WO2022113003A1 - Inhibiteurs de cdk - Google Patents

Inhibiteurs de cdk Download PDF

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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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fluoro
pyridin
pyrimidin
amino
amine
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Debnath Bhuniya
Srikant Viswanadha
Swaroop Kumar Venkata Satya VAKKALANKA
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Rhizen Pharmaceuticals AG
Incozen Therapeutics Pvt Ltd
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Rhizen Pharmaceuticals AG
Incozen Therapeutics Pvt Ltd
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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

La présente invention concerne des composés de formule (I) et des sels pharmaceutiquement acceptables de ceux-ci utilisés comme inhibiteurs de kinases dépendantes des cyclines (une ou plusieurs parmi CDK1, CDK2, CDK4 et CDK6), leurs procédés de préparation, et des compositions pharmaceutiques les contenant. Les composés de la présente invention sont utiles dans le traitement, la prévention et/ou l'amélioration de maladies ou de troubles associés à un ou plusieurs kinases parmi CDK1, CDK2, CDK4 et CDK6. (I)
PCT/IB2021/060994 2020-11-27 2021-11-26 Inhibiteurs de cdk Ceased WO2022113003A1 (fr)

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CN115124511A (zh) * 2022-07-28 2022-09-30 中国人民解放军北部战区总医院 他克林衍生物及其制备方法与作为cdk2/9抑制剂的应用
WO2022236257A1 (fr) * 2021-05-03 2022-11-10 Nuvation Bio Inc. Composés hétérocycliques utilisés comme inhibiteurs de kinase
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WO2024022487A1 (fr) * 2022-07-29 2024-02-01 Allorion Therapeutics Inc Inhibiteurs d'aminohétéroaryl kinase
WO2024088323A1 (fr) * 2022-10-27 2024-05-02 Beigene, Ltd. Composés de 6-(pyrimidin-4-yl)quinoléine substituée utilisés en tant qu'inhibiteurs de kinase dépendante des cyclines
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
WO2025247364A1 (fr) * 2024-05-30 2025-12-04 山东先声生物制药有限公司 Composé hétérocyclique utilisé en tant qu'inhibiteur de cdk et son utilisation
WO2026024674A1 (fr) 2024-07-22 2026-01-29 Genesis Therapeutics, Inc. Méthodes de traitement de cancers associés à skp2

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US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
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