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WO2022113003A1 - Cdk inhibitors - Google Patents

Cdk inhibitors Download PDF

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Publication number
WO2022113003A1
WO2022113003A1 PCT/IB2021/060994 IB2021060994W WO2022113003A1 WO 2022113003 A1 WO2022113003 A1 WO 2022113003A1 IB 2021060994 W IB2021060994 W IB 2021060994W WO 2022113003 A1 WO2022113003 A1 WO 2022113003A1
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WIPO (PCT)
Prior art keywords
fluoro
pyridin
pyrimidin
amino
amine
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PCT/IB2021/060994
Other languages
French (fr)
Inventor
Debnath Bhuniya
Srikant Viswanadha
Swaroop Kumar Venkata Satya VAKKALANKA
Original Assignee
Rhizen Pharmaceuticals Ag
Incozen Therapeutics Pvt. Ltd.
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Publication of WO2022113003A1 publication Critical patent/WO2022113003A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention provides compounds of formula (I) which are cyclin-dependent kinase (one or more of CDK1, CDK2, CDK4, and CDK6) inhibitors (such as inhibitors of CDK2 and/or CDK 4/6), methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of diseases or disorders involving one or more of CDK1, CDK2, CDK4, and CDK6.
  • cyclin-dependent kinase one or more of CDK1, CDK2, CDK4, and CDK6
  • inhibitors such as inhibitors of CDK2 and/or CDK 4/6
  • Cyclin-dependent kinases are serine/threonine kinases whose activity depends on a regulatory subunit - a cyclin. Based on the sequence of the kinase domain, CDKs belong to the CMGC group of kinases (named for the initials of some members), along with mitogen- activated protein kinases (MAPKs), glycogen synthase kinase-3 beta (Gsk3 ), members of the dual-specificity tyrosine-regulated kinase (DYRK) family and CDK-like kinases.
  • MAPKs mitogen- activated protein kinases
  • Gsk3 glycogen synthase kinase-3 beta
  • DYRK dual-specificity tyrosine-regulated kinase
  • CDKs In related kinases such as MAPKs, substrate specificity is conferred by docking sites separated from the catalytic site, whereas CDKs are characterized by dependency on separate protein subunits that provide additional sequences required for enzymatic activity. To aid nomenclature and analysis of CDKs, proteins belonging to this family have been renamed as Cdkl through to Cdk20.
  • CDKs were first discovered by genetic and biochemical studies in model organisms such as yeasts and frogs. This work established the importance of CDKs in promoting transitions through the cell cycle. In addition, these studies showed that the catalytic subunit, the CDK, must associate with a regulatory subunit, the cyclin, whose protein levels are subject to regulation during the cell cycle (this oscillation lent these regulators their cyclin name). Since these pioneer studies conducted in the 1980s, the importance of CDKs acting as a major eukaryotic protein kinase family involved in the integration of extracellular and intracellular signals to modulate gene transcription and cell division has been clearly established. [05] The number of CDKs increased during evolution and was marked by a greater expansion of the cell-cycle related group.
  • Fungi contain 6 to 8 CDKs and 9 to 15 cyclins, whereas flies and echinodermata contain l lCDKs and 14 cyclins, and human cells have 20 CDKs and 29 cyclins.
  • Evolutionary studies suggest that CDKs fall into eight subfamilies represented by Cdkl, Cdk4 and Cdk5 (from the yeast cell-cycle-related CDKs), and Cdk7, Cdk8, Cdk9, Cdkl l and Cdk20 (functioning as transcriptional CDKs). (Marcos Malumbres, Genome Biology, 2014, 15:122).
  • Cyclin-dependent kinase 1 is the major protein kinase that drives cells into normal mitosis.
  • CDK1 is activated by binding to B-type cyclins (mainly cyclin B 1), which then phosphorylates substrates critical for entry into mitosis. Destruction of cyclin B1 provides a mechanism to rapidly inactivate CDK1 and allow the cell to exit mitosis (R.Y.C. Poon, in Encyclopedia of Cell Biology, 2016).
  • CDK1 is present throughout the cell cycle.
  • cyclin B1 accumulates and forms a complex with CDK1 after entering S phase.
  • the complex is kept inactive before mitosis by MYT1 and WEE1 through phosphorylation of CDKl Thrl4/Tyr15 .
  • the stockpile of inactive cyclin B 1-CDKl is activated abruptly by members of the CDC25 phosphatase family.
  • Cyclin B1-CDK1 catalyzes its own activation by simultaneously stimulating CDC25 activation and WEE1 inactivation (Lindqvist et ak, 2009, JCB (2009), 185 (2): 193-202).
  • This bistable system is believed to be kick-started by PLK1, initiating the activation of CDC25 and inactivation of WEE1/MYT1 (Van Vugt and Medema, Oncogene, vol. 24, pages 2844-2859 (2005)).
  • the activation of PLK1 in turn requires phosphorylation of PLKl Thr210 by Aurora A, an event that is assisted by Bora. Binding of Bora to PLK1 is stimulated by cyclin B1-CDK1 -dependent phosphorylation, creating yet another positive feedback loop in the activation of CDKl.
  • CDK1 is a major cell cycle regulator.
  • yeast cell cycle progression is controlled by a single CDK, known as Cdc28 of Saccharomyces cerevisiae and Cdc2 of Schizosaccharomyces pombe, and this binds to specific Cyclins at different stages of the cell cycle.
  • Cdc28 of Saccharomyces cerevisiae
  • Cdc2 of Schizosaccharomyces pombe
  • CDK 1 -Cyclin B1 activation leads to phosphorylation of various proteins that control chromosome condensation, nuclear envelope breakdown, and spindle assembly.
  • CDKl-Cyclin B1 is involved in this event by controlling the activity of separase, which is a protease that cleaves cohesion complexes that hold sister chromatids together.
  • CDK activating kinase The regulation of CDK1 activity is controlled at multiple levels, such as binding with its regulatory subunits (Cyclin A and B), interactions with Cyclin- dependent kinase inhibitors (CKIs), and phosphorylation and dephosphorylation of specific residues by the activating kinase CAK (CDK activating kinase) or by several inhibitor kinases including Weel and Mytl or phosphatase Cdc25. See also Brown etal, Nat Commun., 6, 6769 ( 2015 X
  • CDK2 overexpression is associated with abnormal cell cycle regulation, and CDK2 /Cyclin E is involved in the regulation of cell cycle G1 to S phase.
  • the CDK2 /Cyclin E complex can also catalyze the phosphorylation of Rb, thereby promoting the progression of the cell cycle from the G1 phase to the S phase; in the S phase, the CDK2 /cyclin A complex can promote the DNA replication process.
  • Cyclin E corresponding to CDK2 is commonly seen in tumors.
  • Cyclin El are related to the poor prognosis of ovarian cancer, gastric cancer, and breast cancer. Nakayama et al, Cancer, 2010, 116:2621-34); Etemadmoghadam et al, Clin cancer res, 2013, 19:5960-71; Au-Yeung et al, Clin. Cancer Res. 2017, 30:297-303); Ooi et al., Hum Pathol., 2017, 61:58-67; Noske et al, Oncotarget, 2017, 8: 14794-14805. Cyclin E2 overexpression is associated with breast cancer resistance to endocrine therapy and inhibits CDK2 cells that are resistant to tamoxifen.
  • CDKs 1 and 2 in complexes with cyclins E, A, and B, drive cell cycle progression through S phase and M phase (mitosis), the cyclin D-dependent CDKs act during G 1 phase to propel quiescent cells that have entered the cell cycle, or proliferating cells that have completed mitosis, toward S phase.
  • CDK4 is a surprisingly fastidious enzyme that has a restricted propensity to phosphorylate the retinoblastoma protein (RBI, hereafter RB) and two other RB-family proteins [RB2 (pl30), RBLl (pl07)], but very few other substrates.
  • RB is a canonical tumor-suppressor gene in retinoblastoma and in many other cancers as well.
  • the RB protein undergoes periodic phosphorylation as cells traverse the division cycle.
  • RB is dephosphorylated as cells exit mitosis, and the hypophosphorylated form detected in G 1 phase becomes hyperphosphorylated (inactivated) in late G1 and remains so throughout progression through S phase to mitosis.
  • hypophosphorylated (active) RB to restrict proliferation and act as a potent tumor-suppressor gene was highlighted by studies indicating that RB’s growth-suppressive function could be inactivated by its binding to DNA tumor virus oncoproteins (human papillomavirus E7, adenovirus E1A, and SV40 T antigen;).
  • DNA tumor virus oncoproteins human papillomavirus E7, adenovirus E1A, and SV40 T antigen;
  • CDK4/6-mediated RB phosphorylation was first detected in mid-G 1 phase after induction of cyclin D but prior to activation of cyclin E- and A-dependent CDK2.
  • CDK4 (INK4)-retinoblastoma (Rb) pathway regulates cellular proliferation by controlling the Gl (pre-DNA synthesis) to S (DNA synthesis) cell cycle checkpoint. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway is frequently observed in cancer and contributes to cell cycle progression and continued growth. CDK4/6 mediates the transition from Gl to S phase by associating with D-type cyclins and regulating the phosphorylation state of Rb. Unphosphorylated Rb binds and represses the function of E2 family (E2F) transcription factors; upon phosphorylation, Rb dissociates from E2F transcription factors, freeing them to be able to participate in DNA replication and cell division.
  • E2F E2 family
  • Increased cyclin D-CDK4/6 activity which promotes phosphorylation of Rb, can occur through several mechanisms, including overexpression of D-type cyclins, mutation or amplification of CDK4/6, or loss of cyclin D- CDK4/6 negative regulators such as pl6INK4A, and ultimately leads to cancer cell growth.
  • overexpression of D-type cyclins mutation or amplification of CDK4/6
  • loss of cyclin D- CDK4/6 negative regulators such as pl6INK4A
  • CDK4 and CDK6 play key roles in mammalian cell proliferation, where they help to drive the progression of cells into the DNA synthetic (S) phase of the cell-division cycle.
  • S DNA synthetic phase of the cell-division cycle.
  • CDKs 1 and 2 which act later in the cell cycle in response to periodic oscillations of cyclins E, A, and B to coordinate DNA replication with mitosis
  • the enzymatic activities of CDK4 and CDK6 in the first gap phase (Gl) of the cycle are governed by D-type cyclins expressed in response to various extracellular signals, including stimulatory mitogens, inhibitory cytokines, differentiation inducers, cell-cell contacts, and other spatial cues.
  • the three D-type cyclins (Dl, D2, and D3) are differentially expressed, alone or in combination, in distinct cell lineages, where they assemble with CDK4 and CDK6 to form enzymatically active holoenzyme complexes.
  • An understanding of how the three different D-type cyclins act as environmental sensors in responding dynamically to extracellular cues in various cell types helps to explain how CDK4/6 activities are differentially regulated and predicts the basis of functional interactions between mitogen signaling pathways and CDK4/6 activity in both normal and cancer cells. More than two decades after discovery of CDK4 and CDK6, drugs inhibiting their activities are now demonstrating significant efficacy in cancer treatment.
  • the CDK4/6 inhibitors act at the Gl-to-S cell cycle checkpoint. This checkpoint is tightly controlled by the D-type cyclins and CDK4 and CDK6. When CDK4 and CDK6 are activated by D-type cyclins, they phosphorylate the retinoblastoma-associated protein (pRb). This releases pRb’s suppression of the E2F transcription factor family and ultimately allows the cell to proceed through the cell cycle and divide. In HR+ breast cancer, cyclin D overexpression is common and loss of pRb is rare, making the Gl-to-S checkpoint an ideal therapeutic target. The CDK4/6 inhibitors prevent progression through this checkpoint, leading to cell cycle arrest.
  • pRb retinoblastoma-associated protein
  • HR+/HER2- advanced breast cancer involves sequencing endocrine therapy, targeted therapy, and/or chemotherapy to prolong patients’ lives, delay disease progression, and minimize cancer-related symptoms.
  • the cyclin- dependent kinase 4 and 6 (CDK4/6) inhibitors are rapidly transforming this treatment landscape.
  • CDK4/6 inhibitors There are currently three CDK4/6 inhibitors that have been approved by the U.S. Food and Drug Administration: Palbociclib, Ribociclib, and Abemaciclib.
  • the CDK4/6 inhibitors as a class are generally well tolerated.
  • the most common class wide adverse effects include nausea, diarrhea, fatigue, neutropenia, leukopenia, anemia, and thrombocytopenia.
  • Palbociclib and ribociclib most commonly cause neutropenia, while diarrhea is the unique gastrointestinal (GI) toxicity that is associated with abemaciclib, perhaps because of its greater affinity for CDK4 over CDK6.
  • GI gastrointestinal
  • FDA Food and Drug Administration
  • Patent literature related to CDK inhibitors includes and are not limited to International Publication Nos. WO 2000/064900, WO 2000/035908, WO 2004/031158, WO 2004/046130, WO 2004/101549, WO 2005/111019, WO 2006/105386, WO 2006/040050, WO 2006/040036, WO 2006/002828, WO 2006/040052, WO 2018/033815, WO 2020/223558, WO 2020/205560, WO 2020/180959, WO 2020/168197, WO 2020/157652, WO 2020/223469, WO 2021/072232, WO 2021/030537, WO 2021/170076, WO 2021/073593, WO 2019/161224, WO 2019/148161, WO 2019/170055, WO 2019/222521, WO 2019/035008, WO 2018/106870, WO 2018/108167, WO 2018/113771, WO 2018/045957, WO 2018/0459
  • CDK inhibitors having activity on CDK1, CDK2 and/or CDK4/6 (such as on CDK2 and/or CDK4/6) for the treatment of various diseases and disorders associated with cell proliferation such as cancer.
  • the present invention relates to compounds of formula (I), methods for their preparation, pharmaceutical compositions containing them, and methods of treatment with them.
  • the compounds of formula (I) and their pharmaceutically acceptable salts thereof are useful in the treatment, prevention and/or amelioration of diseases or disorders associated with CDK1, CDK2 and/or CDK4/6.
  • the present invention relates to a compound of formula (I): or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof or pharmaceutically acceptable salt thereof, wherein
  • Y 1 is selected from CR a or N;
  • Y 2 is selected from CR b or N; with the proviso that at least one of Y 1 and Y 2 is N; each occurrence of R a , R b , R c , R d , R e , R f and R g is independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminoalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclylalkyl;
  • Y is selected from CR h or N;
  • Z is selected from CR 1 or N; with the proviso that at least one of Y and Z is N; each occurrence of R h and R 1 is independently selected from hydrogen, halogen, substituted or unsubstituted C(i-3) alkyl, or substituted or unsubstituted C(i-3) haloalkyl;
  • X 1 is selected from is CR 1 or N;
  • X 2 is selected from is CR 2 or N;
  • X 3 is selected from is CR 3 or N;
  • X 4 is selected from is CR 4 or N; each occurrence of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclylalkyl ;
  • Ring A is substituted or unsubstituted heterocyclyl ring; each occurrence of R 7 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl,
  • R z is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted heterocyclylalkyl, or substituted or unsubstituted amino, or any two of R z when bound to a common atom may be joined to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered
  • the present invention relates to a compound of formula (IA), (IB), (IC), or (ID):
  • IC (ID) or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof, or pharmaceutically acceptable salt thereof, wherein all the variables (including Ring A, L, R 5 , R 6 , R 7 , R c , R d , R e , R f , R g , Y 1 , Y 2 , and n) are as defined above in relation to compound of formula (I).
  • Representative compounds of the present invention include those specified below and pharmaceutically acceptable salts thereof. The present invention should not be construed to be limited to them.
  • Yet another embodiment of the present invention is a method for inhibiting one or more of CDK1, CDK2, CDK4 and CDK6 in a patient by administering to the patient an effective amount of at least one compound of the present invention as defined in formula (I), (IA), (IB), (IC), or (ID).
  • One embodiment is a method for inhibiting CDK2, CDK4 and CDK6 (e.g., CDK2 and CDK4/6) in a patient by administering to the patient an effective amount of at least one compound of the present invention as defined in formula (I), (IA), (IB), (IC), or (ID).
  • Yet another embodiment of the present invention is a method for treating an inflammatory, autoimmune, or proliferative disease by administering to a patientin need of such treatment an effective amount of at least one compound of the present invention.
  • the compound of the present invention is administered in an effective amount to inhibit one or more of CDK1, CDK2, CDK4, and CDK6.
  • Yet another embodiment of the present invention is a method for treating a inflammatory, autoimmune or proliferative disease (e.g., via inhibition of one or more of CDK1, CDK2, CDK4, and CDK6) by administering to a patient in need of such treatment an effective amount of at least one compound of the present invention, in combination (simultaneously or sequentially) with at least one other anti-inflammatory, immunomodulator or anti-cancer agent.
  • the compound of the present invention inhibits one or more of CDK1, CDK2, CDK4, and CDK6.
  • the compound of the present invention inhibits CDK2 and/or CDK4/6.
  • the compounds of formula (I), (IA), (IB), (IC), or (ID) and pharmaceutically acceptable esters or salts thereof can be administered for the treatment, prevention and/or amelioration of diseases or disorders associated with a CDK enzyme selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the foregoing, in particular the amelioration of diseases or disorders mediated by such a CDK enzyme, including, but not limited to, inflammatory diseases or disorders, autoimmune diseases or disorders, and cancer and other proliferative diseases or disorders.
  • a CDK enzyme selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the foregoing, in particular the amelioration of diseases or disorders mediated by such a CDK enzyme, including, but not limited to, inflammatory diseases or disorders, autoimmune diseases or disorders, and cancer and other proliferative diseases or disorders.
  • the compounds of the present invention are useful in the treatment of a variety of cancers, including, but not limited to:
  • carcinoma including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer and carcinoma of the esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;
  • lymphoid lineage • hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma;
  • hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia;
  • tumors of mesenchymal origin including fibrosarcoma and rhabdomyosarcoma;
  • tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma and schwannomas;
  • tumors including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
  • the compounds of the present invention are useful in the chemoprevention of cancer.
  • Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse.
  • the compounds described herein are also useful in inhibiting tumor angiogenesis and metastasis.
  • One embodiment of the invention is a method of inhibiting tumor angiogenesis or metastasis in a patient in need thereof by administering an effective amount of one or more compounds of the present invention.
  • the compounds of the present invention are also useful in combination (administered together or sequentially) with known anti -cancer treatments, such as for example but not limited to radiation therapy or with cytostatic, cytotoxic or anticancer agents, such as for example, but not limited to, DNA interactive agents, such as cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, docetaxel or the epothilones (for example ixabepilone), either naturally occurring or synthetic; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; anti-metabolites, such as methotrexate; other tyrosine kinase inhibitors such as Iressa and OSI-774; angiogenesis inhibitors; EGF inhibitors; VEGF inhibitors,
  • the compounds of the present invention are also useful in combination (administered together or sequentially) with one or more steroidal, anti-inflammatory drugs, non-steroidal anti-inflammatory drugs (NSAIDs) or immune selective anti-inflammatory derivatives (ImSAIDs).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • ImSAIDs immune selective anti-inflammatory derivatives
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of the present invention (such as a compound having formula (I), (IA), (IB), (IC), or (ID)) together with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may further comprise one or more of the active ingredients identified above, such as other anti cancer agents.
  • the pharmaceutical composition includes a therapeutically effective amount of one or more compounds of formula (I), (IA), (IB), (IC), or (ID).
  • Yet another embodiment is a method of treating cancer in a patient in need thereof by administering a therapeutically effective amount of a compound of the present invention.
  • the compounds of the present invention are effective for treating hematopoietic tumors of lymphoid lineage, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, acute myelogenous leukemias, chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia.
  • the compounds of the present invention are also effective for treating carcinoma of the bladder, carcinoma of the breast, carcinoma of the colon, carcinoma of the kidney, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladdercancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, squamous cell carcinoma, tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma, tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
  • Yet another embodiment is a method of treating leukemia in a patient in need thereof by administering a therapeutically effective amount of a compound of the present invention.
  • the compounds of the present invention are effective for treating carcinoma of the breast, ovarian cancer, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer or stomach cancer.
  • CDK4/6 refers to both CDK4 and CDK6.
  • inhibition at “CDK4/6” refers to inhibition (to the same or different extent) at both CDK4 and CDK6.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n- pentyl, and 1, 1-dimethylethyl (t-butyl).
  • Ci-6alkyl refers to an alkyl group as defined above having up to 6 carbon atoms. In appropriate circumstances, the term “alkyl” refers to a hydrocarbon chain radical as mentioned above which is bivalent.
  • alkenyl refers to an aliphatic hydrocarbon group containing one or more carbon-carbon double bonds and which may be a straight or branched or branched chain having about 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2- propenyl (allyl), iso-propenyl, 2-methyl- 1-propenyl, 1-butenyl, and 2-butenyl.
  • C2- 6alkenyl refers to an alkenyl group as defined above having up to 6 carbon atoms. In appropriate circumstances, the term “alkenyl” refers to a hydrocarbon group as mentioned above which is bivalent.
  • alkynyl refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having in the range of 2 to up to 12 carbon atoms (with radicals having in the range of 2 to up to 10 carbon atoms presently being preferred) e.g., ethynyl, propynyl, and butnyl.
  • C2-6 alkynyl refers to an alkynyl group as defined above having up to 6 carbon atoms.
  • alkynyl refers to a hydrocarbyl radical as mentioned above which is bivalent.
  • alkoxy unless otherwise specified, denotes an alkyl, cycloalkyl, or cycloalkylalkyl group as defined above attached via an oxygen linkage to the rest of the molecule.
  • substituted alkoxy refers to an alkoxy group where the alkyl constituent is substituted (i.e., -0-(substituted alkyl).
  • alkoxy refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy.
  • alkoxy refers to a group as mentioned above which is bivalent.
  • hydroxyalkyl or “hydroxylalkyl” means alkyl substituted with one or more hydroxyl groups, wherein the alkyl groups are as defined above.
  • examples of “hydroxyalkyl” include but are not limited to hydroxymethyl, hydroxyethyl, hydroxypropyl, propan-2 -ol and the like.
  • aminoalkyl means alkyl substituted with one or more amine group(s), wherein the alkyl groups are as defined above.
  • examples of “aminoalkyl” include but are not limited to aminomethyl, aminoethyl, 2-aminopropyl, and the like.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include perhydronaphthyl, adamantyl and norbomyl groups, bridged cyclic groups, and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
  • C3-6 cycloalkyl refers to a cycloalkyl group as defined above having up to 6 carbon atoms.
  • cycloalkylalkyl refers to a cyclic ring- containing radical containing in the range of about 3 up to 8 carbon atoms directly attached to an alkyl group which isthen attached to the main structure at any carbon from the alkyl group, such as cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • cycloalkenyl refers to cyclic ring -containing radicals containing in the range of about 3 up to 8 carbon atoms with at least one carbon-carbon double bond such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
  • cycloalkenylalkyl refers to a cycloalkenyl group directly attached to an alkyl group which is then attached to the main structure at any carbon from the alkyl group.
  • aryl refers to aromatic radicals having in the range of 6 up to 20 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H5C6H5.
  • heterocyclic ring refers to a non-aromatic 3-to- 15 -member ring radical which consists of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi-, tri- or tetracyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quatemized.
  • the heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom.
  • heterocyclyl refers to a heterocylic ring radical as defined above.
  • the heterocylcyl ring radical may be attached to the main structure at any heteroatom or carbon atom.
  • heterocyclylalkyl refers to a heterocylic ring radical as defined above directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group.
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxox
  • heteroaryl refers to an optionally substituted 5- to- 14-member aromatic ring having one or more heteroatoms selected from N, O, and S as ring atoms.
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • heterocyclic ring or “heteroaryl” radicals include, but are not limited to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl, isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, qui
  • heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom.
  • substituted heteroaryl also includes ring systems substituted with one or more oxide substituents, such as pyridinyl N-oxides.
  • heteroarylalkyl refers to a heteroaryl ring radical as defined above directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom from alkyl group.
  • cyclic ring refers to a cyclic ring containing 3 to 10 carbon atoms.
  • R l , R u and R v in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, or substituted heterocyclylalkyl ring, or any two of R l , R u and R
  • Substitution or the combinations of substituents envisioned by this invention are preferably those that result in the formation of a stable or chemically feasible compound.
  • stable refers to the compounds or the structure that are not substantially altered when subjected to conditions to allow for their production, detection and preferably their recovery, purification and incorporation into a pharmaceutical composition.
  • the substituents in the aforementioned "substituted" groups cannot be further substituted.
  • halo means fluoro, chloro, bromo or iodo.
  • haloalkyl means alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl and fluoroalkoxy include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
  • protecting group refers to a substituent that is employed to block or protect a particular functionality. Other functional groups on the compound may remain reactive.
  • an "amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino- protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxy carbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable hydroxy-protecting groups include, but are not limited to, acetyl and silyl.
  • a "carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Suitable carboxy-protecting groups include, but are not limited to, -CFhCFhSChPh, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, and nitroethyl.
  • protecting groups and their use T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
  • Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Non-limiting examples of intermediate mixtures include a mixture of isomers in a ratio of 10:90, 13:87, 17:83, 20:80, or 22:78.
  • Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques.
  • tautomers refers to compounds, which are characterized by relatively easy interconversion of isomeric forms in equilibrium. These isomers are intended to be covered by this invention.
  • “Tautomers” are structurally distinct isomers that interconvert by tautomerization.
  • “Tautomerization” is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry.
  • Prototropic tautomerization or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g.
  • tautomerization is keto-enol tautomerization.
  • keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • phenol-keto tautomerization is a specific example of phenol-keto tautomerization.
  • phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers.
  • a "leaving group or atom” is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups unless otherwise specified are halogen atoms and mesyloxy, p- nitrobenzensulphonyloxy and tosyloxy groups.
  • prodrug refers to a compound, which is an inactive precursor of a compound, converted into its active form in the body by normal metabolic processes. Prodrug design is discussed generally in Hardma, et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996). A thorough discussion is provided in Higuchi, et al., Prodrugs as Novel Delivery Systems, Vol. 14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).
  • prodrugs can be converted into a pharmacologically active form through hydrolysis of, for example, an ester or amide linkage, thereby introducing or exposing a functional group on the resultant product.
  • the prodrugs can be designed to react with an endogenous compound to form a water-soluble conjugate that further enhances the pharmacological properties of the compound, for example, increased circulatory half-life.
  • prodrugs can be designed to undergo covalent modification on a functional group with, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate. The resulting conjugate can be inactivated and excreted in the urine or rendered more potent than the parent compound.
  • esters refers to a compound, which is formed by reaction between an acid and an alcohol with elimination of water.
  • An ester can be represented by the general formula RCOOR'.
  • the instant invention also includes the compounds which differ only in the presence of one or more isotopically enriched atoms for example replacement of hydrogen with deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine; chiral bases such as alkylphenylamine, glycinol, and phenyl glycinol; salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine quaternary ammonium salts of the compounds of invention with alkyl
  • Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides (e.g., hydrochlorides), acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides (e.g., hydrochlorides), acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • cell proliferation refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.
  • co-administration encompasses administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time .
  • Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
  • the term "effective amount” or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to show the intended application including but not limited to disease treatment, as defined below.
  • the therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g. reduction of platelet adhesion and/or cell migration.
  • the amount of compound administered ranges from about 0.1 mg to 5 g, from about 1 mg to 2.0 g, from about 100 mg to 1.5 g, from about 200 mg to 1.5 g, from about 400 mg to 1.5 g, and from about 400 mg to 1.0 g.
  • treatment As used herein, “treatment,” “treating,” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • subject refers to an animal, such as a mammal, for example a human.
  • the methods described herein can be useful in both human therapeutics and veterinary applications (e.g., dogs, cats, cows, sheep, pigs, horses, goats, chickens, turkeys, ducks, and geese).
  • the patient is a mammal, and in some embodiments, the patient is human.
  • Radionuclides e.g., actinium and thorium radionuclides
  • LET low linear energy transfer
  • beta emitters conversion electron emitters
  • high-energy radiation including without limitation x-rays, gamma rays, and neutrons.
  • compositions include, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, one or more suitable diluents, fdlers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants/flavoring, carriers, buffers, stabilizers, solubilizers, and combinations thereof. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • the methods of the invention may be applied to cell populations in vivo or ex vivo.
  • “In vivo" means within a living individual, as within an animal or human or in a subject's body. In this context, the methods of the invention may be used therapeutically or prophylactically in an individual.
  • "Ex vivo " or “ In vitro ” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including but not limited to fluid or tissue samples obtained from individuals. Such samples may be obtained by methods known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof.
  • the invention may be used for a variety of purposes, including therapeutic and experimental purposes.
  • the invention may be used ex vivo or in vitro to determine the optimal schedule and/or dosing of administration of a CDK inhibitor for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental or diagnostic purposes or in the clinic to set protocols for in vivo treatment.
  • Other ex vivo uses for which the invention may be suited are described below or will become apparent to those skilled in the art.
  • the invention provides a pharmaceutical composition comprising one or more compounds of the present invention.
  • the pharmaceutical composition may include one or more additional active ingredients as described herein.
  • the pharmaceutical composition may be administered for any of the disorders described herein.
  • compositions are typically formulated to provide a therapeutically effective amount of a compound of the present invention as the active ingredient.
  • the pharmaceutical compositions contain a compound of the present invention as the active ingredient and one or more pharmaceutically acceptable carriers or excipients, such as inert solid diluents and fdlers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions.
  • the subject compounds and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.
  • Methods include administration of a compound of the present invention by itself, or in combination as described herein, and in each case optionally including one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants/flavoring, carriers, excipients, buffers, stabilizers, solubilizers, and combinations thereof.
  • the compounds or pharmaceutical composition of the present invention can be administered by any route that enables delivery of the compounds to the site of action, such as oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical administration (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation.
  • routes such as oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical administration (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation.
  • the compounds can also be administered intraadiposally or intrathecally.
  • compositions can be administered in solid, semi-solid, liquid or gaseous form, or may be in dried powder, such as lyophilized form.
  • the pharmaceutical compositions can be packaged in forms convenient for delivery, including, for example, solid dosage forms such as capsules, sachets, cachets, gelatins, papers, tablets, capsules, suppositories, pellets, pills, troches, and lozenges.
  • solid dosage forms such as capsules, sachets, cachets, gelatins, papers, tablets, capsules, suppositories, pellets, pills, troches, and lozenges.
  • the type of packaging will generally depend on the desired route of administration.
  • Implantable sustained release formulations are also contemplated, as are transdermal formulations.
  • the invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including, but not limited to, diseases associated with overexpression of one or more of CDK1, CDK2, CDK4 and CDK6 and/or due to an excess of one or more of CDK1, CDK2, CDK4 and CDK6.
  • the treatment methods provided herein comprise administering to the subject a therapeutically effective amount of a compound of the invention.
  • the present invention provides a method of treating an inflammation disorder, including autoimmune diseases in a mammal. The method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention.
  • the treatment methods of the invention are useful in the fields of human medicine and veterinary medicine.
  • the individual to be treated may be a mammal, preferably human, or another animal.
  • individuals include but are not limited to farm animals including cows, sheep, pigs, horses, and goats; companion animals such as dogs and cats; exotic and/or zoo animals; laboratory animals including mice, rats, rabbits, guinea pigs, and hamsters; and poultry such as chickens, turkeys, ducks, and geese.
  • the invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including, but not limited to, diseases associated with overexpression of one or more of CDK1, CDK2, CDK4 and CDK6 and/or due to an excess of one or more of CDK1, CDK2, CDK4 and CDK6.
  • the treatment methods provided herein comprise administering to the subject a therapeutically effective amount of a compound of the invention.
  • the present invention provides a method of treating an inflammation disorder, including autoimmune diseases in a mammal. The method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention.
  • the treatment methods of the invention are useful in the fields of human medicine and veterinary medicine.
  • the individual to be treated may be a mammal, preferably human, or another animal.
  • individuals include but are not limited to farm animals including cows, sheep, pigs, horses, and goats; companion animals such as dogs and cats; exotic and/or zoo animals; laboratory animals including mice, rats, rabbits, guinea pigs, and hamsters; and poultry such as chickens, turkeys, ducks, and geese.
  • the invention also relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • said method relates to the treatment of broad spectrum of tumors, including all solid tumors and hematological malignancies collectively referred to as cancer.
  • tumors include but are not limited to benign or malignant tumors of the brain, lung (in particular small-cell lung cancer and non-small cell lung cancer), squamous cell, bladder, gastric, pancreatic, breast, head and neck, renal, kidney, ureter, ovarian, prostate, colorectal, esophageal, testicular, gynecological (e.g., uterine sarcomas, carcinoma of the fallopian tubes, endometrial, cervix, vagina or vulva), thyroid, pancreatic, bone, skin, melanoma, uterine, ovarian, rectal, anal, colon, testicular, Hodgkin's disease, esophageal, small intestine, endocrine system (e.g., thyroid, parathyroid, or adrenal glands), sarcomas of soft tissues, urethra, penis, leukemia, lymphomas, neoplasms of the central nervous system,
  • the invention also relates to a method of treating the proliferative disease such as melanoma, lung cancer (including non-small cell lung cancer (NSCLC)), colorectal cancer (CRC), breast cancer, kidney cancer such as e.g., renal cell carcinoma (RCC), liver cancer, endometrial cancer, acute myelogenous leukemia (AML), myelodysplastic syndromes (MDS), thyroid cancer, particularly papillary thyroid cancer, pancreatic cancer, neurofibromatosis, or hepatocellular carcinoma.
  • NSCLC non-small cell lung cancer
  • CRC colorectal cancer
  • RRCC renal cell carcinoma
  • AML acute myelogenous leukemia
  • MDS myelodysplastic syndromes
  • thyroid cancer particularly papillary thyroid cancer, pancreatic cancer, neurofibromatosis, or hepatocellular carcinoma.
  • the invention also relates to a method of treating the proliferative disease such as solid tumor which includes melanoma, breast cancer, ovarian cancer, colorectal cancer, and generally gastrointestinal tract, cervix cancer, lung cancer (including small-cell lung cancer and non-small cell lung cancer), head and neck cancer, bladder cancer, prostate cancer or Kaposi's sarcoma.
  • the proliferative disease such as solid tumor which includes melanoma, breast cancer, ovarian cancer, colorectal cancer, and generally gastrointestinal tract, cervix cancer, lung cancer (including small-cell lung cancer and non-small cell lung cancer), head and neck cancer, bladder cancer, prostate cancer or Kaposi's sarcoma.
  • said method is for treating a disease selected from the group consisting of cancers mediated by one or more of CDK1, CDK2, CDK4 and CDK6 include, for example, solid tumors (e.g., breast cancer (e.g., ER+ breast cancer) and prostate cancer), leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, and myeloid leukemia), lymphoma (e.g., Burkitt's lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin's lymphoma, mantel cell lymphoma, and non-Hodgkin's lymphoma (NHL)), adrenocortical cancer, AIDS-related cancer, anal cancer, astrocytom
  • solid tumors e
  • the invention further provides methods of inhibiting a CDK enzyme selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the foregoing by contacting the CDK enzyme with an amount of a compound of the invention sufficient to inhibit the activity of the CDK enzyme.
  • the invention provides a method of inhibiting a CDK enzyme activity, where the CDK enzyme is selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the foregoing, by contacting the CDK enzyme with an amount of a compound of the invention sufficient to inhibit the activity of the CDK enzyme.
  • the invention provides a method of inhibiting a CDK enzyme activity, where the CDK enzyme is selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the foregoing. Such inhibition can take place in solution, in a cell expressing one or more CDKenzymes selected from CDK1, CDK2, CDK4, and CDK6, in a tissue comprising a cell expressing the CDK enzyme, or in an organism expressing the CDK enzyme.
  • the invention provides methods of inhibiting the CDK enzyme activity in an animal (including mammal such as humans) by contacting said animal with an amount of a compound of the invention sufficient to inhibit the activity of the CDK enzyme in said animal.
  • a compound of formula (a) (wherein X is a leaving group such as halogen) coupled with a compound of formula (b) to form a compound of formula (c).
  • a protecting group is added to a compound of formula (c) to from a compound of formula (d).
  • Compound of formula (d) is converted to compound of formula (e).
  • a compound of formula (a) (wherein X is a leaving group such as halogen) is N-arylated with a compound of formula (j) to form a compound of formula (k).
  • a compound of formula (k) is converted to a compound of formula (1) by reduction.
  • a compound of formula (a) (wherein X is a leaving group such as halogen) upon borylation with bispinacolato diboron form a compound of formula (m).
  • a compound of formula (m) can be coupled with a compound of formula (n) under Heck coupling conditions to form a compound of formula (o).
  • a compound of formula (o) is converted to form a compound of formula (p) by reduction.
  • a compound of formula (f) can be converted to a compound of formula (g) by using bis(pinacolatodiboron) and potassium acetate.
  • a compound of formula (g) can be coupled with a compound of formula (h) under Suzuki reaction conditions, for example, in the presence of a suitable base and a palladium catalyst such as Pd(dppf)2Cl2.CH2Cl2, to form a compound of formula (i).
  • a compound of formula (i) can be coupled with a compound of formula (e) or (p) under Buchwald coupling reaction conditions, for example, in the presence of a suitable base and a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0), to form a compound of formula (la) or (1).
  • a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0)
  • Illustration- 1 Illustration-3 Illustration- 1 Illustration-3:
  • a compound of formula (al) (wherein X is a leaving group such as halogen) can be coupled with a compound of formula (bl) (where LG is a leaving group) to form a compound of formula (cl).
  • a compound of formula (cl) is converted to a compound of formula (el).
  • a compound of formula (f) can be converted to a compound of formula (g) by using bis(pinacolatodiboron) and potassium acetate.
  • a compound of formula (g) can be coupled with a compound of formula (h) under Suzuki reaction conditions, for example, in the presence of a suitable base and a palladium catalyst such as PdidppfkCh.CHiCb, to form a compound of formula (i).
  • a compound of formula (i) can be coupled with a compound of formula (el) under Buchwald coupling reaction conditions, for example, in the presence of a suitable base and a Palladium catalyst such as Tris(dibenzylideneacetone)dipalladium(0), to form a compound of formula (I).
  • N,O-dimethylhydroxylamine hydrochloride (275 mg, 2.82 mmol) was dissolved in DCM, cooled to 0°C, triethylamine (627 mg, 6.2 mmol) was added and stirred for 30 min. at 0 °C.
  • a solution of the acid chloride described above in DCM (16 ml) was added slowly at 0°C. After complete addition, the reaction mixture was allowed to warm up to 25 °C and stirred for 16 h. The reaction was mixture was diluted with water and the layers separated. The aqueous layer was extracted with DCM (2*30 ml). Combined organic layers were washed successively with satd. Aq.
  • Crotonaldehyde (612 mg, 8.74 mmol) was added to a mixture of 4-Bromo-2- fluoroaniline (2.00 g, 10.5 mmol) and aqueous 6N hydrochloric acid (42.1 ml) and stirred at RT for lh.
  • Toluene (11 ml) was added and the mixture heated at 110 °C for 17 h, cooled to RT and the layers were separated. The organic layer was extracted with aq. 6N HC1 (50 ml). Combined aqueous layers were basified to pH 10-11 with aq. 10% sodium hydroxide solution and extracted into DCM (3* 100 ml).
  • Triisopropyl borate (8.1 mL, 35.0 mmol) was added dropwise at -78 °C to a solution of 2-(6-bromo-8-fluoro-2-methylquinolin-4-yl)propan-2-ol (Intermediate 29, 5.1 g, 17 mmol) in dry THF (20 mL) under nitrogen atmosphere.
  • a 2.5M solution of «-Bull in THF (8.1 mL, 35 mmol) was added dropwise to the above mixture and stirred for 2 hrs at the same temperature.
  • the mixture was brought up to RT and acidified with 2N HC1, stirred for 30 min., neutralised by the addition of aq. 10% NaOH, stirred for 20 min.
  • Triisopropyl borate (9.93 mL, 43.0 mmol) was added dropwise at -78 °C to a solution of 6-Bromo-4-(difhioromethyl)-8-fluoro-2-methylquinoline (Intermediate 34, 6.0 g, 20.7 mmol) in dry THF (215 mL) under nitrogen atmosphere.
  • a 2.5M solution of «-Bull in THF (16.1 mL, 40.3 mmol) was added dropwise to the above mixture and stirred for 2 hrs at the same temperature.
  • the mixture was brought up to RT and acidified with 2N HC1, stirred for 30 min., neutralised by the addition of aq. 10% NaOH, stirred for 20 min.
  • Triisopropyl borate (0.792 mL, 3.43 mmol) was added dropwise at -78 °C to a solution of 6-bromo-4-(difluoromethyl)-8-fluoro-2-methylquinoline (Intermediate 37, 500 mg, 1.67 mmol) in dry THF (20 mL) under nitrogen atmosphere.
  • a 2.5M solution of «-Bull in hexane (2.0 mL, 5.0 mmol) was added dropwise to the above mixture and stirred for 2 hrs at the same temperature.
  • the mixture was brought up to RT and acidified with 2N HC1, stirred for 30 min., neutralised by the addition of aq. 10% NaOH, stirred for 20 min.
  • 6-Bromo-7-fluoroquinoline was prepared as described by Fei et. al. in bioorganic & medicinal Chemistry 2016, 24(18), 4281-4290. Following the general procedure-1, the titled compound was synthesized from 6-Bromo-7-fluoroquinoline (500 mg, 2.21 mmol). After work up, crude product was purified by combi-flash using EtOAc and Petether (3:97) as eluent to obtain the titled compound as a yellow liquid (200 mg). Yield: 33 %.Yield: 33%.
  • Step-1 Cyclopropylcarboxylic acid (744 mg, 8.64 mmol) was dissolved in DCM (10 ml) and cooled to 0°C. Oxalyl chloride (1.37 g, 10.8 mmol) and DMF (0.05 ml) was added to the above solution and stirred at rt for 2 h. After 2 h, reaction mixture was distilled out to obtain cyclopropylcarbonyl chloride which can be used in the next step without further purification.
  • Step-2 Intermediate 3 (1.50 g, 7.20 mmol) and Triethylamine (1.09 g, 10.8 mmol) were dissolved in DCM (10 ml) and stirred at 0°C for 30 mins.
  • N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride [246] To a mixture of 5-fluoro-N-(5-(piperazin-l-yl)pyridin-2-yl)-4-(quinolin-3- yl)pyrimidin-2-amine (Example 12, 35 mg, 0.08 mmol) in methanol (2 mL) was added aq. 35% hydrochloric acid (30 mg, 0.81 mmol) and the mixture was stirred at rt for 30 mins.
  • Example 21A 4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine hydrochloride

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Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof as cyclin-dependent kinase inhibitors (one or more of CDK1, CDK2, CDK4, and CDK6), methods of preparing them, and pharmaceutical compositions containing them. The compounds of the present invention are useful in the treatment, prevention and/or amelioration of diseases or disorders associated with one or more of CDK1, CDK2, CDK4, and CDK6.

Description

CDK INHIBITORS
[01] This application claims the benefit of Indian Patent Application No. 202041051646, filed November 27, 2020, which is hereby incorporated by reference.
FIELD OF THE INVENTION
[02] The present invention provides compounds of formula (I) which are cyclin-dependent kinase (one or more of CDK1, CDK2, CDK4, and CDK6) inhibitors (such as inhibitors of CDK2 and/or CDK 4/6), methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of diseases or disorders involving one or more of CDK1, CDK2, CDK4, and CDK6.
BACKGROUND OF THE INVENTION
[03] Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose activity depends on a regulatory subunit - a cyclin. Based on the sequence of the kinase domain, CDKs belong to the CMGC group of kinases (named for the initials of some members), along with mitogen- activated protein kinases (MAPKs), glycogen synthase kinase-3 beta (Gsk3 ), members of the dual-specificity tyrosine-regulated kinase (DYRK) family and CDK-like kinases. In related kinases such as MAPKs, substrate specificity is conferred by docking sites separated from the catalytic site, whereas CDKs are characterized by dependency on separate protein subunits that provide additional sequences required for enzymatic activity. To aid nomenclature and analysis of CDKs, proteins belonging to this family have been renamed as Cdkl through to Cdk20.
[04] CDKs were first discovered by genetic and biochemical studies in model organisms such as yeasts and frogs. This work established the importance of CDKs in promoting transitions through the cell cycle. In addition, these studies showed that the catalytic subunit, the CDK, must associate with a regulatory subunit, the cyclin, whose protein levels are subject to regulation during the cell cycle (this oscillation lent these regulators their cyclin name). Since these pioneer studies conducted in the 1980s, the importance of CDKs acting as a major eukaryotic protein kinase family involved in the integration of extracellular and intracellular signals to modulate gene transcription and cell division has been clearly established. [05] The number of CDKs increased during evolution and was marked by a greater expansion of the cell-cycle related group. Fungi contain 6 to 8 CDKs and 9 to 15 cyclins, whereas flies and echinodermata contain l lCDKs and 14 cyclins, and human cells have 20 CDKs and 29 cyclins. Evolutionary studies suggest that CDKs fall into eight subfamilies represented by Cdkl, Cdk4 and Cdk5 (from the yeast cell-cycle-related CDKs), and Cdk7, Cdk8, Cdk9, Cdkl l and Cdk20 (functioning as transcriptional CDKs). (Marcos Malumbres, Genome Biology, 2014, 15:122).
[06] Cyclin-dependent kinase 1 (CDK1) is the major protein kinase that drives cells into normal mitosis. CDK1 is activated by binding to B-type cyclins (mainly cyclin B 1), which then phosphorylates substrates critical for entry into mitosis. Destruction of cyclin B1 provides a mechanism to rapidly inactivate CDK1 and allow the cell to exit mitosis (R.Y.C. Poon, in Encyclopedia of Cell Biology, 2016). CDK1 is present throughout the cell cycle. In contrast, cyclin B1 accumulates and forms a complex with CDK1 after entering S phase. The complex is kept inactive before mitosis by MYT1 and WEE1 through phosphorylation of CDKlThrl4/Tyr15. At the end of G2 phase, the stockpile of inactive cyclin B 1-CDKl is activated abruptly by members of the CDC25 phosphatase family. Cyclin B1-CDK1 catalyzes its own activation by simultaneously stimulating CDC25 activation and WEE1 inactivation (Lindqvist et ak, 2009, JCB (2009), 185 (2): 193-202). This bistable system is believed to be kick-started by PLK1, initiating the activation of CDC25 and inactivation of WEE1/MYT1 (Van Vugt and Medema, Oncogene, vol. 24, pages 2844-2859 (2005)). The activation of PLK1 in turn requires phosphorylation of PLKlThr210 by Aurora A, an event that is assisted by Bora. Binding of Bora to PLK1 is stimulated by cyclin B1-CDK1 -dependent phosphorylation, creating yet another positive feedback loop in the activation of CDKl.
[07] CDK1 is a major cell cycle regulator. In yeast, cell cycle progression is controlled by a single CDK, known as Cdc28 of Saccharomyces cerevisiae and Cdc2 of Schizosaccharomyces pombe, and this binds to specific Cyclins at different stages of the cell cycle. By genetic studies on mice, the systematic knockout of Cdks of the mouse germline has shown that Cdk2, Cdk4, and Cdk6 are not essential for the cell cycle of most cell types. Only elimination of Cdkl causes cell cycle arrest and embryonic lethality at the two-cell stage. CDK1 activity controls both M phase entry and exit. In G2/M transition, CDK 1 -Cyclin B1 activation leads to phosphorylation of various proteins that control chromosome condensation, nuclear envelope breakdown, and spindle assembly. At the onset of anaphase, CDKl-Cyclin B1 is involved in this event by controlling the activity of separase, which is a protease that cleaves cohesion complexes that hold sister chromatids together. The regulation of CDK1 activity is controlled at multiple levels, such as binding with its regulatory subunits (Cyclin A and B), interactions with Cyclin- dependent kinase inhibitors (CKIs), and phosphorylation and dephosphorylation of specific residues by the activating kinase CAK (CDK activating kinase) or by several inhibitor kinases including Weel and Mytl or phosphatase Cdc25. See also Brown etal, Nat Commun., 6, 6769 ( 2015 X
[08] CDK2 overexpression is associated with abnormal cell cycle regulation, and CDK2 /Cyclin E is involved in the regulation of cell cycle G1 to S phase. At the end of the G1 phase, the CDK2 /Cyclin E complex can also catalyze the phosphorylation of Rb, thereby promoting the progression of the cell cycle from the G1 phase to the S phase; in the S phase, the CDK2 /cyclin A complex can promote the DNA replication process. Asghar et al, Nat. Rev. Drug. Discov., 2015; 14(2): 130-146. Cyclin E corresponding to CDK2 is commonly seen in tumors. The amplification and overexpression of Cyclin El are related to the poor prognosis of ovarian cancer, gastric cancer, and breast cancer. Nakayama et al, Cancer, 2010, 116:2621-34); Etemadmoghadam et al, Clin cancer res, 2013, 19:5960-71; Au-Yeung et al, Clin. Cancer Res. 2017, 30:297-303); Ooi et al., Hum Pathol., 2017, 61:58-67; Noske et al, Oncotarget, 2017, 8: 14794-14805. Cyclin E2 overexpression is associated with breast cancer resistance to endocrine therapy and inhibits CDK2 cells that are resistant to tamoxifen. Caldon et al., Mol Cancer Ther., 2012, 11: 1488-99; Herrera-Abreu et al, Cancer Res., 2016, 76:2301-2313. Cyclin E amplification is also related to trastuzumab resistance in HER2-positive breast cancer. Scaltriti et al, Proc Natl Acad Sci. 2011, 108:3761-6. The presumption that D-type cyclins might allosterically regulate a novel CDK was validated by the discovery of CDK4, which was revealed to physically bind to, and be enzymatically activated by, any of the three D-type cyclins. A related cyclin D-dependent kinase, CDK6, with similar properties was identified 2 years later. Although CDKs 1 and 2, in complexes with cyclins E, A, and B, drive cell cycle progression through S phase and M phase (mitosis), the cyclin D-dependent CDKs act during G 1 phase to propel quiescent cells that have entered the cell cycle, or proliferating cells that have completed mitosis, toward S phase. Unlike CDKs 1 and 2 that phosphorylate many hundreds of cellular protein substrates, CDK4 is a surprisingly fastidious enzyme that has a restricted propensity to phosphorylate the retinoblastoma protein (RBI, hereafter RB) and two other RB-family proteins [RB2 (pl30), RBLl (pl07)], but very few other substrates.
