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WO2025224249A1 - Compounds that mediate protein degradation and methods of use thereof - Google Patents

Compounds that mediate protein degradation and methods of use thereof

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Publication number
WO2025224249A1
WO2025224249A1 PCT/EP2025/061237 EP2025061237W WO2025224249A1 WO 2025224249 A1 WO2025224249 A1 WO 2025224249A1 EP 2025061237 W EP2025061237 W EP 2025061237W WO 2025224249 A1 WO2025224249 A1 WO 2025224249A1
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WIPO (PCT)
Prior art keywords
compound
cancer
pharmaceutically acceptable
acceptable salt
mmol
Prior art date
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Pending
Application number
PCT/EP2025/061237
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French (fr)
Inventor
Andreas RITZÉN
Thomas Ryckmans
Laura Ann Mcallister
Vladimiras OLEINIKOVAS
Bernhard FASCHING
Elisa Liardo
Beatrice RANIERI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Monte Rosa Therapeutics AG
Original Assignee
Monte Rosa Therapeutics AG
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Filing date
Publication date
Application filed by Monte Rosa Therapeutics AG filed Critical Monte Rosa Therapeutics AG
Publication of WO2025224249A1 publication Critical patent/WO2025224249A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the ubiquitin proteasome system can be manipulated with different small molecules to trigger targeted degradation of specific proteins of interest. Promoting the targeted degradation of pathogenic proteins using small molecule degraders is emerging as a new modality in the treatment of diseases.
  • One such modality relies on redirecting the activity of E3 ligases such as cereblon (a phenomenon known as E3 reprogramming) using low molecular weight compounds, which have been termed molecular glues, to promote the poly-ubiquitination and ultimately proteasomal degradation of new protein substrates involved in the development of diseases.
  • E3 ligases such as cereblon (a phenomenon known as E3 reprogramming) using low molecular weight compounds, which have been termed molecular glues, to promote the poly-ubiquitination and ultimately proteasomal degradation of new protein substrates involved in the development of diseases.
  • the molecular glues bind to both the E3 ligase and the target protein, thereby mediating an alteration of the ligase surface and enabling an interaction
  • WO 2023/069700, WO 2023/069720, and PCT/US2023/077781 describe compounds that mediate the degradation of cyclin-dependent kinase 2 (CDK2) and are thus useful in treating diseases. There exists a need for further therapeutics that mediate the degradation of CDK2.
  • CDK2 cyclin-dependent kinase 2
  • the inventors prepared a novel series of CDK2 degraders, which are provided in Table 1 herein. Therefore, described herein is a compound selected from Table 1 or a pharmaceutically acceptable salt thereof.
  • each of R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, halogen, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl (e.g., CF 3 ), and C1-6 haloalkoxy (e.g., OCF 3 );
  • ring A is selected from the group consisting of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl, wherein each of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to
  • a novel CDK2 degrader i.e. a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: i. a compound of Formula (I): wherein each variable is as defined above; or ii. a compound selected from Table 1.
  • described herein is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt described herein and one or more pharmaceutically acceptable excipients.
  • described herein is a method of treating cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein.
  • FIG. 1 shows results from an in vitro experiment to evaluate the effect of Compound 36 on proliferation of MDA-MB-157 breast, Kuramochi ovarian and MKN1 gastric cancer cells.
  • FIG. 2 shows results from an in vitro experiment to evaluate the effect of Compound 36 on the cell cycle of MDA-MB-157 breast, Kuramochi ovarian and MKN1 gastric cancer cells.
  • FIG. 3 shows results from an in vivo experiment to evaluate the pharmacokinetic effects of Compound 36 alone and in combination with ribociclib in a human hormone-receptor positive/HER2- negative breast cancer model.
  • FIG. 4 shows results from an in vivo experiment to evaluate the pharmacodynamic effects of Compound 36 alone and in combination with ribociclib in a human hormone-receptor positive/HER2- negative breast cancer model.
