solution of tert-butyl N-(3-{4-[4-({4-cyclopropoxy-5-[(2,6- dichlorophenyl)carbamoyl]pyrimidin-2-yl}amino)-1 H-pyrazol-1-yl]piperidin-1- yl}propyl)carbamate (0.5 g, 0.77 mmol) in DCM (10 mL) was added 4 M HCI in 1 ,4 dioxane (4.0 mL). The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo. Trituration with Et20 afforded the title compound as light yellow solid (0.46 g, quantitative).

[1420] LCMS (Method 2) RT 1.83 min, m / z 545.2 (MH+)

[1421] Step 3: 4-Cyclopropoxy-N-(2,6-dichlorophenyl)-2-({1 -[1 -(3-{[2-(2,6-dioxopiperidin-3-yl)- 1 ,3-dioxo-2,3-dihydro-1 H-isoindol-4-yl]amino}propyl)piperidin-4-yl]-1 H-pyrazol-4- yl}amino)pyrimidine-5-carboxamide

[1422] To a stirred solution of 2-({1-[1-(3-aminopropyl)piperidin-4-yl]-1 H-pyrazol-4-yl}amino)-4- cyclopropoxy-N-(2,6-dichlorophenyl)pyrimidine-5-carboxamide hydrochloride (0.1 g, 0.17 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1 , 3-dione (CAS 835616-60-9, 0.071 g, 0.26 mmol) in DMSO (2 mL) was added DIPEA (0.133 g, 1.03 mmol). The reaction mixture was stirred under microwave irradiation at 120°C for 1 h. The reaction mixture was poured into ice cold water (10 mL). The precipitated yellow solid was filtered and dried in vacuo. Purification by flash column chromatography (silica, eluting with 4% MeOH in DCM) afforded the title compound as a yellow solid (0.015 g, 11 %). 1 H NMR (DMSO-d6) 5 11.10 (s, 1 H), 10.22 (s, 1 H), 9.23 (s, 1 H), 8.66 (s, 1 H), 8.04 (s, 1 H), 7.69 (s, 1 H), 7.59-7.56 (m, 3H), 7.38 (t, 1 H), 7.15 (d, 1 H), 7.02 (d, 1 H), 6.82 (s, 1 H), 5.06-5.04 (m, 1 H), 4.57 (brs, 1 H), 4.13-4.11 (m, 1 H), 3.35-3.33 (m, 2H), 2.98-2.96 (m, 2H), 2.86-2.82 (m, 2H), 2.06-2.02 (m, 2H), 2.06-1.99 (m, 8H), 1.76-1.74 (m, 2H), 1.01- 0.88 (m, 4H).

[1423] LCMS (Method 2) RT 1 .84 min, m / z 801 .3 (MH+)

[1424] The title compound was prepared according to the following scheme:

[1425] The title compound was prepared as described for step 3, Example 87, except using Example 18 to afford the title compound as a yellow solid (0.2 g, 42%).

[1426] 1 H-NMR (DMSO-d6) 5 10.86 (s, 1 H), 9.90 (brs, 1 H), 9.11 (s, 1 H), 8.70 (s, 1 H), 8.09 (s, 1 H), 7.73-7.69 (m, 2H), 7.54 (d, 2H), 7.40-7.34 (m, 3H), 5.08 (dd, 1 H), 4.61-4.58 (m, 1 H), 4.43-4.41 (m, 1 H), 3.85 (brd, 2H), 3.19-3.09 (m, 2H), 2.9-2.86 (m, 1 H), 2.65-2.54 (m, 2H), 2.19-2.15 (m, 4H), 2.10-2.06 (m, 1 H), 1.00-0.89 (m, 4H).

[1427] LCMS (Method 2) RT 1.68 min, m / z 744.2 (MH+) i-1 H-isoindol-4- idin-4-yll-1 H- -4- 5-carboxamide

[1428] Comparative Example Z was prepared as described for Example 87 following Scheme 7 with the following exceptions:

[1429] In step 3, 4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1 , 3-dione (CAS 2244520-92-9) was used. Purification by column chromatography (silica, eluting with 4%

[1430] MeOH in DCM) afforded the title product as a yellow solid (0.020 g, 14%).