[09] RB is a canonical tumor-suppressor gene in retinoblastoma and in many other cancers as well. The RB protein undergoes periodic phosphorylation as cells traverse the division cycle. RB is dephosphorylated as cells exit mitosis, and the hypophosphorylated form detected in G 1 phase becomes hyperphosphorylated (inactivated) in late G1 and remains so throughout progression through S phase to mitosis. The role of hypophosphorylated (active) RB to restrict proliferation and act as a potent tumor-suppressor gene was highlighted by studies indicating that RB’s growth-suppressive function could be inactivated by its binding to DNA tumor virus oncoproteins (human papillomavirus E7, adenovirus E1A, and SV40 T antigen;). In mammalian cells stimulated by mitogens to enter the division cycle from a quiescent state (GO), CDK4/6-mediated RB phosphorylation was first detected in mid-G 1 phase after induction of cyclin D but prior to activation of cyclin E- and A-dependent CDK2. Together, these results implied that the role of CDK4/6 was to phosphorylate RB, priming it for inactivation by other CDKs later in Gl, and releasing E2F transcription factors from RB constraint to allow their coordinate induction of a suite of genes whose activities are jointly required for initiation of S phase. Sherr etal., Cancer Discovery, April 2016, 6(4):353-367CD-15-0894.
[10] CDK4 (INK4)-retinoblastoma (Rb) pathway regulates cellular proliferation by controlling the Gl (pre-DNA synthesis) to S (DNA synthesis) cell cycle checkpoint. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway is frequently observed in cancer and contributes to cell cycle progression and continued growth. CDK4/6 mediates the transition from Gl to S phase by associating with D-type cyclins and regulating the phosphorylation state of Rb. Unphosphorylated Rb binds and represses the function of E2 family (E2F) transcription factors; upon phosphorylation, Rb dissociates from E2F transcription factors, freeing them to be able to participate in DNA replication and cell division. Increased cyclin D-CDK4/6 activity, which promotes phosphorylation of Rb, can occur through several mechanisms, including overexpression of D-type cyclins, mutation or amplification of CDK4/6, or loss of cyclin D- CDK4/6 negative regulators such as pl6INK4A, and ultimately leads to cancer cell growth. Thus, the development of selective CDK4/6 inhibitors offers a novel therapeutic approach for patients with advanced cancer. Hamilton et al, Cancer Treatment Reviews, 45 (2016) 129— 138.
[11] Cyclin-dependent kinase 4 (CDK4) and closely related CDK6 play key roles in mammalian cell proliferation, where they help to drive the progression of cells into the DNA synthetic (S) phase of the cell-division cycle. Unlike CDKs 1 and 2, which act later in the cell cycle in response to periodic oscillations of cyclins E, A, and B to coordinate DNA replication with mitosis, the enzymatic activities of CDK4 and CDK6 in the first gap phase (Gl) of the cycle are governed by D-type cyclins expressed in response to various extracellular signals, including stimulatory mitogens, inhibitory cytokines, differentiation inducers, cell-cell contacts, and other spatial cues. The three D-type cyclins (Dl, D2, and D3) are differentially expressed, alone or in combination, in distinct cell lineages, where they assemble with CDK4 and CDK6 to form enzymatically active holoenzyme complexes. An understanding of how the three different D-type cyclins act as environmental sensors in responding dynamically to extracellular cues in various cell types helps to explain how CDK4/6 activities are differentially regulated and predicts the basis of functional interactions between mitogen signaling pathways and CDK4/6 activity in both normal and cancer cells. More than two decades after discovery of CDK4 and CDK6, drugs inhibiting their activities are now demonstrating significant efficacy in cancer treatment.
[12] The CDK4/6 inhibitors act at the Gl-to-S cell cycle checkpoint. This checkpoint is tightly controlled by the D-type cyclins and CDK4 and CDK6. When CDK4 and CDK6 are activated by D-type cyclins, they phosphorylate the retinoblastoma-associated protein (pRb). This releases pRb’s suppression of the E2F transcription factor family and ultimately allows the cell to proceed through the cell cycle and divide. In HR+ breast cancer, cyclin D overexpression is common and loss of pRb is rare, making the Gl-to-S checkpoint an ideal therapeutic target. The CDK4/6 inhibitors prevent progression through this checkpoint, leading to cell cycle arrest.
[13] Despite the availability of many therapies, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) -negative (HR+/HER2-) advanced breast cancer is rarely curable. The current treatment paradigm for HR+/HER2- advanced breast cancer involves sequencing endocrine therapy, targeted therapy, and/or chemotherapy to prolong patients’ lives, delay disease progression, and minimize cancer-related symptoms. The cyclin- dependent kinase 4 and 6 (CDK4/6) inhibitors are rapidly transforming this treatment landscape. There are currently three CDK4/6 inhibitors that have been approved by the U.S. Food and Drug Administration: Palbociclib, Ribociclib, and Abemaciclib.
[14] The CDK4/6 inhibitors as a class are generally well tolerated. The most common class wide adverse effects include nausea, diarrhea, fatigue, neutropenia, leukopenia, anemia, and thrombocytopenia. Palbociclib and ribociclib most commonly cause neutropenia, while diarrhea is the unique gastrointestinal (GI) toxicity that is associated with abemaciclib, perhaps because of its greater affinity for CDK4 over CDK6. Shah et al., Oncology (Williston Park), 2018 May 15; 32(5): 216-222. [15] The U.S. Food and Drug Administration (FDA) is warning that Ibrance (palbociclib), Kisqali (ribociclib), and Verzenio (abemaciclib) used to treat some patients with advanced breast cancers may cause rare but severe inflammation of the lungs. See USFDA, Drugs Safety Communications, dated Sep, 13th, 2019, titled “FDA warns about rare severe lung inflammation-Ibrance, Kisqali and Verzeni breast cancer”.
[16] Patent literature related to CDK inhibitors includes and are not limited to International Publication Nos. WO 2000/064900, WO 2000/035908, WO 2004/031158, WO 2004/046130, WO 2004/101549, WO 2005/111019, WO 2006/105386, WO 2006/040050, WO 2006/040036, WO 2006/002828, WO 2006/040052, WO 2018/033815, WO 2020/223558, WO 2020/205560, WO 2020/180959, WO 2020/168197, WO 2020/157652, WO 2020/223469, WO 2021/072232, WO 2021/030537, WO 2021/170076, WO 2021/073593, WO 2019/161224, WO 2019/148161, WO 2019/170055, WO 2019/222521, WO 2019/035008, WO 2018/106870, WO 2018/108167, WO 2018/113771, WO 2018/045957, WO 2018/081211, WO 2018/081204, WO 2017/020065, WO 2017/114512, WO 2017/177836, WO 2017/177837, WO 2017/114351, WO 2017/133701, WO 2017/193872, WO 2017/041535, WO 2017/054484, WO 2016/058501, WO 2016/141881, WO 2016/194831, WO 2016/014904, WO 2016/015597, WO 2015/101293, WO 2015/180642, WO 2014/183520, WO 2011/101417, WO 2011/101409, WO 2010/132725, WO 2009/061345, WO 2006/008874, WO 2002/002550, WO 2021/030623, WO 2019/161224 each of which is incorporated herein by reference in its entirety for all purposes. The CDK 2/4/6 inhibitor PF- 06873600 (WO 2018/033815) developed by Pfizer has selectivity for CDK 2/4/6 isoforms.
[17] There remains an unmet need for CDK inhibitors having activity on CDK1, CDK2 and/or CDK4/6 (such as on CDK2 and/or CDK4/6) for the treatment of various diseases and disorders associated with cell proliferation such as cancer.
SUMMARY OF INVENTION
[18] The present invention relates to compounds of formula (I), methods for their preparation, pharmaceutical compositions containing them, and methods of treatment with them. In particular, the compounds of formula (I) and their pharmaceutically acceptable salts thereof are useful in the treatment, prevention and/or amelioration of diseases or disorders associated with CDK1, CDK2 and/or CDK4/6.
[19] In one aspect, the present invention relates to a compound of formula (I): or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof or pharmaceutically acceptable salt thereof, wherein
Y1 is selected from CRa or N;
Y2 is selected from CRb or N; with the proviso that at least one of Y1 and Y2 is N; each occurrence of Ra, Rb, Rc, Rd, Re, Rf and Rg is independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminoalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclylalkyl;
Y is selected from CRh or N;
Z is selected from CR1 or N; with the proviso that at least one of Y and Z is N; each occurrence of Rh and R1 is independently selected from hydrogen, halogen, substituted or unsubstituted C(i-3) alkyl, or substituted or unsubstituted C(i-3) haloalkyl;
X1 is selected from is CR1 or N;
X2 is selected from is CR2 or N;
X3 is selected from is CR3 or N; X4 is selected from is CR4 or N; each occurrence of R1, R2, R3, R4, R5 and R6 is independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclylalkyl ;
L is absent, NH, O, -S-, -SO-, -SO2-, -C(=0)-, or substituted or unsubstituted alkyl;
Ring A is substituted or unsubstituted heterocyclyl ring; each occurrence of R7 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, oxo (=0), -C(=0)0Rz, -C(=0)Rz, -C(=S)RZ, -C(=0)NRzRz, -C(=0)0NRzRz, -NRZRZ,- NRzC(=0)NRzRz, -NRzS(=0)Rz, -NRzS(=0)2Rz, -N=NRZ, -NRzC(=0)0Rz, -NRzC(=0)Rz, - NRxC(=S)Ry, -NRZC(=S)NRZRZ, -SONRzRz, -S02NRzRz, -ORz, -0C(=0)NRzRz, -
0C(=0)0Rz, -0C(=0)Rz, -0C(=0)NRzRz, -CRxRy-NRzC(=0)Rz, -CRxRy-ORz, -CRxRy- C(=0)0Rz, -CRxRy-C(=0)NRzRz, -CRxRy-0C(=0)Rz, -SRZ, -SORz, -S02Rz, -CRxRyC(=0)Rz, or -CRxRyC(=S)Rz;
Rz is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted heterocyclylalkyl, or substituted or unsubstituted amino, or any two of Rz when bound to a common atom may be joined to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRza and S, or (ii) an oxo (=0), thio (=S) or imino (=NRza) group; wherein Rza, Rx, and Ry at each occurrence are independently selected from hydrogen, halo, hydroxy, amino, alkoxy, C1-5 alkyl, C3-7 cycloalkyl, C5-7 aryl, C5-7 heteroaryl, or C3-7 heterocycloalkyl; and n is an integer selected from 0, 1, 2, 3 and 4.
[20] Further preferred is a compound of formula (I), wherein X1, X2, X3 and X4 are independently selected from CH or N.
[21] Further preferred is a compound of formula (I), wherein X1 and X2 are N.
[22] Further preferred is a compound of formula (I), wherein X1 is N.
[23] Further preferred is a compound of formula (I), wherein X2, X3 and X4 are CH.
[24] Further preferred is a compound of formula (I), wherein Y and Z are independently selected from CH or N.
[25] Further preferred is a compound of formula (I), wherein Y and Z are N.
[26] In another aspect, the present invention relates to a compound of formula (IA), (IB), (IC), or (ID):
Figure imgf000010_0001
Figure imgf000011_0001
(IC) (ID) or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof, or pharmaceutically acceptable salt thereof, wherein all the variables (including Ring A, L, R5, R6, R7, Rc, Rd, Re, Rf, Rg, Y1, Y2, and n) are as defined above in relation to compound of formula (I).
[27] Further preferred is a compound of formula (I), (IA), (IB), (IC), or (ID), wherein Ring A is selected from
Figure imgf000011_0002
Figure imgf000012_0001
[28] Further preferred is a compound of formula (I), (IB), or (ID), wherein L is absent or CHi.
[29] Further preferred is a compound of formula (I), (IB), or (ID), wherein L is absent.
[30] Further preferred is a compound of formula (I), (IB), or (ID), wherein L is CFh.
[31] Further preferred is a compound of formula (I), (IA), (IB), (IC), or (ID), wherein R5 is hydrogen or halogen.
[32] Further preferred is a compound of formula (I), (IA), (IB), (IC), or (ID), wherein R5 is hydrogen or fluorine.
[33] Further preferred is a compound of formula (I), (IA), (IB), (IC), or (ID), wherein R6 is hydrogen. [34] Further preferred is a compound of formula (I), (IA), (IB), (IC), or (ID), wherein Y1 is N.
[35] Further preferred is a compound of formula (IA), (IB), (IC), or (ID), wherein R7 is alkyl (e.g., methyl, ethyl, or isopropyl), hydroxy (-OH), oxo (=0), -N(RZ)RZ (e.g., -N(CH3)2), cycloalkyl (e.g., cyclopropyl), acetyl (-C(0)CH3), haloalkyl (e.g., -CF3 or -CH2CF3), sulfonylalkyl (e.g., -SC Me), -C(0)cycloalkyl (e.g., -C(O)cyclopropyl), or-C(=0)ORz (e.g., - C(=0)0-t-butyl), and n is an integer 1 or 2.
[36] Further preferred is a compound of formula (I), (IA), (IB), (IC), or (ID), wherein n is 1 or 2.
[37] Further preferred is a compound of formula (I), (IA), (IB), (IC) or (ID), wherein ring
Figure imgf000013_0001
[38] Representative compounds of the present invention include those specified below and pharmaceutically acceptable salts thereof. The present invention should not be construed to be limited to them. tert-Butyl 4-(6-((5-fluoro-4-(quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l- carboxylate;
5-Fluoro-N-(5-(piperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2 -amine;
5-Fluoro-N-(5-(piperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2 -amine hydrochloride;
Tert-Butyl 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperazine - 1 -carboxylate ;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2 -amine;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2 -amine hydrochloride;
N-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2 -amine;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2 -amine hydrochloride;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2- amine;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2- amine hydrochloride;
Tert-Butyl 4-(6-((5-fluoro-4-(8-fluoro-2-methyl-4-(prop-l-en-2-yl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3 -yl)piperazine - 1 -carboxylate ;
5-Fluoro-4-(8-fluoro-2 -methyl -4-(prop- 1 -en-2-yl)quinolin-6-yl)-N-(5-(piperazin- 1 -yl)pyridin- 2-yl)pyrimidin-2-amine;
5-Fluoro-4-(8-fluoro-2-methyl-4-(prop-l-en-2-yl)quinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin- 2-yl)pyrimidin-2 -amine hydrochloride ;
5-Fluoro-N-(5-(4-methylpiperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2 -amine ;
5-Fluoro-N-(5-(4-methylpiperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2 -amine hydrochloride;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-methylpiperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine; 5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-methylpiperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine hydrochloride;
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2- amine;
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2- amine hydrochloride;
N-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6- yl)pyrimidin-2 -amine;
N-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6- yl)pyrimidin-2 -amine hydrochloride;
Tert-Butyl 4-(6-((5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin- 3 -yl)piperazine - 1 -carboxylate ;
5-Fluoro-4-(8-fluoro-2-methylquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine;
5-Fluoro-4-(8-fluoro-2-methylquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine hydrochloride;
Tert-Butyl 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3 -yl)piperazine - 1 -carboxylate ;
5-Fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine;
5-Fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine hydrochloride;
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine;
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylpiperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylpiperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine hydrochloride; 5-Fluoro-N-(5-(4-isopropylpiperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2 -amine;
5-Fluoro-N-(5-(4-isopropylpiperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2 -amine hydrochloride;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylpiperazin-l-yl)methyl)pyridin-2- yl)pyrimidin-2 -amine;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylpiperazin-l-yl)methyl)pyridin-2- yl)pyrimidin-2 -amine hydrochloride;
2-(6-(2-((5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8- fluoro-2-methylquinolin-4-yl)propan-2-ol;
2-(6-(2-((5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8- fluoro-2-methylquinolin-4-yl)propan-2-ol hydrochloride;
Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)propan-2-ol;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)propan-2-ol hydrochloride;
2-(6-(2-((5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2- methylquinolin-4-yl)propan-2-ol;
2-(6-(2-((5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2- methylquinolin-4-yl)propan-2-ol hydrochloride;
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4-ethylpiperazin-l-yl)pyridin- 2-yl) -5 -fluoropyrimidin-2 -amine ;
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4-ethylpiperazin-l-yl)pyridin- 2-yl)-5 -fluoropyrimidin-2 -amine hydrochloride;
Tert-butyl 4-(6-((4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoropyrimidin-2- yl)amino)pyridin-3 -yl)piperazine - 1 -carboxylate ;
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine; 4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine hydrochloride;
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-yl)-5 -fluoropyrimidin-2 -amine hydrochloride ;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-(2-fluoropropan-2- yl)-2-methylquinolin-6-yl)pyrimidin-2 -amine;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-(2-fluoropropan-2- yl)-2-methylquinolin-6-yl)pyrimidin-2 -amine hydrochloride ;
Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-fluoropropan-2-yl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate;
5-Fluoro-4-(8-fluoro-4-(2-fluoropropan-2-yl)-2-methylquinolin-6-yl)-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine;
5-Fluoro-4-(8-fluoro-4-(2-fluoropropan-2-yl)-2-methylquinolin-6-yl)-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine hydrochloride;
5-Fluoro-N-(5-((4-methylpiperazin-l-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2- amine;
5-Fluoro-N-(5-((4-methylpiperazin-l-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2- amine hydrochloride;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6- yl)pyrimidin-2 -amine;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6- yl)pyrimidin-2 -amine hydrochloride;
Tert-butyl 4-(6-((5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperazine - 1 -carboxylate ;
5-Fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2 -amine;
5-Fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2 -amine hydrochloride; N-(5 -(4-Ethylpiperazin- 1 -yl)pyridin-2-yl)-5 -fluoro-4-(7 -fluoroquinolin-6-yl)pyrimidin-2- amine;
N-(5 -(4-Ethylpiperazin- 1 -yl)pyridin-2-yl)-5 -fluoro-4-(7 -fluoroquinolin-6-yl)pyrimidin-2- amine hydrochloride;
N-(5-(4-(Dimethylamino)piperidin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2 -amine;
N-(5-(4-(Dimethylamino)piperidin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2 -amine hydrochloride;
4-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2-one;
4-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2-one hydrochloride;
N-(5-(4-Cyclopropylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2 -amine;
N-(5-(4-Cyclopropylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2 -amine hydrochloride;
1 —(4— (6— ((5 -Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 - yl)ethan-l-one;
1 —(4— (6— ((5 -Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 - yl)ethan-l-one hydrochloride;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine hydrochloride;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl)piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl)piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine hydrochloride;
Cyclopropyl(4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperazin- 1 -yl)methanone; Cyclopropyl(4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperazin- l-yl)methanone hydrochloride;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2- methylquinolin-6-yl)pyrimidin-2 -amine;
N-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2- methylquinolin-6-yl)pyrimidin-2 -amine hydrochloride ;
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-
6-yl)pyrimidin-2 -amine ;
N-(5-(4-ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin- 6-yl)pyrimidin-2 -amine hydrochloride ; l-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4- methylpiperidin-4-ol; l-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4- methylpiperidin-4-ol hydrochloride;
(±)-Tert-butyl 4-(6-((4-(4-( 1 -((tert-butoxycarbonyl)amino)ethyl)-8-fluoro-2-methylquinolin- 6-yl)-5 -fluoropyrimidin-2-yl)amino)pyridin-3 -yl)piperazine- 1 -carboxylate ;
(±)-4-(4-(l-Aminoethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine;
(±)-4-(4-(l-Aminoethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine hydrochloride;
(±)-Tert-butyl 4-(6-((4-(4-(l-((tert-butoxycarbonyl)amino)ethyl)-8-fluoroquinolin-6-yl)-5- fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate;
(±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine; (±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine dihydrochloride;
(±)-Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3 -yl)piperazine - 1 -carboxylate ;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -(piperazin- 1 -yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -(piperazin- 1 -yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trimethanesulfonate;
(±)-Tert-butyl (l-(8-fluoro-6-(5-fluoro-2-((5-(4-methylpiperazin-l-yl)pyridin-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethyl)carbamate;
(±)-4-(4-(l-aminoethyl)-8-fluoroquinohn-6-yl)-5-fluoro-N-(5-(4-methylpiperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine;
(±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methylpiperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine trihydrochloride;
(±)- 1 -(6-(2-((5 -(4-Ethylpiperazin- 1 -yl)pyridin-2-yl)amino)-5 -fluoropyrimidin-4-yl)-8- fluoroquinolin-4-yl)ethanol;
(±)- 1 -(6-(2-((5 -(4-Ethylpiperazin- 1 -yl)pyridin-2-yl)amino)-5 -fluoropyrimidin-4-yl)-8- fluoroquinolin-4-yl)ethanol trihydrochloride;
(±)-l-(8-fluoro-6-(5-fluoro-2-((5-(4-isopropylpiperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -(4-isopropylpiperazin- 1 -yl)pyridin-2-yl)amino)pyrimidin- 4-yl)quinolin-4-yl)ethanol trihydrochloride;
N-(5-(4-ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6- yl)pyrimidin-2 -amine;
N-(5-(4-ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6- yl)pyrimidin-2 -amine hydrochloride;
(±)-Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate; (±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -(piperazin- 1 -yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)ethanol;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -(piperazin- 1 -yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)ethan- 1 -ol hydrochloride;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(4-methylpiperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(4-methylpiperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trihydrochloride ;
Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3 -yl)piperazine - 1 -carboxylate ;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4- yl)propan-2-ol;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4- yl)propan-2-ol;
(±)-Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3 -yl)piperazine - 1 -carboxylate ;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -(piperazin- 1 -yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -(piperazin- 1 -yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trihydrochloride ;
(±)-Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3 -yl)piperidine - 1 -carboxylate ;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trihydrochloride ;
Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3 -yl)piperidine - 1 -carboxylate ; 2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4- yl)propan-2-ol;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4- yl)propan-2-ol trihydrochloride;
Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3 -yl)piperidine- 1 -carboxylate ;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)propan-2-ol;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)propan-2-ol trihydrochloride;
(±)-7ert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3 -yl)piperidine- 1 -carboxylate ;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)ethanol;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)ethanol trihydrochloride;
Tert- butyl 4-(2-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2- yl)amino)pyrimidin-5 -yl)piperidine- 1 -carboxylate ;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinolin-
4-yl)propan-2-ol;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinolin- 4-yl)propan-2-ol trihydrochloride;
(±)-7ert-butyl 4-(2-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyrimidin-5 -yl)piperidine- 1 -carboxylate ;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trihydrochloride ; 2-(8-Fluoro-6-(5-fluoro-2-((5-(l-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)propan-2-ol;
2-(8-Fluoro-6-(5-fluoro-2-((5-(l-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)propan-2-ol trihydrochloride;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -( 1 -methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -( 1 -methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trihydrochloride ;
(±)-Tert-butyl 4-(6-((4-(4-(l-((tert-butoxycarbonyl)amino)ethyl)-8-fluoroquinolin-6-yl)-5- fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperidine-l-carboxylate;
(±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperidin-4-yl)pyridin-2- yl)pyrimidin-2 -amine; and
(±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperidin-4-yl)pyridin-2- yl)pyrimidin-2 -amine trihydrochloride ; and pharmaceutically acceptable salts thereof.
Representative structures are shown in Table 1 below.
Table- 1
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
E
Figure imgf000035_0001
Figure imgf000036_0001
4-(4-(l-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l-yl)pyridin-2- yl)pyridin-2-amine ;
4-(4-(2-aminopropan-2-yl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l-yl)pyridin-2- yl)pyridin-2-amine ;
4-(4-(l-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methylpiperazin-l-yl)pyridin-2- yl)pyridin-2-amine ;
4-(4-(l-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperidin-4-yl)pyridin-2- yl)pyrimidin-2 -amine;
4-(4-(2-aminopropan-2-yl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperidin-4-yl)pyridin-2- yl)pyrimidin-2 -amine;
4-(4-(l-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(l-methylpiperidin-4-yl)pyridin-2- yl)pyrimidin-2 -amine;
2-(8-fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyridin-4-yl)quinolin-4- yl)propan-2-ol;
2-(8-fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2-yl)amino)pyridin-4-yl)quinolin-4- yl)propan-2-ol;
2-(8-fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridin-4-yl)quinolin-4- yl)propan-2-ol;
2-(8-fluoro-6-(5-fluoro-2-((r,2',3',6'-tetrahydro-[3,4'-bipyridin]-6-yl)amino)pyrimidin-4- yl)quinolin-4-yl)propan-2-ol; 1-(8-fluoro-6-(5-fluoro-2-((r,2',3',6'-tetrahydro-[3,4'-bipyridin]-6-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethan- 1 -ol;
N-(4-(4-(l-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidin-2-yl)-r,2',3',6'-tetrahydro- [3 ,4'-bipyridin] -6-amine;
2-(8-fluoro-6-(5-fluoro-2-((5-(piperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4- yl)propan-2-ol;
2-(8-fluoro-6-(5-fluoro-2-((5-(piperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)propan-2-ol;
5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(piperidin-3-yl)pyridin-2-yl)pyrimidin-2-amine;
2-(8-fluoro-6-(5-fluoro-2-((5-(pyrrolidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4- yl)propan-2-ol;
1-(8-fluoro-6-(5-fluoro-2-((5-(pyrrolidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4- yl)ethan-l-ol;
4-(4-(l-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(pyrrolidin-3-yl)pyridin-2- yl)pyrimidin-2 -amine;
2-(6-(2-((5-(l-ethylpiperidin-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8- fluoroquinolin-4-yl)propan-2-ol;
2-(8-fluoro-6-(5-fluoro-2-((5-(l-isopropylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)propan-2-ol; and
2-(6-(2-((5-(l-cyclopropylpiperidin-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8- fluoroquinolin-4-yl)propan-2-ol; or pharmaceutically acceptable salt thereof.
Table-la: Prophetic Examples
Figure imgf000038_0001
Figure imgf000039_0001
[39] Yet another embodiment of the present invention is a method for inhibiting one or more of CDK1, CDK2, CDK4 and CDK6 in a patient by administering to the patient an effective amount of at least one compound of the present invention as defined in formula (I), (IA), (IB), (IC), or (ID). One embodiment is a method for inhibiting CDK2, CDK4 and CDK6 (e.g., CDK2 and CDK4/6) in a patient by administering to the patient an effective amount of at least one compound of the present invention as defined in formula (I), (IA), (IB), (IC), or (ID).
[40] Yet another embodiment of the present invention is a method for treating an inflammatory, autoimmune, or proliferative disease by administering to a patientin need of such treatment an effective amount of at least one compound of the present invention. In one embodiment, the compound of the present invention is administered in an effective amount to inhibit one or more of CDK1, CDK2, CDK4, and CDK6. [41] Yet another embodiment of the present invention is a method for treating a inflammatory, autoimmune or proliferative disease (e.g., via inhibition of one or more of CDK1, CDK2, CDK4, and CDK6) by administering to a patient in need of such treatment an effective amount of at least one compound of the present invention, in combination (simultaneously or sequentially) with at least one other anti-inflammatory, immunomodulator or anti-cancer agent. In one embodiment, the compound of the present invention inhibits one or more of CDK1, CDK2, CDK4, and CDK6. In another embodiment, the compound of the present invention inhibits CDK2 and/or CDK4/6.
[42] More particularly, the compounds of formula (I), (IA), (IB), (IC), or (ID) and pharmaceutically acceptable esters or salts thereof can be administered for the treatment, prevention and/or amelioration of diseases or disorders associated with a CDK enzyme selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the foregoing, in particular the amelioration of diseases or disorders mediated by such a CDK enzyme, including, but not limited to, inflammatory diseases or disorders, autoimmune diseases or disorders, and cancer and other proliferative diseases or disorders.
[43] The compounds of the present invention are useful in the treatment of a variety of cancers, including, but not limited to:
• carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer and carcinoma of the esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;
• hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma;
• hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia;
• tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma;
• tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and
• other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
[44] The compounds of the present invention are useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse. The compounds described herein are also useful in inhibiting tumor angiogenesis and metastasis. One embodiment of the invention is a method of inhibiting tumor angiogenesis or metastasis in a patient in need thereof by administering an effective amount of one or more compounds of the present invention.
[45] The compounds of the present invention are also useful in combination (administered together or sequentially) with known anti -cancer treatments, such as for example but not limited to radiation therapy or with cytostatic, cytotoxic or anticancer agents, such as for example, but not limited to, DNA interactive agents, such as cisplatin or doxorubicin; topoisomerase II inhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents, such as paclitaxel, docetaxel or the epothilones (for example ixabepilone), either naturally occurring or synthetic; hormonal agents, such as tamoxifen; thymidilate synthase inhibitors, such as 5-fluorouracil; anti-metabolites, such as methotrexate; other tyrosine kinase inhibitors such as Iressa and OSI-774; angiogenesis inhibitors; EGF inhibitors; VEGF inhibitors; HDAC inhibitors, SRC inhibitors; c-Kit inhibitors; Herl/2 inhibitors; monoclonal antibodies directed against growth factor receptors such as erbitux (EGF) and herceptin (Her2); and other protein kinase modulators as well.
[46] The compounds of the present invention are also useful in combination (administered together or sequentially) with one or more steroidal, anti-inflammatory drugs, non-steroidal anti-inflammatory drugs (NSAIDs) or immune selective anti-inflammatory derivatives (ImSAIDs).
[47] The invention further provides a pharmaceutical composition comprising one or more compounds of the present invention (such as a compound having formula (I), (IA), (IB), (IC), or (ID)) together with a pharmaceutically acceptable carrier. The pharmaceutical composition may further comprise one or more of the active ingredients identified above, such as other anti cancer agents.
[48] In one embodiment, the pharmaceutical composition includes a therapeutically effective amount of one or more compounds of formula (I), (IA), (IB), (IC), or (ID).
[49] Yet another embodiment is a method of treating cancer in a patient in need thereof by administering a therapeutically effective amount of a compound of the present invention. For example, the compounds of the present invention are effective for treating hematopoietic tumors of lymphoid lineage, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, acute myelogenous leukemias, chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia. The compounds of the present invention are also effective for treating carcinoma of the bladder, carcinoma of the breast, carcinoma of the colon, carcinoma of the kidney, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladdercancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, squamous cell carcinoma, tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma, tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
[50] Yet another embodiment is a method of treating leukemia in a patient in need thereof by administering a therapeutically effective amount of a compound of the present invention. For example, the compounds of the present invention are effective for treating carcinoma of the breast, ovarian cancer, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer or stomach cancer.
DETAILED DESCRIPTION OF THE INVENTION
[51] As used herein the following definitions shall apply unless otherwise indicated. Further many of the groups defined herein can be optionally substituted. The listing of substituents in the definition is exemplary and is not to be construed to limit the substituents defined elsewhere in the specification.
[52] Unless otherwise specified, the term “CDK4/6” refers to both CDK4 and CDK6. For instance, inhibition at “CDK4/6” refers to inhibition (to the same or different extent) at both CDK4 and CDK6.
[53] The term “alkyl”, unless otherwise specified, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n- pentyl, and 1, 1-dimethylethyl (t-butyl). The term “Ci-6alkyl” refers to an alkyl group as defined above having up to 6 carbon atoms. In appropriate circumstances, the term “alkyl” refers to a hydrocarbon chain radical as mentioned above which is bivalent.
[54] The term “alkenyl”, unless otherwise specified, refers to an aliphatic hydrocarbon group containing one or more carbon-carbon double bonds and which may be a straight or branched or branched chain having about 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2- propenyl (allyl), iso-propenyl, 2-methyl- 1-propenyl, 1-butenyl, and 2-butenyl. The term “C2- 6alkenyl” refers to an alkenyl group as defined above having up to 6 carbon atoms. In appropriate circumstances, the term “alkenyl” refers to a hydrocarbon group as mentioned above which is bivalent.
[55] The term “alkynyl”, unless otherwise specified, refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having in the range of 2 to up to 12 carbon atoms (with radicals having in the range of 2 to up to 10 carbon atoms presently being preferred) e.g., ethynyl, propynyl, and butnyl. The term “C2-6 alkynyl” refers to an alkynyl group as defined above having up to 6 carbon atoms. In appropriate circumstances, the term “alkynyl” refers to a hydrocarbyl radical as mentioned above which is bivalent.
[56] The term “alkoxy” unless otherwise specified, denotes an alkyl, cycloalkyl, or cycloalkylalkyl group as defined above attached via an oxygen linkage to the rest of the molecule. The term “substituted alkoxy” refers to an alkoxy group where the alkyl constituent is substituted (i.e., -0-(substituted alkyl). For example, “alkoxy" refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy. In appropriate circumstances, the term “alkoxy” refers to a group as mentioned above which is bivalent.
[57] The term “hydroxyalkyl” or “hydroxylalkyl” means alkyl substituted with one or more hydroxyl groups, wherein the alkyl groups are as defined above. Examples of “hydroxyalkyl” include but are not limited to hydroxymethyl, hydroxyethyl, hydroxypropyl, propan-2 -ol and the like.
[58] The term “aminoalkyl” means alkyl substituted with one or more amine group(s), wherein the alkyl groups are as defined above. Examples of “aminoalkyl” include but are not limited to aminomethyl, aminoethyl, 2-aminopropyl, and the like. [59] The term “cycloalkyl”, unless otherwise specified, denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include perhydronaphthyl, adamantyl and norbomyl groups, bridged cyclic groups, and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl. The term “C3-6 cycloalkyl” refers to a cycloalkyl group as defined above having up to 6 carbon atoms.
[60] The term “cycloalkylalkyl”, unless otherwise specified, refers to a cyclic ring- containing radical containing in the range of about 3 up to 8 carbon atoms directly attached to an alkyl group which isthen attached to the main structure at any carbon from the alkyl group, such as cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
[61] The term “cycloalkenyl”, unless otherwise specified, refers to cyclic ring -containing radicals containing in the range of about 3 up to 8 carbon atoms with at least one carbon-carbon double bond such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. The term “cycloalkenylalkyl” refers to a cycloalkenyl group directly attached to an alkyl group which is then attached to the main structure at any carbon from the alkyl group.
[62] The term “aryl”, unless otherwise specified, refers to aromatic radicals having in the range of 6 up to 20 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl.
[63] The term “arylalkyl”, unless otherwise specified, refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H5C6H5.
[64] The term “heterocyclic ring”, unless otherwise specified, refers to a non-aromatic 3-to- 15 -member ring radical which consists of carbon atoms and at least one heteroatom selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a mono-, bi-, tri- or tetracyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quatemized. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom.
[65] The term “heterocyclyl”, unless otherwise specified, refers to a heterocylic ring radical as defined above. The heterocylcyl ring radical may be attached to the main structure at any heteroatom or carbon atom. [66] The term “heterocyclylalkyl”, unless otherwise specified, refers to a heterocylic ring radical as defined above directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group. Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.
[67] The term “heteroaryl”, unless otherwise specified, refers to an optionally substituted 5- to- 14-member aromatic ring having one or more heteroatoms selected from N, O, and S as ring atoms. The heteroaryl may be a mono-, bi- or tricyclic ring system. Examples of such “heterocyclic ring” or “heteroaryl” radicals include, but are not limited to, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl, isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl, pyridazinyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom. The term “substituted heteroaryl” also includes ring systems substituted with one or more oxide substituents, such as pyridinyl N-oxides.
[68] The term “heteroarylalkyl”, unless otherwise specified, refers to a heteroaryl ring radical as defined above directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom from alkyl group.
[69] The term “cyclic ring” refers to a cyclic ring containing 3 to 10 carbon atoms. [70] The term “substituted” unless otherwise specified, refers to substitution with any one or any combination of the following substituents which may be the same or different and are independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted heterocyclylalkyl ring, substituted or unsubstituted guanidine, -COOR1, -C(0)Rv, -C(S)RV, -
Figure imgf000046_0001
RORU, -RlC(0)ORu, -RlC(0)NRuRv, -RlC(0)Ru, -ROC(0)Ru, -SR1, -SOR'. -SOiR'. and - ONO2, wherein Rl, Ru and Rv in each of the above groups can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, or substituted heterocyclylalkyl ring, or any two of Rl, Ru and Rv may be joined to form a substituted or unsubstituted saturated or unsaturated 3-10 membered ring, which may optionally include heteroatoms which may be the same or different and are selected from O, NR1 (e.g., Rl can be hydrogen or Ci-6 alkyl) or S. Substitution or the combinations of substituents envisioned by this invention are preferably those that result in the formation of a stable or chemically feasible compound. The term stable as used herein refers to the compounds or the structure that are not substantially altered when subjected to conditions to allow for their production, detection and preferably their recovery, purification and incorporation into a pharmaceutical composition. The substituents in the aforementioned "substituted" groups cannot be further substituted.
[71] The term "halo", "halide", or, alternatively, "halogen" means fluoro, chloro, bromo or iodo. The terms "haloalkyl," "haloalkenyl," "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
[72] The term "protecting group" or "PG" refers to a substituent that is employed to block or protect a particular functionality. Other functional groups on the compound may remain reactive. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino- protecting groups include, but are not limited to, acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxy carbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy-protecting groups include, but are not limited to, acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Suitable carboxy-protecting groups include, but are not limited to, -CFhCFhSChPh, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, and nitroethyl. For a general description of protecting groups and their use, T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
[73] Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Non-limiting examples of intermediate mixtures include a mixture of isomers in a ratio of 10:90, 13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
[74] The term "tautomers" refers to compounds, which are characterized by relatively easy interconversion of isomeric forms in equilibrium. These isomers are intended to be covered by this invention. "Tautomers" are structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton-shift tautomerization" involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g. in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers.
[75] A "leaving group or atom" is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups unless otherwise specified are halogen atoms and mesyloxy, p- nitrobenzensulphonyloxy and tosyloxy groups.
[76] The term "prodrug" refers to a compound, which is an inactive precursor of a compound, converted into its active form in the body by normal metabolic processes. Prodrug design is discussed generally in Hardma, et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996). A thorough discussion is provided in Higuchi, et al., Prodrugs as Novel Delivery Systems, Vol. 14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). To illustrate, prodrugs can be converted into a pharmacologically active form through hydrolysis of, for example, an ester or amide linkage, thereby introducing or exposing a functional group on the resultant product. The prodrugs can be designed to react with an endogenous compound to form a water-soluble conjugate that further enhances the pharmacological properties of the compound, for example, increased circulatory half-life. Alternatively, prodrugs can be designed to undergo covalent modification on a functional group with, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate. The resulting conjugate can be inactivated and excreted in the urine or rendered more potent than the parent compound. High molecular weight conjugates also can be excreted into the bile, subjected to enzymatic cleavage, and released back into circulation, thereby effectively increasing the biological half-life of the originally administered compound. [77] The term "ester" refers to a compound, which is formed by reaction between an acid and an alcohol with elimination of water. An ester can be represented by the general formula RCOOR'.
[78] These prodrugs and esters are intended to be covered within the scope of this invention.
[79] Additionally, the instant invention also includes the compounds which differ only in the presence of one or more isotopically enriched atoms for example replacement of hydrogen with deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon.
[80] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
[81] Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine; chiral bases such as alkylphenylamine, glycinol, and phenyl glycinol; salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine quaternary ammonium salts of the compounds of invention with alkyl halides, alkyl sulphates such as Mel and (Me^SCri; non-natural amino acids such as D-isomers or substituted amino acids; guanidine; and substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides (e.g., hydrochlorides), acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
[82] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes those embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, that "consist of’ or "consist essentially of’ the described features.
[83] The term "cell proliferation" refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.
[84] The term "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompasses administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time . Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
[85] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to show the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g. reduction of platelet adhesion and/or cell migration. The specific dose will vary depending on the compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. In one embodiment, the amount of compound administered ranges from about 0.1 mg to 5 g, from about 1 mg to 2.0 g, from about 100 mg to 1.5 g, from about 200 mg to 1.5 g, from about 400 mg to 1.5 g, and from about 400 mg to 1.0 g.
[86] As used herein, "treatment," "treating," or "ameliorating" are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
[87] A "therapeutic effect," as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
[88] The term "subject" or “patient” refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications (e.g., dogs, cats, cows, sheep, pigs, horses, goats, chickens, turkeys, ducks, and geese).
[89] . In some embodiments, the patient is a mammal, and in some embodiments, the patient is human.
[90] "Radiation therapy" means exposing a patient, using routine methods and compositions known to the practitioner, to radiation emitters such as alpha-particle emitting radionuclides (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiation emitters (i.e. beta emitters), conversion electron emitters (e.g. strontium-89 and samarium- 153- EDTMP), or high-energy radiation, including without limitation x-rays, gamma rays, and neutrons.
[91] The term "pharmaceutically acceptable excipient" includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, one or more suitable diluents, fdlers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants/flavoring, carriers, buffers, stabilizers, solubilizers, and combinations thereof. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions. [92] The methods of the invention may be applied to cell populations in vivo or ex vivo. "In vivo " means within a living individual, as within an animal or human or in a subject's body. In this context, the methods of the invention may be used therapeutically or prophylactically in an individual. "Ex vivo " or “ In vitro ” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including but not limited to fluid or tissue samples obtained from individuals. Such samples may be obtained by methods known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the invention may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the invention may be used ex vivo or in vitro to determine the optimal schedule and/or dosing of administration of a CDK inhibitor for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental or diagnostic purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the invention may be suited are described below or will become apparent to those skilled in the art.
Pharmaceutical Compositions
[93] The invention provides a pharmaceutical composition comprising one or more compounds of the present invention. The pharmaceutical composition may include one or more additional active ingredients as described herein. The pharmaceutical composition may be administered for any of the disorders described herein.
[94] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present invention as the active ingredient. Where desired, the pharmaceutical compositions contain a compound of the present invention as the active ingredient and one or more pharmaceutically acceptable carriers or excipients, such as inert solid diluents and fdlers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
[95] The pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the subject compounds and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time. [96] Methods include administration of a compound of the present invention by itself, or in combination as described herein, and in each case optionally including one or more suitable diluents, fillers, salts, disintegrants, binders, lubricants, glidants, wetting agents, controlled release matrices, colorants/flavoring, carriers, excipients, buffers, stabilizers, solubilizers, and combinations thereof.
[97] Preparations of various pharmaceutical compositions are known in the art., e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all of which are incorporated by reference herein in their entirety.
[98] The compounds or pharmaceutical composition of the present invention can be administered by any route that enables delivery of the compounds to the site of action, such as oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical administration (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. The compounds can also be administered intraadiposally or intrathecally.
[99] The compositions can be administered in solid, semi-solid, liquid or gaseous form, or may be in dried powder, such as lyophilized form. The pharmaceutical compositions can be packaged in forms convenient for delivery, including, for example, solid dosage forms such as capsules, sachets, cachets, gelatins, papers, tablets, capsules, suppositories, pellets, pills, troches, and lozenges. The type of packaging will generally depend on the desired route of administration. Implantable sustained release formulations are also contemplated, as are transdermal formulations.
Method of Treatment
[100] The invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including, but not limited to, diseases associated with overexpression of one or more of CDK1, CDK2, CDK4 and CDK6 and/or due to an excess of one or more of CDK1, CDK2, CDK4 and CDK6. [101] The treatment methods provided herein comprise administering to the subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides a method of treating an inflammation disorder, including autoimmune diseases in a mammal. The method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention.
[ 102] It will be appreciated that the treatment methods of the invention are useful in the fields of human medicine and veterinary medicine. Thus, the individual to be treated may be a mammal, preferably human, or another animal. For veterinary purposes, individuals include but are not limited to farm animals including cows, sheep, pigs, horses, and goats; companion animals such as dogs and cats; exotic and/or zoo animals; laboratory animals including mice, rats, rabbits, guinea pigs, and hamsters; and poultry such as chickens, turkeys, ducks, and geese.
[103] The invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including, but not limited to, diseases associated with overexpression of one or more of CDK1, CDK2, CDK4 and CDK6 and/or due to an excess of one or more of CDK1, CDK2, CDK4 and CDK6.
[104] The treatment methods provided herein comprise administering to the subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides a method of treating an inflammation disorder, including autoimmune diseases in a mammal. The method comprises administering to the mammal a therapeutically effective amount of a compound of the present invention.
[105] It will be appreciated that the treatment methods of the invention are useful in the fields of human medicine and veterinary medicine. Thus, the individual to be treated may be a mammal, preferably human, or another animal. For veterinary purposes, individuals include but are not limited to farm animals including cows, sheep, pigs, horses, and goats; companion animals such as dogs and cats; exotic and/or zoo animals; laboratory animals including mice, rats, rabbits, guinea pigs, and hamsters; and poultry such as chickens, turkeys, ducks, and geese.
[106] The invention also relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In some embodiments, said method relates to the treatment of broad spectrum of tumors, including all solid tumors and hematological malignancies collectively referred to as cancer. Examples of such tumors include but are not limited to benign or malignant tumors of the brain, lung (in particular small-cell lung cancer and non-small cell lung cancer), squamous cell, bladder, gastric, pancreatic, breast, head and neck, renal, kidney, ureter, ovarian, prostate, colorectal, esophageal, testicular, gynecological (e.g., uterine sarcomas, carcinoma of the fallopian tubes, endometrial, cervix, vagina or vulva), thyroid, pancreatic, bone, skin, melanoma, uterine, ovarian, rectal, anal, colon, testicular, Hodgkin's disease, esophageal, small intestine, endocrine system (e.g., thyroid, parathyroid, or adrenal glands), sarcomas of soft tissues, urethra, penis, leukemia, lymphomas, neoplasms of the central nervous system, sarcomas, myeloma, biliary, liver, neurofibromatosis, acute myelogenous leukemia (AML), myelodysplastic syndromes (MDS), and Kaposi's sarcoma.
[107] The invention also relates to a method of treating the proliferative disease such as melanoma, lung cancer (including non-small cell lung cancer (NSCLC)), colorectal cancer (CRC), breast cancer, kidney cancer such as e.g., renal cell carcinoma (RCC), liver cancer, endometrial cancer, acute myelogenous leukemia (AML), myelodysplastic syndromes (MDS), thyroid cancer, particularly papillary thyroid cancer, pancreatic cancer, neurofibromatosis, or hepatocellular carcinoma.
[108] The invention also relates to a method of treating the proliferative disease such as solid tumor which includes melanoma, breast cancer, ovarian cancer, colorectal cancer, and generally gastrointestinal tract, cervix cancer, lung cancer (including small-cell lung cancer and non-small cell lung cancer), head and neck cancer, bladder cancer, prostate cancer or Kaposi's sarcoma.
[109] In some embodiments, said method is for treating a disease selected from the group consisting of cancers mediated by one or more of CDK1, CDK2, CDK4 and CDK6 include, for example, solid tumors (e.g., breast cancer (e.g., ER+ breast cancer) and prostate cancer), leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, and myeloid leukemia), lymphoma (e.g., Burkitt's lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin's lymphoma, mantel cell lymphoma, and non-Hodgkin's lymphoma (NHL)), adrenocortical cancer, AIDS-related cancer, anal cancer, astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), bile duct cancer, bladder cancer, bone cancer (e.g., fibrosarcoma/osteosarcoma/malignant fibrous histiocytoma), brain tumor (e.g., cerebral astrocytoma, ependymoma, glioma, medulloblastoma, and supratentorial primitive neuroectodermal tumors (PNETs)), brainstem glioma, bronchial adenomas/carcinoids, carcinoid tumors, central nervous system neoplasms, cervical cancer, cholangiocarcinoma, chronic myeloproliferative disorder, colon cancer, endometrial cancer, esophageal cancer, melanoma (e.g., cutaneous or intraocular), gallbladder cancer, gastrointestinal cancer (e.g., colorectal, duodenal, and gastric (stomach) cancer), germ cell tumors, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, islet cell carcinoma, Kaposi's sarcoma, kidney (renal cell) cancer, laryngeal cancer, lip and oral cavity cancer, lung cancer (small cell and non-small cell), Merkel cell carcinoma, mesothelioma, endocrine cancer (e.g., multiple endocrine neoplasia syndrome), multiple myeloma/plasma cell neoplasm mycosis fimgoides, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pituitary cancer, pleuropulmonary blastoma, rectal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing sarcoma, soft tissue sarcoma, Sezary syndrome, squamous cell carcinoma, squamous neck cancer, synovial sarcoma, testicular cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell cancer, trophoblastic tumors, urethral cancer, uterine cancer, fallopian tube cancer, vaginal cancer, visual pathway and hypothalamic glioma, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor.
[110] The invention further provides methods of inhibiting a CDK enzyme selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the foregoing by contacting the CDK enzyme with an amount of a compound of the invention sufficient to inhibit the activity of the CDK enzyme.
[111] In some embodiments, the invention provides a method of inhibiting a CDK enzyme activity, where the CDK enzyme is selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the foregoing, by contacting the CDK enzyme with an amount of a compound of the invention sufficient to inhibit the activity of the CDK enzyme.
[112] In some embodiments, the invention provides a method of inhibiting a CDK enzyme activity, where the CDK enzyme is selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the foregoing. Such inhibition can take place in solution, in a cell expressing one or more CDKenzymes selected from CDK1, CDK2, CDK4, and CDK6, in a tissue comprising a cell expressing the CDK enzyme, or in an organism expressing the CDK enzyme. In some embodiments, the invention provides methods of inhibiting the CDK enzyme activity in an animal (including mammal such as humans) by contacting said animal with an amount of a compound of the invention sufficient to inhibit the activity of the CDK enzyme in said animal.
[113] The following general methodology described herein provides the manner and process of making and using the compounds of the present invention and are illustrative rather than limiting. Further modification of provided methodology and additionally new methods may also be devised to achieve and serve the purpose of the invention. Accordingly, there may be other embodiments which fall within the spirit and scope of the invention as defined by the specification hereto.
General Method of Preparation of Compounds of the Invention
Scheme-1:
Step-1:
Figure imgf000058_0001
Step-2:
Figure imgf000059_0001
Step-1:
[114] A compound of formula (a) (wherein X is a leaving group such as halogen) coupled with a compound of formula (b) to form a compound of formula (c). a protecting group is added to a compound of formula (c) to from a compound of formula (d). Compound of formula (d) is converted to compound of formula (e).