  • each of R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, halogen, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl (e.g., CF 3 ), and C1-6 haloalkoxy (e.g., OCF 3 );
  • ring A is selected from the group consisting of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl, wherein each of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more occurrences of R 5 ;
  • a compound, or a pharmaceutically acceptable salt thereof wherein the compound is: i. a compound of Formula (I): wherein: each of R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, halogen, CN, C1-6 alkyl, and C1-6 alkoxy; ring A is selected from the group consisting of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl, wherein each of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more occurrences of R 5 ; each occurrence of R 5 is independently selected from the group consisting of halogen, Ci- 6 alkyl, C1-6 alkoxy, C3-12 monocyclic
  • Tables 1 and 2 below include the compound number of each compound in accordance with the contents of the present specification.
  • the compound is a compound of Formula (I).
  • each occurrence of R 7 is H or C1-3 alkyl. In some embodiments, each occurrence of R 7 is H or CH3. [0020] In some embodiments, the compound of Formula (I) is a compound of Formula (II):
  • each of R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, halogen, and C1-6 alkyl. In some embodiments, each of R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, halogen, and C1-3 alkyl. In some embodiments, each of R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, F, Cl, and CH 3 .
  • ring A is C3-12 bicyclic cycloalkyl that is optionally substituted with one or more occurrences of R 5 . In some embodiments, ring A is C3-6 bicyclic cycloalkyl that is optionally substituted with one or more occurrences of R 5 . In some embodiments, ring A is bicyclo [l.l.l]pentyl that is optionally substituted with one or more occurrences of R 5 . In some embodiments, ring A is In some embodiments, ring A is . In some embodiments, ring
  • each occurrence of R 5 is C1-6 alkyl that is optionally substituted with one or more occurrences of R 6 . In some embodiments, each occurrence of R 5 is C1-3 alkyl that is optionally substituted with one or more occurrences of R 6 . In some embodiments, each occurrence of R 5 is CH 3 .
  • each occurrence of R 6 is halogen. In some embodiments, each occurrence of R 6 is F.
  • n 0.
  • the compound of Formula (I) is a compound of Formula (IA):
  • compound of Formula (I) is a compound of Formula (ID):
  • the compound of Formula (I) is selected from the group consisting some embodiments, the compound of Formula (I) is selected
  • the compound is a compound selected from Table 1.
  • the compound is a compound selected from Table 3.
  • Table 3
  • the compound is selected from Table 1 and is not a compound of
  • the compound is Compound 36. In some embodiments, the compound is Compound 78. In some embodiments, the compound is Compound 79.
  • a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt described herein and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprises an effective amount of the compound or pharmaceutically acceptable salt.
  • the pharmaceutical composition comprises a therapeutically effective amount of the compound or pharmaceutically acceptable salt.
  • compositions described herein may be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.
  • oral (enteral) administration parenteral (by injection) administration
  • rectal administration transdermal administration
  • intradermal administration intrathecal administration
  • SC subcutaneous
  • IV intravenous
  • IM intramuscular
  • intranasal administration e.g., IM administration
  • compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders.
  • the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.
  • a compound described herein is used to degrade
  • CDK2 in an ex vivo or in vitro system.
  • a compound described herein is used to degrade CDK2 in an ex vivo system.
  • a compound described herein is used to degrade CDK2 in an in vitro system.
  • Described herein is a method of degrading CDK2 comprising combining CDK2 and cereblon with a compound described herein in an ex vivo system or in vitro system.
  • the method comprises combining CDK2 and cereblon with a compound described herein in an ex vivo system.
  • the method comprises combining CDK2 and cereblon with a compound described herein in an in vitro system.
  • Cyclin dependent kinases are a family of closely related kinases that regulate progression through the cell cycle. CDK activity is further modulated by levels of specific cyclins; for example, cyclin El activates cyclin dependent kinase 2 (CDK2).