[1431] 1 H NMR (DMSO-d6) 6 10.22 (s, 1 H), 9.22 (s, 1 H), 8.66 (s, 1 H), 8.06 (s, 1 H), 7.69 (s, 1 H), 7.562-7.56 (m, 3H), 7.38 (t, 1 H), 7.15 (d, 1 H), 7.02 (d, 1 H), 6.87 (s, 1 H), 5.11-5.08 (m, 1 H), 4.57 (s, 1 H), 4.13-4.11 (m, 1 H), 3.35-3.33 (m, 2H), 2.98-2.96 (m, 5H), 2.86-2.82 (m,

[1432] 2H), 2.41-2.411 (m, 2H), 2.01-1.96 (m, 8H), 1.76-1.74 (m, 2H), 1.01-0.88 (m, 4H).

[1433] 82 (m, 2H), 2.41-2.411 (m, 2H), 2.01-1.96 (m, 8H), 1.76-1.74 (m, 2H), 1.01-0.88 (m, 4H).

[1434] LCMS (Method 2) RT 1.90 min, m / z 815.3 (MH+)

[1435] ANALYTICAL DATA FOR SELECTED EXAMPLES

[1436]

[1437]

[1438]

[1439]

[1440]

[1441]

[1442]

[1443]

[1444]

[1445]

[1446]

[1447]

[1448]

[1449] EXAMPLE A - BIOLOGICAL ACTIVITY

[1450] (a) Determination of Wee1 inhibitory activity

[1451] The ability of compounds of the invention to inhibit Wee1 kinase was determined using the LanthaScreen® Eu Kinase Binding Assay and the protocol described below. The assay reagents were prepared as follows: Kinase Buffer contained the following components - 50mM HEPES pH7.5, 0.01% BRIJ-35, 10mM MgCI2, 1mM EGTA. Kinase / Antibody mixtures were diluted to a 2X working concentration in Kinase Buffer, to be tested at a final concentration of 5nM WEE1 kinase and 2nM Eu-Anti-GST antibody. The 4x AlexaFluor labeled Tracer 178 was prepared in Kinase Buffer, to be tested at a final concentration of 50nM.

[1452] The compounds of the examples above were screened in 1% DMSO (final) in the well over an appropriate serial dilution range.

[1453] Method:

[1454] The following components were added to white 384-well plates: 160nl of 100X test compounds in 100% DMSO; 3.84pl of Kinase Buffer; Sul of 2X Kinase / Antibody mixture;

[1455] 4pl of 4X Tracer. The plate was shaken for 30 seconds and then incubated at room temperature for 60 minutes. A fluorescence plate reader was used to read the results.

[1456] The WEE1 inhibitory activities of the compounds of the invention were tested using the protocol described above and the results are shown in the table below.

[1457] (b) Determination of effect on cell viability The ability of compounds of the invention to inhibit proliferation of cells either as a single agent, or to potentiate cell killing caused by gemcitabine when dosed in combination, was determined using the protocol described below.

[1458] HT29 cells were grown in their recommended growth media / supplements (ATCC). Cells were seeded at a concentration of 4000 cells per well into 96 well plates overnight at 37°C, 5% CO2. Cells were treated with relevant concentrations of test compound either alone or concurrently with gemcitabine for 72h. DMSO was kept constant in all wells at 0.1%. After 72h incubation at 37°C 5% CO2, viability was established using CellTiter-Glo

[1459] Reagent as per the manufacturer’s instructions (Promega). Percentage viability was calculated against the mean of the DMSO treated controls samples and IC50 values for inhibition of cell growth were calculated using GraphPad Prism software by nonlinear regression (4 parameter logistic equation). IC50s for the test compounds were determined either as a single agent or in combination with gemcitabine at different concentrations. The results of single agent and in combination with 10nM gemcitabine are shown in the table below for compounds of the invention.

[1460] (c) Wee1 degradation assay in HT29 cells

[1461] Example 87 was assessed for activity in degrading Wee1 in HT29 cells at 6 h and 24 h by western blot. The assay was carried out in the presence of 10% female bovine serum (FBS). Protocols of the western blot assay are described below:

[1462] Cell Seeding

[1463] 1. Prepare complete medium: Add FBS and appropriate additives according to the information sheet provided by the vendor. Mix gently. 2. Check the cell name, complete medium and passage number marked on the flask.