[115] Alternatively, a compound of formula (a) (wherein X is a leaving group such as halogen) is N-arylated with a compound of formula (j) to form a compound of formula (k). A compound of formula (k) is converted to a compound of formula (1) by reduction.
[116] A compound of formula (a) (wherein X is a leaving group such as halogen) upon borylation with bispinacolato diboron form a compound of formula (m). A compound of formula (m) can be coupled with a compound of formula (n) under Heck coupling conditions to form a compound of formula (o). A compound of formula (o) is converted to form a compound of formula (p) by reduction.
Step-2: [117] A compound of formula (f) can be converted to a compound of formula (g) by using bis(pinacolatodiboron) and potassium acetate. A compound of formula (g) can be coupled with a compound of formula (h) under Suzuki reaction conditions, for example, in the presence of a suitable base and a palladium catalyst such as Pd(dppf)2Cl2.CH2Cl2, to form a compound of formula (i). A compound of formula (i) can be coupled with a compound of formula (e) or (p) under Buchwald coupling reaction conditions, for example, in the presence of a suitable base and a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0), to form a compound of formula (la) or (1). A compound of formula (la) is deprotected to form compound of formula (I)
Illustration- 1
Figure imgf000060_0001
Illustration-3:
Figure imgf000061_0001
Illustration-5: Step-2:
(f) (g) (i) (I)
Step-1:
[118] A compound of formula (al) (wherein X is a leaving group such as halogen) can be coupled with a compound of formula (bl) (where LG is a leaving group) to form a compound of formula (cl). A compound of formula (cl) is converted to a compound of formula (el).
Step-2:
[119] A compound of formula (f) can be converted to a compound of formula (g) by using bis(pinacolatodiboron) and potassium acetate. A compound of formula (g) can be coupled with a compound of formula (h) under Suzuki reaction conditions, for example, in the presence of a suitable base and a palladium catalyst such as PdidppfkCh.CHiCb, to form a compound of formula (i). A compound of formula (i) can be coupled with a compound of formula (el) under Buchwald coupling reaction conditions, for example, in the presence of a suitable base and a Palladium catalyst such as Tris(dibenzylideneacetone)dipalladium(0), to form a compound of formula (I).
Illustration-6:
Figure imgf000063_0001
Experimental Data [120] General: Unless otherwise mentioned, work up implies distribution of the reaction mixture into the aqueous and organic phases mentioned in parentheses, separation of the organic layer, drying on anhydrous sodium sulphate, fdtration and evaporation of the organic layer to obtain the crude product.
General Procedure-1: Preparation of Aryl boronic acid pinacol ester:
[121] To a solution of an aryl bromide (1 eq.) in DMSO were added bis(pinacolatodiboron) (1.5 eq) and potassium acetate (3.0 eq). The mixture was degassed with nitrogen for 15 mins. Palladium acetate (0.11 eq) and tricyclohexyl phosphine (0.17 eq) were added and the mixture degassed for further 15 min. and stirred at 80°C until starting material disappeared as monitored by TLC. After completion of the reaction, the reaction mixture was fdtered on celite and the bed washed with Ethyl acetate. Combined fdtrate and washings were washed successively with brine and water and the organic layer dried on anhydrous sodium sulphate and distilled under vacuum to obtain the crude product which was purified by column chromatography.
General Procedure-2: Suzuki coupling reaction:
[122] To a solution of 2,4-dichloro-4-fluoropyrimidine (1 eq.) in dioxane and water (5: 1) were added an arylboronic acid or an arylboronic acid pinacol ester (1.3 eq), tetrakis(triphenylphosphine)palladium(0) (0.08 eq) and potassium carbonate (3.3 eq). The mixture was degassed with nitrogen for 30 min. and refluxed. After completion of reaction as indicated by TLC, Work-up (HiO/AcOEt) and purification gave the desired product.
General Procedure-3: Buchwald coupling reaction:
[123] Chloro compound (1 eq), aniline (1 eq), Xantphos (0.2 eq) and Sodium fert-butoxide (1.6 eq) were suspended in dioxane (15 Vol) and degassed for 15 mins. Tris(dibenzylideneacetone)dipalladium(0) (0.17 eq) was added and degassed for further 15 min. The reaction mixture was stirred at 90 °C for 1.5 h. Progress of the reaction monitored by TLC. After completion of the reaction, filtration through celite, washing the celite pad with DCM-MeOH (9: 1) followed by work up (LhO/DCM-MeOH 9: 1) and purification gave the desired product.
General Procedure-4: Boc deprotection reaction:
[124] Boc protected amine (1 eq) dissolved in DCM (20 Vols) and cooled to 0°C. To this mixture Trifluoroacetic acid (5 eq) was added and stirred at 25°C for 2 h. After completion of the reaction as indicated by TLC, the reaction mixture was basified with aq. satd. NaHCCh solution to pH ~ 8 to obtain a solid. Solid was fdtered and dried to obtain the titled compound. If solid was not formed during basification, work up (FFO/AcOEt) afforded the titled compound.
Intermediate 1: 6-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline:
[125] Following the general procedure-1, the titled compound was synthesized from 6- Bromoquinoline (3.0 g, 14.42 mmol). After work up, the crude product was purified by column chromatography on 60-120 mesh silica gel using EtOAc and Petroleum ether (5:95) as eluent to obtain the titled compound as a brown liquid (3.2 g). Yield: 87%.1H-NMR (d ppm, CDCb, 400 MHz): 8.92-8.96 (m, 1H), 8.35 (s, 1H), 8.19 (dd, J = 8.0, 1.2, 1H), 8.08 (br. s, 2H), 7.41 (dd, J = 8.0, 4.0, 1H), 1.34 (s, 12H).
Intermediate 2: 6-(2-Chloro-5-fluoropyrimidin-4-yl)quinoline:
[126] Following the general procedure-2, the titled compound was synthesized from Intermediate 1 (3.0 g, 11.75 mmol) and 2,4-dichloro-4-fluoropyrimidine (1.96 g, 11.75 mmol). After work up, crude product was purified by combi-flash using EtOAc and Petroleum ether (21:79) as eluent to obtain the titled compound as a pale-yellow solid (1.7 g). Yield: 55%.1H- NMR (d ppm, DMSO-rie, 400 MHz): 8.90-9.05 (m, 2H), 8.74 (s, 1H), 8.62 (d, J = 8.4, 1H), 8.35 (d, J = 8.8, 1H), 8.20 (d, J = 9.2, 1H), 7.65 (dd, J = 8.4, 4.4, 1H).
Intermediate 3: l-(6-nitropyridin-3-yl)piperazine :
[127] 5-Bromo-2-nitropyridine (13 g, 64 mmol), piperazine (7.17 g, 83 mmol), tetrabutylammonium iodide (1.18 g, 3.2 mmol) and potassium carbonate (13 g, 94 mmol) were suspended in DMSO (158 ml). This mixture was stirred at 90 °C for 16 h. After completion of the reaction, reaction mixture diluted with water and extracted with DCM. DCM layer distilled under vacuum to obtain the titled compound as a brown solid. 'H-NMR (d ppm, D SO-t/e. 400 MHz): 8.23 (d, J = 3.2, 1H), 8.13 (d, J = 9.2, 1H), 7.44 (dd, J = 9.2, 3.2, 1H), 3.42 (t, J = 5.2, 4H), 2.85 (t, J = 5.2, 4H).
Intermediate 4: te/i- butyl 4-(6-nitropyridin-3-yl)piperazine-l-carboxylate:
[128] Intermediate 3 (11.6 g, 55.7 mmol) was dissolved in THF (135 ml) and added water (13.5 ml) and sodium bicarbonate (2.81 g, 33.4 mmol). This mixture was stirred for 5 mins and Boc anhydride (6.08 g, 27.9 mmol) was added slowly. The reaction mixture was stirred at rt for 1 h. After 1 h reaction mixture quenched with water and extracted with DCM (2*250 ml). Combined DCM layers washed with brine (250 ml). DCM layer dried on anhydrous NaiSCri and evaporated under vacuum to obtain a yellow solid, which was stirred with diethyl ether (50 ml) for 15 mins and fdtered to obtain the titled compound as a yellow solid (11.2 g). Yield: 65%. ¾-NMR (d ppm, CDCb, 400 MHz): 8.18 (d, J = 9.2, 1H), 8.13 (d, J = 2.8, 1H), 7.21 (dd, J = 9.2, 2.8, 1H), 3.64 (t, J = 5.2, 4H), 3.45 (t, J = 5.2, 4H), 1.49 (s, 9H).
Intermediate 5: tert- butyl 4-(6-aminopyridin-3-yl)piperazine-l-carboxylate:
[129] Intermediate 4 (11 g, 35.7 mmol) was taken in an autoclave, dissolved in a mixture of methanol (110 ml) and ethanol (110 ml) and 5% palladium on carbon (2.42g) was added. This mixture was stirred at rt under 5 kg hydrogen pressure for 5 h. After completion of the reaction, reaction mixture was filtered through celite bed, and the bed washed with a 1 : 1 mixture of methanol and ethanol (200 ml). Filtrate and washings were combined and the solvents evaporated. Water was added to the residue and extracted with EtOAc (2*250 ml). Combined organic layers were washed successively with water (150 ml) and brine (150 ml), dried on anhydrous NaiSCri and distilled to obtain the titled compound as a brown solid (7 g). Yield: 70%.1H-NMR (d ppm, DMSO-rie, 400 MHz): 7.60 (d, J = 2.8, 1H), 7.16 (dd, J = 8.8, 2.8, 1H), 6.38 (d, J = 8.8, 1H), 5.44 (br. s, 2H), 3.41 (t, J = 4.8, 4H), 2.84 (t, J = 4.8, 4H), 1.40 (s, 9H).
Intermediate 6: 8-Fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline:
[130] Following the general procedure-1, the titled compound was synthesized from 6- Bromo-8-fluoroquinoline (3.0 g, 13.27 mmol). After work up, the crude product was purified by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (20:80) as eluent to obtain the titled compound as a brown liquid (1.6 g). Yield: 44%. 'H-NMR (d ppm, CDCb, 400 MHz): 9.00 (dd, J = 4.0, 1.6, 1H), 8.22 (br. d, J = 8.4, 1H), 8.13 (s, 1H), 7.76 (d, J = 9.8, 1H), 7.48 (dd, J = 8.4, 4.4, 1H).
Intermediate 7 : 6-(2-Chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinoline:
[131] Following the general procedure-2, the titled compound was synthesized from Intermediate 6 (1.5 g, 5.49 mmol) and 2,4-dichloro-4-fluoropyrimidine (917 mg, 5.49 mmol). After work up, crude product was purified by combi-flash using EtOAc and Petroleum ether (20:80) as eluent. Pure fractions from combi-flash were combined and distilled to obtain the titled compound as a brown solid (1.1 g). Yield: 80%. 'H-NMR (d ppm, CDCb, 400 MHz): 9.06-9.12 (m, 1H), 8.62 (d, J = 2.8, 1H), 8.53 (s, 1H), 8.35 (d, J = 8.4, 1H), 8.24 (d, J = 11.6, 1H), 7.59 (dd, J = 8.4, 4.0, 1H).
Intermediate 8: l-((6-Bromopyridin-3-yl)methyl)-4-ethylpiperazine: [132] 6-Bromonicotinaldehyde (5 g, 26.9 mmol) and 1-ethylpiperazine (3.38 g, 29.6 mmol) were dissolved in DCM (50 ml) and stirred at rt for 5 min. Sodium triacetoxyborohydride (6.15 g, 29.03 mmol) was added and stirring continued for 18 h. Work up (aq. 2N NaOH/DCM) afforded the crude product which was co-distilled with EtOAc to obtain the titled compound as a brown liquid (7.2 g). Yield: 95%. ¾-NMR (d ppm, CDCb, 400 MHz): 8.28 (d, J = 2.4, 1H), 7.54 (dd, J = 8.0, 2.4, 1H), 7.42 (d, J = 8.0, 1H), 3.46 (s, 2H), 2.49 (br. s, 8H), 2.42 (q, J = 7.2, 2H), 1.08 (t, J = 7.2, 3H).
Intermediate 9: 5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-amine:
[133] Intermediate 8 (21.0 g, 73.6 mmol), (dicyclohexylphosphino)biphenyl (2.6 g, 7.3 mmol) and tris(dibenzylideneacetone)dipalladium (3.3 g, 3.6 mmol) were suspended in THF (210 ml) and degassed with nitrogen for 30 mins. After 30 mins, the mixture was heated to 50°C and a 1M solution of LiHMDS in THF (184.6 ml, 184.6 mmol) was added dropwise. After complete addition, the mixture was heated at 65 °C overnight. The mixture was cooled to RT, water (200 ml) was added and THF was evaporated. To the residual aqueous layer was added aq. 36% solution of hydrochloric acid (200 ml) and washed with DCM (3*250 ml). The aqueous layer was separated, basified with aq. 10% NaOH solution (900 ml) and extracted into DCM (6*500 ml). Combined organic layers were dried over anhydrous sodium sulphate and the solvents evaporated. The residue was washed with diethyl ether to obtain the titled compound as a pale yellow solid (8.6 g). Yield: 52.8 %. ¾-NMR (d ppm, CDCb, 400 MHz): 7.60 (d, J = 2.0, 1H), 7.42 (dd, J 8.4, 2.0, 1H), 6.48 (d, J 8.4, 1H), 4.37 (br. s, 2H), 3.38 (s, 2H), 2.30-2.70 (m, 10H), 1.07 (t, J = 7.2, 3H).
Intermediate 10: l-Methyl-4-(6-nitropyridin-3-yl)piperazine:
[134] 5-Bromo-2-nitropyridine (6 g, 29.56 mmol), 1-methylpiperazine (4.44 g, 44.3 mmol), tetrabutylammonium iodide (546 mg, 1.48 mmol) and potassium carbonate (6.12 g, 44.3 mmol) were suspended in DMSO (60 ml) and stirred at 80°C for 16 h. The reaction mixture was diluted with water (400 ml), extracted with DCM (3*250 ml) and combined organic layers distilled under vacuum to obtain the crude product. Purification by combi-flash using methanol and DCM (3.5:96.5) as eluent gave the titled compound as a yellow solid (4 g). Yield: 61%. ¾- NMR (d ppm, CDCb, 400 MHz): 8.17 (d, J = 9.2, 1H), 8.14 (d, J = 3.2, 1H), 7.20 (dd, J = 9.2, 3.2, 1H), 3.48 (t, J = 4.8, 4H), 2.59 (t, J = 4.8, 4H), 2.37 (s, 3H).
Intermediate 11: 5-(4-Methylpiperazin-l-yl)pyridin-2-amine: [135] Intermediate 10 (4 g, 18.0 mmol) was taken in an autoclave and dissolved in a mixture of methanol (20 ml) and ethanol (20 ml) and 5% palladium on carbon (957 mg) was added. This mixture was stirred at rt under 4.5 kg hydrogen pressure for 5 h. After completion of the reaction, reaction mixture was filtered through a celite bed and the bed washed with a mixture of methanol and ethanol (1: 1, 50 ml). Combined filtrate and washings were evaporated. Water was added to the residue and extracted with EtOAc (2*50 ml). Combined organic layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous NaiSCri and distilled to obtain the crude product. Purification by combi-flash chromatography with 3.5% MeOH in DCM as the eluent gave the titled compound as a maroon colour solid (2.5 g). Yield: 72%. 'H- NMR (d ppm, CDCb, 400 MHz): 7.57 (d, J = 2.8, 1H), 7.14 (dd, J = 8.8, 2.8, 1H), 6.37 (d, J = 8.8, 1H), 5.36 (br. s, 2H), 2.90 (t, J = 4.8, 4H), 2.41 (t, J = 4.8, 4H), 2.19 (s, 3H).
Intermediate 12: 5-Bromo-7-fluoroindoline-2,3-dione:
[136] 7-Fluoroindoline-2,3-dione (50 g, 303 mmol) was dissolved in acetic acid (330 ml) and cooled to 0°C. Bromine (48.4 g, 303 mmol) was added dropwise to the stirred solution and stirring continued for 1 h at 0 to 5°C. After 1 h, the mixture was poured into ice cold water (500 ml). The solid precipitated was filtered, washed with water (100 ml) and dried in an oven to obtain the titled compound as a brick red solid (65 g). Yield: 88%. 'H-NMR (d ppm, CDCb, 400 MHz): 11.66 (s, 1H), 7.87 (dd, J = 9.6, 1.6, 1H), 7.56 (s, 1H).
Intermediate 13: 6-Bromo-8-fluoro-2-methylquinoline-4-carboxylic acid:
[137] Intermediate 12 (65 g, 0.27 mol) was suspended in a solution of potassium hydroxide (103.4 g, 1.84 mol) in water (2.3 L) and acetone (260 ml) was added. This mixture was stirred at 50°C for 4 h. One more lot of acetone (260 ml) was added to the reaction mixture and stirred at 50°C for 16 h. The reaction mixture was cooled to rt and the pH adjusted using 6N HC1 to ~ 3 when a solid was precipitated. The solid was filtered, washed with hot water (650 ml) and dried in an oven at 70°C for 15 h to obtain the titled compound as an off-white solid. 'H-NMR (d ppm, CDCb, 400 MHz): 14.14 (br. s, 1H), 8.72 (s, 1H), 8.00 (s, 1H), 7.90-7.96 (m, 1H), 2.72 (s, 3H).
Intermediate 14: 6-Bromo-8-fluoro-N-methoxy-N,2-dimethylquinoline-4-carboxamide:
[138] Intermediate 13 (800 mg, 2.82 mmol) was dissolved in DCM (16 mL) and cooled to 0°C. To this mixture one drop of DMF was added followed by dropwise addition of oxalyl chloride (429 mg, 3.38 mmol). After complete addition of oxalyl chloride, the reaction mixture was allowed to warm up to rt and stirred for 2 h. Dichloromethane and oxalyl chloride were distilled out from the mixture and co-distilled with DCM (lOmL) to obtain the residue of the acid chloride. Separately, N,O-dimethylhydroxylamine hydrochloride (275 mg, 2.82 mmol) was dissolved in DCM, cooled to 0°C, triethylamine (627 mg, 6.2 mmol) was added and stirred for 30 min. at 0 °C. To this mixture, a solution of the acid chloride described above in DCM (16 ml) was added slowly at 0°C. After complete addition, the reaction mixture was allowed to warm up to 25 °C and stirred for 16 h. The reaction was mixture was diluted with water and the layers separated. The aqueous layer was extracted with DCM (2*30 ml). Combined organic layers were washed successively with satd. Aq. NaHCCb solution (30 ml) and brine (30 ml). The organic layers were dried over sodium sulphate and the solvents distilled out to obtain the crude product. Purification by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (2:8) as eluent gave the titled compound as a yellow solid (500 mg). Yield: 54%. ¾-NMR (d ppm, CDCb, 400 MHz): 7.75 (br. s, 1H), 7.54 (dd, J = 9.6, 1.6, 1H), 7.35 (s, 1H), 3.48 (br. s, 3H), 3.41 (br. s, 3H), 2.79 (s, 3H).
Intermediate 15: l-(6-Bromo-8-fluoro-2-methylquinolin-4-yl)ethan-l-one:
[139] Intermediate 14 (45 g, 137.4 mmol) was dissolved in THF (450 ml) and cooled to 0°C and methylmagnesium chloride (3M in THF, 69 ml, 207 mmol) was added slowly. The mixture was stirred at rt for 2 h. The reaction mixture was quenched with aq. NH4CI solution. And extracted with EtOAc. The organic layer was washed successively with water and brine solution, dried on anhydrous Na2S04 and distilled to obtain the crude product. Purification by combi-flash using EtOAc and petroleum ether (12:88) as eluent gave the titled compound as a brown solid (27.4 g). Yield: 71%.1H-NMR (d ppm, CDCb, 400 MHz): 8.46 (br. s, 1H), 7.61 (s, 1H), 7.57 (dd, J = 10.0, 2.0, 1H), 2.84 (s, 3H), 2.75 (s, 3H).
Intermediate 16: 6-Bromo-8-fhioro-2-methyl-4-(prop-l-en-2-yl)quinoline:
[140] Methyl triphenylphosphonium bromide (50.65 g, 0.142 mol) was dissolved in THF (50 ml), potassium fert-butoxide (15.91 g, 0.142 mol) was added and stirred at rt for 5 mins. A solution of the intermediate 15 (20 g, 71 mol) in THF (100 ml) was added dropwise to this mixture over a period of 30 mins and stirred at rt for 8 h. The reaction was quenched with satd. aq. NaHCCb and extracted with EtOAc (2*500 ml). The Organic layer was washed successively with brine (2*250 ml) and water (250 ml), dried on anhydrous Na2S04 and distilled to obtain the crude product. Purification by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (0.5:99.5) as eluent gave the titled compound as an off-white solid (5.7 g). Yield: 29%.1H-NMR (d ppm, CDCb, 400 MHz): 7.93 (s, 1H), 7.50 (dd, J = 8.0, 1.6, 1H), 7.18 (s, 1H), 5.50 (s, 1H), 5.12 (s, 1H), 2.76 (s, 3H), 3.19 (s, 3H).
Intermediate 17: 8-Fluoro-2-methyl-4-(prop-l-en-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline:
[141] Following the general procedure- 1, the titled compound was synthesized from Intermediate 16 (1.0 g, 3.57 mmol). After work up, crude product was purified by combi-flash using EtOAc and petroleum ether (7:93) as eluent to obtain the titled compound as an off-white solid (500 mg). Yield: 43 %. ¾-NMR (d ppm, CDCb, 400 MHz): 8.22 (s, 1H), 7.72 (d, J = 10.8, 1H), 7.16 (s, 1H), 5.50 (s, 1H), 5.14 (s, 1H), 2.78 (s, 1H), 2.22 (s, 3H), 1.37 (s, 12H).
Intermediate 18: 6-(2-Chloro-5-fluoropyrimidin-4-yl)-8-fluoro-2-methyl-4-(prop-l-en-2- yl)quinoline:
[142] The titled compound was synthesized from Intermediate 17 (2.5 g, 7.64 mmol) and 2,4- dichloro-4-fluoropyrimidine (1.53 g, 9.17 mmol) by general procedure-2 with the following modification: potassium fluoride (1.33 g, 22.9 mmol) was used as base instead of potassium carbonate. After work up (EtO Ac/brine), crude product was purified by combi -flash using petroleum ether and EtOAc (99: 1) as eluent to obtain the titled compound as an off-white solid (1.4 g). Yield: 55 %. ¾-NMR (d ppm, CDCb, 400 MHz):8.65 (s, 1H), 8.57 (d, J = 2.8, 1H), 8.19 (dd, J = 11.6, 1.6, 1H), 7.27 (s, 1H), 5.57 (s, 1H), 5.19 (s, 1H), 2.82 (s, 3H), 2.25 (s, 3H).
Intermediate 19: l-Ethyl-4-(6-nitropyridin-3-yl)piperazine:
[143] 5-Bromo-2-nitropyridine (4 g, 19.7 mmol), 1-ethylpiperazine (3.38 g, 29.56 mmol), tetrabutylammonium iodide (364 mg, 0.99 mmol) and potassium carbonate (4.09 g, 29.6 mmol) were suspended in DMSO (37.5 ml) and stirred at 80°C for 15 h. The reaction mixture was diluted with water (400 ml), extracted with DCM (3*250 ml) and combined organic layers were washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulphate and distilled under vacuum to obtain the crude product. Purification by combi-flash using methanol and DCM (4:96) as eluent gave the titled compound as a yellow solid (3 g). Yield: 64%. ¾- NMR (d ppm, CDCb, 400 MHz): 8.17 (d, J = 9.2, 1H), 8.14 (d, J = 3.2, 1H), 7.20 (dd, J = 9.2, 3.2, 1H), 3.48 (t, J = 5.2, 4H), 2.61 (t, J = 5.2, 4H), 2.49 (q, J = 7.2, 3H), 1.14 (t, J = 7.2, 3H).
Intermediate 20: 5-(4-Ethylpiperazin-l-yl)pyridin-2-amine:
[144] Intermediate 19 (5 g, 18. mmol) was taken in an autoclave and dissolved in a mixture of methanol (25 ml) and ethanol (25 ml) and 5% palladium on carbon (1.13 g) was added. This mixture was stirred at rt under 4.5 kg hydrogen pressure for 5 h. After completion of the reaction, reaction mixture was filtered through a celite bed and the bed washed with a mixture of methanol and ethanol (1: 1, 50 ml). Combined filtrate and washings were evaporated. Water was added to the residue and extracted with EtOAc (2*50 ml). Combined organic layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous NaiSCft and distilled to obtain the crude product. Purification by combi-flash chromatography with 3.2% MeOH in DCM as the eluent gave the titled compound as an ash colour solid (4.0 g). Yield: 92%. 'H- NMR (d ppm, DMSO-t/e, 400 MHz): 7.57 (d, J = 2.8, 1H), 7.14 (dd, J = 8.8, 2.8, 1H), 6.38 (d, J = 8.8, 1H), 5.36 (s, 2H), 2.93-2.85(m, 4H), 2.48-2.42(m, 4H), 2.33 (q, J = 7.2, 2H), 1.00 (t, J = 7.2, 3H).
Intermediate 21: 6-Bromo-8-fluoro-2-methylquinoline:
[145] Crotonaldehyde (612 mg, 8.74 mmol) was added to a mixture of 4-Bromo-2- fluoroaniline (2.00 g, 10.5 mmol) and aqueous 6N hydrochloric acid (42.1 ml) and stirred at RT for lh. Toluene (11 ml) was added and the mixture heated at 110 °C for 17 h, cooled to RT and the layers were separated. The organic layer was extracted with aq. 6N HC1 (50 ml). Combined aqueous layers were basified to pH 10-11 with aq. 10% sodium hydroxide solution and extracted into DCM (3* 100 ml). Combined organic layers were washed successively with brine solution (100 ml) and water (100 ml), dried over sodium sulfate and concentrated. Purification of the residue by combi-flash chromatography system with petroleum ether - EtOAc (95:5) as the eluent gave the titled compound as a pale-yellow solid (1.2 g). Yield: 47%. ¾-NMR (d ppm, CDCb, 400 MHz):7.80 (dd, J = 8.4, 1.2, 1H), 7.74 (s, 1H), 7.51 (dd, J = 9.6, 1.6, 1H), 7.37 (d, J = 8.4, 1H), 2.78 (s, 3H).
Intermediate 22: 8-Fluoro-2-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinoline:
[146] Following the general procedure- 1, the titled compound was synthesized from Intermediate 21 (1.0 g, 3.57 mmol). After work up, crude product was purified by combi-flash using EtOAc and petroleum ether (8:92) as eluent to obtain the titled compound as a pale- yellow solid (3.5 g). Yield: 60%. ¾-NMR (d ppm, CDCb, 400 MHz): 8.03-8.12 (m, 2H), 7.72 (d, J = 11.2, 1H), 7.35 (d, J = 8.4, 1H), 2.80 (s, 3H), 1.37 (s, 12H).
Intermediate 23: 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinoline:
[147] Following the general procedure-2, the titled compound was synthesized from Intermediate 22 (3.5 g, 12.19 mmol) and 2,4-dichloro-4-fluoropyrimidine (2.24 g, 13.41 mmol). After work up, crude product was purified by combi -flash using EtOAc and Petroleum ether (20:80) as eluent to obtain the titled compound as an off-white solid (2.5 g). Yield: 70%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.04 (d, J = 3.2, 1H), 8.45-8.60 (m, 2H), 8.07 (d, J = 12.0, 1H), 7.63 (d, J = 8.4, 1H), 2.73 (s, 3H).
Intermediate 24: l-Isopropyl-4-(6-nitropyridin-3-yl)piperazine:
[148] 5-Bromo-2-nitropyridine (5 g, 25.6 mmol), 1-isopropylpiperazine (4.11 g, 32.0 mmol), tetrabutylammonium iodide (455 mg, 1.23 mmol) and potassium carbonate (5.11 g, 36.9 mmol) were suspended in DMSO (253 ml) and stirred at 90°C for 16 h. The reaction mixture was diluted with water (400 ml), extracted with DCM (3*250 ml) and combined organic layers were washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulphate and distilled under vacuum to obtain the crude product. Purification by combi-flash using methanol and DCM (2:98) as eluent gave the titled compound as a yellow solid (3.4 g). Yield: 55 %. 'H- NMR (d ppm, DMSO-rie, 400 MHz): 8.16 (d, J 8, 1H), 8.13 (d, J 3.2, 1H), 7.19 (d, J 8, 3.2, 1H), 3.46 (t, J 5.2, 4 H), 2.76 (septet, J 6.4, 1H), 2.69 (t, J 5.2, 4H), 1.09 (d, J 6.4, 6H).
Intermediate 25: 5-(4-Isopropylpiperazin-l-yl)pyridin-2-amine:
[149] Intermediate 24 (3.4 g, 14 mmol) was taken in an autoclave and dissolved in a mixture of methanol (35 ml) and ethanol (35 ml) and 5% palladium on carbon (1.13 g) was added. This mixture was stirred at rt under 4.5 kg hydrogen pressure for 5 h. After completion of the reaction, reaction mixture was filtered through a celite bed and the bed washed with a mixture of methanol and ethanol (1: 1, 50 ml). Combined filtrate and washings were evaporated. Water was added to the residue and extracted with EtOAc (2*50 ml). Combined organic layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous Na2S04 and distilled to obtain the crude product. Crude product was triturated with diethyl ether gave the titled compound as a grey colour solid (2.3 g). Yield: 76%. 'H-NMR (d ppm, D SO-t/e. 400 MHz):7.57 (d, J 3.2, 1H), 7.13 (dd, J 8.8, 3.2, 1H), 6.37 (d, J 8.8, 1H), 5.35 (s, 2H), 2.88 (t, J 4.4, 4 H), 2.63 (septet, J 6.8, 1H), 0.98 (d, J 6.8, 6 H).
Intermediate 26: l-((6-Bromopyridin-3-yl)methyl)-4-methylpiperazine :
[150] 6-Bromonicotinaldehyde (5 g, 27 mmol) and 1-Methylpiperazine (2.96 g, 29.5 mmol) were dissolved in DCM (50 ml) and stirred at rt for 5 min. Sodium triacetoxyborohydride (9.25 g, 43.6 mmol) was added and stirring continued for 24 h. Work up (aq. 2N NaOH/DCM) afforded the crude product which was co-distilled with EtOAc to obtain the titled compound as a brown liquid (7.2 g). Yield: 99%. ¾-NMR (d ppm, CDCb, 400 MHz): 8.30 (d, J 2, 1H), 7.56 (dd, J = 8, 2, 1H), 7.43 (d, J 8, 1H), 3.46 (s, 2H), 2.60-2.38 (m, 8H), 2.28 (s, 3H).
Intermediate 27: 5-((4-Methylpiperazin-l-yl)methyl)pyridin-2-amine :
[151] Intermediate 25 (7 g, 25.9 mmol), (dicyclohexylphosphino)biphenyl (908 mg, 2.6 mmol) and tris(dibenzylideneacetone)dipalladium (1.19 g, 1.3 mmol) were suspended in THF (70 ml) and degassed with nitrogen for 30 mins. After 30 mins, the mixture was heated to 50°C and a 1M solution of LiHMDS in THF (64.8 ml, 64.8 mmol) was added dropwise. After complete addition, the mixture was heated at 65 °C overnight. The mixture was cooled to RT, water (200 ml) was added and THF was evaporated. To the residual aqueous layer was added aq. 36% solution of hydrochloric acid (200 ml) and washed with DCM (3*250 ml). The aqueous layer was separated, basified with aq. 10% NaOH solution (900 ml) and extracted into DCM (6*500 ml). Combined organic layers were dried over anhydrous sodium sulphate and the solvents evaporated. The residue was washed with diethyl ether to obtain the titled compound as a pale-yellow solid (3.2 g). Yield: 60 %. ¾-NMR (d ppm, CDCb, 400 MHz): 7.96 (d, J = 2.5, 1H), 7.42 (dd, J = 8.4, 2.5, 1H), 6.48 (d, J = 8.4, 1H), 4.37 (bs, 2H), 3.37 (s, 2H), 2.70-2.30 (m, 8H), 2.27 (s, 3H).
Intermediate 28: Methyl 6-bromo-8-fhioro-2-methylquinoline-4-carboxylate:
[152] Sulfuric acid (12 mL, 0.22 mmol) was added to a solution of 6-Bromo-8-fluoro-2- methylquinoline-4-carboxylic acid, (intermediate 13, 36 g, 130 mmol) in methanol (360 mL) and the mixture refluxed for 48 h. Methanol was removed by distillation and water (200 mL) was added to the residue and basified with satd. aq. NaHCCb solution. The solid was filtered, dissolved in methanol - dichloromethane (1:9, 400 mL). The solution was washed with satd. aq. NaHCCb solution (3* 100 mL), the organic layer dried over sodium sulfate and evaporated to give the title compound as a yellow solid (31.5 g). Yield: 83%. 'H-NMR (d ppm, DMSO-t/e. 400 MHz): 8.61 (d, J = 2.0, 1H), 8.0 (s, 1H), 7.96 (dd, J = 10.0, 2.0, 1H), 3.98 (s, 3H), 2.73 (s, 3H).
Intermediate 29: 2-(6-Bromo-8-fhioro-2-methylquinolin-4-yl)propan-2-ol :
[153] A 1M solution of methylmagnesium bromide in THF (290 mL, 290 mmol) was added slowly at 0 °C to a solution of 6-bromo-8-fluoro-2-methylquinoline-4-carboxylate (intermediate 28, 17 g, 57 mmol) in THF (250 mL) and stirred at the same temperature for 2 h. Aq. satd. ammonium chloride solution (50 mL) was added to the mixture and extracted into ethyl acetate (2*50 mL). The organic layer was washed successively with water (50 mL) and brine (50 mL), dried over sodium sulfate and evaporated to give a residue that was purified by silica gel column chromatography on a combi-flash system, eluting with ethyl acetate-hexane (15:85) to give the title compound as an off-white solid (11 g). Yield: 65%. 'H-NIV1R (5 ppm, DMSO-rie, 400 MHz): 8.89 (br. s, 1H), 7.78 (dd, J = 10.0, 2.0, 1H), 7.50 (s, 1H), 2.65 (s, 3H), 1.64 (s, 6H).
Intermediate 30: (8-Fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)boronic acid :
[154] Triisopropyl borate (8.1 mL, 35.0 mmol) was added dropwise at -78 °C to a solution of 2-(6-bromo-8-fluoro-2-methylquinolin-4-yl)propan-2-ol (Intermediate 29, 5.1 g, 17 mmol) in dry THF (20 mL) under nitrogen atmosphere. A 2.5M solution of «-Bull in THF (8.1 mL, 35 mmol) was added dropwise to the above mixture and stirred for 2 hrs at the same temperature. The mixture was brought up to RT and acidified with 2N HC1, stirred for 30 min., neutralised by the addition of aq. 10% NaOH, stirred for 20 min. and extracted into ethyl acetate (2* 100 mL). The combined organic layers were washed successively with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. The residue was stirred with petroleum ether (10 mL) for 20 min. and the solid formed was filtered and dried. Off-white solid (3.0 g). Yield: 68%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 8.85 (s, 1H), 8.30 (s, 2H), 7.74 (dd, J = 11.6, 1H), 7.32 (s, 1H), 2.65 (s, 3H), 1.69 (s, 6H).
Intermediate 31 : 2-(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4- yl)propan-2-ol :
[155] Following the general procedure-2, the titled compound was synthesized from (8- fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)boronic acid (3.0 g, 11.4 mmol) and 2,4-dichloro-4-fhioropyrimidine (2.09 g, 12.5 mmol). After work up, crude product was purified by combi -flash using MeOH and DCM (1:99) as eluent to obtain the titled compound as a pale-yellow solid (2.5 g). Yield: 63%. ¾-NMR (d ppm, DMSO-rfc, 400 MHz): 9.49 (s, 1H), 9.02 (d, J = 3.2, 1H), 8.02 (d, J = 11.6, 1H), 7.60 (s, 1H), 2.94 (s, 3H), 1.70 (s, 6H).
Intermediate 32: (6-Bromo-8-fluoro-2-methylquinolin-4-yl)methanol:
[156] A solution of methyl 6-bromo-8-fluoro-2-methylquinoline-4-carboxylate (Intermediate 28, lOOg, 335 mmol) in ethanol (1.0 L) was cooled to 10°C and sodium borohydride (50.8, 1.34 mol) was added in portions over 45 min. and the mixture stirred at 60 °C for 90 min. The mixture was cooled to 25 °C, diluted with water (1.5 L) and stirred for 1 h. The solid formed was filtered, washed with water and dried under vacuum for 5 h and then in a hot air oven at 70 °C for 17 h to give the title compound as an off-white solid (74 g). Yield: 82%.
Intermediate 33: 6-Bromo-8-fluoro-2-methylquinoline-4-carbaldehyde:
[157] Dimethyl sulfoxide (45.4 mL, 640 mmol) was added dropwise at -78°C to a solution of oxalyl chloride (36.55, 418 mmol) in dichloromethane (300 mL) over 30 min. and stirred for further 20 min. A solution of (6-bromo-8-fluoro-2-methylquinolin-4-yl)methanol (Intermediate 32, 60 g, 222.1 mmol) in dichloromethane (300 mL) was added to the above mixture at -78°C over 45 min. and stirred for further 30 min. Triethylamine (111 mL, 800 mmol) was added slowly to reaction mixture and stirred for 30 min. After adding water (500 mL), the mixture was warmed up to room temperature and extracted into dichloromethane (2*500 mL). Combined organic layers were washed successively with water (500 mL) and brine (500 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography on a combi-flash system using petroleum ether - EtOAc (90: 10) as the eluent to give the product as an off-white solid (40 g). Yield: 67%. 'H-NIV1R (5 ppm, CDCb, 400 MHz): 10.37 (s, 1H), 9.00 (s, 1H), 7.76 (s, 1H), 7.63 (dd, J = 9.6, 2.0, 1H), 2.90 (s, 3H).
Intermediate 34: 6-Bromo-4-(difhioromethyl)-8-fhioro-2-methylquinoline :
[158] (Diethylamino)sulfur trifluoride (20.97 g, 130.1 mmol) was added at 25° C to a solution of 6-bromo-8-fluoro-2-methylquinoline-4-carbaldehyde (Intermediate 33, 10.0 g, 37.3 mmol) in dichloromethane (108 mL) and the mixture stirred for 16 h. After adjusting the pH between 7.0 and 8.0 by addition of aq. satd. sodium bicarbonate solution at 0 °C, the mixture was extracted into dichloromethane (2*500 mL). Combined organic layers were washed with water (250 mL) and brine (250 mL), dried over sodium sulfate and concentrated. Purification of the residue by silica gel chromatography on a combi-flash system using petroleum ether - EtOAc (92:8) as the eluent gave the product as an off-white solid (8.0 g). Yield: 74%. 'H-NMR (5 ppm, CDCb, 400 MHz): 7.99 (s, 1H), 7.60 (dd, J = 9.6, 2.0, 1H), 7.55 (s, 1H), 7.03 (t, J = 54.0, 1H), 2.83 (s, 3H).
Intermediate 35: (4-(Difhioromethyl)-8-fhioro-2-methylquinolin-6-yl)boronic acid :
[159] Triisopropyl borate (9.93 mL, 43.0 mmol) was added dropwise at -78 °C to a solution of 6-Bromo-4-(difhioromethyl)-8-fluoro-2-methylquinoline (Intermediate 34, 6.0 g, 20.7 mmol) in dry THF (215 mL) under nitrogen atmosphere. A 2.5M solution of «-Bull in THF (16.1 mL, 40.3 mmol) was added dropwise to the above mixture and stirred for 2 hrs at the same temperature. The mixture was brought up to RT and acidified with 2N HC1, stirred for 30 min., neutralised by the addition of aq. 10% NaOH, stirred for 20 min. and extracted into ethyl acetate (2* 100 mL). The combined organic layers were washed successively with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. The residue was stirred with diethyl ether (30 mL) for 30 min. and the solid formed was filtered and dried. Yellow solid (4.1 g). Yield: 78%. TLNMR^ppm, DMSO-rie, 400 MHz): 8.48 (br. s, 2H), 8.37 (s, 1H), 7.89 (d, J =11.6, 1H), 7.73 (s, 1H), 7.62 (t, J = 53.6, 1H), 2.75 (s, 3H).
Intermediate 36: 6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-(difluoromethyl)-8-fluoro-2- methylquinoline:
[160] Following the general procedure-2, the titled compound was synthesized from (4- (difluoromethyl)-8-fhioro-2-methylquinolin-6-yl)boronic acid (Intermediate 35, 4.0 g, 15.7 mmol) and 2,4-dichloro-4-fluoropyrimidine (2.88 g, 17.3 mmol). After work up, crude product was purified by combi -flash using petroleum ether - EtOAc (8:2) as eluent to obtain the titled compound as an off-white solid (2.5 g). Yield: 46.6%. 'H-NMR (5 ppm, CDCb, 400 MHz): 8.70 (br. s, 1H), 8.65 (d, J = 3.2, 1H), 8.30 (d, J = 11.2, 1H), 7.66 (s, 1H), 7.20 (t, J = 54.0, 1H), 2.93 (s, 3H).
Intermediate 37: 6-Bromo-8-fluoro-4-(2-fluoropropan-2-yl)-2-methylquinoline :
[161] (Diethylamino) sulfur trifluoride (5.41 g, 33.5 mmol) was added at 10-15 ° C to a solution of 2-(6-bromo-8-fluoro-2-methylquinolin-4-yl)propan-2-ol (Intermediate 29, 5.0 g, 16.8 mmol) in dichloromethane (50 mL) and the mixture stirred overnight. The mixture was diluted with dichloromethane (100 mL) and washed successively with aq. satd. sodium bicarbonate solution (2*50 mL), water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. Purification of the residue by silica gel chromatography on a combi-flash system using petroleum ether - EtOAc (90:10) as the eluent gave the product as an off-white solid (2.30 g). Yield: 50%. ¾-NMR (d ppm, CDCb, 400 MHz): 8.23 (s, 1H), 7.52 (dd, J = 11.2, 1.2, 1H), 8.30 (d, J = 11.2, 1H), 7.37 (s, 3H), 2.72 (s, 1H), 1.92 (d, J = 22.4, 3H).
Intermediate 38: (8-Fluoro-4-(2-fluoropropan-2-yl)-2-methylquinolin-6-yl)boronic acid:
[162] Triisopropyl borate (0.792 mL, 3.43 mmol) was added dropwise at -78 °C to a solution of 6-bromo-4-(difluoromethyl)-8-fluoro-2-methylquinoline (Intermediate 37, 500 mg, 1.67 mmol) in dry THF (20 mL) under nitrogen atmosphere. A 2.5M solution of «-Bull in hexane (2.0 mL, 5.0 mmol) was added dropwise to the above mixture and stirred for 2 hrs at the same temperature. The mixture was brought up to RT and acidified with 2N HC1, stirred for 30 min., neutralised by the addition of aq. 10% NaOH, stirred for 20 min. and extracted into ethyl acetate (2* 100 mL). The combined organic layers were washed successively with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. The residue was stirred with petroleum ether (20 mL) for 20 min. and the solid formed was filtered and dried. Off-white solid (170 mg). Yield: 38.5%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 8.49 (s, 1H), 8.42 (s, 2H), 7.79 (d, J = 11.2, 1H), 7.52 (s, 1H), 2.69 (s, 3H), 1.92 (d, J = 23.2, 6H).
Intermediate 39: 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-(2-fluoropropan-2-yl)-2- methylquinoline:
[163] Following the general procedure-2, the titled compound was synthesized from (8- fluoro-4-(2-fluoropropan-2-yl)-2-methylquinolin-6-yl)boronic acid (Intermediate 38, 1.80 g, 6.79 mmol) and 2,4-dichloro-4-fluoropyrimidine (1.25 g, 7.47 mmol). After work up, crude product was purified by combi -flash using methanol - dichloromethane (9:1) as eluent. After removal of the solvents from pooled fractions, the residue was stirred with petroleum ether (20 mL), solides filtered and dried to obtain the titled compound as a yellow solid (1.3 g). Yield: 54.4%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.03 (d, J = 3.2, 1H), 8.90 (s, 1H), 8.06 (d, J = 11.6, 1H), 7.65 (s, 1H), 2.74 (s, 1H), 1.93 (d, J =22.4, 6H).
Intermediate 40: 7-Fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline:
[164] 6-Bromo-7-fluoroquinoline was prepared as described by Fei et. al. in bioorganic & medicinal Chemistry 2016, 24(18), 4281-4290. Following the general procedure-1, the titled compound was synthesized from 6-Bromo-7-fluoroquinoline (500 mg, 2.21 mmol). After work up, crude product was purified by combi-flash using EtOAc and Petether (3:97) as eluent to obtain the titled compound as a yellow liquid (200 mg). Yield: 33 %.Yield: 33%. 'H-NMR (d ppm, CDCL, 400 MHz): 8.93 (dd, J = 4.4, 1.6, 1H), 8.31 (d, J = 6.4, 1H), 8.19 (br. d, J = 8.4, 1H), 7.71 (br. d, J = 10.8, 1H), 7.37 (dd, J = 8.4, 4.4, 1H), 1.42 (s, 12H). MS (m/z); 274.24 (M+H); calculated for [C15H17BFNO2+H]: 274.14.
Intermediate 41: 7-Fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline:
[165] Following the general procedure-2, the titled compound was synthesized from 7 -fluoro- 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (Intermediate 40, 5.0 g, 18.3 mmol) and 2,4-dichloro-5-fluoropyrimidine (3.67 g, 22.0 mmol). After work up, crude product was purified by combi-flash using petroleum ether - EtOAc (8:2) as eluent to obtain the titled compound as an off-white solid (3. lg). Yield: 61%. 'H-NIV1R (5 ppm, CDCb, 400 MHz): 9.02 (dd, J = 4.4, 1.6, 1H), 8.63 (d, J = 1.6, 1H), 8.28 (d, J = 8.4, 1H), 8.26 (d, J = 7.6, 1H), 7.91 (d, J = 9.6, 1H), 7.49 (dd, J = 8.0, 4.0, 1H).
Intermediate 42: N,N-dimethyl-l-(6-nitropyridin-3-yl)piperidin-4-amine
[166] 5-Bromo-2-nitropyridine (5 g, 24.6 mmol), N,N-Dimethylpiperidin-4-amine (4.11 g, 32.0 mmol) and potassium carbonate (5.11 g, 36.9 mmol) were suspended in DMSO (50 ml) and stirred at 90°C for 16 h. The reaction mixture was diluted with water (500 ml), extracted with DCM (2*200 ml) and combined organic layers were washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulphate and distilled under vacuum to obtain the crude product. Purification by combi-flash using methanol and DCM (2:98) as eluent gave the titled compound as a yellow solid (3.6 g). Yield: 58 %. ^-NMR id ppm, CDCb, 400 MHz): 8.15 (d, J 9.2, 1H), 8.13 (d, J 3.2, 1H), 7.19 (dd, J 9.2, 3.2, 1H), 4.00-3.93 (m, 2H), 3.10-3.02 (m, 2H), 2.46-2.36 (m, 1H), 2.31 (s, 6H), 2.00 (d, J 12.4, 2H), 1.70-1.56 (m, 2H).
Intermediate 43: 5-(4-(Dimethylamino)piperidin-l-yl)pyridin-2-amine
[167] Intermediate 42 (2.7 g, 11 mmol) was taken in an autoclave and dissolved in a mixture of methanol (25 ml) and ethanol (25 ml) and 5% palladium on carbon (1.08 g) was added. This mixture was stirred at rt under 4.5 kg hydrogen pressure for 4 h. After completion of the reaction, reaction mixture was filtered through a celite bed and the bed washed with a mixture of MeOH and DCM (1:9, 100 ml). Combined filtrate and washings were evaporated to obtain a solid. Solid was triturated with petether gave the titled compound as a grey colour solid (2.1 g). Yield: 88%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 7.58 (d, J 3.0, 1H), 7.14 (dd, J 8.8, 3.0, 1H), 6.36 (d, J 8.8, 1H), 5.35 (s, 2H), 3.40-3.32 (m, 2H), 2.55-2.45 (m, 2H), 2.17 (s, 6H), 2.15-2.06 (m, 1H), 1.78 (d, J 12.4, 2H), 1.52-1.40 (m, 2H).
Intermediate 44: 4-(6-Nitropyridin-3-yl)piperazin-2-one:
[168] 5-Bromo-2-nitropyridine (4.04 g, 19.9 mmol), piperazin-2-one (2.39 g, 23.9 mmol) and DIPEA (9.26 g, 71.6 mmol) were suspended in DMSO (50 ml) and stirred at 120°C for 16 h in a sealed tube. DIPEA was distilled out to obtain a residue. EtOAc (30 ml) was added to residue and stirred for 30 mins to obtain a solid. Solid was filtered and dried under vacuum for 3 h to obtain the titled compound as a yellow solid (2.5 g). Yield: 57 %. 'H-NMR (d ppm, DMSO-t/e. 400 MHz): 8.27 (bs, 1H), 8.22-8.15 (m, 2H), 7.44 (dd, J 9.2, 3, 1H), 4.04 (s, 2H), 3.72-3.65 (m, 2H), 3.41-3.32 (m, 2H). Intermediate 45: 4-(6-Aminopyridin-3-yl)piperazin-2-one:
[169] Intermediate 44 (1.9 g, 8.55 mmol) was taken in an autoclave and dissolved in a mixture of methanol (15 ml) and ethanol (15 ml) and 5% palladium on carbon (760 mg) was added. This mixture was stirred at rt under 4.5 kg hydrogen pressure for 4 h. After completion of the reaction, reaction mixture was filtered through a celite bed and the bed washed with a mixture of MeOH and DCM (1:9, 100 ml). Combined filtrate and washings were evaporated to obtain a solid. Solid was triturated with petether gave the titled compound as a brown colour solid (800 mg). Yield: 49 %. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 7.58 (d, J 3.2, 1H), 7.27 (dd, J 8.8, 3.2, 1H), 6.46 (d, J 8.8, 1H), 5.89 (bs, 2H), 3.48 (s, 2H), 3.27-3.22 (m, 2H), 3.48 (s, 2H), 3.18-3.13 (m, 2H).