  • Mechanisms activating CDK2 in tumors are (i) amplification of cyclin El or cyclin E2, and (ii) loss of the AMBRA1 gene. Elimination of CDK2 is contemplated to treat such disorders.
  • the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein are contemplated as useful in the treatment or prevention of disorders in subjects in need thereof.
  • a compound or pharmaceutical composition described herein is used to degrade CDK2 in a subject.
  • a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein is used to degrade CDK2 for the treatment or prevention of a disorder.
  • described herein is a method of treating or preventing a disorder in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein.
  • the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered to degrade CDK2 in the subject.
  • described herein is a method of degrading CDK2 in a subject suffering from a disorder, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition described herein.
  • the compound binds to cereblon and a CDK2 protein to induce ubiquitination and subsequent proteasomal degradation of the CDK2 protein.
  • Exemplary disorders that can be treated or prevented by the methods of the present disclosure include, but are not limited to, cancer of the bladder, bone, brain, breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, upper aerodigestive tract (including nasal cavity and paranasal sinuses, nasopharynx or cavum, oral cavity, oropharynx, larynx, hypopharynx, and salivary glands), neck, ovaries, pancreas, prostate, rectum, skin, stomach, testis, throat, and uterus.
  • cancer of the bladder including, but are not limited to, cancer of the bladder, bone, brain, breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, upper aerodigestive tract (including nasal cavity and paranasal sinuses, nasopharynx or cavum, oral
  • exemplary disorders include, but are not limited to, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, e.g., neuroendocrine prostate cancer such as castration-resistant neuroendocrine prostate cancer (NEPC) and lung neuroendocrine tumors (Lu- NETs), rectal adenocarcinoma, colorectal cancer, including stage 3 and stage 4 colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, malignant melanoma, malignant mesothelioma, mal
  • the disorder is cancer.
  • the disorder is cancer that comprises a solid tumor.
  • the solid tumor is at least one of the group consisting of: uterine cancer (such as uterine carcinosarcoma and uterine corpus endometrial carcinoma), endometrial cancer, breast cancer, (such as breast invasive carcinoma and triple negative breast cancer, ER+ HER2- breast cancer, and HER2+ breast cancer), ovarian cancer (such as ovarian serous cystadenocarcinoma), stomach cancer (such as stomach adenocarcinoma), gastric cancer (such as gastrointestinal stromal cancer), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (such as B-cell lymphoma), sarcoma, esophageal cancer (such as esophageal carcinoma), bladder cancer (such as bladder urothelial carcinoma), lung cancer (such as lung squamous carcinoma and non-small cell lung cancer including
  • the solid tumor is at least one of the group consisting of: prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, and melanoma.
  • the disorder is cancer that is selected from the group consisting of: ovarian cancer, endometrial cancer, gastric cancer, esophaegeal cancer, breast cancer (such as triple negative breast cancer), and lung adenosarcoma.
  • the disorder is breast cancer, gastric cancer, or ovarian cancer.
  • the disorder is breast cancer or ovarian cancer.
  • the disorder is ovarian cancer.
  • the disorder is breast cancer.
  • the breast cancer is HR+ (hormone receptor positive) breast cancer.
  • the breast cancer is ER+ (estrogen receptor positive) breast cancer.
  • the breast cancer is HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer.
  • the breast cancer is ER+ HER2- breast cancer.
  • the cancer is triple negative breast cancer.
  • the disorder is cancer that comprises a liquid tumor.
  • the liquid tumor is at least one of the group consisting of: diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia/lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell/histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphom
  • DLBCL diffuse large B-cell lymph
  • the liquid tumor is at least one of the group consisting of: acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (such as follicular lymphoma, including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, and multiple myeloma.
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • DLBCL mantle cell lymphoma
  • Non-Hodgkin lymphoma such as follicular lymphoma, including relapsed or refractory NHL and recurrent follicular
  • described herein is a method of treating cancer (e.g., a cancer described herein) in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein.