[1464] 3. Remove and discard culture medium using a vacuum pump. 4. Briefly rinse the cell layer with 0.25% (w / v) Trypsin-0.038% (w / v) EDTA solution to remove all traces of serum that contains trypsin inhibitor.

[1465] 5. Add 3.0 mL of T rypsin-EDTA solution to flask and observe cells under an inverted microscope until cell layer is dispersed.

[1466] 6. Add 8.0 mL of complete growth medium and aspirate cells by gently pipetting.

[1467] 7. Transfer the cell suspension to a centrifuge tube and centrifuge at 1000 rpm for 4 minutes.

[1468] 8. Discard the supernatant using a vacuum pump.

[1469] 9. Add appropriate volume of complete medium. Suspend the cell pellet by gently pipetting.

[1470] 10. Count the cell numbers with Vi-cell XR and adjust cells to appropriate density.

[1471] 11. Seed 3.5E6cells to 10-cm dish and place the plates in the CO2 incubator overnight.

[1472] Compound preparation

[1473] 1. Compound was provided as powder and was diluted in DMSO to 10mM starting concentration.

[1474] 2. Dilute the 10 mM stock to 3 mM, 1 mM, 0.3 mM and 0.1 mM.

[1475] 3. Add 10 pl of 1000x compounds to each dish to reach concentrations (3 pM, 1 pM, 0.3 pM and 0.1 pM) and incubate the cells for 6 hours or 24 hours.

[1476] Cell lysates preparation

[1477] 1. Remove the dishes from incubator, collect the cells into 50ml tubes and add 20 ml of ice cold PBS (without calcium, magnesium) to each tube. Spin at 1000 rpm for 5 minutes, 4 °C.

[1478] 2. Aspirate all supernatant and repeat PBS wash for two times. Remove as much PBS as possible after final wash.

[1479] 3. Prepare cell lysate as below:

[1480] 4. Cell samples were lysed with lysis buffer (1x Cell lysis buffer added protease inhibitor and phosphatase inhibitor) on ice for 10min and spinned at 15,000 rpm in an Eppendorf microfuge for 15 min at 4°C.

[1481] 5. Quantify the protein concentration using BCA kit (Thermo #23225).

[1482] Sample preparation

[1483] 1. Mix protein sample with 5x SDS-PAGE loading buffer. 2. Boil for 5 min.

[1484] 3. Cool at RT or on ice for 5 min.

[1485] 4. Flash spin to bring down condensation prior to loading gel.

[1486] Running the gel

[1487] 1. After flash spinning the samples, 30pg protein were loaded into the wells.

[1488] 2. Using SDS-PAGE running buffer.

[1489] 3. Run with constant voltage (90 V) for 2 hours.

[1490] Membrane transfer

[1491] 1. Assemble "sandwich" for Invitrogen i Blot.

[1492] 2. T ransfer for 9min using P0 program.

[1493] 3. Immerse membrane in Li-COR Intercept blocking buffer for at least 1 hour.

[1494] Antibody incubation and gel detection

[1495] 1. Incubate with primary antibody (diluted in blocking buffer) overnight at 4°C. a. GAPDH antibody # Millipore MAB374, 1 :5000 dilution b. T otal Wee1 antibody # CST 13084, 1 : 1000 dilution

[1496] 2. Wash 4 x 15 min with 0.05% Tween 20 in TBS.

[1497] 3. Incubate with secondary antibody 1:10K diluted in blocking buffer for one hour at RT.

[1498] 4. Wash 3 x 15 minutes with 0.05% Tween 20 in TBS.

[1499] 5. Detect with ODYSSEY (Li-COR).

[1500] Figures 1 and 2 illustrate western blot analysis of Wee1 levels in HT29 cells. Cells were treated with Example 87 and Comparative Example Z (in the presence of 10% FBS) according to the described assay procedure. M: Marker (Beyotime# P0069)

[1501] Figure 1 illustrates the effect at 6 h. Figure 2 illustrates the effect at 24 h. The compound concentration ranged from 0.1 pM to 3 pM.