Intermediate 46: l-Cyclopropyl-4-(6-nitropyridin-3-yl)piperazine:
[170] 5-Bromo-2-nitropyridine (5 g, 24.6 mmol), (Piperazin-l-yl)cyclopropane (3.73 g, 29.6 mmol) and potassium carbonate (5.11 g, 36.9 mmol) were suspended in DMSO (63.25 ml) and stirred at 90°C for 16 h. The reaction mixture was diluted with water (500 ml), extracted with DCM (2*200 ml) and combined organic layers were washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulphate and distilled under vacuum to obtain the crude product. Purification by combi-flash using methanol and DCM (2:98) as eluent gave the titled compound as a yellow solid (4 g). Yield: 65 %. 'H-NMR (d ppm, CDCb, 400 MHz): 8.16 (d, J 9.2, 1H), 8.13 (d, J 3.0, 1H), 7.20 (dd, J 9.2, 3.0 (1H), 3.42 (t, J 5.2, 4H), 2.78 (t, J 5.2, 4H), 1.72-1.65 (m, 1H), 0.55-0.49 (m, 2H), 0.48-0.42 (m, 2H).
Intermediate47: 5-(4-Cyclopropylpiperazin-l-yl)pyridin-2-amine :
[171] Intermediate 46 (2.7 g, 11 mmol) was taken in an autoclave and dissolved in a mixture of methanol (25 ml) and ethanol (25 ml) and 5% palladium on carbon (1.08 g) was added. This mixture was stirred at rt under 4.5 kg hydrogen pressure for 4 h. After completion of the reaction, reaction mixture was filtered through a celite bed and the bed washed with a mixture of MeOH and DCM (1:9, 100 ml). Combined filtrate and washings were evaporated to obtain a solid. Solid was triturated with petether gave the titled compound as a grey colour solid (2.1 g). Yield: 88%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 7.56 (d, J 3, 1H), 7.13 (dd, J 9.2, 3, 1H), 6.37 (d, J 9.2, 1H), 5.36 (s, 2H), 2.85 (t, J 4.8, 4H), 2.62 (t, J 4.8, 4H), 1.62 (quintet, J 3.2, 1H), 0.45-0.38 (m, 2H), 0.32-0.26 (m, 2H).
Intermediate 48: l-(4-(6-Nitropyridin-3-yl)piperazin-l-yl)ethan-l-one [172] Intermediate 3 (1.50 g, 7.20 mmol) and Triethylamine (729 mg, 7.20 mmol) were dissolved in DCM (30 ml) and stirred at 0°C for 30 mins. Acetyl chloride (679 mg, 8.64 mmol) was added to the above mixture and stirred at rt for 30 mins. Reaction mixture quenched with water (100 ml) and separated organic and aqueous layer. Aqueous layer extracted with DCM (3*80 ml). Combined organic layers were distilled to obtain a solid. Solid was triturated with Diethyl ether and fdtered. Filtered solid was dried under vacuum to obtain the titled compound as a yellow solid (1.5 g). Yield: 83%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 8.25 (s, 1H), 8.18 (d, J 9.2, 1H), 7.48 (d, J 9.2, 1H), 3.60 (bs, 6H), 3.52 (bs, 2H), 2.05 (s, 3H).
Intermediate 49: l-(4-(6-Aminopyridin-3-yl)piperazin-l-yl)ethan-l-one:
[173] Intermediate 48 (1.50 g, 5.99 mmol) was taken in an autoclave and dissolved in a mixture of methanol (13 ml) and ethanol (13 ml) and 5% palladium on carbon (600 mg) was added. This mixture was stirred at rt under 4.5 kg hydrogen pressure for 24 h. After completion of the reaction, reaction mixture was fdtered through a celite bed and the bed washed with a mixture of MeOH and DCM (1:9, 170 ml). Combined fdtrate and washings were evaporated to obtain a solid. Solid was triturated with diethylether gave the titled compound as a grey colour solid (1 g). Yield: 80%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 7.60 (d, J 3.0, 1H), 7.17 (dd, J 8.8, 3.0, 1H), 6.39 (d, J 8.8, 1H), 5.44 (s, 2H), 3.53 (q, J 5, 4H), 2.89 (t, J 5, 2H), 2.82 (, J 5, 2H), 2.00 (s, 3H).
Intermediate 50: l-(6-nitropyridin-3-yl)-4-(2,2,2-trifluoroethyl)piperazine:
[174] 5-Bromo-2-nitropyridine (1.5 g, 7.4 mmol), l-(2,2,2-Trifluoroethyl)piperazine (1.5 g, 8.9 mmol) and potassium carbonate (1.5 g, 11 mmol) were suspended in DMSO (20 ml) and stirred at 90°C for 16 h. The reaction mixture was diluted with water (200 ml), extracted with DCM (2*200 ml) and combined organic layers were washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulphate and distilled under vacuum to obtain the crude product. Purification by combi-flash using methanol and DCM (2.5:97.5) as eluent gave the titled compound as a yellow solid (1.1 g). Yield: 51 %. ¾-NMR (d ppm, CDCb, 400 MHz): 8.17 (d, J 9.2, 1H), 8.14 (d, J 3.0, 1H), 7.22 (d, J 9.2, 3.2, 1H), 3.48 (t, J 5, 4H), 3.08 (q, J 9.6, 2H), 2.87 (t, J 5, 4H).
Intermediate 51: 5-(4-(2,2,2-Trifluoroethyl)piperazin-l-yl)pyridin-2-amine:
[175] Intermediate 50 (1.1 g, 3.8 mmol) was taken in an autoclave and dissolved in amixture of methanol (10 ml) and ethanol (10 ml) and 5% palladium on carbon (440 mg) was added. This mixture was stirred at rt under 4.5 kg hydrogen pressure for 4 h. After completion of the reaction, reaction mixture was filtered through a celite bed and the bed washed with a mixture of MeOH and DCM (1:9, 100 ml). Combined filtrate and washings were evaporated to obtain the titled compound as a brown colour solid (800 mg). Yield: 81 %. 'H-NIV1R (5 ppm, DMSO- de, 400 MHz): 7.60 (d, J 2.5, 1H), 7.16 (dd, J 8.8, 3.0, 1H), 6.40 (d, J 8.8, 1H), 5.39 (s, 2H), 3.23 (q, J 10, 2H), 2.92 (t, J 5, 4H), 2.74 (t, J 5, 4H).
Intermediate 52 : l-(Methylsulf onyl)-4-(6-nitropyridin-3-yl)piperazine :
[176] Intermediate 3 (1.50 g, 7.20 mmol) and Triethylamine (729 mg, 7.20 mmol) were dissolved in DCM (30 ml) and stirred at 0°C for 30 mins. Methanesulfonyl chloride (990 mg, 8.64 mmol) was added to the above mixture and stirred at rt for 30 mins. Reaction mixture quenched with water (100 ml) and separated organic and aqueous layer. Aqueous layer extracted with MeOH:DCM (1:9) (2* 100 ml). Combined organic layers were distilled to obtain a solid. Solid was triturated with Diethyl ether and filtered. Filtered solid was dried under vacuum to obtain the titled compound as a yellow solid (1.8 g). Yield: 87%. 'H-NMR (5 ppm, DMSO-rie, 400 MHz): 8.31 (d, J 2.8, 1H), 8.19 (d, J 9.2, 1H), 7.55 (dd, J 9.2, 2.8, 1H), 3.65 (t, J 5, 4H), 3.26 (t, J 5, 4H), 2.93 (s, 3H).
Intermediate 53: 5-(4-(Methylsulfonyl)piperazin-l-yl)pyridin-2-amine:
[177] Intermediate 53 ( 1.7 g, 5.94 mmol) was taken in an autoclave and dissolved in a mixture of methanol (13 ml) and ethanol (13 ml) and 5% palladium on carbon (600 mg) was added. This mixture was stirred at rt under 4.5 kg hydrogen pressure for 4 h. After completion of the reaction, reaction mixture was filtered through a celite bed and the bed washed with a mixture of MeOH and DCM (1:9, 170 ml). Combined filtrate and washings were evaporated to obtain a solid. Solid was triturated with Diethyl ether to obtain the titled compound as a brown colour solid (1.3 g). Yield: 85 %. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 7.64 (d, J 2.8, 1H), 7.20 (d, J 8.8, 2.8, 1H), 6.41 (d, J 8.8, 1H), 5.47 (s, 2H), 3.22 (t, J 4.8, 4H), 3.00 (t, J 4.8, 4H), 2.91 (s, 3H).
Intermediate 54: Cyclopropyl(4-(6-nitropyridin-3-yl)piperazin-l-yl)methanone:
[178] Step-1: Cyclopropylcarboxylic acid (744 mg, 8.64 mmol) was dissolved in DCM (10 ml) and cooled to 0°C. Oxalyl chloride (1.37 g, 10.8 mmol) and DMF (0.05 ml) was added to the above solution and stirred at rt for 2 h. After 2 h, reaction mixture was distilled out to obtain cyclopropylcarbonyl chloride which can be used in the next step without further purification. [179] Step-2: Intermediate 3 (1.50 g, 7.20 mmol) and Triethylamine (1.09 g, 10.8 mmol) were dissolved in DCM (10 ml) and stirred at 0°C for 30 mins. Cyclopropylcarbonyl chloride was added to the above mixture by dissolving in DCM (10 ml) and stirred at rt for 30 mins. Reaction mixture quenched with aq. NaHCCb solution up to pH~7 and separated organic and aqueous layer. Aqueous layer extracted with DCM (2* 100 ml). Combined organic layers were distilled to obtain a solid. Solid was triturated with Diethyl ether and fdtered. Filtered solid was dried under vacuum to obtain the titled compound as a yellow solid (1.6 g). Yield: 80 %. 'H-NMR (d ppm, CDCb, 400 MHz): 8.25 (d, J 2.8, 1H), 8.17 (d, J 9.2, 1H), 7.47 (dd, J 9.2, 2.8, 1H), 3.91-3.80 (m, 2H), 3.70-3.49 (m, 6H), 2.05-1.95 (m, 1H), 0.80-0.68 (m, 4H).
Intermediate 55: (4-(6-Aminopyridin-3-yl)piperazin-l-yl)(cyclopropyl)methanone:
[ 180] Intermediate 54 ( 1.5 g, 5.43 mmol) was taken in an autoclave and dissolved in a mixture of methanol (12 ml) and ethanol (12 ml) and 5% palladium on carbon (600 mg) was added. This mixture was stirred at rt under 4 kg hydrogen pressure for 5 h. After completion of the reaction, reaction mixture was fdtered through a celite bed and the bed washed with a mixture of MeOH and DCM (1:9, 170 ml). Combined fdtrate and washings were evaporated to obtain a solid. Solid was triturated with Diethyl ether to obtain the titled compound as a pink colour solid (1.1 g). Yield: 82 %. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 7.63 (d, J 2.4, 1H), 7.20 (dd, J 8.8, 2.4, 1H), 6.41 (d, J 8.8, 1H), 5.45 (s, 2H), 3.78 (bs, 2H), 3.57 (bs, 2H), 3.00-2.80 (m, 4H), 2.05-2.97 (m, 1H), 0.80-0.65 (m, 4H).
Intermediate 56: 7-(6-Nitropyridin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-
[1.2.4]triazolo[4,3-a]pyrazine:
[181] 5-Fluoro-2-nitropyridine (4.04 g, 19.9 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-
[1.2.4]triazolo[4,3-a]pyrazine (5 g, 26 mmol) and DIPEA (10.1 g, 78.1 mmol) were suspended in DMF (37 ml) and stirred at 120°C for 16 h. Reaction mixture quenched with water (100 ml). Aqueous layer extracted with MeOH:DCM (1:9) (3* 100 ml). Combined organic layers were distilled out to obtain a Crude. Crude was purified by combi-flash using MeOH and DCM (2.2:97.8) as eluent to obtain the titled compound as a yellow solid (2.7 g). Yield: 33 %. 'H- NMR (d ppm, DMSO-rie, 400 MHz): 8.43 (d, J 3.0, 1H), 8.21 (d, J 9.2, 1H), 7.70 (dd, J 9.2, 3.0, 1H), 5.04 (s, 2H), 4.33 (t, J 5.2, 2H), 4.09 (t, J 5.2, 2H).
Intermediate 57 : 5-(3-(T rifluoromethyl)-5, 6-dihydro- [1,2,4] triazolo [4,3-a] pyrazin- 7(8H)-yl)pyridin-2-amine: [ 182] Intermediate 56 (1. l g, 4.16 mmol) was taken in an autoclave and dissolved in a mixture of methanol (9 ml) and ethanol (9 ml) and 5% palladium on carbon (440 mg) was added. This mixture was stirred at rt under 4 kg hydrogen pressure for 5 h. After completion of the reaction, reaction mixture was filtered through a celite bed and the bed washed with a mixture of MeOH and DCM (1:9, 170 ml). Combined filtrate and washings were evaporated to obtain a solid. Solid was triturated with Diethyl ether to obtain the titled compound as a brown colour solid (840 mg). Yield: 86 %. Tl-NMR (d ppm, DMSO-rie, 400 MHz): 7.75 (d, J 2.8, 1H), 7.31 (dd, J 9.2, 2.8, 1H), 6.43 (d, J 9.2, 1H), 5.57 (s, 2H), 4.42 (s, 2H), 4.22 (t, J 5.2, 2H), 3.51 (t, J 5.2, 2H).
Intermediate 58: 4-Methyl-l-(6-nitropyridin-3-yl)piperidin-4-ol:
[183] 5-Bromo-2-nitropyridine (2.18 g, 12.9 mmol), 4-Methylpyrimidin-4-ol (1.48 g, 12.9 mmol) and potassium carbonate (2.23 g, 16.1 mmol) were suspended in DMSO (14 ml) and stirred at 90°C for 16 h. The reaction mixture was diluted with water (200 ml), extracted with DCM (2*200 ml) and combined organic layers were washed with brine (100 ml) and water (100 ml), dried over anhydrous sodium sulphate and distilled under vacuum to obtain the crude product. Purification by combi-flash using methanol and DCM (2.5:97.5) as eluent gave the titled compound as a yellow solid (1.1 g). Yield: 51 %. ¾-NMR (d ppm, CDCb, 400 MHz): 8.23 (d, J 2.8, 1H), 8.10 (d, J 9.6, 1H), 7.44 (dd, J 9.6, 2.8, 1H), 4.47 (s, 1H), 3.79-3.70 (m, 2H), 3.41-3.31 (m, 2H), 1.59-1.48 (m, 4H), 1.14 (s, 3H). MS (m/z): 238.16 (M+H); calculated for [C11H15N3O3+H]: 238.11.
Intermediate 59: l-(6-Aminopyridin-3-yl)-4-methylpiperidin-4-ol :
[184] Intermediate 58 (900 mg, 3.79 mmol) was taken in an autoclave and dissolved in a mixture of methanol (10 ml) and ethanol (10 ml) and 5% palladium on carbon (440 mg) was added. This mixture was stirred at rt under 4 kg hydrogen pressure for 5 h. After completion of the reaction, reaction mixture was filtered through a celite bed and the bed washed with a mixture of MeOH and DCM (1:9, 2000 ml). Combined filtrate and washings were evaporated to obtain a solid. Solid was triturated with Diethyl ether to obtain the titled compound as a brown colour solid (700 mg). Yield: 89 %. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 7.59 (d, J 2.8, 1H), 7.14 (dd, J 9.6, 3.0, 1H), 6.36 (d, J 8.8, 1H), 5.31 (s, 2H), 4.20 (s, 1H), 2.96-2.85 (m, 4H), 1.57-1.50 (m, 4H), 1.12 (s, 3H). MS (m/z): 208.16 (M+H); calculated for [C11H17N3O+H]: 208.28.
Intermediate 60: (±)-l-(6-Bromo-8-fluoro-2-methylquinolin-4-yl)ethan-l-amine: [185] Intermediate 15 (200 g, 0.708 mol) was suspended in 2M Methanolic ammonia (1.88 It, 3.75 mol). To this mixture titanium (IV) isopropoxide (403 g, 1.42 mol) was added and stirred at rt for 16 h. After 16 h, reaction mixture cooled to 0°C and sodium borohydride (40.23 g, 1.06 mol) was added, warmed to rt and stirred at rt for 5 h. After 5 h, reaction mixture was quenched with Aq. Ammonia (2 It) and EtOAc (2 It) to obtain a solid. Solid was filtered and washed the solid with EtOAc (10 It). Combined filtrates were washed with water (3 It) and brine (2.5 It). Aqueous layer was extracted with EtOAc (8 It). Combined EtOAc layers were distilled out to obtain a crude. Crude was co-distilled with (3* 100 ml) toluene to obtain a solid. Solid was stirred with Diethyl ether (1 It) and filtered the solid. Solid was dried under vacuum to obtain titled compound as a brown solid (120.5 g). Yield: 60%. 'H-NIV1R (5 ppm, DMSO- de, 400 MHz): 8.22 (s, 1H), 7.81 (dd, J 10.4, 4, 1H), 7.73 (s, 1H), 4.70 (t, J 6.8, 1H), 2.66 (s, 3H), 2.09 (bs, 2H), 1.34 (d, J 6.8, 3H). MS (m/z): 283.17 (M+H); calculated for [CiiHiiBrFNi+H]: 284.02.
Intermediate 61: (±)-Tert-buty\ (l-(6-bromo-8-fluoro-2-methylquinolin-4- yl)ethyl)carbamate:
[186] Intermediate 60 (16 g, 56.5 mmol) dissolved in DCM (160 ml) and cooled to 0°C. To this solution, triethylamine (8.58 g, 84.76 mmol) was added. Bocanhydride (14.8 g, 67.8 mmol) was added to this mixture and stirred at rt for 2 h. After 2h, reaction mixture diluted with water (900 ml) and separated the organic layer. Aqueous layer again extracted with a mixture of MeOH and DCM (1:9) (3*500 ml). Combined organic layers were washed with water (2*500 ml) and aq. Sodium bicarbonate (3*500 ml). Organic layer dried on anhydrous NaiSOr and distilled to obtain titled compound as an off-white solid (20.8 g). It can be used in next step without further purification. Yield: 96%. 'H-NMR (5 ppm, DMSO-rfc, 400 MHz): 8.22 (s, 1H), 7.86 (dd, J 10.4, 2, 1H), 7.71 (d, J 7.6, 1H), 7.47 (s, 1H), 5.31 (t, J 7.2, 1H), 2.65 (s, 3H), 1.40 (d, J 7.2, 1H), 1.37 (s, 9H). MS (m/z): 383.18 (M+H); calculated for [CnHioBrFNiOi+H]: 383.07.
Intermediate 62: (±)-7’e//-butyl (l-(8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinolin-4-yl)ethyl)carbamate:
[187] Following the general procedure- 1, the titled compound was synthesized from Intermediate 61 (18 g, 47 mmol). After work up, crude product was purified by combi-flash using EtOAc and Petether (20: 80) as eluent to obtain the titled compound as a pale-yellow solid (15.2 g). Yield: 75.2 %. ^-NMR (d ppm, DMSO-tfc, 400 MHz): 8.22 (s, 1H), 7.74 (d, J 7.6, 1H), 7.58 (d, J 10.8, 1H), 7.50 (s, 1H), 5.38 (t, J 6.8, 1H), 2.68 (s, 3H), 1.41 (d, J 6.8, 3H), 1.37 (s, 12 H), 1.15 (s, 9H). MS (m/z): 431.30 (M+H); calculated for [C23H32BFN2O4+H] : 431.33.
Intermediate 63: (±)-7er/-butyl (l-(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-2- methylquinolin-4-yl)ethyl)carbamate:
[188] Following the general procedure-2, the titled compound was synthesized from Intermediate 62 (15 g, 34.86 mmol) and 2,4-dichloro-5-fluoropyrimidine (6.98 g, 41.83 mmol). After completion of reaction, reaction mixture cooled to rt and stirred for 16 h to obtain a solid. Solid was filtered, washed with a mixture of Dioxane and water ( 1 : 1 ) (50 ml) and Petether (100 ml). Solid was co-distilled with toluene (2* 100 ml) at 65°C on rotavapor. Solid was stirred with a mixture of diethyl ether and Petether ( 1 : 1) ( 100 ml) for 30 mins . Solid was filtered and washed with Petether and diethyl ether mixture (1: 1) (50 ml). Solid was dried under vacuum to obtain the titled compound as a white solid (10 g). Yield: 67 %. 'H-NMR (5 ppm, DMSO-rfc, 400 MHz): 9.07 (d, J 3.2, 1H), 8.62 (s, 1H), 8.06 (d, J 11.2, 1H), 7.79 (d, J 3.2, 1H), 7.58 (s, 1H), 5.41 (t, J 6.8, 1H), 2.73 (s, 3H), 1.46 (d, J 6.8, 3H), 1.37 (s, 9H). MS (m/z): 435.24 (M+H); calculated for [C21H21CIF2N4O2+H]: 435.13.
Intermediate 64: 6-Bromo-8-fluoroquinoline-2,4-dicarboxylic acid:
[189] Intermediate 12 (l g, 4.10 mmol) was suspended in a solution of potassium hydroxide (10 g, 40.98 mmol) in water (360 ml) and sodium pyruvate (6.76 mg, 61.5 mmol) was added. This mixture was stirred at 50°C for 16 h. Reaction mixture cooled to 25°C and pH was adjusted to ~3 using 6N HC1 to obtain a solid. Solid was filtered and washed with water (200 ml) and dried in an oven at 70°C for 6 h to obtain the titled compound as a brown solid (8.2 g). Yield: 64%. ^-NMR (d ppm, DMSO-rfc, 400 MHz): 14.01 (bs, 2H), 8.89 (s, 1H), 8.57 (s, 1H), 8.11 (dd, J 10, 1.6, 1H). MS (m/z): 314.08 (M+H); calculated for [CnHsBrFNCri+H]: 313.94.
Intermediate 65: 6-Bromo-8-fluoroquinoline-4-carboxylic acid:
[190] Intermediate 64 (8 g, 25.5 mmol) was suspended in Nitrobenzene (80 ml) and heated to 220°C for 5 h. After 5 h, reaction mixture cooled to rt and diluted with Petether (320 ml) to obtain a solid. This mixture was stirred for 1 h and filtered the solid. Solid was washed with Petether (80 ml). Solid was dried under vacuum for 1 h to obtain the titled compound as a pale- brown solid (6.1 g). Yield: 89%. ¾-NMR (d ppm, DMSO-rfc, 400 MHz): 14.21 (s, 1H), 9.12 (d, J 4.4, 1H), 8.81 (s, 1H), 8.10 (d, J 4.4, 1H), 8.00 (dd, J 10, 2, 1H).
Intermediate 66: 6-Bromo-8-fluoro-N-methoxy-N-methylquinoline-4-carboxamide: [191] Intermediate 65 (3 g, 11.1 mmol), HATU (6.34 g, 16.7 mmol) and DIPEA (5.74 g, 44.4, mmol) were dissolved in DMF (30 ml). N,O-Dimethylhydroxylamine hydrochloride (2.17 g, 22.2 mmol) was added to the reaction mixture and stirred at rt for 16 h. After 16 h, reaction mixture diluted with water (150 ml) and extracted with EtOAc (3*70 ml). Combined organic layers were washed with aq. NaHCCh (3*100 ml) and brine (100 ml). Organic layer distilled to obtain crude. Crude was suspended in a mixture of Diethyl ether and Petether (1: 1) (40 ml) and stirred for 30 mins to obtain solid. Solid was filtered and washed with Diethyl ether and Petether (1: 1) (20 ml). Solid was dried under vacuum to obtain the titled compound as a pale- brown solid (2.5 g). Yield: 72%. ¾-NMR (d ppm, DMSO-tfc, 400 MHz): 9.06 (d, J 4, 1H), 8.00 (dd, J 10, 1, 1H), 7.81 (t, J 1.6, 1H), 7.77 (d, J 4, 1H), 3.41 (bs, 6H). MS (m/z): 313.15 (M+H); calculated for [CiiHioBrFNiOi+H]: 312.99.
Intermediate 67: l-(6-Bromo-8-fluoroquinolin-4-yl)ethan-l-one:
[192] Intermediate 66 (2.5 g, 7.98 mmol) was dissolved in THF (25 ml) and cooled to 0°C. Methylmagnesium chloride (3M in THF, 24.53 ml, 12 mmol) was added slowly. The mixture was stirred at rt for 3 h. The reaction mixture was quenched with aq. NHrCl solution and extracted with EtOAc (2*25 ml). The organic layer was washed successively with water (25 ml) and brine solution (25 ml), dried on anhydrous Na2S04 and distilled to obtain the crude product. Purification by combi-flash using EtOAc and petroleum ether (14:86) as eluent gave the titled compound as an off-white solid (900 mg). 'H-NMR (d ppm, D SO-A. 400 MHz): 9.17 (d, J 4.4, 1H), 8.46 (s, 1H), 8.15 (d, J 4.4, 1H),8.01 (dd, J 10. 1.6, 1H), 2.76 (s, 3H). MS (m/z): 268.15 (M+H); calculated for [CnHrBrFNO+H]: 267.97.
Intermediate 68: (±)-l-(6-Bromo-8-fluoroquinolin-4-yl)ethan-l-amine:
[193] Intermediate 67 (900 mg, 3.4 mmol) was suspended in 2M Methanolic ammonia (8.4 ml, 17mol). To this mixture titanium (IV) isopropoxide (1.9 g, 6.7 mol) was added and stirred at rt for 16 h. After 16 h, reaction mixture cooled to 0°C and sodium borohydride (190 mg, 5.03 mol) was added, warmed to rt and stirred at rt for 5 h. After 5 h, reaction mixture was quenched with Aq. Ammonia (9 ml) and EtOAc (25 ml) to obtain a solid. Solid was filtered and washed the solid with EtOAc (25 ml). Combined filtrates were washed with water (100 ml) and brine (100 ml). Aqueous layer was extracted with EtOAc (2*30 ml). Combined EtOAc layers were distilled out to obtain a crude. Crude was purified by combi-flash using MeOH and DCM (3:97) as eluent to obtain titled compound as an off-white solid (500 mg). Yield: 55 %. 'H-NMR (d ppm, DMSO-tfc, 400 MHz): 8.94 (d, J 4.4, 1H), 8.30 (s, 1H), 7.88 (dd, J 10, 1.6, 1H), 7.85 (d, J 4.4, 1H), 4.76 (q, J 6.4, 1H), 1.34 (d, J 6.8, 3H). MS (m/z): 269.16 (M+H); calculated for [CiiHioBrFNi+H]: 270.12.
Intermediate 69: (±)-7E/-/-butyl (l-(6-bromo-8-fluoroquinolin-4-yl)ethyl)carbamate:
[194] Intermediate 68 (2.1 g, 7.8 mmol) dissolved in DCM (21 ml) and cooled to 0°C. To this solution, triethylamine ( 1.18 g, 11.7 mmol) was added. Bocanhydride (2.04 g, 9.36 mmol) was added to this mixture and stirred at rt for 2 h. After 2h, reaction mixture diluted with water (100 ml) and separated the organic layer. Aqueous layer again extracted with DCM (3*70 ml). Combined organic layers were washed with water (100 ml) and aq. Sodium bicarbonate (3* 100 ml). Organic layer dried on anhydrous Na2S04 and distilled to obtain titled compound as an off-white solid (2.8 g). It can be used in next step without further purification. Yield: 97%. 'H- NMR (d ppm, DMSO-tfc, 400 MHz): 8.96 (d, J 4.4, 1H), 8.31 (s, 1H), 7.92 (dd, J 10, 1.6, 1H), 7.78 (d, J 7.6, 1H), 7.61 (d, J 4.4, 1H), 5.36 (t, J 6.8, 1H), 1.40 (d, J 6.8, 3H), 1.37 (s, 9H). MS (m/z): 369.12 (M+H); calculated for [CieHisBrFNiOi+H]: 369.05.
Intermediate 70: (±)-7e//-butyl (l-(8-fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl) quin olin-4-yl)ethyl)carb am ate :
[195] Following the general procedure- 1, the titled compound was synthesized from Intermediate 69 (2.8 g, 7.58 mmol). After work up, crude product was purified by combi-flash using EtOAc and Petether (23 : 77) as eluent to obtain the titled compound as a pale-yellow solid (1.7 g). Yield: 94 %. ¾-NMR (d ppm, DMSO-tfc, 400 MHz): 8.99 (d, J 4.4, 1H), 8.29 (s, 1H), 7.81 (d, J 7.6, 1H), 7.64 (d, J 7.2, 1H), 7.62 (s, 1H), 5.42-5.33 (m, 1H), 1.43 (d, J 6.8, 3H), 1.37 (s, 12 H), 1.35 (s, 9H). MS (m/z): 417.32 (M+H); calculated for [C22H30BFN2O4+H] : 417.23.
Intermediate 71: (±)-7er/-butyl (l-(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinolin- 4-yl)ethyl)carbamate:
[196] Following the general procedure-2, the titled compound was synthesized from Intermediate 70 (1.7 g, 4.08 mmol) and 2,4-Dichloro-5-fluoropyrimidine (818 mg, 4.9 mmol). After completion of reaction, water (100 ml) was added to reaction mixture and extracted with DCM (3*70 ml). Organic layer washed with water (100 ml) and distilled to obtain crude. Crude was purified by combi-flash using EtOAc and Petether (27:63) as eluent to obtain the titled compound as an off-white solid (600 mg). Yield: 30 %. 'H-NMR (d ppm, DMSO-rfc, 400 MHz): 9.09 (d, J 3.2, 1H), 9.07 (d, J 4.4, 1H), 8.68 (s, 1H), 8.11 (d, J 11.2, 1H), 7.84 (d, J 7.6, 1H), 7.70 (d, J 4.4, 1H), 5.49-5.38 (m, 1H), 1.47 (d, J 7, 3H), 1.36 (s, 9H). MS (m/z): 421.11 (M+H); calculated for [C20H19CIF2N4O2+H] : 421.12.
Intermediate 72: (±)-l-(6-Bromo-8-fluoroquinolin-4-yl)ethanol:
[197] Intermediate 67 (10 g, 37.3 mmol) was dissolved in a mixture of MeOH (100 ml) and THF (100 ml). To this mixture NaBFF (7.05 g, 186.5 mmol) was added and refluxed this mixture for 3 h. After 3 h, reaction mixture cooled to rt and water (500 ml) was added. Aqueous layer extracted with EtOAc (3*300 ml). Combined organic layers were washed with water (100 ml) and brine (100 ml). Organic layer distilled under reduced pressure to obtain a solid. Solid was suspended in diethyl ether (50 ml) and stirred for 30 mins. After 30 mins, filtered the solid and washed with diethyl ether (20 ml). Solid was dried under vacuum to obtain the titled compound as a yellow solid (9 g). Yield: 89 %. ^-NMR (d ppm, DMSO-rfc, 400 MHz): 8.96 (d, J 4.4, 1H), 8.28 (s, 1H), 7.89 (d, J 10, 1H), 7.74 (d, J 4.4, 1H), 5.69 (d, J 4.4, 1H), 5.50-5.43 (m, 1H), 1.45 (d, J 6.4, 3H). MS (m/z): 270.21 (M+H); calculated for [CnH9BrFNO+H]: 269.99.
Intermediate 73: (±)-l-(8-Fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinolin-4-yl)ethanol :
[198] Following the general procedure- 1, the titled compound was synthesized from Intermediate 72 (3.6 g, 13.3 mmol). After work up, crude product was purified by combi-flash using EtOAc and Petether (35:65) as eluent to obtain the titled compound as an off-white solid (900 mg). Yield: 21 %. ¾-NMR (d ppm, DMSO-rfc, 400 MHz): 8.98 (d, J 4.8, 1H), 8.34 (s, 1H), 7.73 (d, J 4.8, 1H), 7.61 (d, J 10, 1H), 5.68 (d, J 4.8, 1H), 5.50-5.42 (m, 1H), 1.49 (d, J 6.4, 3H), 1.35 (s, 12H). MS (m/z): 318.40 (M+H); calculated for [C17H21BFNO3+H]: 318.16.
Intermediate 74: (±)-l-(6-(2-Chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4- yl)ethanol :
[199] Following the general procedure-2, the titled compound was synthesized from Intermediate 73 (900 mg, 2.84 mmol) and 2,4-Dichloro-5-fluoropyrimidine (474 mg, 2.84 mmol). After completion of reaction, reaction mixture stirred at rt for 16 h to obtain a solid. Solid was filtered and washed with a mixture of Dioxane and water (1: 1) (17 ml) and Petether (100 ml). Solid was co-distilled with toluene at 65 °C. Solid was suspended in diethyl ether (20 ml) and stirred for 30 mins. After 30 mins solid was filtered and washed with diethyl ether (20 ml). Solid was dried under vacuum to obtain the titled compound as an off- white solid (600 mg). Yield: 66 %. ¾-NMR (d ppm, DMSO-tfc, 400 MHz): 9.07 (d, J 3.2, 1H), 9.06 (d, J 4.4, 1H), 8.76 (s, 1H), 8.09 (d, J 11.6, 1H), 7.82 (d, J 4.4, 1H), 5.79 (d, J 4, 1H), 5.53-5.45 (m, 1H), 1.53 (d, J 6.4, 3H). MS (m/z): 322.25 (M+H); calculated for [C15H10CIF2N3O+H]: 322.05.
Intermediate 75: (±)-l-(6-Bromo-8-fluoro-2-methylquinolin-4-yl)ethan-l-ol :
[200] To a solution of Intermediate 15 (2.7 g, 9.57 mmol) in a mixture of Methanol (27 ml) and THF (27 ml), sodium borohydride (50.8, 1.34 mol) was added in portions. The reaction mixture was stirred at 80 °C for 3 h. The mixture was cooled to 25 °C, diluted with water (150 ml) and aqueous layer was extracted with EtOAc (3*80 ml). Combined organic layers were washed with water (100 ml) and brine (100 ml). Organic layer was distilled to obtain crude. Crude was stirred with Petether (40 ml) for 30 mins to obtain a solid. Solid was fdtered and washed with pethether (20 ml). Solid was dried under vacuum to obtain the titled compound as an off-white solid (2.3 g). Yield: 85%. 'H-NMR (d ppm, DMSO-tfc, 400 MHz): 8.20 (s, 1H), 7.83 (dd, J 10.4, 2, 1H), 7.61 (s, 1H), 5.65 (d, J 4.4, 1H), 5.43-5.35 (m, 1H), 2.66 (s, 3H), 1.43 (d, J 6.4, 3H). MS (m/z): 284.20 (M+H); calculated for [CnHnBrFNO+H]: 285.13.
Intermediate 76: (±)-l-(8-Fluoro-2-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinolin-4-yl)ethan-l-ol :
[201] Following the general procedure- 1, the titled compound was synthesized from Intermediate 75 (2.3 g, 8.10 mmol). After work up, crude product was purified by combi-flash using EtOAc and Petether (35:65) as eluent to obtain the titled compound as an off-white solid (1 g). Yield: 37 %. ¾-NMR (d ppm, DMSO-tfc, 400 MHz): 8.27 (s, 1H), 7.60 (s, 1H), 7.56 (d, J 10.8, 1H), 5.64 (bs, 1H), 5.43-5.41 (m, 1H), 2.69 (s, 3H), 1.47 (d, J 6.4, 3H), 1.34 (s, 12 H). MS (m/z): 332.36 (M+H); calculated for [C18H23BFNO3+H]: 332.19.
Intermediate 77: (±)-l-(6-(2-Chloro-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin- 4-yl)ethan-l-ol :
[202] Following the general procedure-2, the titled compound was synthesized from Intermediate 76 (950 mg, 2.9 mmol) and 2,4-dichloro-5-fluoropyrimidine (570 mg, 3.4 mmol). After completion of reaction, reaction mixture cooled to rt and water was added to obtain a solid. Solid was filtered and washed with a mixture of Dioxane and water(Tl) (10 ml). Solid was further washed with petether (20 ml). Solid was stirred with diethyl ether (20 ml). Solid was filtered and washed with Diethyl ether. Solid was again stirred with Diethylether (20 ml) for 30 mins and filtered the solid. Solid was dried to obtain the titled compound as an off-white solid (670 mg). Yield: 70%. ¾-NMR (d ppm, DMSO-rfc, 400 MHz): 9.05 (s, 1H), 8.69 (s, 1H), 8.04 (d, J 10, 1H), 7.69 (s, 1H), 5.76 (s, 1H), 5.50-5.40- (m, 1H), 2.73 (s, 3H), 1.51 (d, J 6.4, 3H). MS (m/z): 336.27 (M+H); calculated for [C16H12CIF2N3O+H]: 336.74.
Intermediate 78: 8-Fluoro-4-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline :
[203] Intermediate 17 (1.8 g, 5.5 mmol) was dissolved in MeOH (90 ml) and EtOH (90 ml). To this mixture 5% Pd/C (720 mg) was added and stirred in an autoclave reactor under 1 KG hydrogen atmosphere for 2 h. After 2 h, reaction mixture filtered on a cealite bed and bed washed with MeOH and DCM (1:9) (200 ml) mixture. Combined filtrates distilled to obtain a crude. Crude was purified by combi-flash using EtOAc and Petether (8:92) as eluent to obtain the titled compound as an off-white solid (1.35 g). Yield: 75%. 'H-NMR (d ppm, CDCb, 400 MHz): 8.29 (s, 1H), 7.70 (d, J 10.8, 1H), 7.25 (d, J 5.2, 1H), 3.81 (septet, J 6.4, 1H), 2.77 (s, 3H), 1.39 (s, 6H), 1.37 (s, 12 H).
Intermediate 79: 6-(2-Chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropyl-2- methylquinoline:
[204] Following the general procedure-2, the titled compound was synthesized from Intermediate 78 (1.3 g, 3.95 mmol) and 2,4-dichloro-5-fluoropyrimidine (791 mg, 4.74 mmol). After completion of the reaction, precipitated product in the reaction mass was filtered. Solid was dried under vacuum for 2 h to obtain the titled compound as an off-white solid (1.1 g). Yield: 83%. ¾-NMR (d ppm, CDCb, 400 MHz): 8.70 (s, 1H), 8.59 (d, J 2.8, 1H), 8.16 (d, J 12.4, 1H), 7.33 (s, 1H), 3.76 (septet, J 6.8, 1H), 2.81 (s, 3H), 1.43 (s, 6H).
Intermediate 80: Methyl 6-bromo-8-fluoroquinoline-4-carboxylate
[205] Sulfuric acid (6 mL, 0.1 mmol) was added to a solution of Intermediate 65 (6 g, 22.2 mmol) in methanol (6 ml) and the mixture refluxed for 16 h. Methanol was removed by distillation and residue was dissolved in water (600 ml). Aqueous layer was extracted with EtOAc (3*300 ml) and washed the organic layer with satd. aq. NaHC03 solution (300 ml) followed by water (200 ml) and brine (200 ml). Organic layer distilled to obtain a crude. Crude product was purified by combi-flash using EtOAc and Petether (5:95) as eluent to obtain the title compound as a yellow solid (4.5 g). Yield: 71%. 'H-NMR (d ppm, DMSO-rfc, 400 MHz): 9.08 (d, J 4.4, 1H), 8.60 (t, J 1.6, 1H), 8.03 (d, J 4.4, 1H), 7.63 (dd, J 9.2, 2, 1H), 4.06 (s, 3H). MS (m/z): 284.15 (M+H); calculated for [CiiHyBrFNOi+H]: 283.96. Intermediate 81: 2-(6-Bromo-8-fluoroquinolin-4-yl)propan-2-ol :
[206] A 2M solution of methylmagnesium bromide in THF (46 mL, 93 mmol) was added slowly at 0 °C to a solution of Intermediate 80 (3.3 g, 12 mmol) in THF (51.2 mL) and stirred at the same temperature for 2 h. Aq. satd. ammonium chloride solution (50 mL) was added to the mixture and extracted into ethyl acetate (200 mL). The organic layer was washed successively with water (100 mL) and brine (200 mL), dried over sodium sulfate and evaporated to give a residue that was purified by silica gel column chromatography on a combi- flash system, eluting with ethyl acetate -hexane (15:85) to give the title compound as an off- white solid (1.5 g). Yield: 46 %. ¾-NMR (d ppm, DMSO-tfc, 400 MHz): 8.98 (s, 1H), 8.89 (d, J 4.4, 1H), 7.86 (dd, J 10, 2, 1H), 7.61 (d, J 4.4, 1H), 5.72 (s,l H), 1.65 (s, 6H). MS (m/z): 284.25 (M+H); calculated for [CnHiiBrFNO+H]: 284.00.
Intermediate 82: (8-Fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)boronic acid :
[207] Triisopropyl borate (8.1 mL, 35.0 mmol) was added dropwise at -78 °C to a solution of 2-(6-bromo-8-fluoro-2-methylquinolin-4-yl)propan-2-ol (Intermediate 81, 5.1 g, 17 mmol) in dry THF (176 mL) under nitrogen atmosphere. A 2.5M solution of «-Bull in hexane (8.1 mL, 35 mmol) was added dropwise to the above mixture and stirred for 2 hrs at the same temperature. The mixture was brought up to RT and acidified with 2N HC1, stirred for 30 min., neutralised by the addition of aq. 10% NaOH, stirred for 20 min. and extracted into ethyl acetate (2* 100 mL). The combined organic layers were washed successively with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated. The residue was stirred with petroleum ether (10 mL) for 20 min. and the solid formed was filtered and dried. Off-white solid (3.0 g). Yield: 68%. ¾-NMR (d ppm, DMSO-tfc, 400 MHz): 8.94 (s, 1H), 8.86 (d, J 4.4, 1H), 8.37 (s, 2H), 7.80 (d, J 11.6, 1H), 7.67 (d, J 4.4, 1H), 5.54 (s, 1H), 1.70 (s, 6H). MS (m/z): 249.90 (M+H); calculated for [C12H13BFNO3+H]: 250.10.
Intermediate 83: 2-(6-(2-Chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl)propan-2- ol:
[208] Following the general procedure-2, the titled compound was synthesized from Intermediate 82 (400 mg, 1.61 mmol) and 2,4-dichloro-5-fluoropyrimidine (322 mg, 3.85 mmol). After work up, crude product was purified by combi-flash using EtOAc and Petether (1: 1) as eluent to obtain the titled compound as an Off-White solid (260 mg). Yield: 48%. 'H- NMR (d ppm, DMSO-tfc, 400 MHz): 9.55 (s, 1H), 9.04 (d, J 3.2, 1H), 8.99 (d, J 4.4, 1H), 8.06 (d, J 11.6, 1H), 7.72 (d, J 4.4, 1H), 5.78 (s, 1H), 1.71 (s, 6H). MS (m/z): 336.22 (M+H); calculated for [C16H12CIF2N3O+H]: 336.06.
Intermediate 84: Tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine- l(2H)-carboxylate:
[209] Diisopropylamine (8.5 ml, 60.23 mmol) and dry THF (300 ml) were taken in an RBF. This mixture was cooled to -78°C and n-BuLi (24.03 ml, 60.23 mmol) was added slowly and stirred at -78°C for 40 mins. After 40 mins, tert- butyl 4-oxopiperidine-l-carboxylate (10 g, 50.2 mmol) dissolved in THF (60 ml) was added to above mixture dropwise for 30 mins. 1,1,1- trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)metlianesulfonamide (19.72 g, 55.2 mmol) dissolved in THF (57 ml) was added to the above reaction mixture dropwise for 30 mins. This reaction mixture warmed to rt and stirred at rt for 2 h. After 2 h, reaction mixture quenched with aq. NaHCCb (260 ml), stirred for 1 h and extracted into EtOAc (2* 300 ml). Combined EtOAc layers were washed with brine. EtOAc layer distilled under vacuum to obtain a crude. Crude was purified by column chromatography on 60-120 mesh silica gel using EtOAc and Petether (8:92) as eluent to obtain the titled compound as a yellow liquid (12 g). Yield: 72.17%. ¾-NMR (d ppm, DMSO-rfc, 400 MHz): 5.76 (bs, 1H), 4.09-4.01 (m, 2H), 3.68-3.59 (m, 2H), 2.48-2.40 (m, 2H), 1.47 (s, 9H).
Intermediate 85: 2-Nitro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine:
[210] Following the general procedure- 1 , the titled compound was synthesized from 2-Nitro- 5-bromopyridine (20.0 g, 99 mmol). After work up, crude product was purified by column chromatography on 60-120 mesh silica gel using EtOAc and petroleum ether (3:7) as eluent to obtain the titled compound as a brown solid (4.5 g). Yield: 18 %. 'H-NMR (d ppm, DMSO-rfc, 400 MHz): 8.81 (d, J 1.6, 1H), 8.42 (dd, J 8.0, 1.6, 1H), 8.30 (d, J 8, 1H),1.34 (s, 12 H). MS (m/z): 251.24 (M+H); calculated for [C11H15BN2O4+H]: 251.11.
Intermediate 86: Tert- butyl 6-nitro-5',6'-dihydro-[3,4'-bipyridine]-l'(2'H)-carboxylate:
[211] Following the general procedure-2, the titled compound was synthesized from Intermediate 85 (1.5 g, 6 mmol) and Intermediate 84 (2.38 g, 7.2 mmol). After completion of reaction, workup followed by column purification afforded the titled compound as a pale- brown solid (1.4 g). Yield: 76 %. ¾-NMR (d ppm, DMSO-tfc, 400 MHz): 8.77 (d, J 2, 1H), 8.30 (d, J 8.4, 1H), 8.24 (dd, J 8.8, 2.4, 1H), 6.56 (bs, 1H), 4.11-4.05 (m, 2H), 3.60-3.52 (m, 2H), 2.58-2.52 (m, 2H), 1.43 (s, 9H). MS (m/z): 306.17 (M+H); calculated for [C15H19N3O4+H]: 306.14.
Intermediate 87: Tert-butyl 4-(6-aminopyridin-3-yl)piperidine-l-carboxylate
[212] Intermediate 86 (1.8 g, 5.9 mmol) was dissolved in a mixture of MeOH (125 ml) and THF (125 ml). 5% Palladium on carbon (1.8 g) was added to above solution and stirred at rt under H2 atmosphere for 44 h. After 44 h, reaction mixture filtered on cealite bed and bed washed with EtOAc. Combined filtrates were distilled to obtain titled compound as a yellow gummy liquid (1.6 g). Yield: 98%. ¾-NMR (d ppm, DMSO-tfc, 400 MHz): 7.76 (d, J 2.4, 1H), 7.25 (dd, J 8.4, 2.4, 1H), 6.38 (d, J 8.4, 1H), 5.65 (s, 2H), 4.10-4.00 (m, 2H), 2.88-2.70 (m, 2H), 2.50-2.43 (m, 1H), 1.80-1.71 (m, 2H), 1.45-1.35 (m, 11H). MS (m/z): 278.18 (M+H); calculated for [C15H23N3O2+H]: 278.18.
Intermediate 88: Tert- butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-1 (2H)-carboxylate :
[213] Following the general procedure- 1, the titled compound was synthesized from Intermediate 84 (20.0 g, 99 mmol). PdCh(dppf).CH2Cl2used as catalyst and 1,4-Dioane used as solvent in this reaction. After work up, crude product was purified by combi-flash using EtOAc and petroleum ether (5:95) as eluent to obtain the titled compound as an off-white solid (600 mg). Yield: 64 %. ¾-NMR (d ppm, DMSO-rfc, 400 MHz): 6.38 (s, 1H), 3.86 (s, 2H), 3.35-3.30 (m, 2H), 2.10-2.04 (m, 2H), 1.39 (s, 9H), 1.20 (s, 12 H). MS (m/z): 210.24 (M+H- C5H9O2); calculated for [C16H28BNO4+H-C5H9O2]: 210.21.
Intermediate 89: 7er/-butyl 4-(2-aminopyrimidin-5-yl)-5,6-dihydropyridine-l(2H)- carboxylate:
[214] Following the general procedure-2, the titled compound was synthesized from 2- Amino-5-bromopyrimidine (270 mg, 1.6 mmol) and Intermediate 88 (580 mg, 1.9 mmol). After completion of reaction, workup followed by column purification afforded the titled compound as a pale-brown solid (190 mg). Yield: 44 %. ¾-NMR (d ppm, DMSO-rfc, 400 MHz): 8.32 (s, 2H), 6.65 (s, 2H), 6.02 (s, 1H), 3.98-3.92 (m, 2H), 3.54-3.47 (m, 2H), 2.41-2.34 (m, 2H), 1.41 (s, 9H). MS (m/z): 277.15 (M+H); calculated for [C14H20N4O2+H] : 277.16.
Intermediate 90: Tert- butyl 4-(2-aminopyrimidin-5-yl)piperidine-l-carboxylate:
[215] Intermediate 89 (180 mg, 0.65 mmol) was dissolved in a mixture of MeOH (6 ml) and THF (6 ml). 5% Palladium on carbon (180 mg) was added to above solution and stirred at rt under H2 atmosphere for 44 h. After 44 h, reaction mixture filtered on cealite bed and bed washed with a mixture of DCM and MeOH (9: 1) (100 ml). Combined filtrates were distilled to obtain titled compound as a brown gummy solid (180 mg). Yield: 99%. 'H-NIV1R (5 ppm, DMSO-rfc, 400 MHz): 8.12 (s, 2H), 6.39 (s, 2H), 4.10-4.00 (m, 2H), 2.82-2.68 (m, 2H), 1.74- 1.65 (m, 2H), 1.50-1.35 (m, 2H), 1.40 (s, 9H). MS (m/z): 179.25 (M+H- C5H9O2); calculated for [C14H22N4O2+H- C5H9O2]: 179.17.