  • described herein is a method of degrading CDK2 in a subject suffering from cancer (e.g., a cancer described herein), wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein.
  • described herein is a method of treating a solid tumor (e.g., a solid tumor described herein) in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein.
  • a solid tumor e.g., a solid tumor described herein
  • the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein.
  • a method of treating a liquid tumor e.g., a liquid tumor described herein
  • the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein.
  • the liquid tumor is that of a haematological cancer (e.g., a haematological cancer described herein).
  • the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered as a first-line therapy.
  • the subject to which the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered is a treatment-naive subject, i.e. a subject that has not yet been treated with the standard of care.
  • the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein can be administered as single agents or in combination with one or more additional therapeutic agents such as additional anticancer agents, in particular standard of care agents appropriate for the particular disorder (e.g., the particular cancer) to be treated. Therefore, in some embodiments, the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered in combination with an additional therapeutic agent, for example an additional anticancer agent.
  • the compounds, salts, or compositions of the invention may be for use in therapy in combination with an additional therapeutic agent, for example an additional anticancer agent.
  • a therapeutic agent for example an anticancer agent, may be for use in therapy with the compounds, salts, or compositions of the invention.
  • Additional anticancer agents that can be administered in the methods of the present disclosure include anticancer agents of the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and/or serine/threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immuno -oncology agents, and the like.
  • the additional anticancer agent may be an anticancer agent of one of the following classes: endocrine agents, PIK3CA inhibitors, antibody-drug conjugates, PLK1 inhibitors, Estrogen PROTAC, anti-angiogenesis agents, signal transduction inhibitors such as kinase inhibitors and cell cycle inhibitors, classical antineoplastic agents such as hormonal modulators, epigenetic modulators, immunomodulatory agents, and EGFR inhibitors.
  • the additional therapeutic agent is a CDK4/6 inhibitor such as palbociclib, ribociclib, abemaciclib, lerociclib, trilaciclib, dalpiciclib, birociclib,BPI-16350, or in each case a pharmaceutically acceptable salt thereof.
  • CDK4/6 inhibitor is palbociclib, ribociclib, abemaciclib, or in each case a pharmaceutically acceptable salt thereof.
  • the CDK4/6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof, or ribociclib or a pharmaceutically acceptable salt thereof.
  • the CDK4/6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof.
  • the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof such as ribociclib succinate. In some embodiments, the CDK4/6 inhibitor is abemaciclib or a pharmaceutically acceptable salt thereof.
  • additional therapeutic agents are particularly suitable when the disorder to be treated is breast cancer (such as HR+ breast cancer, ER+ breast cancer, HR+ HER2- breast cancer, or ER+ HER2- breast cancer).
  • the breast cancer has progressed despite treatment with a CDK4/6 inhibitor.
  • the breast cancer is resistant to treatment with a CDK4/6 inhibitor.
  • the subject with breast cancer is a treatment-naive subject.
  • the CDK4/6 inhibitor is administered in combination with endocrine therapy. In some embodiments, the CDK4/6 inhibitor is administered in combination with endocrine therapy and the endocrine therapy is administered in combination with a luteinising hormone- releasing hormone (LHRH) agonist.
  • the endocrine therapy is an estrogen receptor antagonist such as fulvestrant, or an aromatase inhibitor such as letrozole. In some embodiments, the endocrine therapy is fulvestrant.
  • the CDK4/6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof, or ribociclib or a pharmaceutically acceptable salt thereof, and is administered in combination with fulvestrant.
  • the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof and is administered in combination with fulvestrant.
  • the CDK4/6 inhibitor may be present in the form of a pharmaceutically acceptable salt.
  • ribociclib if present, may be in the form of a succinate salt, i.e. as ribociclib succinate.
  • the compound is Compound 36 and the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.
  • the compound is Compound 78 and the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.