[1502] Degradation of Wee1 was observed at all concentrations of Example 87 with the hook effect at high concentrations. No effect on Wee1 level was observed for the control, Comparative Example Z.

[1503] EXAMPLE B- PHARMACEUTICAL FORMULATIONS (i) Tablet Formulation

[1504] A tablet composition containing a compound as defined in any one of Embodiments 1.1 to 1.100 may be prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as diluent, and 3 mg magnesium stearate as a lubricant and compressing to form a tablet in known manner.

[1505] (ii) Capsule Formulation

[1506] A capsule formulation is prepared by mixing 100 mg of a compound as defined in any one of Embodiments 1.1 to 1.100 with 100 mg lactose and filling the resulting mixture into standard opaque hard gelatin capsules.

[1507] (iii) Injectable Formulation I

[1508] A parenteral composition for administration by injection can be prepared by dissolving a compound as defined in any one of Embodiments 1.1 to 1.100 in water containing 10% propylene glycol to give a concentration of active compound of 1.5 % by weight. The solution is then sterilised by filtration, filled into an ampoule and sealed.

[1509] (iv) Injectable Formulation

[1510] A parenteral composition for injection is prepared by dissolving in water a compound as defined in any one of Embodiments 1.1 to 1.100 (2 mg / ml) and mannitol (50 mg / ml), sterile filtering the solution and filling into sealable 1 ml vials or ampoules.

[1511] (v) Injectable formulation III

[1512] A formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound as defined in any one of Embodiments 1.1 to 1.100 (e.g. in a salt form) in water at 20 mg / ml. The vial is then sealed and sterilised by autoclaving.

[1513] (vi) Injectable formulation IV

[1514] A formulation for i.v. delivery by injection or infusion can be prepared by dissolving the compound as defined in any one of Embodiments 1.1 to 1.100 (e.g. in a salt form) in water containing a buffer (e.g. 0.2 M acetate pH 4.6) at 20mg / ml. The vial is then sealed and sterilised by autoclaving.

[1515] (vii) Subcutaneous Injection Formulation A composition for sub-cutaneous administration is prepared by mixing as defined in any one of Embodiments 1.1 to 1.100 with pharmaceutical grade corn oil to give a concentration of 5 mg / ml. The composition is sterilised and filled into a suitable container. (viii) Lyophilised formulation

[1516] Aliquots of formulated compound as defined in any one of Embodiments 1.1 to 1.100 are put into 50 ml vials and lyophilized. During lyophilisation, the compositions are frozen using a one-step freezing protocol at (-45 °C). The temperature is raised to -10 °C for annealing, then lowered to freezing at -45 °C, followed by primary drying at +25 °C for approximately 3400 minutes, followed by a secondary drying with increased steps if temperature to 50 °C. The pressure during primary and secondary drying is set at 80 millitor.

[1517] Equivalents

[1518] The foregoing examples are presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application.

Claims

CLAIMS1 . A compound having the formula (1):or being a salt or tautomer thereof; wherein:R1is a C1-6 hydrocarbyl group, wherein one of the carbon atoms in the hydrocarbyl group may be optionally replaced with an O or N atom, wherein the hydrocarbyl group is optionally substituted with one or more substituents selected from fluorine, methoxy, cyano, amino, methylamino, dimethylamino and hydroxyl; n is 1 , 2 or 3; each R2is independently selected from halogen, hydroxyl, cyano, C1-4 hydrocarbyl and O-C1-4 hydrocarbyl;R3is hydrogen or a group Q-R4;Q is absent or a C1-3 hydrocarbyl linker (e.g. CH2 or CH2CH2);R4is a C1-4 hydrocarbyl group or a 4-7 membered non-aromatic heterocyclic ring containing one or two heteroatom ring members selected from N, O, S and SO2, wherein the hydrocarbyl group or non-aromatic heterocyclic ring is optionally substituted with one or more substituents R5,R5is selected from halogen, hydroxyl, methoxy, amino, mono-Ci-2-alkylamino, di- Ci-2-alkylamino, acetyl, cyano, C1-3 hydrocarbyl, hydroxy-Ci-3-hydrocarbyl, methoxy-Ci-3- hydrocarbyl and a 4-8 membered non-aromatic carbocyclic or heterocyclic ring containing one or two heteroatom ring members selected from N and O, and wherein when two R5substituents are present on the same atom, these may join to form a C3-6 carbocyclic or heterocyclic non-aromatic ring;and wherein, in each substituent consisting of or containing a hydrocarbyl group, the hydrocarbyl group is selected from alkyl, alkenyl, alkynyl and cycloalkyl groups and combinations thereof.