Intermediate 91: l-Methyl-l,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate:
[216] Diisopropylamine (15 ml, 106 mmol) and dry THF (300 ml) were taken in an RBF. This mixture was cooled to -78°C and n-BuLi (2M in Hexane) (42.42 ml, 106 mmol) was added slowly and stirred at -78°C for 40 mins. After 40 mins, l-methylpiperidin-4-one (10 g, 88.4 mmol) dissolved in THF (60 ml) was added to above mixture dropwise for 30 mins. 1,1,1- trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (34.72 g, 97.2 mmol) dissolved in THF (100 ml) was added to the above reaction mixture dropwise for 30 mins. This reaction mixture warmed to rt and stirred at rt for 2.5 h. After 2.5 h, reaction mixture quenched with aq. NaHCCb (260 ml), stirred for 1 h and extracted into EtOAc (2* 300 ml). Combined EtOAc layers were washed with brine. EtOAc layer distilled under vacuum to obtain a crude. Crude was purified by column chromatography on 60-120 mesh silica gel using EtOAc and Petether (1: 1) as eluent to obtain the titled compound as a brown liquid (19 g). Yield: 88%. 'H- NMR (d ppm, CDCb, 400 MHz): 5.76-5.71 (m, 1H), 3.14-3.09 (m, 2H), 2.74-2.68 (m, 2H), 2.51-2.44 (m, 2H), 2.41 (s, 3H). MS (m/z): 246.10 (M+H); calculated for [C7H10F3NO3S+H]: 246.03.
Intermediate 92: l'-Methyl-6-nitro-l',2',3',6'-tetrahydro-3,4'-bipyridine:
[217] Following the general procedure-2, the titled compound was synthesized from Intermediate 85 (2 g, 8 mmol) and Intermediate 91 (2.35 g, 9.6 mmol). After completion of reaction, workup followed by column purification afforded the titled compound as a brown solid (580 mg). Yield: 33 %. ¾-NMR (d ppm, DMSO-rfc, 400 MHz): 8.77 (d, J 2.4, 1H), 8.27 (d, J 8.8, 1H), 8.23 (dd, J 8.8, 2.4, 1H), 6.61-6.57 (m, 1H), 3.12-3.07 (m, 2H), 2.63-2.59 (m, 2H), 2.57-2.52 (m, 2H), 2.30 (s, 3H). MS (m/z): 220.20 (M+H); calculated for [C11H13N3O2+H]: 220.10.
Intermediate 93: 5-(l-Methylpiperidin-4-yl)pyridin-2-amine : Intermediate 92 (580 mg, 2.6 mmol) was dissolved in a mixture of MeOH (30 ml) and THF (30 ml). 5% Palladium on carbon (1.16 g) was added to above solution and stirred at rt under H2 atmosphere for 45 h. After 45 h, reaction mixture filtered on cealite bed and bed washed with EtOAc (200 ml). Combined filtrates were distilled to obtain titled compound as a brown gummy solid (460 mg). Yield: 91%. ¾-NMR (d ppm, DMSO-tfc, 400 MHz): 7.75 (d, J 2.4, 1H), 7.25 (dd, J 8.4, 2.4, 1H), 6.38 (d, J 8.4, 1H), 5.63 (s, 2H), 2.86-2.78 (m, 2H), 2.30-2.21 (m, 1H), 2.16 (s, 3H), 1.95-1.85 (m, 2H), 1.68-1.50 (m, 4H). MS (m/z): 192.22 (M+H); calculated for [C11H17N3+H]: 192.14.
Example 1
Tert- Butyl 4-(6-((5-fluoro-4-(quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperazine-l-carboxylate
[218] Following the general procedure-3, the titled compound was synthesized from Intermediate 2 (500 mg, 1.93 mmol) and Intermediate 5 (590 mg, 2.1 mmol). After work up (EtO Ac/brine, then FhO), crude product was purified by combi-flash using methanol and DCM (2.7:97.3) as eluent to obtain the titled compound as a yellow solid (120 mg). Yield: 12.4 %. M.P.: 223-225 °C. ¾-NMR (d ppm, CDCb, 400 MHz): 9.02-8.99 (m, 1H), 8.62 (br. s, 1H), 8.49-8.44 (m, 2H), 8.36-8.23 (m, 3H), 8.15 (br. s, 1H), 8.05 (d, J 2.8, 1H), 7.50 (dd, J 8.4, 4.4, 1H), 7.38 (dd, J 9.2, 2.8, 1H), 3.61 (t, J 4.8, 4H), 3.10 (t, J 4.8, 4H), 1.49 (s, 9H). MS (m/z): 502.33 (M+H); calculated for [C27H28FN7O2+H] : 502.24.
Example 1A
5-Fluoro-N-(5-(piperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine
[219] Following the general procedure-4, the titled compound was synthesized from tert- butyl 4-(6-((5-fluoro-4-(quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Example 1) (110 mg, 0.22 mmol) as a pale yellow solid (35 mg). Yield: 40 %. ¾-NMR (d ppm, DMSO-flfe + CDCb, 400 MHz): 9.70 (s, 1H), 9.02-8.95 (m, 1H), 8.70-8.65 (m, 2H), 8.53 (d, J 8.4, 1H), 8.40 (d, J 9.2, 1H), 8.17 (d, J 8.8, 1H), 8.09 (d, J 9.2, 1H), 7.97 (br. s, 1H), 7.60 (dd, J 8.4, 4.4, 1H), 7.38-7.45 (m, 1H), 3.01 (br. s, 4H), 2.85 (br. s, 4H).
Example IB
5-Fluoro-N-(5-(piperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride [220] 5-Fluoro-N-(5-(piperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine (Example 1A) (27 mg, 0.067 mmol) was dissolved in methanol (2.7 ml) and added HC1 (25 mg, 0.67 mmol) to obtain a clear solution. This solution was stirred at rt for 30 mins. After 30 mins, methanol was distilled out to obtain a residue. Residue was co-distilled with toluene (5 ml) to obtain the titled compound as a yellow solid. M.P.: 220-222 °C. 'H-NIV1R (5 ppm, DMSO-r/e, 400 MHz): 11.74 (br. s, 1H) 9.50 (br. s, 2H), 9.19 (br. s, 1H), 9.00-8.80 (m, 3H), 8.51 (br. s, 1H), 8.39 (t, J 8.4, 1H), 8.16 (br. s, 1H), 8.02 (s, 1H), 7.90-7.80 (m, 2H), 3.50-3.40 (br. s, 4H), 3.30-3.20 (br. s, 4H). MS (m/z): 402.1 (M+H); calculated for [C22H20FN7+H] : 402.1.
Example 2
Tert-Butyl 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperazine-l-carboxylate
[221] Following the general procedure-3, the titled compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 5 (551 mg, 1.98 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (2.5:97.5) as eluent to obtain the titled compound as a yellow solid (130 mg). Yield: 14 %. M.P.: 227-229 °C. ¾- NMR (d ppm, CDCb, 400 MHz): 9.08-9.04 (m, 1H), 8.49 (d, J = 3.6, 1H), 8.36-8.19 (m, 4H), 8.07 (d, J 2.4, 1H), 7.57 (dd, J 8.0, 4.0, 1H), 7.40 (dd, J 9.2, 2.8, 1H), 3.61 (t, J = 4.8, 4H), 3.11 (t, J = 4.8, 4H), 1.50 (s, 9H). MS (m/z): 520.32 (M+H); calculated for [C27H27F2N7O2+H] : 520.23.
Example 2A
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine
[222] Following the general procedure-4, the titled compound was synthesized from tert- butyl
4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l- carboxylate (Example 2) (120 mg, 0.23 mmol) as a pale yellow solid (55 mg). Yield: 57 %. 1H-NMR (d ppm, DMSO-r/6, 400 MHz): 9.82 (s, 1H), 9.06 (br. s, 1H), 8.72 (d, J 3.2, 1H), 8.67 (d, J 8.0, 1H), 8.56 (s, 1H), 8.21 (d, J = 12.4, 1H), 8.06-7.96 (m, 2H), 7.74 (dd, J 8.4, 4.0, 1H), 7.44 (d, J = 8.8, 1H), 3.02 (br. s, 4H), 2.84 (br. s, 4H).
Example 2B
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride [223] 5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine (Example 2A) (50 mg, 0.12 mmol) was dissolved in methanol (2.5 ml) and added HC1 (43 mg, 1.2 mmol) to obtain a clear solution. This solution was stirred at rt for 30 mins. After 30 mins, methanol was distilled out to obtain a residue. Residue was co-distilled with toluene (5 ml) to obtain the titled compound as a yellow solid (45 mg). Yield: 83% M.P.: 220-222°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): M.P.: 262-264°C. 1H-NMR (d ppm, DMSO-d6, 400 MHz): 11.78 (br. s, 1H), 9.56 (br. s, 2H), 9.08 (br. s, 1H), 8.94 (br. s, 1H), 8.70 (d, J 8.4, 1H), 8.61 (s, 1H), 8.12-8.23 (m, 2H), 8.01 (s, 1H), 7.84 (d, J 8.8, 1H), 7.77 (dd, J 8.4, 4.0, 1H), 3.49-3.41(m, 4H), 3.28-3.20 (m, 4H). MS (m/z): 420.39 (M+H-HC1); calculated for [C22H19F2N7.HCI+H-HCI]: 420.17.
Example 3
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2-amine
[224] Following the general procedure-3, the titled compound was synthesized from Intermediate 7 (500 mg, 1.8 mmol) and Intermediate 9 (400 mg, 1.8 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (11.5:88.5) as eluent to obtain the titled compound as a yellow solid (280 mg). Yield: 34 %. M.P.: 246-248°C. 'H-NMR (d ppm, DMSO-rie, 400 MHz): 10.12 (s, 1H), 9.08 (d, J 3.6, 1H), 8.81 (d, J 3.2, 1H), 8.69 (d, J 8.0, 1H), 8.60 (s, 1H), 8.30-8.20 (m, 3H), 7.80-7.70 (m, 1H), 7.40-7.30 (m, 1H), 3.47 (br. s, 2H) 2.70-2.20 (m, 10H), 1.00 (br. s, 3H). MS (m/z): 462.29 (M+H); calculated for [C25H25F2N7+H]: 462.22.
Example 3A
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2-amine hydrochloride
[225] N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2-amine (Example 3) (250 mg, 0.54 mmol) was suspended in methanol (6 ml) and added aq. 35% hydrochloric acid (197 mg, 5.4 mmol) to obtain a clear solution. This mixture was stirred at rt for 30 mins. Methyl tert- butyl ether (18 ml) was added and stirred for 1 hr to obtain a solid that was filtered, washed with methyl tert- butyl ether (20 ml) and dried to obtain titled compound as a brown solid (230 mg). Yield: 85 %. M.P.: 289-291°C. 'H-NMR (d ppm, DMSO-rie, 400 MHz): M.P.: 289-291°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.89 (br. s, 1H), 11.40 (br. s, 1H), 9.08-9.13 (br. s, 1H), 8.92-8.97 (br. s, 1H), 8.72 (d, J = 8.4, 1H), 8.60-8.70 (m, 2H), 8.25-8.40 (m, 2H), 8.12 (d, J = 8.8, 1H), 7.75-8.15 (m, 1H), 4.45 (br. s, 2H), 3.15-3.82 (m, 10H), 1.27 (t, J = 7.2, 3H). MS (m/z): 461.8 (M+H-HC1); calculated for [C25H25F2N7.HCI+H-HCI]: 462.2.
Example 4
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2- amine
[226] Following the general procedure-3, the titled compound was synthesized from Intermediate 2 (500 mg, 1.9 mmol) and Intermediate 9 (420 mg, 1.9 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (13:87) as eluent to obtain the titled compound as a yellow solid (200 mg). Yield: 23 %. M.P.: 289-291 °C. ¾- NMR (d ppm, DMSO-rie, 400 MHz): 10.07 (s, 1H), 9.04 (s, 1H), 8. 80-8. 70 (m, 2H), 8.60 (d, J 8.0, 1H), 8.45 (d, J 8.0, 1H), 8. 30-8. 20 (m, 3H), 7. 80-7. 60 (m, 1H), 7.55-7.40 (m, 1H), 3.42 (s, 2H), 2. 80-2. 10 (m, 10H), 1.24 (br. s, 3H). MS (m/z): 444.32 (M+H); calculated for [C25H26FN7+H]: 444.23.
Example 4A
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2- amine hydrochloride
[227] N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6- yl)pyrimidin-2-amine (Example 4) (190 mg, 0.43 mmol) was suspended in methanol (5 ml) and added aq. 35% hydrochloric acid (160 mg, 4.4 mmol) to obtain a clear solution. This solution was stirred at rt for 30 mins. Methyl tert- butyl ether (15 ml) was added and stirred for 1 hr to obtain a solid that was filtered, washed with methyl tert- butyl ether (20 ml) and dried to obtain titled compound as a brown solid (60 mg). Yield: 85 %. M.P.: 255-257°C. 'H-NMR (d ppm, DMSO-rie, 400 MHz): 11.99 (br. s, 1H), 11.32 (br. s, 1H), 9.21 (d, J = 4.4, 1H), 9.05-8.90 (m, 3H), 8.52-8.51 (m, 2H), 8.42 (d, J 8.8, 1H), 8.30 (d, J 8.8, 1H), 8.14 (d, J 8.8, 1H), 7.90 (dd, J 8.0, 4.8, 1H), 4.44 (br. s, 2H), 3.80-3.00 (m, 10H), 1.27 (t, J = 7.2, 3H). MS (m/z): 443.8 (M+H-HC1); calculated for [C25H26FN7.HCI+H-HCI]: 444.2.
Example 5 7er/-Butyl 4-(6-((5-fluoro-4-(8-fluoro-2-methyl-4-(prop-l-en-2-yl)quinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate
[228] Following the general procedure-3, the titled compound was synthesized from Intermediate 18 (500 mg, 1.51 mmol) and Intermediate 5 (420 mg, 1.51 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (1.8:98.2) as eluent to obtain the titled compound as a yellow solid (180 mg). Yield: 21%. M.P.: 150-152 oC. 1H- NMR (d ppm, CDC13, 400 MHz): 8.66 (s, 1H), 8.45 (d, J 3.6, 1H), 8.30 (d, J 9.2, 1H), 8.16 (d, J 12.0, 1H), 8.10 (s, 1H), 8.05 (d, J 2.8, 1H), 7.37 (dd, J 9.2, 3.2, 1H), 5.56 (s, 1H), 5.20 (s, 1H), 3.66-3.59(m, 4H), 3.14-3.08(m , 4H), 2.26 (s, 3H), 1.62 (s, 3H), 1.50 (s, 9H). MS (m/z): 574.35 (M+H); calculated for [C31H33F2N7O2 + H]: 574.28.
Example 5A
5-Fluoro-4-(8-fluoro-2-methyl-4-(prop-l-en-2-yl)quinolin-6-yl)-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2-amine
[229] Following the general procedure-4, the titled compound was synthesized from Tert- Butyl 4-(6-((5-fluoro-4-(8-fhioro-2-methyl-4-(prop-l-en-2-yl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Example 5) (150 mg, 0.26 mmol) as a yellow solid (110 mg). Yield: 89 %. M.P.: 165-167 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.82 (s, 1H), 8.67 (d, J 2.4, 1H), 8.61 (s, 1H), 8.14 (d, J 11.6, 1H), 8.10-7.95 (m, 2H), 7.49 (s, 1H), 7.40 (d, J 8.0, 1H), 5.61 (s, 1H), 5.19 (s, 1H), 3.10-3.00 (m, 4H), 2.90-2.82 (m, 4H), 2.72 (s, 3H), 2.23 (s, 3H). MS (m/z): 474.53 (M+H); calculated for [C26H25F2N7 + H]: 474.2.
Example 5B
5-Fluoro-4-(8-fluoro-2-methyl-4-(prop-l-en-2-yl)quinolin-6-yl)-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride:
[230] 5-Fluoro-4-(8-fluoro-2-methyl-4-(prop-l-en-2-yl)quinolin-6-yl)-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2-amine (Example 5A) (100 mg, 0.21 mmol) was suspended in methanol (2 ml) and added aq. 35% hydrochloric acid (221 mg, 2.1 mmol) to obtain a clear solution. This mixture was stirred at rt for 30 mins. Methyl tert- butyl ether (6 ml) was added and stirred for 1 hr to obtain a solid that was filtered, washed with methyl tert- butyl ether (2 ml) and dried to obtain the titled compound as a yellow solid (95 mg). Yield: 80 %. M.P.: 213- 215°C. M.P.: 213-215°C. 1H-NMR (6 ppm, DMSO-rie, 400 MHz): 11.74 (br. s, 1H), 9.53 (br. s, 2H), 8.88 (s, 1H), 8.58 (s, 1H), 8.20-8.10 (m, 2H), 7.98 (s, 1H), 7.83 (d, J 9.6, 1H), 7.54 (s, 1H), 5.63 (s, 1H), 5.21 (s, 1H), 3.49-3.41 (m, 4H), 3.30-3.19 (m, 4H), 2.73 (s, 3H), 2.23 (s, 3H). MS (m/z): 474.5 (M+H); calculated for [C26H25F2N7 + H]: 474.2.
Example 6
5-Fluoro-N-(5-(4-methylpiperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2- amine
[231] Following the general procedure-3, the titled compound was synthesized from Intermediate 2 (400 mg, 1.54 mmol) and Intermediate 11 (296 mg, 1.54 mmol). After work up, crude product was purified by combi -flash using methanol and DCM (8:92) as eluent to obtain the titled compound after washing with diethyl ether (5 mL) as a yellow solid (150 mg). Yield: 23%. M.P.: 255-258 oC. ¾-NMR (d ppm, DMSO-r 6, 400 MHz): 9.69 (s, 1H), 9.00 (dd, J 4.0, 2.8, 1H), 8.70 (s, 1H), 8.67 (d, J 3.6, 1H), 8.55 (d, J 8.8, 1H), 8.43 (d, J 8.8, 1H), 8.19 (d, J 9.2, 1H), 8.12 (d, J 9.2, 1H), 8.01 (d, J 2.8, 1H), 7.62 (dd, J 8.4, 4.0, 1H), 7.45 (dd, J 9.2, 2.8, 1H), 3.30-3.22 (m, 4H), 3.15-3.10(m, 4H), 2.25 (s, 3H). MS (m/z); 416.44 (M+H); calculated for [C23H22FN7+H] : 416.20.
Example 6A
5-Fluoro-N-(5-(4-methylpiperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride:
[232] 5-Fluoro-N-(5-(4-methylpiperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2- amine (Example 6) (120 mg, 0.29 mmol) was suspended in methanol (2.5 ml) and added aq. 35% hydrochloric acid (105 mg, 2.9 mmol) to obtain a clear solution for a short while followed by precipitation of a solid. This mixture was stirred at rt for 30 mins. The solid was filtered, washed with methanol (2 ml) and dried to obtain the titled compound as a yellow solid (80 mg). Yield: 61 %. M.P.: 272-274°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.76 (br. s, 1H), 11.47 (br. s, 1H), 9.19 (br. s, 1H), 8.98-8.82 (m, 3H), 8.54 (d, J 8.4, 1H), 8.18 (d, J 9.2, 1H), 8.04 (s, 1H), 8.04 (s, 1H), 7.86-7.81 (m, 2H), 3.85 (d, J 11.6, 2H), 3.52 (d, J 10.4, 1H), 3.32- 3.10 (m, 4H), 2.80 (s, 3H). MS (m/z); 416.46 (M+H); calculated for [C23H22FN7+H] : 416.20.
Example 7
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-methylpiperazin-l-yl)pyridin-2-yl)pyrimidin-
2-amine
[233] Following the general procedure-3, the titled compound was synthesized from Intermediate 7 (500 mg, 1.8 mmol) and Intermediate 11 (350 mg, 1.8 mmol). After work up, crude product was purified by combi -flash using methanol and DCM (9:91) as eluent to obtain the titled compound after washing with diethyl ether (5 mL) as a yellow solid (290 mg). Yield: 34%. M.P.: 244-246 °C. ¾-NMR (d ppm, DMSO-r e, 400 MHz): 9.83 (s, 1H), 9.06 (d, J 2.8, 1H), 8.72 (d, J 3.6, 1H), 8.67 (d, J 8.4, 1H), 8.56 (s, 1H), 8.20 (d, J 8.0, 1H), 8.07-8.00 (m, 2H), 7.74 (dd, J 8.4, 4.4, 1H), 7.47 (dd, J 9.2, 2.8, 1H), 3.18-3.09 (m, 4H), 2.40-2.55 (m, 4H), 2.23 (s, 3H). MS (m/z); 434.43 (M+H); calculated for [C23H22F2N7+H] : 434.19.
Example 7A
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-methylpiperazin-l-yl)pyridin-2-yl)pyrimidin-
2-amine hydrochloride:
[234] 5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-methylpiperazin-l-yl)pyridin-2- yl)pyrimidin-2-amine (Example 7) (280 mg, 0.65 mmol) was suspended in methanol (7.3 ml) and added aq. 35% hydrochloric acid (240 mg, 6.5 mmol) during which the mixture turned a clear solution for a short while and a precipitate was formed immediately. The heterogeneous mixture was stirred at rt for 30 mins. The solid was filtered, washed successively with methanol (3 ml) and diethyl ether (15 ml) and dried to obtain the titled compound as a yellow solid (240 mg). Yield: 79 %. M.P.: 286-288 °C. ¾-NMR (d ppm, DMSO-r e, 400 MHz): 11.83 (br. s, 1H), 11.44 (br. s, 1H), 9.09 (d, J 4.0, 1H), 8.95 (d, J 3.2, 1H), 8.71 (d, J 8.0, 1H), 8.61 (s, 1H), 8.24-8.17 (m, 2H), 8.01 (d, J 2.0, 1H), 7.84 (d, J 9.6, 1H), 7.78 (dd, J 8.4, 4.0, 1H), 3.90-3.82 (m, 2H), 3.54-3.49 (m, 2H), 3.30-3.10 (m, 4H), 2.80 (d, J 4.0, 3H). MS (m/z); 434.42 (M+H- HC1); calculated for [C23H21F2N7.HCI+H-HCI]: 434.19.
Example 8
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2- amine
[235] Following the general procedure-3, the titled compound was synthesized from Intermediate 7 (400 mg, 1.4 mmol) and Intermediate 20 (300 mg, 1.5 mmol). After work up, crude product was purified by combi -flash using methanol and DCM (7:93) as eluent to obtain the titled compound after washing with diethyl ether (5 mL) as a yellow solid (350 mg). Yield: 54%. M.P.: 254-256 °C. ¾-NMR (d ppm, DMSO-r/e, 400 MHz): 9.06 (d, J 2.8, 1H), 8.70 (d, J 3.6, 1H), 8.64 (d, J 8.4, 1H), 8.55 (s, 1H), 8.20 (d, J 11.6, 1H), 8.05 (d, J 9.2, 1H), 8.01 (d, J 2.4, 2H), 7.72 (dd, J 8.4, 4.4, 1H), 7.46 (dd, J 9.2, 3.2, 1H), 4.04 (s, 4H), 3.15-3.08 (m, 4H), 2.38 (q, J 7.2, 2H), 1.03 (t, J 7.2, 2H). MS (m/z); 448.43 (M+H); calculated for [C23H21F2N7+H]: 448.21. Example 8A
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2- amine hydrochloride:
[236] N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2-amine (Example 8) (210 mg, 0.47 mmol) was suspended in methanol (5.3 ml) and added aq. 35% hydrochloric acid (170 mg, 4.7 mmol) during which the mixture turned a clear solution. The mixture was stirred at rt for 30 mins. Methyl tert- butyl ether (24 ml) was added and stirred for 1 h at rt. The solid precipitated was filtered, washed with methyl tert- butyl ether (15 ml) and dried to obtain the titled compound as a yellow solid (165 mg). Yield: 79%. M.P.: 273-275 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.87 (s, 1H), 11.40 (br. s, 1H), 9.09 (br. s, 1H), 8.95 (s, 1H), 8.70 (d, J 7.2, 1H), 8.61 (s, 1H), 8.27-8.06 (m, 2H), 8.02 (s, 1H), 7.84 (d, J 9.2, 1H), 7.78 (dd, J 8.4, 4.4, 1H), 3.90-3.80 (m, 2H), 3.62-3.55 (m, 2H), 3.34-3.22 (m, 2H), 3.20-3.02 (m, 4H), 1.30 (t, J 7.2, 3H). MS (m/z); 448.43 (M+H-HC1); calculated for [C24H23F2N7.HCI+H-HCI]: 448.21.
Example 9
N-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-
6-yl)pyrimidin-2-amine
[237] Following the general procedure-3, the titled compound was synthesized from Intermediate 23 (400 mg, 1.4 mmol) and Intermediate 9 (300 mg, 1.4 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (7.4:92.6) as eluent to obtain the titled compound as a yellow solid (120 mg). Yield: 18%. M.P.: 203-205 oC. 1H- NMR (d ppm, DMSO-r 6, 400 MHz): 10.10 (s, 1H), 8.77 (d, J 3.6, 1H), 8.56-8.51 (m, 2H), 8.22-8.16 (m, 3H), 7.72 (dd, J 8.4, 2.0, 1H), 7.62 (d, J 8.8, 1H), 3.44 (s, 2H), 2.73 (s, 3H), 2.30-2.60 (m, 10H), 0.98 (t, J 7.2, 3H). MS (m/z): 476.22 (M+H); calculated for [C26H27F2N7 + H]: 476.23.
Example 9A
N-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-
6-yl)pyrimidin-2-amine hydrochloride
[238] N-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2- methylquinolin-6-yl)pyrimidin-2-amine (Example 9, 120 mg, 0.25 mmol) was suspended in methanol (3 ml) and added aq. 35% hydrochloric acid (92 mg, 2.5 mmol) to obtain a clear solution. This mixture was stirred at rt for 30 mins. The mixture was concentrated, the residue dissolved in water (20 ml) and washed with DCM-MeOH 9: 1 (3*50 ml). The aqueous layer was evaporated and the residual solid was coevaporated with water to obtain the titled compound as a yellow solid (15 mg). Yield: 12%. M.P.: 257-259 °C. 1H-NMR(6ppm, DMSO- d6, 400 MHz): 12.02 (br. s, 1H), 11.51 (br. s, 1H), 8.91 (d, J 2.4, 1H), 8.67-8.54 (m, 3H), 8.40- 8.30 (m, 1H), 8.20 (d, J 12.0, 1H), 8.40-8.12 (m, 1H), 7.65 (d, J 8.8, 1H), 4.47 (br. s, 2H), 3.80-3.35 (m, 8H), 3.17 (br. s, 2H), 2.74 (s, 3H), 1.25 (t, J 7.2, 3H). MS (m/z): 475.3 (M+H); calculated for [C26H27F2N7 + H]: 476.2.
Example 10
7e/·/- Butyl 4-(6-((5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazine-l-carboxylate
[239] Following the general procedure-3, the titled compound was synthesized from Intermediate 23 (500 mg, 1.7 mmol) and Intermediate 5 (480 mg, 1.7 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (7.8:92.2) as eluent to obtain the titled compound as a yellow solid (100 mg). Yield: 11%. 'H-NMR (d ppm, CDCb, 400 MHz): 8.46 (d, J 3.6, 1H), 8.41 (br. s, 1H), 8.29 (d, J 8.8, 1H), 8.23-8.20 (m, 1H), 8.10 (s, 1H), 8.18 (d, J 1.6, 1H), 8.12 (br. s., 1H), 8.07-8.04 (m, 1H), 7.44 (d, J 8.4, 1H), 7.40 (dd, J 8.8, 2.8, 1H), 3.61 (t, J 4.8, 4H), 3.12 (t, J 4.8, 4H), 2.85 (s, 3H), 1.50 (s, 9H).
Example 10A
5-Fluoro-4-(8-fluoro-2-methylquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2- yl)pyrimidin-2-amine
[240] Following the general procedure-4, the titled compound was synthesized from tert- Butyl 4-(6-((5-fhioro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperazine-l-carboxylate (Example 10, 90 mg, 0.17 mmol) as a brown solid (55 mg). Yield: 75%. ¾-NMR (d ppm, DMSO-r/e, 400 MHz): 9.78 (s, 1H), 8.70 (d, J 3.6, 1H), 8.55-8.48 (m, 2H), 8.16 (d, J 11.6, 1H), 8.03 (d, J 9.2, 1H), 7.99 (d, J 2.4, 1H), 7.62 (d, J 8.4, 1H), 7.45 (dd, J 8.8, 2.8, 1H), 3.08-3.02(m, 4H), 2.88-2.81 (m, 4H), 2.79 (s, 3H).
Example 10B
5-Fluoro-4-(8-fluoro-2-methylquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2- yl)pyrimidin-2-amine hydrochloride: [241] 5-Fluoro-4-(8-fluoro-2-methylquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine (Example 10A, 42 mg, 0.097 mmol) was suspended in methanol (2 ml) and added aq. 35% hydrochloric acid (35 mg, 0.97 mmol) to obtain a clear solution. This mixture was stirred at rt for 30 mins. Removal of the solvent under vacuum followed by co evaporation with toluene gave the titled compound as a yellow solid (25 mg). Yield: 85%. M.P.: 220-222 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.78 (br. s, 1H), 9.56 (br. s, 2H), 8.91 (s, 1H), 8.61-8.51 (m, 2H), 8.22-8.12 (m, 2H), 8.00 (s, 1H), 7.83 (d, J 9.6, 1H), 7.65 (d, J 8.4, 1H), 3.50-3.40 (m, 4H), 3.29-3.20 (m, 4H), 2.74 (s, 3H). MS (m/z): 434.46 (M+H); calculated for [C23H21F2N7 + H]: 434.19.
Example 11
Tert-Butyl 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazine-l-carboxylate
[242] To a solution of Tert-Butyl 4-(6-((5-fluoro-4-(8-fluoro-2-methyl-4-(prop-l-en-2- yl)quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (example 5, 160 mg, 0.261 mmol) in a 3:2 mixture of methano and EtOAc (15 ml), 20% palladium hydroxide on carbon was added and the mixture hydrogenated at a hydrogen pressure of 8kg/cm2 at room temperature for 64 h. The mixture was diluted with DCM-methanol (9: 1, 50 ml) and fdtered through a celite bed which was washed with DCM-methanol (9: 1, 150 ml). Combined fdtrates were evaporated to give the crude product. Purification by combi-flash chromatography system using methanol and DCM (1.8:98.2) as eluent gave the titled compound as a green solid (100 mg). Yield: 66%. M.P.: 178-180 °C. ¾-NMR (d ppm, CDCb, 400 MHz): 8.72 (s, 1H), 8.46 (d, J 3.6, 1H), 8.31 (d, J 9.2, 1H), 8.15 (d, J 12.8, 1H), 8.08-8.03 (m, 2H), 7.37 (dd, J 9.2, 2.8, 1H), 7.33 (s, 1H), 3.77 (septet, J = 6.8, 1H), 3.67-3.59 (m, 4H), 3.15-3.08 (m, 4H), 2.82 (s, 3H), 1.50 (s, 9H), 1.46 (d, J 6.8, 6H). MS (m/z): 576.29 (M+H); calculated for [C31H35F2N7O2 + H]: 576.29.
Example 11A
5-Fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2- yl)pyrimidin-2-amine
[243] Following the general procedure-4, the titled compound was synthesized from tert-
Butyl 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Example 11, 100 mg, 0.174 mmol) as a yellow solid (60 mg). Yield: 83%. M.P.: 217-219 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.84 (s, 1H), 8.72-8.67 (m, 2H), 8.10 (d, J 11.6, 1H), 8.07-7.97 (m, 2H), 7.53 (s, 1H), 7.40 (dd, J 9.2, 2.4, 1H), 3.75 (septet, J = 6.8, 1H), 3.08-3.00 (m, 4H), 2.89-2.82(m, 4H), 2.71 (s, 3H), 1.38 (d, J 6.8, 6H).
Example 11B
5-Fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2- yl)pyrimidin-2-amine hydrochloride:
[244] 5-Fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine (Example 11 A) (55 mg, 0.12 mmol) was suspended in methanol (1.1 ml) and added aq. 35% hydrochloric acid (42 mg, 1.2 mmol) to obtain a clear solution. This mixture was stirred at rt for 30 mins. Removal of solvent under vacuum and co evaporation with toluene gave the titled compound as a pale green solid (40 mg). Yield: 67%. M.P.: 245-247 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.77 (br. s, 1H), 9.54 (br. s, 2H), 8.91 (d, J 2.4, 1H), 8.70 (s, 1H), 8.20-8.10 (m, 2H), 7.99 (s, 1H), 7.85 (d, J 9.6, 1H), 7.59 (s, 1H), 3.76 (septet, J 6.8, 1H), 3.25 (br. s, 4H), 3.15 (br. s, 4H), 2.73 (s, 3H), 1.38 (d, J = 6.8, 3H). MS (m/z): 476.3 (M+H); calculated for [C26H27F2N7 + H]: 476.2.
Example 12
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine
[245] Following the general procedure-3, the titled compound was synthesized from Intermediate 2 (500 mg, 1.93 mmol) and Intermediate 20 (397 mg, 1.93 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (5.6:94.4) as eluent. The pooled fractions were evaporated and the residue was strirred for 30 min. with diethyl ether (10 mL), filtered, washed with diethyl ether (5 mL) and dried to obtain the titled compound as a yellow solid (45 mg). Yield: 5.4%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.78 (s, 1H), 9.01 (dd, J 4.0, 2.0, 1H), 8.72-8.68 (m, 2H), 8.57 (d, J 8.4, 1H), 8.41 (d, J 8.8, 1H), 8.19 (d, J 9.2, 1H), 8.08 (d, J 9.2, 1H), 8.01 (d, J 2.8, 1H), 7.63 (dd, J 8.4, 4.0, 1H), 7.47 (dd, J 8.8, 3.2, 1H), 3.18-3.10 (m, 4H), 2.60-2.35 (m, 10H), 1.04 (t, J 7.2, 3H). MS (m/z): 430.44 (M+H); calculated for [C24H24FN7+ H]: 430.22.
Example 12A
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride [246] To a mixture of 5-fluoro-N-(5-(piperazin-l-yl)pyridin-2-yl)-4-(quinolin-3- yl)pyrimidin-2-amine (Example 12, 35 mg, 0.08 mmol) in methanol (2 mL) was added aq. 35% hydrochloric acid (30 mg, 0.81 mmol) and the mixture was stirred at rt for 30 mins. The solid formed was filtered, washed with diethyl ether (5 mL) and dried under vacuum to give the titled compound as ayellow solid (17 mg). Yield: 44%. M.P.: 291-294 °C. ^-NMR (d ppm, DMSO- de, 400 MHz): 11.65 (bs, 1H), 11.20 (bs, 1H), 9.15 (bs, 1H), 8.93 (d, J 3.2, 1H), 8.83 (bs, 2H), 8.50 (d, J 9.2, 1H), 8.35 (d, J 9.2, 1H), 8.15 (d, J 8.4, 1H), 8.03 (d, J 2.8, 1H), 7.88-7.78 (m,
2H), 3.85 (d, J 12.4, 2H), 3.59 (d, J 12.0, 2H), 3.32-3.05 (m, 6H), 1.30 (t, J 7.2, 3H). MS (m/z):
430.44 (M+H); calculated for [C24H24FN7+H] : 430.22.
Example 13
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylpiperazin-l-yl)pyridin-2- yl)pyrimidin-2-amine
[247] Following the general procedure-3, the titled compound was synthesized from
Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 25 (397 mg, 1.80 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (8:92) as eluent. The pooled fractions were evaporated and the residue was strirred for 30 min. with diethyl ether (10 mL), filtered and dried to obtain the titled compound as a yellow solid (80 mg). Yield: 9.6%. M.P.: 258-261°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.83 (s, 1H), 9.05, (dd, J 4, 1.8, 1H), 8.72 (d, J 3.6, 1H), 8.66 (d, J 8.4, 1H), 8.56 (s, 1H), 8.20 (d, J 11.6, 1H), 8.03 (d, J 8.8,
1H), 8.01 (d, J 2.8, 1H), 7.74 (dd, J 8.4, 4, 1H), 7.46 (dd, J 9.2, 2.8, 1H), 3.15-3.05 (m, 4H),
2.70-2.66 (m, 1H), 2.61-2.54 (m, 4H), 1.00 (d, J 6.4, 6H). MS (m/z): 462.44 (M+H); calculated for [C25H25F2N7 + H]: 462.22.
Example 13A
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylpiperazin-l-yl)pyridin-2- yl)pyrimidin-2-amine hydrochloride
[248] To a mixture of 5-fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylpiperazin-l- yl)pyridin-2-yl)pyrimidin-2-amine (Example 13, 80 mg, 0.17 mmol) in methanol (2 mL) was added aq. 35% hydrochloric acid (63 mg, 1.7 mmol). After 10 min. of addition, a clear solution was obtained and the mixture was stirred at rt for 30 mins. A solid that was formed during stirring. The mixture was diluted with methyl fert-butyl ether (5 mL) and the solid was filtered, washed with methyl fert-butyl ether (10 mL) and dried under vacuum to give the titled compound as ayellow solid (50 mg). Yield: 58%. M.P.: 295-297 °C. ^-NMRidppm, DMSO- de, 400 MHz): 11.76 (s, 1H), 11.25 (s, 1H), 9.09 (dd, J 4.0, 1.6, 1H), 8.94 (d, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.61 (s, 1H), 8.23-8.17 (m, 2H), 8.01 (d, J 2.8, 1H), 7.83 (d, J 11.2, 1H), 7.78 (dd, J 8.4, 4, 1H), 3.85 (d, J 12.4. 2H), 3.58-3.48 (m, 3H), 3.35 (t, J 11.6, 2H), 3.20-3.10 (m, 2H), 1.32 (d, J 6.4, 6H). MS (m/z): 462.2 (M+H); calculated for [C25H25F2N7 + H]: 462.22.
Example 14
5-Fluoro-N-(5-(4-isopropylpiperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2- amine
[249] Following the general procedure-3, the titled compound was synthesized from Intermediate 2 (500 mg, 1.93 mmol) and Intermediate 25 (424 mg, 1.93 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (10:90) as eluent. The pooled fractions were evaporated and the residue was starred for 30 min. with diethyl ether (10 mL), filtered, washed with diethyl ether (5 mL) and dried to obtain the titled compound as a yellow solid (200 mg). Yield: 23.4%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.72 (s, 1H), 9.04-8.93 (m, 1H), 8.68-8.64 (m, 2H), 8.53 (d, J 8, 1H), 8.40 (d, J 8.8, 1H), 8.18 (d, J 9.2, 1H), 8.10 (d, J 9.2, 1H), 8.00 (d, J 2.8, 1H), 7.61 (dd, J 8.4, 3.6, 1H), 3.18-3.05 (m, 4H), 2.71-2.55 (m, 5H), 1.02 (d, J 6.4, 6H). MS (m/z): 444.48 (M+H); calculated for [C25H26FN7 + H] : 444.23.
Example 14A
5-Fluoro-N-(5-(4-isopropylpiperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2- amine hydrochloride
[250] To a mixture of 5-fluoro-N-(5-(4-isopropylpiperazin-l-yl)pyridin-2-yl)-4-(quinolin-6- yl)pyrimidin-2 -amine (Example 14, 200 mg, 0.45 mmol) in methanol (2 mL) was added aq. 35% hydrochloric acid (164 mg, 4.5 mmol). The solution turned clear for a while and then a solid was formed during stirring. The mixture was stirred for 30 min. and the solid filtered, washed successively with methanol (5 mL) and diethyl ether (10 mL) and dried under vacuum to give the titled compound as ayellow solid (90 mg). Yield: 41%. M.P.: 278-280 °C. ¾-NMR (d ppm, DMSO-flfe, 400 MHz): 11.78 (s, 1H), 11.35 (s, 1H), 9.19 (dd, J 4.8, 1.6, 1H), 8.95 (d, J 3.2, 1H), 8.92 (d, J 8.4, 1H), 8.86 (s, 1H), 8.54 (d, J 9.2, 1H), 8.41 (d, J 9.2, 1H), 8.19 (dd, J 9.6, 2.4, 1H), 8.04 (d, J 2.4, 1H), 7.90-7.82 (m, 2H), 3.85 (d, J 13.2, 2H), 3.57-3.48 (m, 3H), 3.37 (d, J 13.2, 2H), 3.20-3.09 (m, 2H). MS (m/z): 444.47 (M+H); calculated for [C25H26FN7 + H]: 444.23. Example 15
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylpiperazin-l-yl)methyl)pyridin-2- yl)pyrimidin-2-amine
[251] Following the general procedure-3, the titled compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 27 (371 mg, 1.80 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (10:90) as eluent. The pooled fractions were evaporated and the residue was strirred for 30 min. with diethyl ether (10 mL), filtered, washed with diethyl ether (5 mL) and dried to obtain the titled compound as a pale green solid (150 mg). Yield: 17.4%. M.P.: 250-252 °C. ¾-NMR (d ppm, DMSO-r e, 400 MHz): 10.17 (s, 1H), 9.06 (d, J 4, 1H), 8.80 (d, J 3.2, 1H), 8.67 (d, J 8.4, 1H), 8.58 (s, 1H), 8.22 (t, J 10.8, 1H), 7.75 (dd, J 8, 4, 1H), 3.52 (s, 2H), 3.00-2.90 (m, 4H), 2.61-2.52 (m, 4H). MS (m/z): 448.3 (M+H); calculated for [C24H23F2N7 + H]: 448.21
Example 15A
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylpiperazin-l-yl)methyl)pyn din-2- yl)pyrimidin-2-amine hydrochloride
[252] To a mixture of 5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylpiperazin-l- yl)methyl)pyridin-2-yl)pyrimidin-2-amine (Example 15, 500 mg, 0.34 mmol) in methanol (3 mL) was added aq. 35% hydrochloric acid (122 mg, 3.4 mmol). The solution turned clear for a while and then a solid was formed during stirring. The mixture was stirred for 30 min. and the solid filtered, washed successively with methanol (5 mL) and diethyl ether (10 mL) and dried under vacuum to give the titled compound as a yellow solid (130 mg). Yield: 80%. M.P.: 250- 253 °C. ¾-NMR (d ppm, DMSO-r e, 400 MHz): 11.98 (s, 1H), 11.69 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.95-8.91 (m, m, 1H), 8.70 (d, J 8.4, 1H), 8.66-8.59 (m, 2H), 8.42-8.31 (m, 1H), 8.24 (d, J 12, 1H), 8.11-8.04 (m, 1H), 7.77 (dd, J 8.4, 4, 1H), 4.45 (s, 2H), 3.75-3.60 (m, 4H), 3.45- 3.30 (m, 4H), 2.80 (s, 3H). MS (m/z): 448.26 (M+H); calculated for [C24H23F2N7 + H]: 448.21.
Example 16
2-(6-(2-((5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-
8-fluoro-2-methylquinolin-4-yl)propan-2-ol
[253] Following the general procedure-3, the titled compound was synthesized from Intermediate 31 (500 mg, 1.43 mmol) and Intermediate 9 (315 mg, 1.43 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (12:88) as eluent. The pooled fractions were evaporated, and the residue was starred for 20 min. with petroleum ether (10 mL), fdtered and dried to obtain the titled compound as a yellow solid (180 mg). Yield: 23.6%. M.P.: 253-256°C. ^-NMR (d ppm, DMSO-rie, 400 MHz): 10.09 (s, 1H), 9.51 (s, 1H), 8.75 (d, J 7.6, 1H), 8.27 (d, J 8.8, 1H), 8.18 (d, J 2, 1H), 8.10 (d, J 12, 1H), 7.71 (dd, J 8.8, 2, 1H), 7.60 (s, 1H), 3.43 (s, 2H), 2.71 (s, 3H), 2.50-2.20 (m, 10H), 0.96 (t, J 6.8, 3H). MS (m/z): 534.35 (M+H); calculated for [C29H33F2N7O + H]: 534.28.
Example 16A
2-(6-(2-((5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)- 8-fluoro-2-methylquinolin-4-yl)propan-2-ol hydrochloride
[254] To a mixture of 2-(6-(2-((5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)amino)-5- fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4-yl)propan-2-ol (Example 16, 180 mg, 0.34 mmol) in methanol (3 mL) was added aq. 35% hydrochloric acid (123 mg, 3.4 mmol). The solution turned clear for a while and then a solid was formed during stirring. The mixture was stirred for 30 min. and the solid fdtered, washed with diethyl ether (10 mL) and dried under vacuum to give the titled compound as a yellow solid (110 mg). Yield: 57.2%. M.P.: 275-278 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.92 (bs, 1H), 11.44 (bs, 1H), 9.53 (s, 1H), 8.89 (d, J 3.6, 1H), 8.61 (d, J 1.2, 1H), 8.37-8.32 (m, 1H), 8.20-8.12 (m, 2H), 7.64 (s, 1H), 4.47 (s, 2H), 3.75-3.55 (m, 4H), 3.50-3.38 (m, 6H), 2.74 (s, 3H), 1.74 (s, 6H), 1.25 9t, J 7.2, 3H). MS (m/z): 534.37 (M+H); calculated for [C29H33F2N7O+H] : 534.28.
Example 17
7er/-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate
[255] Following the general procedure-3, the titled compound was synthesized from Intermediate 31 (500 mg, 1.43 mmol) and Intermediate 5 (398 mg, 1.43 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (3.5:96.5) as eluent. The pooled fractions were evaporated, and the residue was stirred for 20 min. with diethyl ether (10 mL), filtered and dried to obtain the titled compound as a pale yellow solid (145 mg). Yield: 17.1%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.83 (s, 1H), 9.47 (s, 1H), 8.70 (d, J 3.6, 1H), 8.14 (d, J 8.8, 1H), 8.08 (d, J 12.4, 1H), 8.04 (d, J 3.6, 1H), 7.60 (s, 1H), 7.48-7.44 (m, 1H), 5.69 (s, 1H), 3.50-3.44 (m, 4H), 3.10-3.05 (m, 4H), 2.71 (s, 3H), 1.72 (s, 6H), 1.41 (s, 9H). MS (m/z): 592.44 (M+H); calculated for [C31H35F2N7O3+H]: 592.29. Example 17A
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)propan-2-ol
[256] Following the general procedure-4, the titled compound was synthesized from tert- butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Example 17, 140 mg, 0.28 mmol) as a pale- yellow solid (60 mg). Yield: 54%. M.P.: 258-261°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.79 (s, 1H), 9.47 (s, 1H), 8.69 (d, J 3.6, 1H), 8.11 (d, J 9.2, 1H), 8.07 (d, J 11.6, 1H), 8.00 (d, J 2.8, 1H), 7.60 (s, 1H), 7.42 (dd, J 8.8, 2.8, 1H), 5.69 (s, 1H), 3.05-2.99 (m, 4H), 2.88-2.81 (m, 4H), 2.71 (s, 3H), 1.72 (s, 6H). MS (m/z): 492.49 (M+H); calculated for [C26H27F2N7O + H]: 492.23.
Example 17B
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)propan-2-ol hydrochloride
[257] To a mixture of 2-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-2-methylquinohn-4-yl)propan-2-ol (Example 17A, 70 mg, 0.14 mmol) in methanol (2 mL) was added aq. 35% hydrochloric acid (52 mg, 3.4 mmol). The solution turned clear for a while and then a solid was formed during stirring. The mixture was stirred for 30 min., diluted with methyl tert- butyl ether (5 mL) and the solid filtered, washed with methyl tert- butyl ether (10 mL) and dried under vacuum to give the titled compound as a yellow solid (37 mg). Yield: 49%. M.P.: 278-280°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.74 (s, 1H), 9.55-9.45 (m, 3H), 8.91 (d, J 3.6, 1H), 8.17 (d, J 12.8, 1H), 8.00 (d, J 2.4, 1H), 7.88 (d, J 9.6, 1H), 7.63 (s, 1H), 3.49-3.42 (m, 4H), 3.29-3.20(m, 4H), 2.73 (s, 3H), 1.72(s, 6H). MS (m/z): 492.49 (M+H-HC1); calculated for [C26H27F2N7O.HCI + H-HC1]: 492.23.
Example 18
2-(6-(2-((5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-
2-methylquinolin-4-yl)propan-2-ol
[258] Following the general procedure-3, the titled compound was synthesized from Intermediate 31 (500 mg, 1.43 mmol) and Intermediate 20 (295 mg, 1.43 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (10:90) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (10 mL), filtered, washed with diethyl ether (5 mL) and dried to obtain the titled compound as a pale yellow solid (110 mg). Yield: 14.8%. M.P.: 206-208 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.80 (s, 1H), 9.47 (s, 1H), 8.69 (d, J = 3.6, 1H), 8.12 (d, J = 8.8, 1H), 8.08 (d, J = 12.0, 1H), 8.01 (d, J = 2.8, 1H), 7.60 (s, 1H), 7.44 (dd, J = 8.8, 2.8, 1H), 5.70 (s, 1H), 3.12 (br. s, 4H), 2.72 (s, 3H), 2.42-2.51 (m, 4H under DMSO signal), 2.37 (q, J = 7.2, 2H), 1.72 (s, 6H), 1.03 (t, J = 7.2, 3H). MS (m/z): 520.52 (M+H); calculated for [C28H31F2N7O + H]: 520.27.
Example 18A
2-(6-(2-((5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro- 2-methylquinolin-4-yl)propan-2-ol hydrochloride
[259] To a mixture of 2-(6-(2-((5-(4-ethylpiperazin-l-yl)pyridin-2-yl)amino)-5- fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4-yl)propan-2-ol (Example 18, 100 mg, 0.19 mmol) in methanol (2.5 mL) was added aq. 35% hydrochloric acid (70 mg, 1.9 mmol). The resulting clear solution was stirred for 30 min., diluted with diethyl ether (5 mL) and the solid formed was filtered, washed with diethyl ether (10 mL) and dried under vacuum to give the titled compound as a yellow solid (25 mg). Yield: 37%. M.P.: 215-220°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.69 (s, 1H), 11.27 (s, 1H), 9.50 (s, 1H), 8.90 (d, J 3.2, 1H), 8.18 (br. s, 1H), 8.10 (d, J 12.4, 1H), 8.02 (d, J 2.8, 1H), 7.89 (d, J 9.6, 1H), 7.63 (s, 1H), 3.85 (d, J 12.8, 2H), 3.59 (d, J 11.6, 2H), 3.27 (t, J 12.8, 2H), 3.23-3.05 (m, 4H), 2.73 (s, 1H), 1.73 (s, 6H), 1.30 (t, J 7.2, 3H). MS (m/z): 520.51 (M+H); calculated for [C28H31F2N7O + H]: 520.27.