  • the compound is Compound 79 and the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.
  • the additional anticancer agent is an endocrine agent such as an aromatase inhibitor, a SERD (Selective Estrogen-Receptor Downregulators), or a SERM (Selective Estrogen Receptor Modulator).
  • aromatase inhibitors include exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), and formestane.
  • SERDs include fulvestrant, SZ102, G1T48, RADI 901, elacestrant, GDC-9545, giredestrant, SAR439859, amcenestrant, AZD9833, camizestrant, LY3484356, Zn-c5, and D-0502.
  • SERMs include tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, apeledoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF 4227 (Cheisi).
  • the additional anticancer agent is a PIK3CA inhibitor such as alpelisib (PIQRAY), BEBT-908, BPI-21668, bupalisib, inavolisib, TQB-3525, RLY-2608, miransertib, MEN-1611, LOXO-783, HS-10352, HH-CYH33, gedatolisib, or fimepinostat.
  • PIK3CA inhibitor such as alpelisib (PIQRAY), BEBT-908, BPI-21668, bupalisib, inavolisib, TQB-3525, RLY-2608, miransertib, MEN-1611, LOXO-783, HS-10352, HH-CYH33, gedatolisib, or fimepinostat.
  • the additional anticancer agent is an antibody-drug conjugate such as Trastuzumab deruxtecan (Enhertu), Trastuzumab duocarmazine, Trastuzumab emtansine (Kadcyla), Upifitamab rilsodotin, mirvetuximab soravtansine, Tisotumab vedotin (Tivdak), Praluzatamab ravtansine, Sacituzumab govitecan or Sacituzumab Govitecan-hziy (Trodelvy), Datopotamab deruxtecan, Ladiratuzumab vedotin, Patritumab deruxtecan, STRO-002, MORab-202, DS-6000, Anetumab, avtansine, XMT-2056, or Disitamab Vedotin (RC48-ADC,
  • the additional anticancer agent is a PLK1 inhibitor such as onvansertib, B12536, BI6727, GSK461364A, TAK960, or rigosertib.
  • the additional anticancer agent is Estrogen PROTAC (ARV-471,
  • the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered in combination with a standard of care agent.
  • the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered in combination with endocrine therapy, for example, an agent such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.
  • the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered in combination with a chemotherapeutic agent, for example, docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, vinorelbine, or liposomal doxorubicin.
  • the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered in combination with an anti-HER2 agent, for example, trastuzumab or pertuzumab.
  • the additional therapeutic agent is carboplatin, ribociclib or a pharmaceutically acceptable salt thereof, fulvestrant, or a combination thereof.
  • the additional anticancer agent is an anti-angiogenesis agent such as an anti-angiogenesis agent selected from the group consisting of: VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, PKCb inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha- v/beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (matrix-metalloproteinase 9) inhibitors.
  • an anti-angiogenesis agent selected from the group consisting of: VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, PKCb inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha- v/beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (mat
  • Preferred anti-angiogenesis agents include sunitinib (SutentTM), bevacizumab (AvastinTM), axitinib (AG 13736), SU 14813 (Pfizer), and AG 13958 (Pfizer).
  • Further antiangiogenesis agents include vatalanib (CGP 79787), Sorafenib (NexavarTM), pegaptanib octasodium (MacugenTM), vandetanib (ZactimaTM), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (LucentisTM), NeovastatTM (AE 941), tetrathiomolybdate (CoprexaTM), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352), and CP-868,596 (Pfizer).
  • anti-angiogenesis agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (SelbexTM), and UCN 01 (Kyowa Hakko).
  • Yet further anti-angiogenesis agents include celecoxib (CelebrexTM), parecoxib (DynastatTM), deracoxib (SC 59046), lumiracoxib (PreigeTM), valdecoxib (BextraTM), rofecoxib (VioxxTM), iguratimod (CareramTM), IP 751 (invedus), SC-58125 (Pharmacia), and etoricoxib (ArcoxiaTM).