2. A compound according to claim 1 wherein R1is cyclopropyl.

3. A compound according to claim 1 or claim 2 wherein n is 2 or 3 and each R2is independently selected from halogen.

4. A compound according to claim 1 or claim 2 wherein the compound has the formula (2):or is a salt or tautomer thereof; wherein R1and R3are as defined in claim 1 or claim 2; m is 0 or 1 ; andR2A, R2Band R2Care independently selected from hydrogen, halogen, hydroxyl and C1-4 hydrocarbyl, provided that one of R2Aand R2Bis other than hydrogen.

5. A compound according to claim 4 wherein R2A, R2Band R2Care independently selected from hydrogen, halogen and hydroxyl.

6. A compound according to claim 4 wherein m is 0, and R2Aand R2Bare both chlorine.

7. A compound according to any one of claims 1 to 6 wherein Q is absent.

8. A compound according to any one of claims 1 to 7 wherein R4is a C1-4 hydrocarbyl group or a 4-6 membered non-aromatic heterocyclic ring containing one or two heteroatom ring members selected from N and O, wherein the hydrocarbyl group or non-aromatic heterocyclic ring is optionally substituted with one or more substituents R5.

9. A compound according to any one of claims 1 to 8 wherein R4is a 4-piperidinyl group optionally substituted with one or more substituents R6.

10. A compound according to any one of claims 1 to 9 wherein R4is a 1- methylpiperidin-4-yl group.

11. A compound according to claim 1 which is the title compound of Examples 1 to 87.

12. A compound according to claim 1 which is 4-cyclopropoxy-N-(2,6-dichlorophenyl)- 2-{[1-(1-methylpiperidin-4-yl)-1 H-pyrazol-4-yl]amino}pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof.

13. A compound having the formula (4):M-L-E (4) or being a salt or tautomer thereof, wherein:M is a compound of formula (1) as defined in any one of claims 1 to 12, wherein a hydrogen atom of the compound M is replaced by the moiety L-E;L is a covalent bond or a linker group; andE is an E3 ligase engager.

14. A compound having the formula (5)or being a salt or tautomer thereof, wherein R1, R2, n and Q are as defined in any one of claims 1 to 12; L and E are as defined in claim 13; and T is a 4-7 membered non-aromatic heterocyclic ring containing one or two heteroatom ring members selected from N, O, S and SO2 optionally substituted with one or more substituents R5, as defined in any one of claims 1 to 12.

15. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 14 and a pharmaceutically acceptable excipient.

16. A compound according to any one of claims 1 to 14 for use in medicine, for example for use as a Wee1 kinase inhibitor in the treatment of cancer.

17. A method for preparing a compound according to any one of claims 1 to 12, which method comprises the reaction of a compound of the formula (10):or a protected form thereof, wherein X is a leaving group, such as -SOCH3, -SO2CH3, halogen or a sulfonate (e.g. mesylate or tosylate), with a compound of the formula (11):or a protected form thereof; and thereafter optionally: a) removing any protecting group(s) present; and / or b) interconverting a compound of formula (1) or a protected derivative thereof to a further compound of formula (1) or a protected derivative thereof and optionally removing any protecting group present. wherein R1, R2, R3and n are as defined in any one of claims 1 to 10.

18. A compound having the formula (10):or being a salt or tautomer isomer thereof, wherein R1, R2, R3and n are as defined in any one of claims 1 to 10 and X is as defined in claim 15.

19. A combination of a compound according to any one of claims 1 to 14 with another therapeutic (e.g. anti-cancer) agent).

20. An invention as defined in any one of Embodiments 1 .1 to 1.100, 2.1 to 2.37, 3.1 and 4.1 to 4.12.

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