Example 19
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4-ethylpiperazin-l- yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine
[260] Following the general procedure-3, the titled compound was synthesized from Intermediate 36 (500 mg, 1.46 mmol) and Intermediate 20 (302 mg, 1.46 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (4.6:95.4) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (10 mL), solids filtered, washed with diethyl ether (5 mL) and dried to obtain the titled compound as a yellow solid (50 mg). Yield: 6.7%. M.P.: 237-238 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.87 (s, 1H), 8.73 (d, J 3.6, 1H), 8.71 (br. s, 1H), 8.24 (d, J 9.0, 1H), 8.10-8.02 (m, 2H), 7.86 (s, 1H), 7.68 (t, J 53.6, 1H), 7.43 (dd, J 9.2, 3.2, 1H), 3.14 (br. s, 4H), 2.80 (s, 3H), 2.54 (br (s, 4H), 2.45-2.32 (m, 2H), 1.04 (t, J 7.2, 3H). MS (m/z): 512.46 (M+H); calculated for [C26H25F4N7 + H]: 512.22.
Example 19A
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4-ethylpiperazin-l- yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine hydrochloride
[261] To a mixture of 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4- ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine (Example 19, 40 mg, 0.08 mmol) in methanol (1 mL) was added aq. 35% hydrochloric acid (29 mg, 0.8 mmol). The resulting clear solution was stirred for 30 min., diluted with diethyl ether (4 mL) and the solid formed was fdtered, washed with diethyl ether (2 mL) and dried under vacuum to give the titled compound as ayellow solid (35 mg). Yield: 79%. M.P.: 195-197 °C. ^-NMR (d ppm, DMSO- de, 400 MHz): 11.36 (s, 1H), 10.95 (s, 1H), 8.91 (d, J 3.2, 1H), 8.68 (s, 1H), 8.25 (d, J 11.6, 1H), 8.10-7.97 (m, 2H), 7.86-7.92 (m, 2H), 7.69 (t, J 53.2, 1H), 3.84 (d, J 10.8, 2H), 3.59 (d, J 11.6, 2H), 3.30-3.05 (m, 6H), 2.81 (s, 3H), 1.29 (t, J 7.2, 3H). MS (m/z): 512.52 (M+H); calculated for [C26H25F4N7 + H]: 512.22.
Example 20
7h//-butyl 4-(6-((4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5- fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate
[262] Following the general procedure-3, the titled compound was synthesized from Intermediate 36 (500 mg, 1.46 mmol) and Intermediate 5 (407 mg, 1.46 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (3.5:96.5) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (10 mL), solids filtered, and dried to obtain the titled compound as a yellow solid (110 mg). Yield: 12.9%. M.P.: 224-227 °C. Tf-NMR (d ppm, CDCb, 400 MHz): 8.77 (s, 1H), 8.51 (d, J 3.6, 1H), 8.34 (d, J 9.2, 1H), 8.31-8.17 (m, 2H), 8.08 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J 9.2, 3.2, 1H), 7.19 (t, J 54.4, 1H), 3.68-3.61 (m, 4H), 3.18-3.10 (m, 4H), 1.52 (s, 9H). MS (m/z): 584.23 (M+H); calculated for [C29H29F4N7O2 + H]: 584.24.
Example 20A
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2-amine [263] Following the general procedure-4, the titled compound was synthesized from tert- butyl 4-(6-((4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoropyrimidin-2- yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Example 20, 100 mg, 0.17 mmol) as a yellow solid (50 mg). Yield: 60 %. M.P.: 262-264 °C. ¾-NMR (d ppm, CDCb, 400 MHz): 9.86 (s, 1H), 8.72 (d, J 8.36, 1H), 8.70 (br. s, 1H), 8.23 (d, J 11.6, 1H), 8.05 (d, J 8.8, 1H), 8.01 (d, J 3.2, 1H), 7.86 (s, 1H), 7.68 (t, J 53.6, 1H), 7.40 (dd, J 9.2, 3.2, 1H), 3.08-3.03 (m, 4H), 2.91- 2.85 (m, 4H), 2.79 (s, 3H). MS (m/z): 484.45 (M+H); calculated for [C24H21F4N7 + H]: 484.19.
Example 20B
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride
[264] To a mixture of 4-(4-(difluoromethyl)-8-fhioro-2-methylquinolin-6-yl)-5-fluoro-N-(5- (piperazin-l-yl)pyridin-2-yl)pyrimidin-2 -amine (Example 20A, 40 mg, 0.08 mmol) in methanol (1 mL) was added aq. 35% hydrochloric acid (30 mg, 0.8 mmol). The resulting clear solution was stirred for 30 min., diluted with diethyl ether (4 mL) and the solid formed was fdtered, washed with diethyl ether (2 mL) and dried. Obtained solid was dissolved in methanol -dichloromethane 1:4 (20 mL), fdtered and the fdtrate concentrated under vacuum and the residue co-distilled with toluene (5.0 mL) to give the titled compound as a yellow solid (25 mg). Yield: 67%. M.P.: 263-265 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 10.76 (br. s, 1H), 9.06 (br. s, 2H), 8.84 (d, J 3.2, 1H), 8.69 (s, 1H), 8.25 (d, J 12.0, 1H), 8.03 (d, J 2.8, 1H), 7.97 (d, J 9.2, 1H), 7.89 (s, 1H), 7.80 (br. s, 1H), 7.69 (t, J 54, 1H), 3.41-3.35 (m, 4H), 3.30-3.22 (m, 4H), 2.80 (s, 3H). MS (m/z): 484.49 (M+H); calculated for [C24H21F4N7 + H]: 484.19.
Example 21
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine
[265] Following the general procedure-3, the titled compound was synthesized from Intermediate 36 (500 mg, 1.46 mmol) and Intermediate 9 (322 mg, 1.46 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (12:88) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (10 mL), solids filtered, and dried to obtain the titled compound as a yellow solid (140 mg). Yield: 18.2%. M.P.: 219-222 °C. MS (m/z): 526.3 (M+H); calculated for [C27H27F4N7 + H]: 526.24.
Example 21A 4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine hydrochloride
[266] To a mixture of 4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-((4- ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine (Example 21, 100 mg, 0.19 mmol) in methanol (2.5 mL) was added aq. 35% hydrochloric acid (69 mg, 1.9 mmol). The resulting clear solution was stirred for 30 min., diluted with diethyl ether (4 mL) and the solid formed was filtered, washed with diethyl ether (2 mL) and dried. Obtained solid was dissolved in methanol dichloromethane 1:4 (20 mL), filtered and the filtrate concentrated under vacuum and the residue co-distilled with toluene (5.0 mL) to give the titled compound as a brown solid (53 mg). Yield: 50%. M.P.: 218-220 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.82 (br. s, 1H), 11.19 (br. s, lH), 8.90 (d, J 3.2, 1H), 8.72 (s, 1H), 8.58 (s, 1H), 8.30-8.13 (m, 3H), 7.89 (s, 1H), 7.70 (t, J 53.6, 1H), 5.0-4.6 (m, 7H), 3.80-3.10 (m, 9H), 1.25 (t, J = 7.2, 3H). MS (m/z): 526.25 (M+H-HC1); calculated for [C27H27P4N7.HCI + H-HC1]: 526.24.
Example 22
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-(2- fluoropropan-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-amine
[267] following the general procedure-3, the titled compound was synthesized from Intermediate 39 (500 mg, 1.42 mmol) and Intermediate 9 (313 mg, 1.42 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (6.7:93.3) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (10 mL), solids filtered, washed with diethyl ether (5 mL) and dried to obtain the titled compound as a pale brown solid (170 mg). Yield: 22.3%. M.P.: 207-209 °C. ^-NMR (d ppm, DMSO-flfe, 400 MHz): 10.14 (s, 1H), 8.99 (s, 1H), 8.76 (d, J 3.6, 1H), 8.28 (m, 3H), 7.68 (dd, J 8.8, 2.4, 1H), 7.64 (s, 1H), 3.45 (s, 2H), 2.75 (s, 3H), 2.60-2.20 (m, 10H), 1.95 (d, J 22.8, 6H), 0.98 (t, J 7.2, 3H). MS (m/z): 536.33 (M+H); calculated for [C29H32P3N7 + H]: 536.27.
Example 22A
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-(2- fluoropropan-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-amine hydrochloride (
[268] To a mixture of N-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8- fluoro-4-(2-fluoropropan-2-yl)-2-methylquinolin-6-yl)pyrimidin-2 -amine (Example 22, 150 mg, 0.28 mmol) in methanol (3 mL) was added aq. 35% hydrochloric acid (102 mg, 2.8 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (6 mL) and stirred for 30 min. The solid formed was fdtered, washed with methyl tert- butyl (5 mL) and dried to give the titled compound as a pale yellow solid (60 mg). Yield: 37%. M.P.: 250- 253 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.56 (br. s, 1H), 10.95 (br. s, 1H), 8.64 (s, 1H), 8.54 (d, J 3.2, 1H), 8.25 (s, 1H), 7.96 (d, J 8.8, 1H), 7.88-7.80 (m, 2H), 7.32 (s, 3H), 4.10 (br. s, 2H), 3.40-2.70 (m, 10H), 2.41 (s, 3H), 2.20-2.00 (m, 2H), 1.63 (d, J 22.8, 6H), 0.91 (t, J
7.2, 3H). MS (m/z): 536.39 (M+H-HC1); calculated for [C29H32F3N7.HCI + H]: 536.27.
Example 23
Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-fluoropropan-2-yl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate
[269] Following the general procedure-3, the titled compound was synthesized from Intermediate 39 (500 mg, 1.42 mmol) and Intermediate 5 (396 mg, 1.42 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (6.5:93.5) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (10 mL), solids filtered, washed with diethyl ether (5 mL) and dried to obtain the titled compound as a yellow solid (220 mg). Yield: 26.1%. M.P.: 224-226 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 8.94 (s, 1H), 8.47 (d, J 3.6, 1H), 8.33 (d, J 8.8, 1H), 8.20-8.14 (m, 2H), 8.06 (d, J 2.8, 1H), 7.48 (s, 1H), 7.37 (dd, J 8.8, 2.8, 1H), 3.62 (t, J 4.8, 4H), 3.11 (t, J 4.8, 4H), 2.85 (s, 3H), 2.00 (d, J 22.4, 6H), 1.50 (s, 9H). MS (m/z): 594.34 (M+H); calculated for [C31H34F3N7O2 + H]: 594.28.
Example 23A
5-Fluoro-4-(8-fluoro-4-(2-fluoropropan-2-yl)-2-methylquinolin-6-yl)-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2-amine
[270] Following the general procedure-4, the titled compound was synthesized from fert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-fluoropropan-2-yl)-2-methylquinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Example 23, 200 mg, 0.34 mmol) as a yellow solid (120 mg). Yield: 72%. M.P.: 204-206 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.88 (s, 1H), 8.94 (s, 1H), 8.71 (d, J 3.6, 1H), 8.14 (d, J 11.6, 1H), 8.07 (d, J 8.8, 1H), 8.03 (d, J
3.2, 1H), 7.64 (s, 1H), 7.42 (dd, J 9.2, 3.2, 1H), 3.14 (t, J 5.2, 4H), 2.99 (t, J 5.2, 4H), 2.74 (s, 3H), 1.95 (d, J 22.8, 6H). MS (m/z): 494.49 (M+H); calculated for [C27H27F4N7 + H]: 494.23.
Example 23B 5-Fluoro-4-(8-fluoro-4-(2-fluoropropan-2-yl)-2-methylquinolin-6-yl)-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride
[271] To a mixture of 5-fluoro-4-(8-fluoro-4-(2-fluoropropan-2-yl)-2-methylquinolin-6-yl)- N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2 -amine (Example 23 A, 80 mg, 0.16 mmol) in methanol (2 mL) was added aq. 35% hydrochloric acid (59 mg, 1.6 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (6 mL) and stirred for 30 min. The solid formed was filtered, washed with methyl tert- butyl ether (5 mL) and dried to give the titled compound as a pale yellow solid (60 mg). Yield: 68%. M.P.: 240-243 °C. ¾- NMR (d ppm, DMSO-rie, 400 MHz): 11.77 (br. s, 1H), 9.53 (br. s, 2H), 8.95-8.89 (m, 2H), 8.22-8.12 (m, 2H), 7.97 (d, J 2.8, 1H), 7.86 (d, J 9.2, 1H), 7.67 (s, 1H), 3.46 (br. s, 4H), 3.25 (br. s, 4H), 2.75 (s, 3H), 1.95 (d, J 22.4, 6H). MS (m/z): 494.47 (M+H-HC1); calculated for [C27H27F4N7.HCI + H-HC1] : 494.23.
Example 24
5-Fluoro-N-(5-((4-methylpiperazin-l-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2- amine
[272] Following the general procedure 3, the titled compound was synthesized from Intermediate 2 (500 mg, 1.93 mmol) and Intermediate 27 (397 mg, 1.93 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (11.5:89.5) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (10 mL), solids filtered, washed with diethyl ether (5 mL) and dried to obtain the titled compound as a yellow solid (320 mg). Yield: 38.7%. M.P.: 196-198 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 10.08 (s, 1H), 9.01 (dd, J 4.4, 1.2, 1H), 8.77 (d, J 3.2, 1H), 8.71 (s, 1H), 8.59 (d, J 7.6, 1H), 8.42 (d, J 9.2, 1H), 8.27-8.16 (m, 3H), 7.72 (dd, J 8.4, 2.4, 1H), 7.64 (dd, J 8.0, 4.0, 1H), 3.42 (s, 2H), 2.56-2.24 (m, 8H,), 2.15 (s, 3H). MS (m/z): 430.29 (M+H); calculated for [C24H24FN7 + H]: 430.22.
Example 24A
5-Fluoro-N-(5-((4-methylpiperazin-l-yl)methyl)pyridin-2-yl)-4-(quinolin-6- yl)pyrimidin-2-amine hydrochloride
[273] To a mixture of 5-fluoro-N-(5-((4-methylpiperazin-l-yl)methyl)pyridin-2-yl)-4- (quinolin-6-yl)pyrimidin-2 -amine (Example 24, 300 mg, 0.70 mmol) in methanol (7.5 mL) was added aq. 35% hydrochloric acid (260 mg, 7.1 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (15 mL) and stirred for 1 h. The solid formed was filtered, washed with methyl tert- butyl ether (15 mL) and dried to give the titled compound as a pale brown solid (60 mg). Yield: 68%. M.P.: 235-238 °C. ^-NMR (d ppm, DMSO-rfc, 400 MHz): 12.00 (br. s, 1H), 11.47 (br. s, 1H), 9.23 (dd, J 4.8, 1.2, 1H), 9.01 (d, J 8.4, 1H), 8.94 (d, J 2.8, 1H), 8.91 (s, 1H), 8.64-8.57 (m, 2H), 8.44 (d, J 9.2, 1H), 8.33 (d, J 9.2, 1H), 8.10 (d, J 9.2, 1H), 8.10 (d, J 9.2, 1H), 8.10 (d, J 9.2, 1H), 7.92 (dd, J 8.4, 4.8, 1H), 4.44 (br. s, 2H), 3.70-3.55 (m, 4H), 3.50-3.30 (m, 4H), 2.80 (s, 3H). MS (m/z): 430.33 (M+H-HC1); calculated for [C24H24FN7.HCI+ H-HC1]: 430.22.
Example 25
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6- yl)pyrimidin-2-amine
Following the general procedure-3, the titled compound was synthesized from Intermediate 41 (500 mg, 1.80 mmol) and Intermediate 9 (400 mg, 1.80 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (8.7:91.3) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (10 mL), solids filtered, washed with diethyl ether (5 mL) and dried to obtain the titled compound as a pale yellow solid (370 mg). Yield: 44.5%. M.P.: 198-200°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 10.19 (s, 1H), 9.03 (br. d, J 3.2, 1H), 8.00 (d, J 1.6, 1H), 8.59 (d, J 8.0, 1H), 8.47 (d, J 8.0, 1H), 8.21-8.15 (m, 2H), 7.99 (d, J 11.2, 1H), 7.68-7.60 (m, 2H), 3.39 (s, 2H), 2.40-2.20 (m, 10H), 0.96 (t, J = 10.8, 3H). MS (m/z): 462.34 (M+H); calculated for [C25H25F2N7 + H]: 462.22.
Example 25A
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6- yl)pyrimidin-2-amine hydrochloride
[274] To a mixture of N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7- fluoroquinolin-6-yl)pyrimidin-2-amine (Example 25, 330 mg, 0.72 mmol) in methanol (8.25 mL) was added aq. 35% hydrochloric acid (260 mg, 7.1 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (24.7 mL) and stirred for 1 h. The solid formed was filtered, washed with methyl tert- butyl ether (20 mL) and dried to give the titled compound as a pale yellow solid (290 mg). Yield: 81%. M.P.: 255-257°C. ^-NMR (d ppm, DMSO-rie, 400 MHz): 11.94 (br. s, 1H), 11.51 (br. s, 1H), 9.12 (dd, J = 4.4, 1.6, 1H), 8.96 (d, J = 1.6, 1H), 8.74 (d, J = 7.4, 1H), 8.62-8.56 (m, 2H), 8.28 (d, J = 9.2, 1H), 8.14-8.04 (m, 2H), 7.74 (dd, J = 8.4, 4.8, 1H), 4.43 (br. s, 2H), 3.80-3.10 (m, 10H), 1.24 (t, J = 7.2, 3H). MS (m/z): 462.35 (M+H-HC1); calculated for [C25H25F2N7.HCI + H-HC1]: 462.22.
Example 26
7<?/7-butyl 4-(6-((5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperazine-l-carboxylate
Following the general procedure-3, the titled compound was synthesized from Intermediate 41 (500 mg, 1.80 mmol) and Intermediate 5 (500 mg, 1.80 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (2.3:97.7) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (10 mL), solids filtered, washed with diethyl ether (5 mL) and dried to obtain the titled compound as a yellow solid (360 mg). Yield: 38.5%. M.P.: 248-250°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.93 (s, 1H), 9.03 (dd, J 4.0, 1.6, 1H), 8.74 (d, J 1.6, 1H), 8.58 (d, J 7.6, 1H), 8.06- 7.95 (m, 3H), 7.63 (dd, J 8.4, 4.4, 1H), 7.42 (dd, J 9.2, 3.2, 1H), 3.48-3.42 (m, 4H), 3.08-3.02 (m, 4H), 1.41 (s, 9H). MS (m/z): 520.31 (M+H); calculated for [C27H27F2N7O2 + H]: 520.22.
Example 26A
5-Fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine
Following the general procedure-4, the titled compound was synthesized from tert-butyl 4-(6- ((5 -fhioro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3 -yl)piperazine- 1 - carboxylate (Example 26, 330 mg, 0.64 mmol) as a yellow solid (250 mg). Yield: 93%. M.P.: 228-230°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.89 (s, 1H), 9.05-9.00 (m, 1H), 9.03 (s, 1H), 8.58 (d, J 7.6, 1H), 8.45 (d, J 7.6, 1H), 8.02-7.87 (m, 3H), 7.63 (dd, J 8.4, 4.0, 1H), 7.37 (d, J 8.8, 1H), 3.02-2.94 (m, 4H), 2.84-2.78 (m, 4H). MS (m/z): 420.47 (M+H); calculated for [C22H19F2N7 + H]: 420.17.
Example 26B
5-Fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride
[275] To a mixture of 5-fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine (Example 26A, 230 mg, 0.55 mmol) in methanol (5.75 mL) was added aq. 35% hydrochloric acid (200 mg, 5.48 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (17.3 mL) and stirred for 1 h. The solid formed was fdtered, washed with methyl tert- butyl ether (20 mL) and dried to give the titled compound as a brown solid (190 mg). Yield: 76%. M.P.: 259-262°C. Tf-NMR^ppm, DMSO-rie, 400 MHz): 11.87 (br. s, 1H), 9.66 (br. s, 2H), 9.08-9.13 (m, 1H), 8.98 (d, J = 2.0, 1H), 8.72 (d, J = 8.4, 1H), 8.59 (d, J = 7.6, 1H), 8.16 (d, J = 9.2, 1H), 8.10 (d, J = 11.6, 1H), 7.99 (d, J = 2.8, 1H), 7.84 (d, J = 9.6, 1H), 7.72 (dd, J = 8.0, 4.4, 1H), 3.42 (bs, 4H), 3.22 (bs, 4H). MS (m/z): 420.48 (M+H); calculated for [C22H19P2N7.HCI + H-HC1]: 420.17.
Example 27
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fhioro-4-(7-fhioroquinolin-6-yl)pyrimidin-2-amine following the general procedure-3, the titled compound was synthesized from Intermediate 41 (500 mg, 1.80 mmol) and Intermediate 20 (371 mg, 1.80 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (5.8:94.2) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (10 mL), solids filtered, washed with diethyl ether (5 mL) and dried to obtain the titled compound as a yellow solid (200 mg). Yield: 24.8%. M.P.: 258-260°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.88 (s, 1H), 9.03-9.01 (m, 1H), 8.73 (bs, 1H), 8.58 (d, J 7.6, 1H), 8.45 (d, J 7.6, 1H), 8.02-7.88 (m, 3H), 7.63 (dd, J 8.4, 4.4 1H), 7.42-7.38 (m, 1H), 3.03 (bs, 4H), 2.60-2.40 (m, 4H), 2.40-2.30 (m, 2H), 1.02 (t, J = 6.8, 3H). MS (m/z): 448.47. (M+H); calculated for [C24H23P2N7 + H]: 448.20.
Example 27A
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-amine hydrochloride
[276] To a mixture of N-(5-(4-ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(7- fluoroquinolin-6-yl)pyrimidin-2 -amine (Example 27, 180 mg, 0.40 mmol) in methanol (4.5 mL) was added aq. 35% hydrochloric acid (147 mg, 4.02 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (13.5 mL) and stirred for 1 h. The solid formed was fdtered, washed with methyl tert- butyl ether (20 mL) and dried to give the titled compound as a yellow solid (160 mg). Yield: 82.5%. M.P.: 240-242°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.91 (bs, 1H), 11.42 (bs, 1H), 9.11 (dd, J 4.4, 1.2, 1H), 8.99(d, J 1.6, 1H), 8.72 (d, J 8.4, 1H), 8.59 (d, J 8.0, 1H), 8.20 (dd, J 9.6, 2.4, 1H), 8.10 (d, J 11.6, 1H), 8.00 (d, J 2.4, 1H), 7.82 (d, J 9.6, 1H), 7.73 (d, J 8.0, 4.4, 1H), 3.84 (d, J 12.8, 2H), 3.57 (d, J 11.6, 2H), 3.27 (d, J 12.0, 2H), 3.04-3.00 (m, 4H), 1.29 (t, J 7.2, 3H). MS (m/z): 448.46. (M+H); calculated for [C24H23P2N7.HCI + H-HC1]: 448.20. Example 28
N-(5-(4-(Dimethylamino)piperidin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2-amine
Following the general procedure-3, the titled compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 43 (400 mg, 1.80 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (16:84) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (20 mL), solids filtered, washed with diethyl ether (20 mL) and dried to obtain the titled compound as a yellow solid (270 mg). Yield: 32 %. M.P.: 238-240°C. M.P.: 238-240°C. ¾-NMR (5 ppm, DMSO-r e, 400 MHz): 9.48 (s, 1H), 9.06 (d, J 2.8, 1H), 8.73 (d, J 4, 1H), 8.66 (d, J 8.4, 1H), 8.56 (s, 1H), 8.20 (d, J 12, 1H), 8.07-8.01 (m, 2H), 7.74 (dd, J 8.4, 4, 1H), 7.50 (dd, J 9.2, 2.8, 1H), 3.76 (d, J 12, 2H), 2.72-2.64 (m, 2H), 2.61-2.50 (m, 7H), 1.99 (d, J 12, 2H), 1.72-1.60 (m, 2H). MS (m/z): 462.40. (M+H); calculated for [C25H25F2N7 + H]: 462.21.
Example 28A
N-(5-(4-(Dimethylamino)piperidin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2-amine hydrochloride
[277] To a mixture of N-(5-(4-(Dimethylamino)piperidin-l-yl)pyridin-2-yl)-5-fhioro-4-(8- fluoroquinohn-6-yl)pyrimidin-2-amine (Example 28, 250 mg, 0.54 mmol) in methanol (6.25 mL) was added aq. 35% hydrochloric acid (20 mg, 5.4 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (18.75 mL) and stirred for 1 h. The solid formed was filtered, washed with methyl tert- butyl ether (20 mL) and dried to give the titled compound as a brown solid (230 mg). Yield: 85%. M.P.: 292-294°C. 1H-NMR(5ppm, DMSO- de, 400 MHz): 11.87 (bs, 1H), 11.14 (bs, 1H), 9.08 (dd, J 4, 1.6, 1H), 8.95 (d, J 4, 1H), 8.70 (dd, J 8.8, 1.6, 1H), 8.61 (s, 1H), 8.25 (d, J 9.6, 1H), 8.21 (dd, J 12, 1.2, 1H), 7.97 (d, J 2.4, 1H), 7.82-7.76 (m, 2H), 3.86 (d, J 12, 2H), 3.38-3.28 (m, 1H), 2.81 (t, J 12, 2H), 2.71 (s, 3H), 2.70 (s, 3H), 2.17 (d, J 12, 2H), 1.85-1.72 (m, 2H). MS (m/z): 462.40. (M+H); calculated for [C25H25F2N7.HCI + H-HC1] : 462.21.
Example 29
4-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2- one Following the general procedure-3, the titled compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 45 (350 mg, 1.80 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (5.7:94.3) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (20 mL), solids filtered, washed with diethyl ether (20 mL) and dried to obtain the titled compound as a yellow solid (180 mg). Yield: 23 %. M.P.: 205-207°C. ¾-NMR (d ppm, DMSO-r e, 400 MHz): 9.87 (s, 1H), 9.06 (dd, J 4, 1.6, 1H), 8.73 (d, J 3.2, 1H), 8.66 (d, J 8.8, 1H), 8.56 (s, 1H), 8.20 (d, J 12, 1H), 8.06 (d, J 9.2, 2H), 8.03 (d, J 2.8, 1H), 7.74 (dd, J 8.8, 4.4, 1H), 3.71 (s, 2H), 3.42- 3.37 (m, 2H), 3.40-3.30 (m, 2H). MS (m/z): 434.42. (M+H); calculated for [C22H17F2N7O + H]: 434.15.
Example 29A
4-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2- one hydrochloride
[278] To a mixture of 4-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazin-2-one (Example 29, 150 mg, 0.35 mmol) in methanol (3.75 mL) was added aq. 35% hydrochloric acid (13 mg, 3.5 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (11.25 mL) and stirred for 1 h. The solid formed was filtered, washed with methyl tert- butyl ether (20 mL) and dried to give the titled compound as a brown solid (125 mg). Yield: 77%. M.P.: 236-238°C. ^-NMR^ppm, DMSO- de, 400 MHz): 11.91 (s, 1H), 9.08 (d, J 4, 1H), 8.94 (d, J 2.4, 1H), 8.70 (d, J 8, 1H), 8.59 (s, 1H), 8.25-8.17 (m, 3H), 7.89 (d, J 2.8, 1H), 7.77 (dd, J 8, 3.6, 2H), 3.81 (s, 2H), 3.50-3.45 (m, 2H), 3.38-3.32 (m, 2H). MS (m/z): 434.38. (M+H); calculated for [C22H17F2N7O.HCI + H- HC1]: 434.15
Example 30
N-(5-(4-Cyclopropylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2-amine
Following the general procedure-3, the titled compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 47 (390 mg, 1.80 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (6.8:93.2) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (10 mL) to obtain a solid, solids filtered, washed with diethyl ether (5 mL) and dried to obtain the titled compound as a yellow solid (180 mg). Yield: 27 %. M.P.: 246-248°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.83 (s, 1H), 9.06 (dd, J 4, 1.6, 1H), 8.72 (d, J 4, 1H), 8.67 (d, J 8.4, 1H), 8.56 (s, 1H), 8.21 (d, J 12.8, 1H), 8.03 (d, J 9.2, 1H), 8.00 (d, J 3.2, 1H), 7.75 (dd, J 8.4, 4, 1H), 7.47 (dd, J 8.8, 2.8, 1H), 3.11-3.05 (m, 4H), 2.71-2.65 (m, 4H), 1.65 (quintet, J 3.6, 1H), 0.46- 0.41 (m, 2H), 0.36-0.31 (m, 2H). MS (m/z): 460.40. (M+H); calculated for [C25H23F2N7 + H]: 460.20.
Example 30A
N-(5-(4-Cyclopropylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2-amine hydrochloride
[279] To a mixture of N-(5-(4-Cyclopropylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8- fluoroquinolin-6-yl)pyrimidin-2 -amine (Example 30, 200 mg, 0.435 mmol) in methanol (4 mL) was added aq. 35% hydrochloric acid (159 mg, 4.35 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (12 mL) and stirred for 1 h. The solid formed was fdtered, washed with methyl tert- butyl ether (15 mL) and dried to give the titled compound as a brown solid (200 mg). Yield: 91 %. M.P.: 296-298°C. ¾-NMR (d ppm, DMSO- de, 400 MHz): 11.64 (s, 1H), 9.09 (dd, J 4, 1.6, 1H), 8.98-8.92 (m, 1H), 8.20 (d, J 8.4, 1H), 8.61 (s, 1H), 8.20 (dd, J 12, 1.6, 1H), 8.18-8.12 (m, 1H), 8.00 (d, J 2.8, 1H), 7.84-7.75 (m, 2H), 3.84 (d, J 12, 2H), 3.59 (d, J 10, 2H), 3.39-3.22 (m,4H), 2.95-2.87 (m, 1H), 1.22-1.149m, 2H), 0.85- 0.78 (m, 2H). MS (m/z): 460.40. (M+H); calculated for [C25H23F2N7.HCI + H-HC1]: 459.50.
Example 31 l-(4-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperazin-l-yl)ethan-l-one
Following the general procedure-3, the titled compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 49 (400 mg, 1.80 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (4.8:95.2) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (20 mL) to obtain solid, solids filtered, washed with diethyl ether (20 mL) and dried to obtain the titled compound as a yellow solid (300 mg). Yield: 40 %. M.P.: 240-242°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.87 (s, 1H), 9.06 (dd, J 4, 1.6, 1H), 8.73 (d, J 4, 1H), 8.67 (d, J 8.8, 1H), 8.56 (s, 1H), 8.21 (d, J 13.2, 1H), 8.06 (d, J 9.2, 1H), 8.04 (d, J 3.2, 1H), 7.75 (dd, J 8.8, 4, 1H), 7.51 (dd, J 9.2, 3.2, 1H), 3.62-3.56 (m, 4H), 3.18-3.12 (m, 2H), 3.10-3.05 (m, 2H), 2.03 (s, 3H). MS (m/z): 462.49. (M+H); calculated for [C24H21F2N7O + H]: 462.18
Example 31A l-(4-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyri din-3- yl)piperazin-l-yl)ethan-l-one hydrochloride
[280] To a mixture of l-(4-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazin-l-yl)ethan-l-one (Example 31, 260 mg, 0.56 mmol) in methanol (6.5 mL) was added aq. 35% hydrochloric acid (210 mg, 5.6 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (20 mL) and stirred for 1 h. The solid formed was fdtered, washed with methyl tert- butyl ether (20 mL) and dried to give the titled compound as abrown solid (200 mg). Yield: 96 %. M.P.: 228-230°C. 'H-NMR (d ppm, DMSO-rie, 400 MHz): 11.97 (s, 1H), 9.09 (dd, J 4, 1.2, 1H), 8.95 (d, J 3.2, 1H), 8.71 (d, J 8, 1H), 8.61 (s, 1H), 8.27 (dd, J 9.2, 3.5, 1H), 8.19 (d, J 11.6, 1H), 7.92 (d, J 3.5, 1H), 7.80- 7.74 (m, 2H), 3.62 (t, J 4.8, 4H), 3.24 (t, J 4.8, 2H), 3.17 (t, J 4.8, 2H), 2.05 (s, 3H). MS (m/z): 462.49. (M+H); calculated for [C24H21F2N7O.HCI + H-HC1]: 462.18
Example 32
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)pyridin-2- yl)pyrimidin-2-amine
[281] Following the general procedure-3, the titled compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 51 (469 mg, 1.80 mmol). After work up, crude product was suspended in MeOH (50 ml) and DCM (50 ml) stirred for 30 mins to obtain a solid. Solid was fdtered and dried under vacuum to obtain the titled compound as a yellow solid (280 mg). Yield: 31 %. M.P.: 260-262°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.86 (s, 1H), 9.05 (dd, J 4, 2.8, 1H), 8.72 (d, J 3.2, 1H), 8.66 (d, J 8.4, 1H), 8.55 (s, 1H), 8.11 (d, J 12, 1H), 8.04 (d, J 9.2, 1H), 8.02 (d, J 2.8, 1H), 7.74 (dd, J 8.4, 4, 1H), 7.48 (dd, J 8.4, 2.8, 1H), 3.25 (q, J 10.4, 2H), 3.17-3.11 (m, 4H), 2.80-2.73 (m, 4H). MS (m/z): 502.52 (M+H); calculated for [C24H20F5N7 + H]: 502.17
Example 32A
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)pyridin-2- yl)pyrimidin-2-amine hydrochloride [282] To a mixture of 5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2- trifluoroethyl)piperazin-l-yl)pyridin-2-yl)pyrimidin-2 -amine (Example 32, 250 mg, 0.50 mmol) in methanol (5 mL) was added aq. 35% hydrochloric acid (182 mg, 5.0 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (15 mL) and stirred for 1 h. The solid formed was fdtered, washed with methyl tert- butyl ether (10 mL) and dried to give the titled compound as a brown solid (200 mg). Yield: 75 %. M.P.: 238-240°C. Tf-NMR (d ppm, DMSO-rie, 400 MHz): 11.89 (s, 1H), 9.09 (dd, J 4, 1.2, 1H), 8.95 (d, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.61 (s, 1H), 8.24-8.18 (m, 2H), 7.90 (bs, 1H), 7.78 (dd, J 8.4, 4.0, 1H), 7.22 (d, J 9.6, 1H), 3.45-3.31 (m, 2H), 3.29-3.23 (m, 4H), 2.90-2.82 (m, 4H). MS (m/z): 502.50 (M+H); calculated for [C24H20F5N7.HCI + H-HC1]: 502.17.
Example 33
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl)piperazin-l-yl)pyridin-2- yl)pyrimidin-2-amine
Following the general procedure-3, the titled compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 53 (469 mg, 1.80 mmol). After work up, crude product was suspended in MeOH (1 ml) and DCM (9 ml) stirred for 30 mins to obtain a solid. Solid was fdtered, washed with diethyl ether (20 ml) and dried under vacuum to obtain the titled compound as a yellow solid (220 mg). Yield: 25 %. M.P.: 295-297 °C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.90 (s, 1H), 9.06 (d, J 2.8, 1H), 8.74 (d, J 2.8, 1H), 8.67 (d, J 8.4, 1H), 8.57 (s, 1H), 8.21 (d, J 12.4, 2H), 8.10-8.05 (m, 1H), 7.75 (d, J 8.4, 1H), 7.53 (d, J 12.4, 1H), 3.28-3.20 (m, 4H), 2.93 (s, 3H), 2.60-2.50 (m, 4H).
Example 33A
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl)piperazin-l-yl)pyridin-2- yl)pyrimidin-2-amine hydrochloride
[283] To a mixture of 5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl)piperazin- l-yl)pyridin-2-yl)pyrimidin-2-amine (Example 33, 200 mg, 0.40 mmol) in methanol (5 mL) was added aq. 35% hydrochloric acid (150 mg, 4.0 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (15 mL) and stirred for 1 h. The solid formed was fdtered, washed with methyl tert- butyl ether (20 mL) and dried to give the titled compound as a yellow solid (210 mg). Yield: 98%. M.P.: 258-260°C. dT-NMR^ppm, DMSO- de, 400 MHz): 12.01 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.94 (t, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.59 (s, 1H), 8.27 (d, J 9.6, 1H), 8.00 (d, J 11.6, 1H), 7.95 (d, J 2.4, 1H), 7.84-7.74 (m, 2H), 3.34- 3.25 (m, 8H), 2.95 (s, 3H). MS (m/z): 497.80. (M+H); calculated for [C23H21F2N7O2S.HCI + H-HC1] : 498.14.
Example 34
Cyclopropyl(4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyri din-3- yl)piperazin-l-yl)methanone
Following the general procedure-3, the titled compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 55 (440 mg, 1.80 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (4.7:95.3) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (20 mL), solids filtered, washed with diethyl ether (20 mL) and dried to obtain the titled compound as a yellow solid (300 mg). Yield: 34 %. M.P.: 236-238°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.89 (s, 1H), 9.06 (d, J 3, 1H), 8.73 (d, J 3, 1H), 8.67 (d, J 7.6, 1H), 8.56 (s, 1H), 8.21 (d, J 12.8, 1H), 8.10-8.03 (m, 2H), 7.74 (dd, J 8.4, 4.4, 1H), 7.53 (dd, J 8.4, 2.4, 1H), 3.88-3.80 (m, 2H), 3.67-3.58 (m, 2H), 3.20-3.03 (m, 4H), 2.07-1.98 (m, 1H), 0.78-0.65 (m, 4H). MS (m/z): 488.47. (M+H); calculated for [C26H23F2N7O + H]: 488.19.
Example 34A
Cyclopropyl(4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyri din-3- yl)piperazin-l-yl)methanone hydrochloride
[284] To a mixture of Cyclopropyl(4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazin-l-yl)methanone (Example 34, 260 mg, 0.53 mmol) in methanol (5 mL) was added aq. 35% hydrochloric acid (150 mg, 4.0 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (20 mL) and stirred for 1 h. The solid formed was fdtered, washed with methyl tert- butyl ether (20 mL) and dried to give the titled compound as a yellow solid (280 mg). Yield: 100%. M.P.: 228-230°C. ^-NMR (d ppm, DMSO-rie, 400 MHz): 11.98 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.95-8.92 (m, 1H), 8.70 (d, J 8.4, 1H), 8.60 (s, 1H), 8.27 (dd, J 9.6, 2.8, 1H), 8.20 (d, J 12, 1H), 7.93 (d, J 2.8, 1H), 7.82- 7.74 (m, 2H), 3.87 (bs, 2H), 3.65 (bs, 2H), 3.27 (bs, 2H), 3.19 (bs, 2H), 2.09-2.01 (m, 1H), 0.79-0.70 (m, 4H). MS (m/z): 488.0. (M+H); calculated for [C26H23F2N7O.HCI + H-HC1]: 488.19.
Example 35 5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(3-(trifluoromethyl)-5,6-dihydro-
[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine
Following the general procedure-3, the titled compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 57 (510 mg, 1.80 mmol). After work up, crude product was suspended in MeOH (2 ml) and DCM (18 ml) mixture and stirred for 30 mins to obtain a solid. Solid was filtered, washed with diethyl ether (20 ml) and dried under vacuum to obtain the titled compound as a pale-yellow solid (90 mg). Yield: 10 %. M.P.: 288-290°C. 'H-NIV1R (d ppm, DMSO-t/e, 400 MHz): 9.97 (s, 1H), 9.07 (d, J 4.4, 1H), 8.75 (d, J 3.6, 1H), 8.67 (d, J
7.6, 1H), 8.57 (s, 1H), 8.25-8.19 (m, 2H), 8.13 (d, J 9.2, 1H), 7.75 (dd, J 8.4, 4, 1H), 7.68 (d, J
9.2, 1H), 4.68 (s, 2H), 4.29 (d, J 5.6, 2H), 3.77 (t, J 5.6, 2H). MS (m/z): 526.48. (M+H); calculated for [C24H16F5N9 + H]: 526.14.
Example 35A
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(3-(trifluoromethyl)-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride
[285] To a mixture of 5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(3-(trifluoromethyl)-5,6- dihydro- [ 1 ,2,4]triazolo [4,3 -a]pyrazin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine (Example 35 , 70 mg, 0.1 mmol) in methanol (1.75 mL) was added aq. 35% hydrochloric acid (50 mg, 1 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (5.25 mL) and stirred for 1 h. The solid formed was filtered, washed with methyl tert- butyl ether (10 mL) and dried to give the titled compound as a yellow solid (60 mg). Yield: 80 %. M.P.: 270-272°C. ¾-NMR (d ppm, DMSO-r e, 400 MHz): 11.80 (s, 1H), 9.08 (dd, J 4, 1.2, 1H), 8.94 (d, J 3.2, 1H), 8.70 (d, J 8.4, 1H), 8.60 (s, 1H), 8.32 (dd, J 9.6, 2.8, 1H), 8.10 (d, J
11.6, 1H), 8.11 (d, J 2.8, 1H), 7.87 (d, J 9.6, 1H), 7.77 (dd, J 8.4, 4, 1H), 4.80 (s, 2H), 4.32 (t, J
5.2, 2H), 3.87 (t, J 5.2, 2H). MS (m/z): 524.54. (M-H); calculated for [C24H16F5N9 - H]: 524.45.
Example 36
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2- methylquinolin-6-yl)pyrimidin-2-amine
Following the general procedure-3, the titled compound was synthesized from Intermediate 79 (400 mg, 1.20 mmol) and Intermediate 9 (264 mg, 1.20 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (7.5:92.5) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (10 mL) to obtain solid, solids fdtered, washed with diethyl ether (5 mL) and dried to obtain the titled compound as a yellow solid (300 mg). Yield: 24 %. M.P.: 182-184°C. ^-NMR (d ppm, DMSO-t e, 400 MHz): 10.14 (s, 1H), 8.75 (d, J 3.6, 1H), 8.74 (s, 1H), 8.20 (d, J 4.4, 1H), 8.18 (s, 1H), 8.11 (d, J 12, 1H), 7.68 (dd, J 8.4, 1.6, 1H), 7.52 (s, 1H), 3.76 (septet, J 6.8, 1H), 3.43 (s, 2H), 3.45-3.35 (m, 2H), 2.70 (s, 3H), 2.45-2.25 (m, 8H), 1.39 (d, J 6.8, 6H), 0.96 (t, J 7.2, 3H). MS (m/z): 518.39. (M+H); calculated for [C29H33F2N7 + H]: 518.28
Example 36A
N-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2- methylquinolin-6-yl)pyrimidin-2-amine hydrochloride
To a mixture of N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4- isopropyl-2-methylquinolin-6-yl)pyrimidin-2-amine (Example 36, 140 mg, 0.27 mmol) in methanol (1.75 mL) was added aq. 35% hydrochloric acid (98.6 mg, 2.70 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl /t' / -butyl ether (12 mL) and stirred for 1 h. The solid formed was filtered, washed with methyl /t77-butyl ether (15 mL) and dried to give the titled compound as a pale-yellow solid (100 mg). Yield: 66 %.M.P.: 208-210°C. ¾- NMR (d ppm, DMSO-de, 400 MHz): 12.05 (bs, 1H), 11.56 (bs, 1H), 8.90 (d, J 3.2, 1H), 8.74 (s, 1H), 8.65-8.59 (m, 1H), 8.40-8.30 (m, 1H), 8.17 (d, J 11.6, 1H), 8.11 (d, J 8.8, 1H), 7.61 (s, 1H), 4.48 (bs, 2H), 3.78 (septet, J 6.8, 1H), 3.70-3.60 (m, 4H), 3.50-3.38 (m, 4H), 3.72-3.10 (m, 2H), 2.74 (s, 3H), 1.40 (d, J 6.8, 6H), 1.25 (t, J 7.2, 3H). MS (m/z): 518.35. (M+H); calculated for [C29H33F2N7.HCI + H-HC1]: 518.28.
Example 37
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2- methylquinolin-6-yl)pyrimidin-2-amine
Following the general procedure-3, the titled compound was synthesized from Intermediate 79 (400 mg, 1.20 mmol) and Intermediate 20 (247 mg, 1.20 mmol). After work up, crude product was purified by combi-flash using methanol and DCM (7.8:92.2) as eluent. The pooled fractions were evaporated, and the residue was stirred for 30 min. with diethyl ether (10 mL) to obtain solid, solids filtered, washed with diethyl ether (5 mL) and dried to obtain the titled compound as a pale-yellow solid (150 mg). Yield: 24 %. M.P.: 211-213°C. ^-NMR (d ppm, DMSO-de, 400 MHz): 9.84 (s, 1H), 8.71 (s, 1H), 8.69 (d, J 3.6, 1H), 8.10 (d, J 11.6, 1H), 8.03 (d, J 8.8, 1H), 8.02 (s, 1H), 7.52 (s, 1H), 7.42 (dd, J 9.2, 3.2, 1H), 3.74 (septet, J 6.8, 1H), 3.15- 3.09 (m, 4H), 2.70 (s, 3H), 2.55-2.45 (m, 4H), 2.37 (q, J 6.8, 2H), 1.38 (d, J 6.8, 6H), 1.02 (t, J 6.8, 3H). MS (m/z): 504.55. (M+H); calculated for [C28H31F2N7 + H]: 504.26.
Example 37A
N-(5-(4-ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2- methylquinolin-6-yl)pyrimidin-2-amine hydrochloride
[286] To a mixture of N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fhioro-4-(8-fhioro-4- isopropyl-2-methylquinolin-6-yl)pyrimidin-2-amine (Example 37, 140 mg, 0.278 mmol) in methanol (2.8 mL) was added aq. 35% hydrochloric acid (101 mg, 2.78 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (8.4 mL) and stirred for 1 h. The solid formed was fdtered, washed with methyl tert- butyl ether (15 mL) and dried to give the titled compound as a pale-yellow solid (110 mg). Yield: 71 %. M.P.: 228-230°C. Tf-NMR ^ ppm, DMSO-rie, 400 MHz): 11.84 (s, 1H), 11.42 (bs, 1H), 8.92 (d, J 3.2, 1H), 8.70 (s, 1H), 8.22 (d, J 9.6, 2.8, 1H), 8.13 (d, J 11.6, 1H), 8.00 (d, J 2.8, 1H), 7.85 (d, J 9.6, 1H), 7.60 (s, 1H), 3.85 (d, J 12.8, 2H), 3.76 (septet, J 7.0, 1H), 3.59 (d, J 11.6, 2H), 3.29 (t, J 11.6, 2H), 3.20-3.05 (m, 4H), 2.73 (s, 3H), 1.38 (d, J 7, 6H), 1.30 (t, J 7.2, 3H). MS (m/z): 504.61. (M+H); calculated for [C28H31F2N7.HCI + H-HC1]: 504.26.
Example 38 l-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4- methylpiperidin-4-ol
Following the general procedure-3, the titled compound was synthesized from Intermediate 7 (500 mg, 1.80 mmol) and Intermediate 59 (373 mg, 1.80 mmol). After work up, crude product was stirred with a mixture of DCM (50 ml) and MeOH (50 ml) for 45 mins to obtain a solid. Solid was filtered and washed with DCM (20 ml). Solid was triturated with diethyl ether (10 ml) and filtered the solid. Solid was washed with diethyl ether (5 ml) and dried to obtain the titled compound as a yellow solid (210 mg). Yield: 26 %. M.P.: 198-200°C. ^-NMR (d ppm, DMSO-rie, 400 MHz): 9.79 (s, 1H), 9.05 (d, J 4, 1H), 8.71 (d, J 3.2, 1H), 8.66 (d, J 8.4, 1H), 8.55 (s, 1H), 8.20 (d, J 12, 1H), 8.02 (s, 1H), 8.01 (d, J 5.2, 1H), 7.74 (dd, J 8.4, 3.2, 1H), 7.46 (dd, J 9.2, 2.8, 1H), 4.29 (s, 1H), 3.29-3.21 (m, 2H), 3.13-3.06 (m, 2H), 1.60-1.55 (m, 4H), 1.14 (s, 3H). MS (m/z): 449.44 (M+H); calculated for [C24H22F2N6O+ H]: 449.18.
Example 38A l-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4- methylpiperidin-4-ol hydrochloride
[287] To a mixture of l-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)-4-methylpiperidin-4-ol (Example 38, 200 mg, 0.446 mmol) in methanol (4 mL) was added aq. 35% hydrochloric acid (163 mg, 4.46 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (12 mL) and stirred for 1 h. The solid formed was filtered, washed with methyl tert- butyl ether (15 mL) and dried to give the titled compound as a red solid (195 mg). Yield: 71 %. M.P.: 249-251°C. Ή-NMK (d ppm, DMSO-rie, 400 MHz): 11.67 (s, 1H), 9.08 (dd, J 4.4, 1.6, 1H), 8.92 (d, J 2.8, 1H), 8.70 (d, J 8.4, 1H), 8.60 (s, 1H), 8.29 (dd, J 9.2, 2.4, 1H), 8.21 (d, J 11.6, 1H), 7.90 (bs, 1H), 7.77 (dd, J 8.4, 4, 1H), 5.33 (bs, -OH), 3.43-3.36 (m, 2H), 3.35-3.25 (m, 2H), 1.81-1.70 (m, 2H), 1.69-1.60 (m, 2H), 1.18 (s, 3H). MS (m/z): 449.46 (M+H); calculated for [C24H22F2N6O+ H]: 449.48.
Example 39
(±)-7er/-butyl 4-(6-((4-(4-(l-((tert-butoxycarbonyl)amino)ethyl)-8-fluoro-2- methylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l- carboxylate
Following the general procedure-3, the titled compound was synthesized from Intermediate 63 (500 mg, 1.15 mmol) and Intermediate 5 (320 mg, 1.15 mmol). After work up, crude product was purified by combi-flash using MeOH and DCM (2:98) as eluent. Combined pure fractions from column were distilled to obtain a solid. Solid was triturated with diethyl ether (10 ml). Solid was filtered and washed with diethyl ether (5 ml) to obtain the titled compound as a yellow solid (210 mg). Yield: 32.1 %. ¾-NMR (d ppm, DMSO-rie, 400 MHz):9.93 (s, 1H), 8.73 (s, 1H), 8.72 (s, 1H), 8.18-8.10 (m, 2H), 8.06 (d, J 3.6, 1H), 7.86 (d, J 7.6, 1H), 7.56 (s, 1H), 7.50 (d, J 6, 1H), 5.50-5.43 (m, 1H), 3.51-3.45 (m, 4H), 3.11-3.05 (m, 4H), 2.27 (s, 3H), 1.45 (d, J 7.2, 3H), 1.42 (s, 9H), 1.38 (s, 9H). MS (m/z): 677.44 (M+H); calculated for [C35H42F2N8O4+H]: 677.33.