  • antiangiogenesis agents include exisulind (AptosynTM), salsalate (AmigesicTM), diflunisal (DolobidTM), ibuprofen (MotrinTM), ketoprofen (OrudisTM), nabumetone (RelafenTM), piroxicam (FeldeneTM), naproxen (AleveTM, NaprosynTM), diclofenac (VoltarenTM), indomethacin (IndocinTM), sulindac (ClinorilTM), tolmetin (TolectinTM), etodolac (LodineTM), ketorolac (ToradolTM), and oxaprozin (DayproTM).
  • anti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (MetastatTM), and PCK 3145 (Procyon).
  • anti-angiogenesis agents include ponatinib (Iclusig), BT1718, anlotinib, lenvatinib (Lenvima), tivozanib (Fotivda), dovitinib, brolucizumab (Beovu), aflibercept (Eylea), and faricimab.
  • antiangiogenesis agents include acitretin (NeotigasonTM), plitidepsin (aplidineTM), cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4 HPR), halofuginone (TempostatinTM), PanzemTM (2 ⁇ methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (RemovabTM), lenalidomide (RevlimidTM), squalamine (EVIZONTM), thalidomide (ThalomidTM), UkrainTM (NSC 631570), VitaxinTM (MED1522), and zoledronic acid (ZometaTM).
  • acitretin NeotigasonTM
  • plitidepsin aplidineTM
  • cilengtide EMD 121974
  • CA4P comb
  • the additional anticancer agent is a signal transduction inhibitor
  • Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors also include kinase inhibitors (such as tyrosine kinase inhibitors and serine/threonine kinase inhibitors) and cell cycle inhibitors.
  • signal transduction inhibitors include famesyl protein transferase inhibitors, EGF inhibitors, ErbB-1 (EGER), ErbB-2, pan erb, IGF 1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, inhibitors of the WNT pathway, and multitargeted kinase inhibitors.
  • signal transduction inhibitors examples include BMS 214662 (Bristol- Myers Squibb), lonafamib (SarasarTM), pelitrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCiM h-R3TM), panitumumab (VectibixTM), Vandetanib (ZactimaTM), pazopanib (SB 786034), ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer Ingelheim), and CerveneTM (TP 38).
  • BMS 214662 Bristol- Myers Squibb
  • SarasarTM lonafamib
  • pelitrexol AG 2037
  • matuzumab EMD 7200
  • nimotuzumab TheraCiM h-R3TM
  • panitumumab VectibixTM
  • Vandetanib Z
  • signal transduction inhibitors include gefitinib (IressaTM), cetuximab (ErbituxTM), erlotinib (TarcevaTM), trastuzumab (HerceptinTM), sunitinib (SutentTM), imatinib (GleevecTM), crizotinib (Pfizer), lorlatinib (Pfizer), dacomitinib (Pfizer), bosutinib (Pfizer), gedatolisib (Pfizer), canertinib (Cl 1033), pertuzumab (OmnitargTM), lapatinib (TycerbTM), pelitinib (EKB 569), miltefosine (MiltefosinTM), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T (NeuvengeTM), NeuVaxTM (E75 cancer vaccine), OsidemTM (IDM 1), mubrirt
  • signal transduction inhibitors include ABT 751 (Abbott), alvocidib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 112 (One Bio), BMS 387032 (Bristol-Myers Squibb), palbociclib (Pfizer), and AG 024322 (Pfizer).
  • the additional anticancer agent is a classical antineoplastic agent.
  • Classical antineoplastic agents include hormonal modulators such as hormonal, anti-hormonal, androgen agonist, androgen antagonist and anti-estrogen therapeutic agents, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing agents or gene activating agents, ribonucleases, proteosomics, Topoisomerase I inhibitors, Camptothecin derivatives, Topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (P ARP-1) inhibitors (such as talazoparib, olapariv, rucaparib, niraparib, iniparib, veliparib), microtubulin inhibitors, antibiotics, plant derived spindle inhibitors, platinum-coordinated compounds, gene therapeutic agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins.