Example 39A
(±)-4-(4-(l-Aminoethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2-amine
Following the general procedure-4, the titled compound was synthesized from Tert-butyl 4-(6- ((4-(4-(l-((tert-butoxycarbonyl)amino)ethyl)-8-fluoro-2-methylquinolin-6-yl)-5- fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Example 39, 250 mg, 0.37 mmol) as an off-white solid (80 mg). Yield: 45%. M.P.: 241-243°C. ^-NMR (d ppm, DMSO- de, 400 MHz): 9.86 (s, 1H), 8.77 (s, 1H), 8.71 (d, J 4, 1H), 8.11 (d, J 12.4, 1H), 8.07 (d, J 8.8, 1H), 8.01 (d, J 2.8, 1H), 7.81 (s, 1H), 7.43 (dd, J 9.2, 2.8, 1H), 4.86-4.79 (m, 1H), 3.07-3.01 (m, 4H), 2.88-2.82 (m, 4H), 2.72 (s, 3H), 1.43 (d, J 6.8, 3H). MS (m/z): 477.54 (M+H); calculated for [CisHieFiNs+H] : 477.22.
Example 39B
(±)-4-(4-(l-Aminoethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride
[288] To a mixture of 4-(4-(l-Aminoethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5- (piperazin-l-yl)pyridin-2-yl)pyrimidin-2 -amine (Example 39A, 60 mg, 0.13 mmol) in methanol (1.2 mL) was added aq. 35% hydrochloric acid (46 mg, 1.3 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (3.6 mL) and stirred for 1 h. The reaction mixture distilled under vacuum to afford solid. To the solid diethyl ether (12 ml) was added. Filtered the solid and washed with diethyl ether (5 mL) and dried to give the titled compound as a yellow solid (35 mg). Yield: 54 %. M.P.: 253-256°C. 'H-NMR (d ppm, DMSO-rie, 400 MHz): 11.77 (bs, 1H), 9.60-9.45 (m, 2H), 9.17 (bs, 3H), 8.96 (s, 1H), 8.69 (s, 1H), 8.23-8.15 (m, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.88 (d, J 8.8, 1H), 5.35-5.25 (m, 1H), 3.55- 3.45 (m, 4H), 3.30-3.20 (m, 4H), 2.76 (s, 3H), 1.69 (d, J 6.8, 3H). MS (m/z): 477.53 (M+H); calculated for [CisHieFiNs+H-HCl] : 477.22.
Example 40
(±)-7b//-butyl 4-(6-((4-(4-(l-((tert-butoxycarbonyl)amino)ethyl)-8-fluoroquinolin-6-yl)- 5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate
Following the general procedure-3, the titled compound was synthesized from Intermediate 71 (500 mg, 1.15 mmol) and Intermediate 5 (320 mg, 1.15 mmol). After work up, crude product was purified by combi-flash using MeOH and DCM (2:98) as eluent. Combined pure fractions from column were distilled to obtain a solid. Solid was triturated with diethyl ether (10 ml). Solid was filtered and washed with diethyl ether (5 ml) to obtain the titled compound as a yellow solid (210 mg). Yield: 32.1 %. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.93 (s, 1H), 9.04 (d, J 4.4, 1H), 8.78 (s, 1H), 8.74 (d, J 3.6, 1H), 8.17 (d, J 12, 1H), 8.11 (d, J 8.8, 1H), 8.07 (d, J 3.2, 1H), 7.92 (d, J 7.2, 1H), 7.69 (d, J 4.4, 1H), 7.48 (dd, J 9.2, 2.8, 1H), 5.55-5.45 (m, 1H), 3.52-3.45 (m, 4H), 3.11-3.05 (m, 4H), 1.46 (d, J 6.8, 3H), 1.43 (s, 9H), 1.38 (s, 9H). MS (m/z): 663.51 (M+H); calculated for [C34H40F2N8O4+H]: 663.31.
Example 40A
(±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l-yl)pyri din-2- yl)pyrimidin-2-amine
Following the general procedure-4, the titled compound was synthesized from Tert-butyl 4-(6- ((4-(4-(l-((tert-butoxycarbonyl)amino)ethyl)-8-fluoroquinohn-6-yl)-5-fluoropyrimidin-2- yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Example 40, 850 mg, 1.28 mmol) as an off- white solid (325 mg). Yield: 55%. M.P.: >270°C.1H-NMR (d ppm, DMSO-rie, 400 MHz): 9.84 (s, 1H), 9.02 (d, J 4.4, 1H), 8.84 (s, 1H), 8.72 (d, J 3.6, 1H), 8.15 (d, J 11.6, 1H), 8.07 (d, J 9.2, 1H), 8.01 (d, J 2.8, 1H), 7.92 (d, J 4.4, 1H), 7.43 (dd, J 9.2, 2.8, 1H), 4.90-4.82 (m, 1H), 3.07- 3.01 (m, 4H), 2.88-2.82 (m, 4H), 2.20 (bs, 3H), 1.44 (d, J 6.4, 3H). MS (m/z): 463.55 (M+H); calculated for [C24H24F2N8+H] : 463.21
Example 40B
(±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l-yl)pyri din-2- yl)pyrimidin-2-amine dihydrochloride
[289] To a mixture of 4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperazin- l-yl)pyridin-2-yl)pyrimidm-2-amine (Example 40A, 60 mg, 0.13 mmol) in methanol (1.2 mL) was added aq. 35% hydrochloric acid (46 mg, 1.3 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (3.6 mL) and stirred for 1 h. The reaction mixture distilled under vacuum to afford solid. To the solid diethyl ether (12 ml) was added. Filtered the solid and washed with diethyl ether (5 mL) and dried to give the titled compound as a yellow solid (35 mg). Yield: 54 %. M.P.: 253-256°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.37 (bs, 1H), 9.55-9.50 (m, 2H), 9.27 (bs, 3H), 9.17 (d, J 4.4, 1H), 8.92 (s, 1H), 8.75 (s, 1H), 8.21 (d, J 11.2, 1H), 8.10-8.00 (m, 3H), 7.96 (d, J 7.2, 1H), 5.40-5.30 (m, 1H), 3.51- 3.45 (m, 4H), 3.29-3.20 (m, 4H), 1.71 (d, J 6.8, 3H). MS (m/z): 463.47 (M+H-2HC1); calculated for [C24H24F2N8.2HCI+H-2HCI]: 463.21.
Example 41
( ±)-Tert-buty\ 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazine-l-carboxylate [290] Following the general procedure-3, the titled compound was synthesized from Intermediate 74 (500 mg, 1.6 mmol) and Intermediate 5 (430 mg, 1.6 mmol). After work up, crude product was purified by combi-flash using MeOH and DCM (4:96) as eluent. Combined pure fractions from column were distilled to obtain a solid. Solid was triturated with diethyl ether (20 ml). Solid was filtered and washed with diethyl ether (20 ml) to obtain the titled compound as a yellow solid (70 mg). Yield: 8 %. ^NMR (d ppm, DMSO-flfe, 400 MHz): 9.90 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.73 (d, J 3.6, 1H), 8.16 (d, J 11.6, 1H), 8.10 (d, J 8.8, 1H), 8.06 (d, J 2.8, 1H), 7.81 (d, J 4.4, 1H), 7.47 (d, J 9.2, 3.2, 1H), 5.78 (d, J 4, 1H), 5.58-5.50 (m, 1H), 3.52-3.44 (m, 4H), 3.12-3.05 (m, 4H), 1.54 (d, J 6.8, 3H), 1.42 (s, 9H). MS (m/z): 564.49 [M+H]; calculated for [C29H31F2N7O3+H]: 564.25.
Example 41A
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol
[291] Following the general procedure-4, the titled compound was synthesized from Tert- butyl 4-(6-((5-fhioro-4-(8-fhioro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Example 41, 310 mg, 0.55 mmol) as a yellow solid (120 mg). Yield: 47%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.86 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.72 (d, J 3.2, 1H), 8.15 (d, J 12, 1H), 8.08 (d, J 8.8, 1H), 8.02 (d, J 2.8, 1H), 7.81 (d, J 4.4, 1H), 7.43 (d, J 8.8, 2.8, 1H), 5.85-5.80 (m, 1H), 5.60-5.50 (m, 1H), 3.08- 3.00 (m, 4H), 2.90-2.80 (m, 4H), 1.54 (d, J 6.4, 3H). MS (m/z): 464.59 [M+H]; calculated for [C24H23F2N7O+H]: 464.19.
Example 41B
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trimethanesulfonate
[292] To a mixture of l-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 41A, 50 mg, 0.108 mmol) in methanol (1 mL) was added CH3SO3H (15.6 mg, 0.162 mmol). The resulting clear solution was stirred for 30 min., diluted with methyl fert-butyl ether (5 mL) and stirred for 1 h. The reaction mixture distilled under vacuum to afford solid. To the solid diethyl ether (10 ml) was added. Filtered the solid and washed with diethyl ether (10 mL) and dried to give the titled compound as a yellow solid (35 mg). Yield: 58 %. M.P.: Hygroscopic ¾-NMR (d ppm, DMSO-rfc, 400 MHz): 11.56 (s, 1H), 9.07 (d, J 3.6, 1H), 8.94 (d, J 2.4, 1H), 8.89 (bs, 2H), 8.80 (s, 1H), 8.17 (d, J 11.6, 1H), 8.12 (d, J 9.6, 1H), 8.00 (s, 1H), 7.83 (d, J 4.4, 1H), 7.80 (d, J 9.6, 1H), 5.57- 5.50 (m, 1H), 3.48-3.40 (m, 4H), 3.35-3.25 (m, 4H), 2.35 (s, 9H), 1.55 (d, J 6.4, 3H). MS (m/z): 464.10 [M+H-3CH3SO3H]; calculated for [C24H23F2N70.(3CH3S03H)+H-3CH3SC>3H]: 464.19.
Example 42
(±)-7er/-butyl (l-(8-fluoro-6-(5-fluoro-2-((5-(4-methylpiperazin-l-yl)pyridin-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethyl)carbamate
[293] Following the general procedure-3, the titled compound was synthesized from Intermediate 71 (1 g, 2.38 mmol) and Intermediate 11 (457 mg, 2.38 mmol). After work up, crude product was purified by combi-flash using MeOH and DCM (9:91) as eluent. Combined pure fractions from column were distilled to obtain a solid. Solid was triturated with diethyl ether (10 ml). Solid was filtered and washed with diethyl ether (5 ml) to obtain the titled compound as a yellow solid (310 mg). Yield: 23 %. 'H-NMR (5 ppm, D SO-t/e. 400 MHz): 9.88 (s, 1H), 9.04 (d, J 4.4, 1H), 8.78 (s, 1H), 8.74 (d, J 3.6, 1H), 8.17 (d, J 11.6, lH), 8.10 (d, J 9.2, 1H), 8.04 (d, J 2.8, 1H), 7.91 (d, J 7.2, 1H), 7.69 (d, J 4.8, 1H), 7.48 (dd, J 9.2, 2.8, 1H), 5.55-5.45 (m, 1H), 3.18-3.10 (m, 4H), 2.50-2.44 (m, 4H), 2.24 (s, 3H), 1.47 (d, J 7.6, 3H), 1.37 (s, 9H). MS (m/z): 577.48 (M+H); calculated for [C30H34F2N8O2+H] : 577.28.
Example 42A
(±)-4-(4-(l-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methylpiperazin-l- yl)pyridin-2-yl)pyrimidin-2-amine
[294] Following the general procedure-4, the titled compound was synthesized from (±)-'/ erl- butyl (l-(8-fhioro-6-(5-fhioro-2-((5-(4-methylpiperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethyl)carbamate (Example 42, 300 mg, 0.52 mmol) as ayellow solid (190 mg). Yield: 77 %. ftf-NMR d ppm, DMSO-rie, 400 MHz): 9.86 (s, 1H), 9.02 (d, J 4.4, 1H), 8.83 (s, 1H), 8.72 (d, J 3.6, 1H), 8.15 (d, J 11.6, 1H), 8.07 (d, J 9.2, 1H), 8.03 (d, J 4.8, 1H), 7.92 (d, J 3.6, 1H), 7.45 (dd, J 9.2, 3, 1H), 4.90-4.82 (m, 1H), 3.20-3.09 (m, 4H), 2.52-2.45 (m, 4H), 2.25 (bs, 2H), 2.23 (s, 3H), 1.44 (d, J 6.4, 3H). MS (m/z): 476.61 (M+H); calculated for [C25H26F2N8+H] : 477.22.
Example 42B (±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methylpiperazin-l- yl)pyridin-2-yl)pyrimidin-2-amine trihydrochloride
[295] To a mixture of 4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4- methylpiperazin-l-yl)pyridin-2-yl)pyrimidin-2-amine (Example 42A, 180 mg, 0.378 mmol) in methanol (2.6 mL) was added aq. 35% hydrochloric acid (138 mg, 3.78 mmol) by dissolving in MeOH (1 ml). The resulting clear solution was stirred for 30 min., diluted with methyl tert- butyl ether (10.8 mL) and stirred for 1 h. Filtered the solid and dried the solid under vacuum to obtain the titled compound as a yellow solid (170 mg). Yield: 87 %. M.P.: 260-62°C. ¾-NMR (d ppm, DMSO-rfc, 400 MHz): 11.41 (bs, 1H), 11.10 (bs, 1H), 9.19 (d, J 4.4, 1H), 9.17-9.10 (m, 3H), 8.95 (d, J 3.2, 1H), 8.74 (s, 1H), 8.21 (d, J 11.2, 1H), 8.12-8.04 (m, 2H), 8.01 (d, J 4.8, 1H), 7.92 (d, J 10, 1H), 5.41-5.32 (m, 1H), 3.90-3.80 (m, 3H), 3.55-3.49 (m, 3H), 3.22-3.15 (m, 2H), 2.82 (d, J 4.4, 3H), 1.70 (d, J 6.4, 3H). MS (m/z): 477.4 (M+H-3HC1); calculated for [C25H26F2N8.3HC1+H-3HC1] : 477.22.
Example 43
(±)-l-(6-(2-((5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8- fluoroquinolin-4-yl)ethanol
[296] Following the general procedure-3, the titled compound was synthesized from Intermediate 74 (500 mg, 1.55 mmol) and Intermediate 20 (321 mg, 1.55 mmol). After work up, crude product was triturated with a mixture of DCM and MeOH (9:1) (10 ml) to obtain a solid. Filtered the solid and washed the solid with DCM (5 ml). Solid was dried under vacuum at 55°C on rotavapour to obtain the titled compound as a yellow solid (100 mg). Yield: 13 %. ¾-NMR (d ppm, DMSO-t e, 400 MHz): 9.86 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.73 (d, J 3.6, 1H), 8.15 (d, J 12, 1H), 8.08 (d, J 8.8, 1H), 8.03 (d, J 2.8, 1H), 7.80 (d, J 4.4, 1H), 7.45 (dd, J 9.2, 3.2, 1H), 5.81 (d, J 4.4, 1H), 5.57-5.50 (m, 1H), 3.18-3.10 (m, 4H), 2.55-2.48 (m, 4H), 2.38 (q, J 7.2, 2H), 1.54 (d, J 6.4, 3H), 1.03 (t, J 7.2, 3H). MS (m/z): 492.54 (M+H); calculated for [C26H27F2N7O+H] : 492.22.
Example 43A
(±)-l-(6-(2-((5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8- fluoroquinolin-4-yl)ethanol trihydrochloride
[297] To a mixture of 4-(4-(l-Aminoethyl)-8-fluoroquinohn-6-yl)-5-fluoro-N-(5-(4- methylpiperazin-l-yl)pyridin-2-yl)pyrimidin-2-amine (Example 43, 95 mg, 0.19 mmol) in methanol (1 mL) was added aq. 35% hydrochloric acid (138 mg, 3.78 mmol) by dissolving in MeOH (0.9 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl tert- butyl ether (5.7 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum to obtain the titled compound as a yellow solid (80 mg). Yield: 76 %. M.P.: 249-251°C. Tf-NMR (d ppm, DMSO-rie, 400 MHz): 11.75 (s, 1H), 11.51 (s, 1H), 9.06 (d, J 4.4, 1H), 8.93 (d, J 3.2, 1H), 8.82 (s, 1H), 8.25-8.14 (m, 2H), 8.04 (d, J 2.8, 1H), 7.93 (d, J 9.6, 1H), 7.83 (d, J 4.4, 1H), 5.58-5.50 (m, 1H), 3.90-3.83 (m, 2H), 3.63-3.56 (m, 2H), 3.39- 3.28 (m, 2H), 3.20-3.08 (m, 4H), 1.54 (d, J 6.8, 3H), 1.31 (t, J 7.2, 3H). MS (m/z): 492.58 (M+H-3HC1); calculated for [C26H27F2N7O.3HCI+H-3HCI]: 492.22.
Example 44
(±)-l-(8-fluoro-6-(5-fluoro-2-((5-(4-isopropylpiperazin-l-yl)pyridin-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol
[298] Following the general procedure-3, the titled compound was synthesized from Intermediate 74 (500 mg, 1.55 mmol) and Intermediate 25 (342 mg, 1.55 mmol). After work up, crude product was triturated with Diethyl ether (10 ml) to obtain a solid. Filtered the solid and solid was dried under vacuum at 55°C on rotavapor to obtain the titled compound as a yellow solid (320 mg). Yield: 41 %. M.P.: 238-240°C. ¾-NMR (d ppm, DMSO-rfc, 400 MHz): 9.84 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.72 (d, J 3.6, 1H), 8.15 (d, J 12, 1H), 8.07 (d, J 9.2, 1H), 8.03 (d, J 2.8, 1H), 7.80 (d, J 4.4, 1H), 7.44 (dd, J 9.2, 3.2, 1H), 5.78 (d, J 4.4, 1H), 5.58-5.50 (m, 1H), 3.17-3.09 (m, 4H), 2.72-2.63 (m, 1H), 2.62-2.55 (m, 4H), 1.54 (d, J 6.4, 3H), 1.01 (d, J 6.4, 6H). MS (m/z): 506.64 (M+H); calculated for [C27H29F2N7O+H] : 506.24.
Example 44A
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(4-isopropylpiperazin-l-yl)pyridin-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol trihydrochloride
[299] To a mixture of (±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(4-isopropylpiperazin-l-yl)pyridin- 2-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 44, 300 mg, 0.593 mmol) in methanol (5 mL) was added aq. 35% hydrochloric acid (216 mg, 5.93 mmol) by dissolving in MeOH (1 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl /t' /7-butyl ether (18 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum at 55°C on rotavapor to obtain the titled compound as a yellow solid (290 mg). M.P.: 245-247°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.74 (s, 1H), 11.32 (s, 1H), 9.06 (d, J 4.4, 1H), 8.94 (d, J 3.2, 1H), 8.81 (s, 1H), 8.22-8.15 (m, 2H), 8.03 (d, J 2.8, 1H), 7.89 (d, J 9.6, 1H), 7.83 (, J 4.8, 1H), 5.58-5.50 (m, 1H), 3.91-3.83 (m, 2H), 3.60-3.50 (m, 3H), 3.41-3.32 (m, 2H), 3.22-3.10 (m, 2H), 1.54 (d, J 6.8, 3H), 1.34 (d, J 6.8, 6H). MS (m/z): 506.65 (M+H-3HC1); calculated for [C27H29F2N7O+H-3HCI] : 506.24.
Example 45
N-(5-(4-ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6- yl)pyrimidin-2-amine
[300] Following the general procedure-3, the titled compound was synthesized from Intermediate 23 (500 mg, 1.55 mmol) and Intermediate 20 (342 mg, 1.55 mmol). After work up, crude product was purified by combi-flash using MeOH and DCM (6:94) as eluent. Pure compound from column chromatography was suspended in Diethyl ether (20 ml) and stirred for 30 mins to obtain a solid. Solid was filtered and washed with Diethyl ether. Solid was dried under vacuum to obtain the titled compound as a yellow solid (200 mg). Yield: %. 'H-NMR (d ppm, DMSO-rie, 400 MHz): 9.81 (s, 1H), 8.70 (d, J 3.6, 1H), 8.52 (d, J 8.8, 1H), 8.49 (s, 1H), 8.15 (d, J 12. 1H), 8.03 (d, J 9.2, 1H), 8.01 (d, J 2.4, 1H), 7.61 (d, J 8.8, 1H), 7.47 (dd, J
8.8, 2.4, 1H), 3.18-3.10 (m, 4H), 2.72 (s, 3H), 2.60-2.50 (m, 4H), 2.42-2.36 (m, 2H), 1.03 (t, J
6.8, 3H). MS (m/z): 462.45 (M+H); calculated for [C25H25F2N7+H] : 462.21.
Example 45A
/V-(5-(4-ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6- yl)pyrimidin-2-amine hydrochloride
[301] To a mixture of A-(5-(4-cthylpipcrazin- 1 -yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2- methylquinolin-6-yl)pyrimidin-2 -amine (Example 45, 180 mg, 0.39 mmol) in methanol (4.5 mL) was added aq. 35% hydrochloric acid (216 mg, 5.93 mmol). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl tert- butyl ether (13.5 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum at 55°C on rotavapor to obtain the titled compound as a yellow solid (150 mg). M.P.: 265-267°C. 'H-NMR (d ppm, DMSO-rie, 400 MHz): 11.82 (bs, 1H), 11.33 (bs, 1H), 8.93 (d, J 3.2, 1H), 8.57 (d, J 9.2, 1H), 8.55 (s, 1H), 8.23 (dd, J 9.2, 2.4, 1H), 8.17 (d, J 11.6, 1H), 8.01 (d, J 2.4, 1H), 7.82 (d, J 9.2, 1H), 7.65 (d, J 8.4, 1H), 3.90-3.80 (m, 2H), 3.63-3.55 (m, 2H), 3.33-3.24 (m, 2H), 3.20-3.05 (m, 4H), 2.74 (s, 3H), 1.29 (t, J 7.2, 3H). MS (m/z): 462.49 (M+H-HC1); calculated for [C25H25F2N7.HCI+H-HCI]: 462.21. Example 46
(±)-7’e//-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate
[302] Following the general procedure-3, the titled compound was synthesized from Intermediate 77 (500 mg, 1.55 mmol) and Intermediate 5 (342 mg, 1.55 mmol). After work up, crude product was purified by combi -flash using MeOH and DCM (3:97) as eluent. Pure compound from column chromatography was suspended in Diethyl ether (20 ml) and stirred for 30 mins to obtain a solid. Solid was filtered and washed with Diethyl ether (20 ml). Solid was dried under vacuum to obtain the titled compound as a yellow solid (200 mg). Yield: 12 %. ^-NMR (d ppm, DMSO-rie, 400 MHz): 9.89 (s, 1H), 8.75 (s, 1H), 8.72 (d, J 3.5, 1H), 8.15- 8.03 (m, 3H), 7.68 (s, 1H), 7.46 (dd, J 9.0, 2.4, 1H), 5.75 (d, J 4.0, 1H), 5.50-5.42 (m, 1H), 3.52-3.44 (m, 4H), 3.11-3.05 (m, 4H), 2.73 (s, 3H), 1.53 (d, J 6.5, 3H), 1.42 (s, 9H). MS (m/z): 578.38 (M+H); calculated for [C30H33F2N7O3+H]: 578.26.
Example 46A
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)ethanol
[303] Following the general procedure-4, the titled compound was synthesized from (±)-'/ en- butyl 4-(6-((5-fhioro-4-(8-fhioro-4-(l-hydroxyethyl)-2-methylquinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Example 46, 190 mg, 0.33 mmol) as a yellow solid (90 mg). Yield: 60%. Tl-NMR^ppm, DMSO-rie, 400 MHz): 9.82 (s, 1H), 8.80-8.69 (m, 2H), 8.20-8.00 (m, 3H), 7.68 (s, 1H), 7.43 (d, J 8.6, 1H), 5.80-5.70 (m, 1H), 5.51-5.44 (m, 1H), 3.45-3.35 (m, 4H), 3.10-3.00 (m, 2H), 2.90-2.82 (m, 2H), 2.73 (s, 3H), 1.53 (d, J 6.3, 3H). MS (m/z): 478.50 (M+H); calculated for [C25H25F2N7O+H] : 478.21.
Example 46B
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)ethan-l-ol hydrochloride
[304] To a mixture of l-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)ethan-l-ol (Example 46A, 90 mg, 0.2 mmol) in methanol (4.5 mL) was added aq. 35% hydrochloric acid (30 mg, 0.8 mmol) by dissolving in MeOH (0.1 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl tert- butyl ether (5.4 mL) and stirred for 1 h to obtain a solid. Filtered the solid and washed with methyl tert- butyl ether (20 mL). Solid dried under vacuum at 55°C on rotavapor to obtain the titled compound as a yellow solid (75 mg). M.P.: 238-240°C. 'H-NIV1R (5 ppm, DMSO-flfe, 400 MHz): 11.92 (s, 1H), 9.60 (bs, 2H), 8.95-8.90 (m, 1H), 8.79-8.72 (m, 1H), 8.25- 8.18 (m, 1H), 8.14 (dd, J 11.2, 4, 1H), 8.00 (s, 1H), 7.88 (dd, J 9.2, 4.8, 1H), 7.73 (d, J 4.8, 1H), 5.51-5.40 (m, 1H), 3.50-3.42 (m, 4H), 3.30-3.20 (m, 4H), 2.75 (d, J 4.4, 3H), 1.11 (d, J 4.8, 3H). MS (m/z): 478.50 (M+H-HC1); calculated for [C25H25F2N7O+H-HCI] : 478.21.
Example 47
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(4-methylpiperazin-l-yl)pyridin-2-yl)amino)pyrimidin-
4-yl)quinolin-4-yl)ethanol
[305] Following the general procedure-3, the titled compound was synthesized from Intermediate 74 (500 mg, 1.55 mmol) and Intermediate 11 (299 mg, 1.55 mmol). After work up, crude product was purified by combi-flash using MeOH and DCM (13:87) as eluent. Pure fractions from column were distilled to obtain a residue. Residue was triturated with Diethyl ether (20 ml) to obtain a solid. Filtered the solid and solid was washed with Diethyl ether (10 ml). Solid dried under vacuum at 55°C on rotavapor to obtain the titled compound as a yellow solid (330 mg). Yield: 45 %. M.P.: 235-237°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.84 (s, 1H), 9.03 (d, J 4.8, 1H), 8.81 (s, 1H), 8.72 (d, J 3.6, 1H), 8.14 (d, J 12, 1H), 8.08 (d, J 9.2, 1H), 8.03 (d, J 2.8, 1H), 7.80 (d, J 4.8, 1H), 7.45 (dd, J 9.2, 3.2, 1H), 5.78 (d, J 4.4, 1H), 5.56- 5.48 (m, 1H), 3.18-3.10- (m, 4H), 2.50-2.42 (m, 4H), 2.23 (s, 3H), 1.54 (d, J 6.4, 3H). MS (m/z): 478.50 (M+H); calculated for [C25H25F2N7O+H] : 478.21.
Example 47A
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(4-methylpiperazin-l-yl)pyridin-2-yl)amino)pyrimidin- 4-yl)quinolin-4-yl)ethanol trihydrochloride
[306] To a mixture of (±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(4-methylpiperazin-l-yl)pyridin-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 47, 300 mg, 0.63 mmol) in methanol (5 mL) was added aq. 35% hydrochloric acid (229 mg, 6.3 mmol) by dissolving in MeOH (1 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl tert- butyl ether (18 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum at 55°C on rotavapor to obtain the titled compound as a yellow solid (270 mg). M.P.: 268-270°C. ^-NMR (d ppm, DMSO-rie, 400 MHz): 11.66 (s, 1H), 11.33 (s, 1H), 9.06 (d, J 4.4, 1H), 8.93 (d, J 2.8, 1H), 8.81 (s, 1H), 8.20-8.13 (m, 2H), 8.02 (d, J 2.8, 1H), 7.89 (d, J 9.2, 1H), 7.83 (d, J 4.8, 1H), 5.58-5.50 (m, 1H), 3.90-3.82 (m, 2H), 3.59-3.50 (m, 2H), 3.30- 3.12 (m, 4H), 2.83 (s, 3H), 1.55 (d, J 6.8, 3H). MS (m/z): 478.50 (M+H-3HC1); calculated for [C25H25F2N7O+H-3HCI]: 478.21.
Example 48
Tert- butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin- 2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate
[307] Following the general procedure-3, the titled compound was synthesized from Intermediate 83 (810 mg, 2.5 mmol) and Intermediate 5 (700 mg, 2.5 mmol). After work up, crude product was purified by combi -flash using MeOH and DCM (3:97) as eluent. Pure compound from column chromatography was suspended in Diethyl ether (50 ml) and stirred for 30 mins to obtain a solid. Solid was filtered and washed with Diethyl ether (50 ml). Solid was dried under vacuum to obtain the titled compound as a pale-green solid (760 mg). Yield: 54 %. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.86 (bs, 1H), 9.53 (s, 1H), 8.97 (d, J 4.4, 1H), 8.67 (bs, 1H), 8.13 (d, J 12.4, 1H), 8.12-8.05 (m, 1H), 8.03 (d, J 2.8, 1H), 7.73 (d, J 4.4, 1H), 7.45 (dd, J 9.2, 2.8, 1H), 5.88 (bs, 1H), 3.51-3.44 (m, 4H), 3.11-3.04 (m, 4H), 1.74 (s, 6H), 1.42 (s, 9H). MS (m/z): 578.63 (M+H); calculated for [C30H33F2N7O3+H]: 578.26.
Example 48A
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)propan-2-ol
[308] Following the general procedure-4, the titled compound was synthesized from Tert- butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Example 48, 490 mg, 0.87 mmol) as a yellow solid (370 mg). Yield: 77%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.81 (s, 1H), 9.55 (s, 1H), 8.98 (d, J 4.8, 1H), 8.72 (d, J 3.6, 1H), 8.17-8.10 (m, 2H), 8.01 (d, J 3.2, 1H), 7.81 (d, J 4.4, 1H), 7.43 (dd, J 9.2, 3.2, 1H), 5.83 (bs, 1H), 5.59-5.50 (m, 1H), 3.08-3.01 (m, 4H), 2.88-2.81 (m, 4H), 1.75 (s, 6H). MS (m/z): 478.67 (M+H); calculated for [C25H25F2N7O+H] : 478.21.
Example 48B
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)propan-2-ol
[309] To a mixture of l-(8-Fluoro-6-(5-fluoro-2-((5-(4-methylpiperazin-l-yl)pyridin-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 48 A, 300 mg, 0.63 mmol) in methanol (5 mL) was added aq. 35% hydrochloric acid (229 mg, 6.3 mmol) by dissolving in MeOH (1 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl tert- butyl ether (18 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum at 55°C on rotavapor to obtain the titled compound as a yellow solid (270 mg). M.P.: 268-270°C. Tf-NMR (d ppm, DMSO-rie, 400 MHz): 11.81 (s, 1H), 9.60 (bs, 1H), 9.57 (s, 1H), 9.01 (d, J 4.8, 1H), 8.94 (d, J 3.2, 1H), 8.21 (d, J 9.6, 1H), 8.16 (d, J 12.4, 1H), 8.02 (d, J 2.8, 1H), 7.91 (d, J 9.6, 1H), 7.75 (d, J 4.8, 1H), 3.52-3.44 (m, 4H), 3.30-3.21 (m, 4H), 1.75 (s, 6H). MS (m/z): 478.65 (M+H-3HC1); calculated for [C25H25F2N7O.3HCI+H- 3HC1]: 478.21.
Example 49
(±)-7b/y-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazine-l-carboxylate
[310] Following the general procedure-3, the titled compound was synthesized from Intermediate 74 (1.8 g, 5.6 mmol) and Intermediate 5 (1.56 g, 5.6 mmol). After work up, crude product was purified by combi-flash using MeOH and DCM (3:97) as eluent. Pure compound from column chromatography was suspended in Diethyl ether (50 ml) and stirred for 30 mins to obtain a solid. Solid was filtered and washed with Diethyl ether (50 ml). Solid was dried under vacuum to obtain the titled compound as a pale-green solid (1.8 g). Yield: 57 %. 'H- NMR (d ppm, DMSO-rie, 400 MHz): 9.90 (s, 1H), 9.03 (d, J 4.4, 1H), 8.81 (s, 1H), 8.73 (d, J 3.6, 1H), 8.16 (d, J 11.6, 1H), 8.10 (d, J 8.8, 1H), 8.06 (d, J 2.8, 1H), 7.81 (d, J 4.4, 1H), 7.47 (dd, J 9.2, 3.2, 1H), 5.78 (d, J 4, 1H), 5.57-5.50 (m, 1H), 3.52-3.44 (m, 4H), 3.12-3.05 (m, 4H), 1.54 (d, J 6.8, 3H), 1.43 (s, 9H). MS (m/z): 564.49 (M+H); calculated for [C29H31F2N7O3+H] : 564.25.
Example 49A
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol
[311] Following the general procedure-4, the titled compound was synthesized from (±)-'/ en- butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperazine-l-carboxylate (Example 49, 1.0 g, 1.77 mmol) as a yellow solid (650 mg). Yield: 79%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.86 (s, 1H), 9.03 (d, J 4.4, 1H), 8.82 (s, 1H), 8.73 (d, J 3.6, 1H), 8.15 (d, J 12, 1H), 8.08 (d, J 9.2, 1H), 8.02 (d, J 2.8, 1H), 7.80 (d, J 4.4, 1H), 7.43 (dd, J 9.2, 2.8, 1H), 5.79 (d, J 4, 1H), 5.57-5.49 (m, 1H), 3.09- 3.01 (m, 4H), 2.90-2.83 (m, 4H), 1.54 (d, J 6.4, 3H). MS (m/z): 464.54 (M+H); calculated for [C24H23F2N7O+H]: 464.19.
Example 49B
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trihydrochloride
[312] To a mixture of (±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 49A, 300 mg, 0.65 mmol) in methanol (6 mL) was added aq. 35% hydrochloric acid (229 mg, 6.3 mmol) by dissolving in MeOH (1 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl tert- butyl ether (18 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum at 55°C on rotavapor to obtain the titled compound as a yellow solid (320 mg). Yield: 93%. M.P.: 236-238°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.88 (s, 1H), 9.63 (bs, 2H), 9.07 (d, J 4.4, 1H), 8.95 (d, J 3.2, 1H), 8.81 (s, 1H), 8.22 (d, J 9.6, 1H), 8.18 (d, J 11.6, 1H), 8.01 (d, J 2.8, 1H), 7.888 (d, J 9.6, 1H), 7.84 (d, J 4.4, 1H), 5.56-5.49 (m, 1H), 3.52-3.44 (m, 4H), 3.30-3.20 (m, 4H), 1.54 (d, J 6.8, 3H). MS (m/z): 464.63 (M+H-3HC1); calculated for [C24H23F2N7O+H-3HCI] : 464.19.
Example 50
(±)-Jbr/-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperidine-l-carboxylate
[313] Following the general procedure-3, the titled compound was synthesized from Intermediate 74 (810 mg, 2.5 mmol) and Intermediate 87 (700 mg, 2.5 mmol). After work up, crude product was purified by combi -flash using MeOH and DCM (3:97) as eluent. Pure compound from column chromatography was suspended in Diethyl ether (50 ml) and stirred for 30 mins to obtain a solid. Solid was filtered and washed with Diethyl ether (50 ml). Solid was dried under vacuum to obtain the titled compound as a pale-green solid (760 mg). Yield: 54 %. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 10.09 (s, 1H), 9.04 (d, J 4.4, 1H), 8.83 (s, 1H), 8.78 (d, J 3.6, 1H), 8.22 (d, J 2.4, 1H), 8.21-8.14 (m, 2H), 7.81 (d, J 4.4, 1H), 7.70 (dd, J 8.8, 2.4, 1H), 5.79 (d, J 4.4, 1H), 5.58-5.50 (m, 1H), 4.12-4.05 (m, 2H), 2.90-2.75 (m, 2H), 2.74- 2.65 (m, 1H), 1.81-1.74 (m, 2H), 1.60-1.50 (m, 5H), 1.42 (s, 9H). MS (m/z): 563.45 (M+H); calculated for [C30H32F2N6O3+H]: 563.25. Example 50A
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol
[314] Following the general procedure-4, the titled compound was synthesized from (±)-'/ erl- butyl 4-(6-((5-fhioro-4-(8-fhioro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperidine-l-carboxylate (Example 50, 490 mg, 0.87 mmol) as a yellow solid (310 mg). Yield: 77%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 10.07 (s, 1H), 9.04 (d, J 4.4, 1H), 8.83 (s, 1H), 8.77 (d, J 3.2, 1H), 8.22-8.12 (m, 3H), 7.81 (d, J 4.4, 1H), 7.66 (dd, J 8.8, 2.5, 1H), 5.83 (bs, 1H), 5.58-5.50 (m, 1H), 3.08-2.99 (m, 2H), 2.62-.2.54 (m, 3H), 1.72- 1.64 (m, 2H), 1.55 (d, J 6.4, 3H), 1.55-1.45 (m, 2H). MS (m/z): 463.19 (M+H); calculated for [C25H24F2N6O+H]: 463.67.
Example 50B
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trihydrochloride
[315] To a mixture of (±)-l-(8-Fluoro-6-(5-fhioro-2-((5-(piperidin-4-yl)pyridin-2- yl)amino)pyrimidin-4-yl)quinohn-4-yl)ethanol (Example 50A, 190 mg, 0.41 mmol) in methanol (2.8 mL) was added aq. 35% hydrochloric acid (150 mg, 4.1 mmol) by dissolving in MeOH (1 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl tert- butyl ether (19 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum at 55°C on rotavapor to obtain the titled compound as a yellow solid (190 mg). Yield: 59%. M.P.: 250-252°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.98 (s, 1H), 9.31-9.22 (m, 2H), 9.06 (d, J 4.4, 1H), 8.96 (d, J 2.8, 1H), 8.83 (s, 1H), 8.31 (d, J 2.5, 1H), 8.19 (d, J 11.2, 1H), 7.97 (d, J 8.8, 1H), 7.84 (d, J 4.8, 1H), 5.58-5.50 (m, 1H), 3.41-3.35 (m, 2H), 3.08-2.95 (m, 3H), 2.05-1.90 (m, 4H), 1.55 (d, J 6.4, 3H). MS (m/z): 463.58 (M+H-3HC1); calculated for [C25H24F2N6O.3HCI+H-3HCI]: 463.67.
Example 51
Tert- butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin- 2-yl)amino)pyridin-3-yl)piperidine-l-carboxylate
[316] Following the general procedure-3, the titled compound was synthesized from Intermediate 83 (540 mg, 1.6 mmol) and Intermediate 87 (450 mg, 1.6 mmol). After work up, crude product was purified by combi-flash using MeOH and DCM (2.5:97.5) as eluent. Pure compound from column chromatography was suspended in Diethyl ether (30 ml) and stirred for 30 mins to obtain a solid. Solid was fdtered and washed with Diethyl ether (30 ml). Solid was dried under vacuum to obtain the titled compound as a pale-green solid (400 mg). Yield: 43 %. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 10.04 (s, 1H), 9.57 (s, 1H), 8.98 (d, J 4.4, 1H), 8.77 (d, J 3.6, 1H), 8.25 (d, J 8.8, 1H), 8.21 (d, J 2.4, 1H), 8.15 (d, J 12, 1H), 7.73 (d, J 4.4, 1H), 7.70 (dd, J 8.8, 2.4, 1H), 5.76 (s, 1H), 4.12-4.03 (m, 2H), 2.90-2.78 (m, 2H), 2.75-2.65 (m, 1H), 1.82-1.73 (m, 8H), 1.60-1.50 (m, 2H), 1.42 (s, 9H). MS (m/z): 577.48 (M+H); calculated for [C31H34F2N6O3+H] : 577.27.
Example 51A
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)propan-2-ol
[317] Following the general procedure-4, the titled compound was synthesized from Tert- butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperidine-l-carboxylate (Example 51, 370 mg, 0.64 mmol) as a yellow solid (290 mg). Yield: 95%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 10.02 (s, 1H), 9.57 (s, 1H), 8.99 (d, J 4.8, 1H), 8.77 (d, J 3.6, 1H), 8.24 (d, J 8.8, 1H), 8.19 (d, J 2.5, 1H), 8.16 (d, J 12.4, 1H), 7.73 (d, J 4.8, 1H), 7.67 (d, J 8.4, 2.5, 1H), 5.78 (s, 1H), 3.05-2.98 (m, 2H), 2.62- 2.52 (m, 3H), 2.00 (bs, NH), 1.79 (s, 6H), 1.72-1.65 (m, 2H), 1.57-1.48 (m, 2H). MS (m/z): 477.60 (M+H); calculated for [CieHieFiNeO+H] : 477.21.
Example 51B
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)propan-2-ol trihydrochloride
[318] To a mixture of 2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol (Example 51A, 240 mg, 0.5 mmol) in methanol (2.8 mL) was added aq. 35% hydrochloric acid (180 mg, 5 mmol) by dissolving in MeOH (1 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl tert- butyl ether (14.4 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum at 55°C on rotavapor to obtain the titled compound as an off- white solid (250 mg). Yield: 78 %. M.P.: 223-225°C. ^-NMR d ppm, DMSO-rie, 400 MHz): 12.30-12.10 (m, 1H), 9.59 (s, 1H), 9.40-9.28 (m, 2H), 9.02 (d, J 4.8, 1H), 8.98 (d, J 3.2, 1H), 8.32 (bs, 1H), 8.30-8.22 (m, 1H), 8.19 (d, J 11.6, 1H), 7.97 (d, J 8.8, 1H), 7.76 (d, J 4.8, 1H), 5.94 (bs, 1H), 3.42-3.33 (m, 2H), 3.09-2.92 (m, 3H), 2.05-1.90 (m, 4H), 1.76 (s, 6H). MS (m/z): 477.56 (M+H-3HC1); calculated for ICieHieFiNeO.SHCl +H-3HC1]: 477.21.
Example 52
7er/-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperidine-l-carboxylate
[319] Following the general procedure-3, the titled compound was synthesized from Intermediate 31 (530 mg, 1.5 mmol) and Intermediate 87 (420 mg, 1.5 mmol). After work up, crude product was purified by combi-flash using MeOH and DCM (2.5:97.5) as eluent. Pure compound from column chromatography was suspended in Diethyl ether (30 ml) and stirred for 30 mins to obtain a solid. Solid was filtered and washed with Diethyl ether (30 ml). Solid was dried under vacuum to obtain the titled compound as a pale-green solid (380 mg). Yield: 42 %. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 10.01 (s, 1H), 9.50 (s, 1H), 8.75 (d, J 3.6, 1H), 8.25 (d, J 8.4, 1H), 8.21 (d, J 2.4, 1H), 8.10 (d, J 11.6, 1H), 7.70 (dd, J 8.8, 2.4, 1H), 7.61 (s, 1H), 5.70 (s, 1H), 4.12-4.06 (m, 2H), 2.90-2.75 (m, 2H), 2.74-2.65 (m, 4H), 1.81-1.70 (m, 8H), 1.60-1.45 (m, 2H), 1.42 (s, 9H). MS (m/z): 591.52 (M+H); calculated for [CiifteFiNeOi+H]: 591.28.
Example 52A
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)propan-2-ol
[320] Following the general procedure-4, the titled compound was synthesized from Tert- butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrimidin- 2-yl)amino)pyridin-3-yl)piperidine-l-carboxylate (Example 52, 360 mg, 0.61 mmol) as an off- white solid (260 mg). Yield: 87%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 9.99 (s, 1H), 9.50 (s, 1H), 8.75 (d, J 3.6, 1H), 8.25 (d, J 8.8, 1H), 8.19 (d, J 2.4, 1H), 8.11 (d, J 12, 1H), 7.67 (dd, J 8.4, 2.4, 1H), 7.62 (s, 1H), 5.71 (s, 1H), 3.08-3.00 (m, 2H), 2.73 (s, 3H), 2.62-2.52 (m, 3H), 2.00 (bs, 1H, NH), 1.78-1.68 (m, 8H), 1.60-1.48 (m, 2H). MS (m/z): 491.62 (M+H); calculated for [CivHisFiNeO+H]: 491.23.
Example 52B
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)propan-2-ol trihydrochloride [321] To a mixture of 2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)propan-2-ol (Example 52A, 230 mg, 0.47 mmol) in methanol (3.6 mL) was added aq. 35% hydrochloric acid (170 mg, 4.7 mmol) by dissolving in MeOH (1 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl tert- butyl ether (13.8 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum at 55°C on rotavapor to obtain the titled compound as an off-white solid (250 mg). Yield: 78 %. M.P.: 221-223°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 12.17 (s, 1H), 9.53 (s, 1H), 9.27 (bs, 2H), 8.96 (d, J 3.2, 1H), 8.32 (s, 1H), 8.26 (d, J 8.8, 1H), 8.15 (d, J 11.6, 1H), 7.96 (d, J 8.8, 1H), 7.65 (s, 1H), 5.23 (bs, 1H), 3.43-3.34 (m, 2H), 3.10-2.95 (m, 3H), 2.75 (s, 3H), 2.05-1.88 (m, 4H), 1.74 (s, 6H). MS (m/z): 491.61 (M+H- 3HC1); calculated for [C27H28F2N6O.3HCI +H-3HC1]: 491.61.
Example 53
(±)-Tert- butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperidine-l-carboxylate
[322] Following the general procedure-3, the titled compound was synthesized from Intermediate 77 (540 mg, 1.6 mmol) and Intermediate 87 (450 mg, 1.6 mmol). After work up, crude product was purified by combi-flash using MeOH and DCM (2.5:97.5) as eluent. Pure compound from column chromatography was suspended in Diethyl ether (20 ml) and stirred for 30 mins to obtain a solid. Solid was filtered and washed with Diethyl ether (20 ml). Solid was dried under vacuum to obtain the titled compound as a yellow solid (300 mg). Yield: 32 %. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 10.05 (s, 1H), 8.77 (s, 1H), 8.76 (d, J 3.6, 1H), 8.22 (d, J 2.4, 1H), 8.20 (d, J 8.8, 1H), 8.12 (d, J 12, 1H), 7.71-7.66 (m, 2H), 5.75 (d, J 4, 1H), 5.52- 5.44 (m, 1H), 4.12-4.05 (m, 2H), 2.90-2.76 (m, 2H), 2.73 (s, 3H), 2.75-2.65 (m, 1H), 1.81-1.72 (m, 2H), 1.60-1.45 (m, 2H), 1.54 (d, J 6.4, 3H), 1.42 (s, 9H). MS (m/z): 577.43 (M+H); calculated for [CriftrFiNeOr+H]: 577.27.
Example 53A
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)ethanol
[323] Following the general procedure-4, the titled compound was synthesized from Tert- butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)-2-methylquinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3-yl)piperidine-l-carboxylate (Example 53, 280 mg, 0.49 mmol) as an off- white solid (180 mg). Yield: 78%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 10.03 (s, 1H), 8.77 (s, 1H), 8.75 (d, J 3.6, 1H), 8.20 (d, J 2.0, 1H), 8.19 (d, J 3.6, 1H), 8.12 (d, J 12, 1H), 7.68 (s, 1H), 7.66 (d, J 8.8, 2, 1H), 5.75 (s, 1H), 5.53-5.45 (m, 1H), 3.08-3.00 (m, 2H), 2.73 (s, 3H), 2.63-2.56 (m, 3H), 1.74-1.68 (m, 2H), 1.60-1.45 (m, 2H), 1.54 (d, J 6.8, 3H). MS (m/z): 477.62 (M+H); calculated for [CieHieFiNeO+H] : 477.21.
Example 53B
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)ethanol trihydrochloride
[324] To a mixture of l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2- yl)amino)pyrimidin-4-yl)-2-methylquinolin-4-yl)ethanol (Example 53A, 160 mg, 0.34 mmol) in methanol (2.2 mL) was added aq. 35% hydrochloric acid (120 mg, 3.4 mmol) by dissolving in MeOH (1 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl tert- butyl ether (16 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum at 55°C on rotavapor to obtain the titled compound as an off- white solid (180 mg). Yield: 56 %. M.P.: 220-222°C.1H-NMR (d ppm, DMSO-rie, 400 MHz): 12.17 (s, 1H), 9.26 (bs, 2H), 8.96 (d, J 3.2, 1H), 8.78 (s, 1H), 8.31 (s, 1H), 8.24 (d, J 8.8, 1H), 8.15 (d, J 12, 1H), 7.93 (d, J 8.8, 1H), 7.73 (s, 1H), 5.52-5.45 (m, 1H), 3.42-3.33 (m, 2H), 3.10- 2.92 (m, 3H), 2.76 (s, 3H), 2.05-1.89 (m, 4H), 1.54 (d, J 6.4, 3H). MS (m/z): 477.56 (M+H- 3HC1); calculated for [CieHieFiNeO.SHCl +H-3HC1]: 477.21.
Example 54
Tert- butyl 4-(2-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin- 2-yl)amino)pyrimidin-5-yl)piperidine-l-carboxylate
[325] Following the general procedure-3, the titled compound was synthesized from Intermediate 83 (217 mg, 0.65 mmol) and Intermediate 90 (180 mg, 0.65 mmol). After work up, crude product was purified by combi-flash using MeOH and DCM (4:96) as eluent. Pure compound from column chromatography was suspended in Diethyl ether (20 ml) and stirred for 30 mins to obtain a solid. Solid was filtered and washed with Diethyl ether (5 ml). Solid was dried under vacuum to obtain the titled compound as an Off-White solid (65 mg). Yield: 17 %. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 10.47 (s, 1H), 9.53 (s, 1H), 8.97 (d, J 4.4, 1H), 8.79 (d, J 3.6, 1H), 8.56 (s, 2H), 8.21 (d, J 12, 1H), 7.74 (d, J 4.8, 1H), 5.71 (s, 1H), 4.14-4.05 (m, 2H), 2.90-2.62 (m, 3H), 1.84-1.77 (m, 2H), 1.74 (s, 6H), 1.62-1.51 (m, 2H), 1.42 (s, 9H). MS (m/z): 578.48 (M+H); calculated for [C30H33F2N7O3+H]: 578.26.
Example 54A
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)propan-2-ol
[326] Following the general procedure-4, the titled compound was synthesized from Tert- butyl 4-(2-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2- yl)amino)pyrimidin-5-yl)piperidine-l-carboxylate (Example 54, 300 mg, 0.52 mmol) as an off- white solid (215 mg). Yield: 87%. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 10.45 (bs, 1H), 9.52 (s, 1H), 8.98 (d, J 3.2, 1H), 8.79 (d, J 3.6, 1H), 8.52 (s, 2H), 8.21 (d, J 12, 1H), 7.75 (d, J 4.8, 1H), 5.73 (s, 1H), 3.08-2.99 (m, 2H), 2.70-2.52 (m, 4H), 2.10 (bs, 1H, NH), 1.74 (s, 8H), 1.61-1.49 (m, 2H). MS (m/z): 478.50 (M+H); calculated for [C25H25F2N7O+H] : 478.21.
Example 54B
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)propan-2-ol trihydrochloride
To a mixture of 2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol (Example 54A, 200 mg, 0.42 mmol) in methanol (3 mL) was added aq. 35% hydrochloric acid (153 mg, 4.2 mmol) by dissolving in MeOH (1 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl tert- butyl ether (20 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum at 55°C on rotavapor to obtain the titled compound as an off-white solid (180 mg). Yield: 56 %. M.P.: 257-259°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 11.08 (bs, 1H), 9.55 (s, 1H), 9.23 (bs, 1H), 9.08 (bs, 1H), 9.00 (d, J 4.4, 1H), 8.63 (d, J 3.2, 1H), 8.22 (d, J 12, 1H), 7.77 (d, J 4.8, 1H), 3.41-3.34 (m, 2H), 3.07-2.90 (m, 3H), 2.07-1.90 (m, 4H), 1.75 (s, 6H). MS (m/z): 478.48 (M+H-3HC1); calculated for [C25H25F2N7O.3HCI +H-3HC1]: 478.51.
Example 55
( ±)-Tert-buty\ 4-(2-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyrimidin-5-yl)piperidine-l-carboxylate
[327] Following the general procedure-3, the titled compound was synthesized from Intermediate 77 (500 mg, 1.55 mmol) and Intermediate 90 (433 mg, 1.55 mmol). After work up, crude product was purified by combi-flash using MeOH and DCM (4:96) as eluent. Pure compound from column chromatography was suspended in Diethyl ether (20 ml) and stirred for 30 mins to obtain a solid. Solid was filtered and washed with Diethyl ether (15 ml). Solid was dried under vacuum to obtain the titled compound as a Pale-Brown solid (270 mg). Yield: 31 %. ¾-NMR (d ppm, DMSO-r e, 400 MHz): 10.50 (s, 1H), 9.03 (d, J 4.4, 1H), 8.84 (s, 1H), 8.80 (d, J 3.6, 1H), 8.56 (s, 2H), 8.21 (d, J 12, 1H), 7.81 (d, J 4.4, 1H), 5.76 (d, J 4.4, 1H), 5.57- 5.49 (m, 1H), 4.14-4.06 (m, 2H), 2.90-2.78 (m, 2H), 2.77-2.65 (m, 1H), 1.85-1.78 (m, 2H), 1.64-1.55 (m, 2H), 1.53 (d, J 6.4, 3H), 1.42 (s, 9H). MS (m/z): 564.37 (M+H); calculated for [C29H31F2N7O3+H]: 564.25.
Example 55A
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol
[328] Following the general procedure-4, the titled compound was synthesized from Tert- butyl 4-(2-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyrimidin-5-yl)piperidine-l-carboxylate (Example 55, 250 mg, 0.44 mmol) as an off- white solid (200 mg). Yield: 97%. ¾-NMR (d ppm, DMSO-re, 400 MHz): 10.50 (s, 1H), 9.03 (d, J 4.4, 1H), 8.85 (s, 1H), 8.80 (d, J 3.6, 1H), 8.53 (s, 2H), 8.21 (d, J 12, 1H), 7.81 (d, J 4.4, 1H), 5.77 (s, 1H), 5.58-5.49 (m, 1H), 3.08-3.00 (m, 2H), 2.68-2.53 (m, 3H), 1.78-1.70 (m, 2H), 1.62-1.53 (m, 2H), 1.53 (d, J 6.8, 3H). MS (m/z): 464.46 (M+H); calculated for [C24H23F2N7O+H]: 464.19.
Example 55B
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trihydrochloride
[329] To a mixture of l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 55A, 200 mg, 0.43 mmol) in methanol (3 mL) was added aq. 35% hydrochloric acid (157 mg, 4.3 mmol) by dissolving in MeOH (1 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl tert- butyl ether (20 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum at 55°C on rotavapor to obtain the titled compound as an off-white solid (200 mg). Yield: 59 %. M.P.: 220-222°C. ¾-NMR (d ppm, DMSO-r/e, 400 MHz): 11.08 (s, 1H), 9.28-9.20 (m, 1H), 9.15-9.08 (m, 1H), 9.05 (d, J 4.4, 1H), 8.87 (d, J 3.2, 2H), 8.63 (s, 2H), 8.23 (d, J 12, 1H), 7.84 (d, J 4.4, 1H), 5.58-5.51 (m, 1H), 3.42-3.34 (m, 2H), 3.06-2.92 (m, 3H), 2.07-1.90 (m, 4H), 1.55 (d, J 6.4, 3H). MS (m/z): 464.43 (M+H); calculated for [C24H23F2N7O.3HCI+H-3HCI]: 464.19.
Example 56
2-(8-Fluoro-6-(5-fluoro-2-((5-(l-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)propan-2-ol
[330] Following the general procedure-3, the titled compound was synthesized from Intermediate 83 (700 mg, 2.1 mmol) and Intermediate 93 (400 mg, 2.1 mmol). After work up, crude product was suspended in a mixture of Et20 and EtOAc (1:1) (20 ml) and stirred for 30 mins to obtain a solid. Solid was filtered and washed with a mixture of Et20 and EtOAc (1:1) (10 ml). Solid was dried under vacuum to obtain the titled compound as an Off-White solid (200 mg). Yield: 20 %. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 10.03 (s, 1H), 9.57 (s, 1H), 8.98 (d, J 4.4, 1H), 8.77 (d, J 3.6, 1H), 8.25 (d, J 8.4, 1H), 8.21 (d, J 2, 1H), 8.15 (d, J 12, 1H), 7.73 (d, J 4.4, 1H), 7.69 (d, J 8.4, 2, 1H), 5.77 (s, 1H), 2.95-2.86 (m, 2H), 2.55-2.49 (m, 1H), 2.24 (s, 3H), 2.09-1.99 (m, 2H), 1.80-1.65 (m, 4H), 1.75 (s, 6H). MS (m/z): 491.57 (M+H); calculated for [C27H28F2N6O+H] : 491.23.
Example 56A
2-(8-Fluoro-6-(5-fluoro-2-((5-(l-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)propan-2-ol trihydrochloride
[331] To a mixture of 2-(8-Fluoro-6-(5-fluoro-2-((5-(l-methylpiperidin-4-yl)pyridin-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol (Example 56, 200 mg, 0.41 mmol) in methanol (3 mL) was added aq. 35% hydrochloric acid (150 mg, 4.1 mmol) by dissolving in MeOH (1 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl tert- butyl ether (12 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum at 55°C on rotavapor to obtain the titled compound as an off-white solid (200 mg). Yield: 59 %. M.P.: 238-240°C. Tf-NMR (d ppm, DMSO-rie, 400 MHz): 12.11 (s, 1H), 11.12 (s, 1H), 9.59 (s, 1H), 9.02 (d, J 4.8, 1H), 8.97 (d, J 3.2, 1H), 8.33 (d, J 2.5, 1H), 8.25 (dd, J 9.2, 2.5, 1H), 8.18 (d, J 12, 1H), 7.97 (d, J 9.2, 1H), 7.75 (d, J 4.8, 1H), 3.55-3.47 (m, 2H), 3.12-3.03 (m, 2H), 3.02-2.94 (m, 1H), 2.76 (d, J 4.8, 3H), 2.13-2.04 (m, 4H), 1.76 (s, 6H). MS (m/z): 491.52 (M+H-3HC1); calculated for [C27H28F2N6O.3HCI+H-3HCI]: 491.23.
Example 57 (±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(l-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-
4-yl)quinolin-4-yl)ethanol
[332] Following the general procedure-3, the titled compound was synthesized from Intermediate 77 (780 mg, 2.4 mmol) and Intermediate 93 (460 mg, 2.4 mmol). After work up, crude product was suspended in a mixture of Et20 and MeOH (1: 1) (20 ml) and stirred for 30 mins to obtain a solid. Solid was filtered and washed with a mixture of Et20 and MeOH (1:1) (10 ml). Solid was suspended in Et20 and stirred for 30 mins. Solid was filtered and dried under vacuum to obtain the titled compound as a yellow solid (230 mg). Yield: 20 %. 'H-NMR (d ppm, DMSO-rie, 400 MHz): 10.08 (s, 1H), 9.04 (d, J 4.4, 1H), 8.83 (s, 1H), 8.77 (d, J 3.6, 1H), 8.23-8.12 (m, 3H), 7.81 (d, J 4.4, 1H), 7.69 (dd, J 8.8, 2.5, 1H), 5.80 (d, J 4.4, 1H), 5.58- 5.49 (m, 1H), 2.91-2.84 (m, 2H), 2.50-2.43 (m, 1H), 2.21 (s, 3H), 2.03-1.94 (m, 2H), 1.79-1.62 (m, 4H), 1.55 (d, J 6.4, 3H). MS (m/z): 477.57 (M+H); calculated for [CieHieFiNeO+H] : 477.21.
Example 57A
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(l-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin- 4-yl)quinolin-4-yl)ethanol trihydrochloride
[333] To a mixture of l-(8-Fluoro-6-(5-fluoro-2-((5-(l-methylpiperidin-4-yl)pyridin-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethanol (Example 57, 200 mg, 0.42 mmol) in methanol (3 mL) was added aq. 35% hydrochloric acid (150 mg, 4.2 mmol) by dissolving in MeOH (1 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl tert- butyl ether (20 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum at 55°C on rotavapor to obtain the titled compound as an off- white solid (200 mg). Yield: 44 %. M.P.: 238-240°C. ¾-NMR (d ppm, DMSO-rie, 400 MHz): 12.22 (bs, 1H), 11.13 (s, 1H), 9.07 (d, J 4.4, 1H), 8.99 (d, J 3.2, 1H), 8.83 (s, 1H), 8.33 (d, J 2.4, 1H), 8.27 (dd, J 8.8, 2.4, 1H), 8.19 (d, J 12, 1H), 7.93 (d, J 9.2, 1H), 7.84 (d, J 4.4, 1H), 5.58-5.50 (m, 1H), 3.55-3.46 (m, 2H), 3.12-3.03 (m, 2H), 3.02-2.93 (m, 1H), 2.76 (d, J 4.8, 3H), 2.18-2.05 (m, 4H), 1.56 (d, J 6.8, 3H). MS (m/z): 477.57 (M+H-3HC1); calculated for
[CieHieFiNeO .3HC1+H-3HC1] : 477.53.
Example 58
(±)-Tert- butyl 4-(6-((4-(4-(l-((tert-butoxycarbonyl)amino)ethyl)-8-fluoroquinolin-6-yl)- 5-fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperidine-l-carboxylate Following the general procedure-3, the titled compound was synthesized from Intermediate 71 (600 mg, 1.43 mmol) and Intermediate 87 (395 mg, 1.43 mmol). After work up, crude product was purified by combi-flash using MeOH and DCM (3:97) as eluent. Pure compound from column chromatography was suspended in Diethyl ether (20 ml) and stirred for 30 mins to obtain a solid. Solid was filtered and washed with Diethyl ether (10 ml). Solid was dried under vacuum to obtain the titled compound as a Pale-Yellow solid (370 mg). Yield: 39 %.1H-NMR (d ppm, DMSO-rie, 400 MHz): 10.11 (s, 1H), 9.05 (d, J 4.4, 1H), 8.81 (s, 1H), 8.79 (d, J 3.2, 1H), 8.25-8.15 (m, 3H), 7.98-7.89 (m, 1H), 7.74-7.65 (m, 2H), 5.57-5.49 (m, 1H), 4.14-4.05 (m, 2H), 2.88-2.78 (m, 2H), 2.72-2.65 (m, 1H), 1.81-1.74 (m, 2H), 1.59-1.47 (m, 2H), 1.46 (d, J 6.8, 3H), 1.42 (s, 9H), 1.38 (s, 9H). MS (m/z): 662.36 (M+H); calculated for [C35H41F2N7O4+H]: 662.32.
Example 58A
(±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperidin-4-yl)pyri din-2- yl)pyrimidin-2-amine
[334] Following the general procedure-4, the titled compound was synthesized from (±)-'/ - butyl 4-(6-((4-(4-(l-((tert-butoxycarbonyl)amino)ethyl)-8-fluoroquinolin-6-yl)-5- fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperidine-l-carboxylate (Example 58, 350 mg, 0.53 mmol) as a Yellow solid (37 mg). Yield: 97%. ^-NMR (d ppm, DMSO-rfc, 400 MHz): 10.08 (s, 1H), 9.03 (d, J 4.4, 1H), 8.85 (s, 1H), 8.77 (d, J 3.6, 1H), 8.21-8.14 (m, 3H), 7.92 (d, J 4.4, 1H), 7.67 (d, J 8.8, 2.4, 1H), 4.91-4.83 (m, 1H), 3.10-3.00 (m, 2H), 2.69-2.55 (m, 3H), 1.76- 1.68 (m, 2H), 1.62-1.49 (m, 2H), 1.45 (d, J 6.4, 3H). MS (m/z): 462.49 (M+H); calculated for [C25H25F2N7+H] : 462.21.
Example 58B
(±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperidin-4-yl)pyri din-2- yl)pyrimidin-2-amine trihydrochloride
[335] To a mixture of (±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5- (piperidin-4-yl)pyridin-2-yl)pyrimidin-2 -amine (Example 58A, 80 mg, 0.17 mmol) in methanol (2 mL) was added aq. 35% hydrochloric acid (63 mg, 1.7 mmol) by dissolving in MeOH (1 ml). The resulting clear solution was stirred for 30 min. After 30 mins, diluted with methyl +' / -butyl ether (10 mL) and stirred for 1 h to obtain a solid. Filtered the solid and dried the solid under vacuum at 55°C on rotavapor to obtain the titled compound as an off-white solid (70 mg). Yield: 87 %. M.P.: 246-248°C. ¾-NMR (d ppm, DMSO-flfe, 400 MHz): 11.59 (s, 1H), 9.35-9.20 (m, 4H), 9.18 (d, J 4.4, 1H), 8.76 (s, 1H), 8.32 (d, J 2, 1H), 8.24 (d, J 12, 1H), 8.11 (d, J 8.4, 1H), 8.07 (d, J 4.4, 1H), 8.03 (d, J 8.8, 1H), 5.41-5.32 (m, 1H), 3.40-3.32 (m 2H), 3.08-2.94 (m, 3H), 2.05-1.90 (m, 4H), 1.72 (d, J 6.8, 3H). MS (m/z): 462.48 (M+H-3HC1); calculated for [C25H25F2N7.3HCI+H-3HCI]: 462.21.
BIOLOGICAL ASSAY
[336] The pharmacological properties of the compounds of this invention may be confirmed by several pharmacological assays. The pharmacological assays which can be carried out with the compounds according to the invention and/or their pharmaceutically acceptable salts is exemplified below.
Example-A
CDK1 Enzyme Assay protocol for screening or ICso determination of compounds of formula (I)
Objective
To screen for % inhibition or perform ICso for compounds of present invention for activity against CDK1 enzyme using ADP-Glo kinase assay.
Kit
ADP-glow kinase kit was used for the CDK1 enzyme assay.
ADP-Glo Kinase Assay Protocol
Kinase Assay has 3 steps: a) Enzymatic reaction, b) ATP -Depletion c) Kinase detection. The following protocol is designed for a 384-well plate using a 1: 1:2 ratio for the 3 steps, respectively. a) Enzymatic Reaction:
¨ Total volume of kinase reaction was 5pL. 1 pL of DMSO/drug (diluted in Kinase buffer as 5X) and final concentration in the well was IX. 2 pL enzyme (prepared in kinase buffer as 1 ng / pL). 2 pL of ATP/Susbtrate (Histone) mixture (2.5 x prepared in Kinase buffer) was added so that the final concentration of ATP/well was 50 pM and Histone per well was 125 ng.
• 1 pL of 5X concentration of test compound was added to each well. For control wells (Blank and Enzyme Blank), lpL of DMSO prepared in IX buffer was added. Final concentration of DMSO in all the wells was maintained at 0.5 %. • 2pL (1 ng/mΐ) of CDKl/cyclin A2 enzyme was added to Enzyme blank and drug treatment wells. 2pL of IX kinase reaction buffer was added to the control (Blank) wells.
• Centrifuged the plate for 10 seconds and incubated at room temperature for 15 minutes.
• 2pL of ATP (2.5X) + Substrate (Histone protein) solution was added to each well (Final concentration of ATP/well was 50 mM and Histone protein was 125 ng/well).
• Centrifuged the plate for 10 seconds and incubated at room temperature for 60 minutes. b) ATP-Depletion:
• ADP-glo reagent was thawed to room temperature before use.
• 5pL of ADP-Glo Reagent was added to stop the kinase reaction to deplete the unconsumed ATP.
• Centrifuged the plate for 10 seconds and incubated at room temperature for 40 minutes. c) Kinase Detection:
• Kinase detection buffer was thawed to room temperature before use.
• 10 pL of Kinase Detection Reagent was added to convert ADP to ATP and introduce luciferase and luciferin to detect ATP.
• The plate was incubated at room temperature for 30 minutes.
• Luminescence was recorded using BMG Labtech, FLUOstar Omega.
Calculation for Screening:
1) Average for each well was calculated.
2) Average of Blank wells was subtracted from Average of each enzyme blank and treatment well.
3) Average of blank subtracted wells was calculated
4) % inhibitions were calculated based on the below formula
100 - (Average of blank subtracted treatment well * 100) / (Average of blank subtracted Enzyme Blank wells)
5) For IC50 calculations, Average blank subtracted values were used for plotting IC50 curve using GraphPad Prism. Example-B
CDK2 Enzyme Assay Protocol for Screening or IC50 Determination of compounds of formula (I)
Objective
To screen for % inhibition or perform IC50 determination for compounds of present invention for activity against CDK2 enzyme using ADP-Glo kinase assay.
Kit:
ADP-glow kinase kit was used for the CDK2 enzyme assay.
ADP-Glo Kinase Assay Protocol
Kinase Assay has 3 steps: a) Enzymatic reaction, b) ATP -Depletion c) Kinase detection. The following protocol is designed for a 384-well plate using a 1:1:2 ratio for the 3 steps, respectively. a) Enzymatic reaction:
• Total volume of kinase reaction was 5pL. 1 pL of DMSO/drug (diluted in Kinase buffer as 5X) and final concentration in the well was IX. 2 pL enzyme (prepared in kinase buffer as 1 ng / pL). 2 pLof ATP/Susbtrate (Histone) mixture (2.5 x prepared in Kinase buffer) was added so that the final concentration of ATP/well was 50 pM and Histone per well was 125 ng.
• 1 pL of 5X concentration of test compound was added to each well. For control wells (Blank and Enzyme Blank), lpL of DMSO prepared in IX buffer was added. Final concentration of DMSO in all the wells was maintained at 0.5 %.
• 2pL ( 1 ng/pl) of CDK2/cyclin A2 enzyme was added to Enzyme blank and drug treatment wells. 2pL of IX kinase reaction buffer was added to the control (Blank) wells.
• Centrifuged the plate for 10 seconds and incubated at room temperature for 15 minutes.
• 2pL of ATP (2.5X) + Substrate (Histone protein) solution was added to each well (Final concentration of ATP/well was 50 pM and Histone protein was 125 ng/well).
• Centrifuged the plate for 10 seconds and incubated at room temperature for 20 minutes. b) ATP-Depletion: • ADP-glo reagent was thawed to room temperature before use.
• 5pL of ADP-Glo Reagent was added to stop the kinase reaction to deplete the unconsumed ATP.
• Centrifuged the plate for 10 seconds and incubated at room temperature for 40 minutes. c) Kinase Detection:
• Kinase detection buffer was thawed to room temperature before use.
• 10 pL of Kinase Detection Reagent was added to convert ADP to ATP and introduce luciferase and luciferin to detect ATP.
• The plate was incubated at room temperature for 30 minutes.
• Luminescence was recorded using BMG Labtech, FLUOstar Omega.
Calculation for screening:
1) Average for each well calculated
2) Average of Blank wells was subtracted from Average of each enzyme blank and treatment well.
3) Average of blank subtracted wells was calculated
4) % inhibitions were calculated based on the below formula
100 - (Average of blank subtracted treatment well * 100)/ (Average of blank subtracted Enzyme Blank wells).
5) For IC50 calculations, Average blank subtracted values were used for plotting IC50 curve using GraphPad Prism.
Example-C
CDK4 Enzyme Assay protocol for screening or IC50 determination of compounds of formula (I)
Objective
To screen for % inhibition and/or perform IC50 for compounds of the present invention against CDK4 enzyme using ADP-Glo kinase assay.
Kit:
ADP-glow kinase kit was used for the CDK4 enzyme assay.
ADP-Glo Kinase assay protocol Kinase Assay has 3 steps: a) Enzymatic reaction, b) ATP-Depletion c) Kinase detection. The following protocol is designed for a 384-well plate using a 1:1:2 ratio for the 3 steps, respectively. a) Enzymatic reaction:
• Total volume of kinase reaction was 5pL. 1 pL of DMSO/drug (diluted in Kinase buffer as 5X) and final concentration in the well was IX. 2 pL enzyme (prepared in kinase buffer as 20 ng / pL). 2 pL ATP (2.5 x prepared in Kinase buffer)/substrate (Rb protein) so that the final concentration of ATP/well was 100 pM and Rb protein per well was 0.005 pg.
• lpL of 5X concentration of test compound was added to each well. For control wells (Blank and Enzyme Blank), lpL of DMSO prepared in IX buffer was added. Final concentration of DMSO in all the wells was maintained at 0.5 %.
• 2pL (20 ng/pl) of CDK4/cyclin D3 enzyme was added to Enzyme blank and drug treatment wells. 2pL of IX kinase reaction buffer was added to the control (Blank) wells. Centrifuged the plate for 10 seconds and incubated at room temperature for 15 minutes.
• 2pL of ATP (2.5X) + Substrate (Rb protein) solution was added to each well (Final concentration of ATP/well was 100 pM and Rb protein was 0.005 pg).
• Centrifuged the plate for 10 seconds and incubated at room temperature for 60 minutes. b) ATP-Depletion:
• ADP-glo reagent was thawed to room temperature before use.
• 5pL of ADP-Glo Reagent was added to stop the kinase reaction to deplete the unconsumed ATP. Centrifuged the plate for 10 seconds and incubated at room temperature for 40 minutes. c) Kinase detection:
• Kinase detection buffer was thawed to room temperature before use.
• 10 pL of Kinase Detection Reagent was added to convert ADP to ATP and introduce luciferase and luciferin to detect ATP.
• The plate was incubated at room temperature for 30 minutes.
• Luminescence was recorded using BMG Labtech, FLUOstar Omega.
Calculation for screening:
1) Average for each well calculated 2) Average of Blank wells was subtracted from Average of each enzyme blank and treatment well.
3) Average of blank subtracted wells was calculated
4) % inhibitions were calculated based on the below formula
: 100-(Average of blank subtracted treatment well* 100)/ (Average of blank subtracted Enzyme Blank wells)
5) For IC50 calculations, Average blank subtracted values were used for plotting IC50 curve using GraphPad Prism.
Example-D
CDK6 Enzyme Assay protocol for screening or IC50 determination of compounds of formula (I):
Objective
To screen for % inhibition and/or perform IC50 for compounds of the present invention against CDK6 enzyme using ADP-Glo kinase assay.
Kit
ADP-glow kinase kit was used for the CDK6 enzyme assay. Kit components included kinase detection reagent, ADP-glo reagent, ATP, substrate (Histone) and CDK6 enzyme. All the reagents were prepared and stored according to manufacturer’s instructions.
ADP-Glo Kinase assay protocol
Kinase Assay has 3 steps: a) Enzymatic reaction, b) ATP-Depletion c) Kinase detection. The following protocol is designed for a 384-well plate using a 1:1:2 ratio for the 3 steps, respectively. a) Enzymatic reaction:
• Total volume of kinase reaction was 5pL. 1 pL of DMSO/drug (diluted in Kinase buffer as 5X) and final concentration in the well was IX. 2 pL enzyme (prepared in kinase buffer as 10 ng / pL). 2 pL ATP (2.5 x prepared in Kinase buffer)/substrate (Histone) so that the final concentration of ATP/well was 250 pM and Histone per well was 0.025 pg • 1 pL of 5X concentration of test compound was added to each well. For control wells (Blank and Enzyme Blank), 1 pL of DMSO prepared in IX buffer was added. Final concentration of DMSO in all the wells was maintained at 0.5 %.
• 2 pL (10 ng/pl) of CDK6/cycbn D3 enzyme was added to Enzyme blank and drug treatment wells. 2 pL of IX kinase reaction buffer was added to the control (Blank) wells.
• Centrifuged the plate for 10 seconds and incubated at room temperature for 15 minutes.
• 2 pL of ATP (2.5X) + Substrate solution was added to each well (Final concentration of ATP/well was 250 pM and histone was 0.025 pg.
• Centrifuged the plate for 10 seconds and incubated at room temperature for 60 minutes. b) ATP-Depletion:
• ADP-glo reagent was thawed to room temperature before use.
• 5 pL of ADP-Glo Reagent was added to stop the kinase reaction to deplete the unconsumed ATP.
• Centrifuged the plate for 10 seconds and incubated at room temperature for 40 minutes. c) Kinase detection:
• Kinase detection buffer was thawed to room temperature before use.
• 10 pL of Kinase Detection Reagent was added to convert ADP to ATP and introduce luciferase and luciferin to detect ATP.
• The plate was incubated at room temperature for 30 minutes.
• Luminescence was recorded using BMG Labtech, FLUOstar Omega.
Calculation for screening:
1) Average for each well calculated
2) Average of Blank wells was subtracted from Average of each enzyme blank and treatment well.
3) Average of blank subtracted wells was calculated
4) % inhibitions were calculated based on the below formula : 100-(Average of blank subtracted treatment well* 100)/ (Average of blank subtracted Enzyme Blank wells)
5) For IC50 calculations, Average blank subtracted values were used for plotting IC50 curve using GraphPad Prism.
Results: % inhibitions values are given below in table-2 and 3 and IC50 values are given below in table-4:
Example-E
Cell Proliferation assay protocol in breast cancer cell line for screening for GI50 for selected compounds of formula (I)
Objective:
To perform cell proliferation assay in Breast Cancer cell line (ZR.75.1, MCF-7, and MDA-MB-231) to determine the GBo for the selected compounds of the present invention using MTT assay.
Method: MTT assay (3— 2,5-diphenyltetrazolium bromide)
Procedure: The cells were processed, pelleted, and counted. Cells were plated in 100 mΐ/well in complete media in a 96-well plate in triplicates at desired density and plates were incubated at 37 °C and 5% CO2. Cells in each well were treated with the inhibitor dilutions prepared in complete media, in triplicates and plates were incubated at 37 °C and 5% CO2 for 144 h. After 144 h, 15 pL of 5 mg/mL (final concentration of IX) of MTT were added to the test wells and mixed well. Plates were incubated at 37 °C and 5% CO2 for 3.5 hours. After incubation, cells are pelleted down at 4000 rpm for 10 min. Media was aspirated and 150 pL of DMSO per well were added. Crystals were dissolved by repeated pipetting. Absorbance was read at A560 nm and A640 nm. GI50 values were calculated using GraphPad Prism.
Results: GI50 values were determined for the selected compounds of the invention below in the table 4.
Table-2
Figure imgf000160_0001
Table-3
Figure imgf000161_0001
Figure imgf000162_0001
% Inhibition: A represents >75% to 100%; B represents >50% to <75%; C represents >25% to <50% and D represents <25%;
Table-4
Figure imgf000163_0001
IC50: “+++-1-1-” represents 1 to <25nM; “++++” represents >25 to <50nM; “+++” represents >50 to <100nM; “++” is represents >100-<200nM, “+” represents >200nM;
GI50: “a” represents 100 to <200nM; “b” represents >200 to <500nM; “c” represents >500 to <1000nM; “d” is represents >1000-<10000nM, “e” represents >10000nM;
[337] Although the invention herein has been described with reference to embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above . It is intended that the appended claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
[338] All publications and patent and/or patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

We claim:
1. A compound of formula (I):
Figure imgf000165_0001
or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof or pharmaceutically acceptable salt thereof, wherein
Y1 is selected from CRa or N;
Y2 is selected from CRb or N; with the proviso that at least one of Y1 and Y2 is N; each occurrence of Ra, Rb, Rc, Rd, Re, Rf and Rg is independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aminoalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclylalkyl;
Y is selected from CRh or N;
Z is selected from CR1 or N; with the proviso that at least one of Y and Z is N; each occurrence of Rh and R1 is independently selected from hydrogen, halogen, substituted or unsubstituted Cp-3) alkyl, or substituted or unsubstituted C(i-3) haloalkyl;
X1 is selected from is CR1 or N; X2 is selected from is CR2 or N;
X3 is selected from is CR3 or N;
X4 is selected from is CR4 or N; each occurrence of R1, R2, R3, R4, R5 and R6 is independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclylalkyl;
L is absent, NH, O, S-, -SO-, -SO2-, -C(=0)-, or substituted or unsubstituted alkyl;
Ring A is substituted or unsubstituted heterocyclyl ring; each occurrence of R7 is independently selected from hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, oxo (=0), -C(=0)0Rz, -C(=0)Rz, -C(=S)RZ, -C(=0)NRzRz, -C(=0)0NRzRz, -NRZRZ,- NRzC(=0)NRzRz, -NRzS(=0)Rz, -NRzS(=0)2Rz, -N=NRZ, -NRzC(=0)0Rz, -NRzC(=0)Rz, - NRxC(=S)Ry -NRZC(=S)NRZRZ, -SONRzRz, -S02NRzRz, -ORz, -0C(=0)NRzRz, -0C(=0)0Rz, -0C(=0)Rz, -0C(=0)NRzRz, -CRxRy-NRzC(=0)Rz, -CRxRy-ORz, -CRxRy-C(=0)0Rz, - CRxRy -C(=0)NRzRz, -CRxRy -0C(=0)Rz, SRZ, -SORz, -S02Rz, -CRxRyC(=0)Rz, or - CRxRyC(=S)Rz;
Rz is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted heterocyclylalkyl, or substituted or unsubstituted amino, or any two of Rz when bound to a common atom may be joined to form (i) a substituted or unsubstituted saturated or unsaturated 3-14 membered ring, which may optionally include one or more heteroatoms which may be the same or different and are selected from O, NRza and S, or (ii) an oxo (=0), thio (=S) or imino (=NRza) group; wherein Rza, Rx, and Ry at each occurrence are independently selected from hydrogen, halo, hydroxy, amino, alkoxy, C1-5 alkyl, C3-7 cycloalkyl, C5-7 aryl, C5-7 heteroaryl, or C3-7 heterocycloalkyl; and n is an integer selected from 0, 1, 2, 3 and 4.
2. The compound of claim 1, wherein X1, X2, X3 and X4 are independently selected from CH orN.
3. The compound of claim 2, wherein X1 and X2 are N.
4. The compound of claim 2, wherein X1 is N.
5. The compound of claim 2, wherein X2, X3, and X4 are independently selected from CH.
6. The compound of claim 1, wherein Y and Z are independently selected from CH or N.
7. The compound of claim 6, wherein Y is N.
8. The compound of claim 6, wherein Z is N.
9. The compound of claim 1, wherein the compound of formula (IA), (IB), (IC), or (ID):
Figure imgf000167_0001
Figure imgf000168_0001
or a tautomer thereof, prodrug thereof, N-oxide thereof, stereoisomer thereof, pharmaceutically acceptable ester thereof or pharmaceutically acceptable salt thereof, wherein all the variables (including Ring A, L, R5, R6, R7, Rc, Rd, Re, Rf, Rg, Y1, Y2 and n) are as defined in formula (I).
10. The compound of any one of claims 1-9, wherein Ring A is selected from
Figure imgf000168_0002
Figure imgf000169_0001
11 The compound of any one of claims 1-10, wherein L is absent or Cth.
12. The compound of claim 11, wherein L is absent.
13. The compound of claim 11, wherein L is CTb.
14. The compound of any one of claims 1-13, wherein R5 is hydrogen or halogen.
15. The compound of claim 14, wherein R5 is hydrogen or fluorine.
16. The compound of any one of claims 1-15, wherein R6 is hydrogen.
17. The compound of any one of claims 1-16, wherein Y1 is N.
18. The compound of any one of claims 1-17, wherein ring
Figure imgf000169_0002
selected from
Figure imgf000170_0001
19. A compound selected from: tert-Butyl 4-(6-((5-fluoro-4-(quinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l- carboxylate;
5-Fluoro-N-(5-(piperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2 -amine;
5-Fluoro-N-(5-(piperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2 -amine hydrochloride;
Tert-Butyl 4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperazine - 1 -carboxylate ;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2 -amine;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2 -amine hydrochloride;
N-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2 -amine;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2 -amine hydrochloride;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2- amine; N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2- amine hydrochloride;
Tert-Butyl 4-(6-((5-fluoro-4-(8-fluoro-2-methyl-4-(prop-l-en-2-yl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3 -yl)piperazine - 1 -carboxylate ;
5-Fluoro-4-(8-fluoro-2 -methyl -4-(prop- 1 -en-2-yl)quinolin-6-yl)-N-(5-(piperazin- 1 -yl)pyridin- 2-yl)pyrimidin-2-amine;
5-Fluoro-4-(8-fluoro-2-methyl-4-(prop-l-en-2-yl)quinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin- 2-yl)pyrimidin-2 -amine hydrochloride ;
5-Fluoro-N-(5-(4-methylpiperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2 -amine ;
5-Fluoro-N-(5-(4-methylpiperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2 -amine hydrochloride;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-methylpiperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-methylpiperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine hydrochloride;
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2- amine;
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2- amine hydrochloride;
N-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6- yl)pyrimidin-2 -amine;
N-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6- yl)pyrimidin-2 -amine hydrochloride;
Tert-Butyl 4-(6-((5-fluoro-4-(8-fluoro-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)pyridin- 3 -yl)piperazine - 1 -carboxylate ;
5-Fluoro-4-(8-fluoro-2-methylquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine;
5-Fluoro-4-(8-fluoro-2-methylquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine hydrochloride; Tert-Butyl 4-(6-((5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3 -yl)piperazine - 1 -carboxylate ;
5-Fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine;
5-Fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine hydrochloride;
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine;
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(quinolin-6-yl)pyrimidin-2-amine hydrochloride;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylpiperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-isopropylpiperazin-l-yl)pyridin-2-yl)pyrimidin-2- amine hydrochloride;
5-Fluoro-N-(5-(4-isopropylpiperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2 -amine;
5-Fluoro-N-(5-(4-isopropylpiperazin-l-yl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2 -amine hydrochloride;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylpiperazin-l-yl)methyl)pyridin-2- yl)pyrimidin-2 -amine;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-((4-methylpiperazin-l-yl)methyl)pyridin-2- yl)pyrimidin-2 -amine hydrochloride;
2-(6-(2-((5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8- fluoro-2-methylquinolin-4-yl)propan-2-ol;
2-(6-(2-((5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8- fluoro-2-methylquinolin-4-yl)propan-2-ol hydrochloride;
Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)propan-2-ol; 2-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)propan-2-ol hydrochloride;
2-(6-(2-((5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2- methylquinolin-4-yl)propan-2-ol;
2-(6-(2-((5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-8-fluoro-2- methylquinolin-4-yl)propan-2-ol hydrochloride;
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4-ethylpiperazin-l-yl)pyridin- 2-yl) -5 -fluoropyrimidin-2 -amine ;
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-(4-ethylpiperazin-l-yl)pyridin- 2-yl)-5 -fluoropyrimidin-2 -amine hydrochloride;
Tert-butyl 4-(6-((4-(4-(difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoropyrimidin-2- yl)amino)pyridin-3 -yl)piperazine - 1 -carboxylate ;
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine;
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine hydrochloride;
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;
4-(4-(Difluoromethyl)-8-fluoro-2-methylquinolin-6-yl)-N-(5-((4-ethylpiperazin-l- yl)methyl)pyridin-2-yl)-5 -fluoropyrimidin-2 -amine hydrochloride ;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-(2-fluoropropan-2- yl)-2-methylquinolin-6-yl)pyrimidin-2 -amine;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-(2-fluoropropan-2- yl)-2-methylquinolin-6-yl)pyrimidin-2 -amine hydrochloride ;
Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-fluoropropan-2-yl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate;
5-Fluoro-4-(8-fluoro-4-(2-fluoropropan-2-yl)-2-methylquinolin-6-yl)-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine; 5-Fluoro-4-(8-fluoro-4-(2-fluoropropan-2-yl)-2-methylquinolin-6-yl)-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine hydrochloride;
5-Fluoro-N-(5-((4-methylpiperazin-l-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2- amine;
5-Fluoro-N-(5-((4-methylpiperazin-l-yl)methyl)pyridin-2-yl)-4-(quinolin-6-yl)pyrimidin-2- amine hydrochloride;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6- yl)pyrimidin-2 -amine;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(7-fluoroquinolin-6- yl)pyrimidin-2 -amine hydrochloride;
Tert-butyl 4-(6-((5-fluoro-4-(7-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperazine - 1 -carboxylate ;
5-Fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2 -amine;
5-Fluoro-4-(7-fluoroquinolin-6-yl)-N-(5-(piperazin-l-yl)pyridin-2-yl)pyrimidin-2 -amine hydrochloride;
N-(5 -(4-Ethylpiperazin- 1 -yl)pyridin-2-yl)-5 -fluoro-4-(7 -fluoroquinolin-6-yl)pyrimidin-2- amine;
N-(5 -(4-Ethylpiperazin- 1 -yl)pyridin-2-yl)-5 -fluoro-4-(7 -fluoroquinolin-6-yl)pyrimidin-2- amine hydrochloride;
N-(5-(4-(Dimethylamino)piperidin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2 -amine;
N-(5-(4-(Dimethylamino)piperidin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2 -amine hydrochloride;
4-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2-one;
4-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-2-one hydrochloride;
N-(5-(4-Cyclopropylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2 -amine; N-(5-(4-Cyclopropylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoroquinolin-6- yl)pyrimidin-2 -amine hydrochloride;
1 —(4— (6— ((5 -Fluoro-4-(8-fluoroquinohn-6-yl)pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 - yl)ethan-l-one;
1 —(4— (6— ((5 -Fluoro-4-(8-fluoroquinohn-6-yl)pyrimidin-2-yl)amino)pyridin-3 -yl)piperazin- 1 - yl)ethan-l-one hydrochloride;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(2,2,2-trifluoroethyl)piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine hydrochloride;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl)piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(4-(methylsulfonyl)piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine hydrochloride;
Cyclopropyl(4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperazin- 1 -yl)methanone;
Cyclopropyl(4-(6-((5-fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3- yl)piperazin- l-yl)methanone hydrochloride;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine;
5-Fluoro-4-(8-fluoroquinolin-6-yl)-N-(5-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)pyridin-2-yl)pyrimidin-2-amine hydrochloride;
N-(5-((4-Ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2- methylquinolin-6-yl)pyrimidin-2-amine;
N-(5-((4-ethylpiperazin-l-yl)methyl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2- methylquinolin-6-yl)pyrimidin-2 -amine hydrochloride ;
N-(5-(4-Ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin-
6-yl)pyrimidin-2 -amine ; N-(5-(4-ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-4-isopropyl-2-methylquinolin- 6-yl)pyrimidin-2 -amine hydrochloride ; l-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4- methylpiperidin-4-ol; l-(6-((5-Fluoro-4-(8-fluoroquinolin-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4- methylpiperidin-4-ol hydrochloride;
(±)-Tert-butyl 4-(6-((4-(4-( 1 -((tert-butoxycarbonyl)amino)ethyl)-8-fluoro-2-methylquinolin- 6-yl)-5 -fluoropyrimidin-2-yl)amino)pyridin-3 -yl)piperazine- 1 -carboxylate ;
(±)-4-(4-(l-Aminoethyl)-8-fluoro-2-methylquinohn-6-yl)-5-fluoro-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine;
(±)-4-(4-(l-Aminoethyl)-8-fluoro-2-methylquinohn-6-yl)-5-fluoro-N-(5-(piperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine hydrochloride;
(±)-Tert-butyl 4-(6-((4-(4-(l-((tert-butoxycarbonyl)amino)ethyl)-8-fluoroquinolin-6-yl)-5- fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate;
(±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine;
(±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperazin-l-yl)pyridin-2- yl)pyrimidin-2 -amine dihydrochloride;
(±)-Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3 -yl)piperazine - 1 -carboxylate ;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -(piperazin- 1 -yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -(piperazin- 1 -yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trimethanesulfonate;
(±)-Tert-butyl (l-(8-fluoro-6-(5-fluoro-2-((5-(4-methylpiperazin-l-yl)pyridin-2- yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethyl)carbamate;
(±)-4-(4-(l-aminoethyl)-8-fluoroquinobn-6-yl)-5-fluoro-N-(5-(4-methylpiperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine; (±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(4-methylpiperazin-l- yl)pyridin-2-yl)pyrimidin-2 -amine trihydrochloride;
(±)- 1 -(6-(2-((5 -(4-Ethylpiperazin- 1 -yl)pyridin-2-yl)amino)-5 -fluoropyrimidin-4-yl)-8- fluoroquinolin-4-yl)ethanol;
(±)- 1 -(6-(2-((5 -(4-Ethylpiperazin- 1 -yl)pyridin-2-yl)amino)-5 -fluoropyrimidin-4-yl)-8- fluoroquinolin-4-yl)ethanol trihydrochloride;
(±)-l-(8-fluoro-6-(5-fluoro-2-((5-(4-isopropylpiperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -(4-isopropylpiperazin- 1 -yl)pyridin-2-yl)amino)pyrimidin- 4-yl)quinolin-4-yl)ethanol trihydrochloride;
N-(5-(4-ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinohn-6- yl)pyrimidin-2 -amine;
N-(5-(4-ethylpiperazin-l-yl)pyridin-2-yl)-5-fluoro-4-(8-fluoro-2-methylquinolin-6- yl)pyrimidin-2 -amine hydrochloride;
(±)-Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-l-carboxylate;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -(piperazin- 1 -yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)ethanol;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -(piperazin- 1 -yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)ethan- 1 -ol hydrochloride;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(4-methylpiperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(4-methylpiperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trihydrochloride ;
Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3 -yl)piperazine - 1 -carboxylate ;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4- yl)propan-2-ol; 2-(8-Fluoro-6-(5-fluoro-2-((5-(piperazin-l-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4- yl)propan-2-ol;
(±)-Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3 -yl)piperazine - 1 -carboxylate ;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -(piperazin- 1 -yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -(piperazin- 1 -yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trihydrochloride ;
(±)-Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3 -yl)piperidine - 1 -carboxylate ;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trihydrochloride ;
Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2- yl)amino)pyridin-3 -yl)piperidine - 1 -carboxylate ;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4- yl)propan-2-ol;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)quinolin-4- yl)propan-2-ol trihydrochloride;
Tert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3 -yl)piperidine- 1 -carboxylate ;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)propan-2-ol;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)propan-2-ol trihydrochloride;
(±)-7ert-butyl 4-(6-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)-2-methylquinolin-6- yl)pyrimidin-2-yl)amino)pyridin-3 -yl)piperidine- 1 -carboxylate ; (±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)ethanol;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2- methylquinolin-4-yl)ethanol trihydrochloride;
Tert-butyl 4-(2-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2- yl)amino)pyrimidin-5 -yl)piperidine- 1 -carboxylate ;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinolin-
4-yl)propan-2-ol;
2-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)quinolin- 4-yl)propan-2-ol trihydrochloride;
(±)-7ert-butyl 4-(2-((5-fluoro-4-(8-fluoro-4-(l-hydroxyethyl)quinolin-6-yl)pyrimidin-2- yl)amino)pyrimidin-5 -yl)piperidine- 1 -carboxylate ;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol;
(±)-l-(8-Fluoro-6-(5-fluoro-2-((5-(piperidin-4-yl)pyrimidin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trihydrochloride ;
2-(8-Fluoro-6-(5-fluoro-2-((5-(l-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)propan-2-ol;
2-(8-Fluoro-6-(5-fluoro-2-((5-(l-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)propan-2-ol trihydrochloride;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -( 1 -methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol;
(±)- 1 -(8-Fluoro-6-(5 -fluoro-2-((5 -( 1 -methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4- yl)quinolin-4-yl)ethanol trihydrochloride ;
(±)-Tert-butyl 4-(6-((4-(4-(l-((tert-butoxycarbonyl)amino)ethyl)-8-fluoroquinolin-6-yl)-5- fluoropyrimidin-2-yl)amino)pyridin-3-yl)piperidine-l-carboxylate;
(±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperidin-4-yl)pyridin-2- yl)pyrimidin-2 -amine; (±)-4-(4-(l-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoro-N-(5-(piperidin-4-yl)pyridin-2- yl)pyrimidin-2 -amine trihydrochloride ; and pharmaceutically acceptable salts thereof.
20. A pharmaceutical composition comprising a compound of any one of claims 1-19 and a pharmaceutically acceptable carrier.
21. The pharmaceutical composition of claim 20, further comprising one or more additional therapeutic agents.
22. The pharmaceutical composition of claim 21, wherein the one or more additional therapeutic agents is an anti-cancer agent, anti-inflammatory agent, immunosuppressive agent, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, or any combination of any of the foregoing.
23. A method of inhibiting a catalytic activity of a CDK enzyme selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the foregoing present in a cell comprising contacting the cell with an effective amount of a compound of any one of claims 1-19.
24. The method of claim 23, wherein the inhibition takes place in a subject suffering from a disease or disorder which is cancer, a bone disorder, an inflammatory disease, an immune disease, a nervous system disease, a metabolic disease, a respiratory disease, thrombosis, or cardiac disease.
25. Use of a compound of any one of claims 1-19 in the manufacture of a medicament for the treatment of a disease, disorder, or condition that would benefit from inhibiting catalytic activity of a CDK enzyme selected from CDK1, CDK2, CDK4, CDK6, and any combination of any of the foregoing.
26. A method for the treatment of a disease, disorder, or condition associated with CDK1, CDK2, CDK4, CDK6, or any combination of any of the foregoing comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-19.
27. The method of claim 26, further comprising the step of administering simultaneously or sequentially to the subject at least one other anti-cancer agent, anti-inflammatory agent, immunosuppressive agent, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, or any combination of any of the foregoing.
28. The method of claim 26 or claim 27, wherein the disease, disorder or condition is an immune system-related disease, a disease or disorder involving inflammation, cancer or other proliferative disease, a hepatic disease or disorder, or a renal disease or disorder.
29. The method of claim 26 or claim 27, wherein the disease, disorder or condition is selected from inflammation, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation, graft rejection, graft-versus-host disease, lupus erythematosus, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis, atopic dermatitis, asthma, Sjogren's syndrome, organ transplant rejection, multiple sclerosis, Guillain-Barre, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti- phospholipid syndrome, vasculitides, Wegener's granulomatosis, Behcet's disease, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, vitiligo, Crohn's disease, colitis, ulcerative colitis, primary biliary cirrhosis, autoimmune hepatitis, Type 1 or immune -mediated diabetes mellitus, Grave's disease, Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, autoimmune disorder of the adrenal gland, systemic lupus erythematosus, polymyositis, dermatomyositis, ankylosing spondylitis, transplant rejection, skin graft rejection, arthritis, bone diseases associated with increased bone resorption, ileitis, Barrett's syndrome, adult respiratory distress syndrome, chronic obstructive airway disease; comeal dystrophy, trachoma, onchocerciasis, sympathetic ophthalmitis, endophthalmitis, gingivitis, periodontitis, tuberculosis, leprosy, uremic complications, nephrosis, sclerodermatitis, psoriasis, chronic demyelinating diseases of the nervous system, AIDS-related neurodegeneration, Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis viral or autoimmune encephalitis, autoimmune disorders, immune -complex vasculitis, systemic lupus and erythematodes, systemic lupus erythematosus (SLE), cardiomyopathy, ischemic heart disease hypercholesterolemia, atherosclerosis, preeclampsia, chronic liver failure, brain and spinal cord trauma, and cancer.
30. The method of claim 26 or claim 27, wherein the disease, disorder or condition is selected from hematopoietic tumors of lymphoid lineage, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma, hematopoietic tumors of myeloid lineage, acute myelogenous leukemias, chronic myelogenous leukemias, myelodysplastic syndrome, promyelocytic leukemia, carcinoma of the bladder, carcinoma of the breast, carcinoma of the colon, carcinoma of the kidney, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, squamous cell carcinoma, tumors of mesenchymal origin, fibrosarcoma, rhabdomyosarcoma, tumors of the central and peripheral nervous system, astrocytoma, neuroblastoma, glioma, schwannoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer, brain cancer and Kaposi's sarcoma.
31. The method of claim 26 or claim 27, wherein the disease, disorder or condition is selected from carcinoma of the breast, ovarian cancer, carcinoma of the liver, carcinoma of the lung, small cell lung cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, brain cancer or stomach cancer.
32. The method of claim 26 or claim 27, wherein the disease, disorder or condition is carcinoma of the breast or ovarian cancer.
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