  • HDAC histone deacetylase
  • antineoplastic agents include glucocorticoids such as dexamethasone, prednisone, prednisolone, methyl prednisolone, hydrocortisone, and progestins such as medroxyprogesterone, megestrol acetate (Megace), mifepristone (RU-486), Selective Estrogen Receptor Modulators (SERMs, such as tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, avaloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF 4227 (Cheisi)), Selective Estrogen-Receptor Downregulators (SERDs, such as fulvestrant, SZ102, G1T48, RADI 901, elacestrant,
  • SERMs Selective Estrogen-Receptor Modulators
  • antineoplastic agents include suberolanilide hydroxamic acid (SAHA, Merck Inc./Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M- 777, MS-275, pivaloyloxymethyl butyrate and PXD-101; Onconase (ranpimase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, irinotecan HC1 (Camptosar), lurtotecan, Orathecin (rubitecan, Supergen), SN-38, topotecan, camptothecin, 10-hydroxy camptothecin, 9-aminoearaptothec
  • antineoplastic cytotoxic agents include Abraxane (Abraxis Bio Science, Inc.), Batabulin (Amgen), EPO 906 (Novartis), Vinflunine (Bristol-Myers Squibb Company), actinomycin D, bleomycin, mitomycin C, neocarzinostatin (Zinostatin), vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxei (Taxotere), Ortataxel, paclitaxel (including Taxoprexin, a DHA/paciltaxel conjugate), cisplatin, carboplatin, Nedaplatin, oxaliplatin (Eloxatin), Satraplatin, Camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), Taxotere alitretinoin, Canfosfamide (TelcytaTM), DMX
  • antineoplastic agents include Advexin (ING 201), TNFerade (GeneVec, a compound which expresses TNF alpha in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Oblimersen, Genta), Combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, Pfizer Inc.), Provastatin (Pravachol, Bristol-Myers Squibb), Lovastatin (Mevacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin, Niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, and combinations thereof.
  • the additional anticancer agent is an epigenetic modulator such as an inhibitor of EZH2, SMARCA4, PBRM1, ARID1A, ARID2, ARID IB, DNMT3A, TET2, MLL1/2/3, NSD1/2, SETD2, BRD4, DOTIL, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1/2, or BCL6.
  • an epigenetic modulator such as an inhibitor of EZH2, SMARCA4, PBRM1, ARID1A, ARID2, ARID IB, DNMT3A, TET2, MLL1/2/3, NSD1/2, SETD2, BRD4, DOTIL, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1/2, or BCL6.
  • the additional anticancer agent is an immunomodulatory agent such as an inhibitor of CTLA-4 (for example, ipilimumab), PD-1 or PD-L1 (for example, pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab, or dosterlimab), LAG-3 (for example, relatlimab), TIM-3, TIGIT, 4-1BB, 0X40, GITR, or CD40, or a CAR-T-cell therapy.
  • CTLA-4 for example, ipilimumab
  • PD-1 or PD-L1 for example, pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab, or dosterlimab
  • LAG-3 for example, relatlimab
  • TIM-3 for example, TIGIT, 4-1BB, 0X
  • the additional anticancer agent is an EGFR inhibitor such as afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, or gefitinib, or an EGFR antibody such as cetuximab, panitumumab, or necitumumab.
  • an EGFR inhibitor such as afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, or gefitinib
  • an EGFR antibody such as cetuximab, panitumumab, or necitumumab.
  • the additional anticancer agent is an anticancer agent that is not an anticancer agent
  • EGFR inhibitor for example selected from MEK, including mutant MEK, inhibitors (trametinib, cobimetinib, binimetinib, selumetinib, refametinib); c-MET, including mutant c-Met, inhibitors (savolitinib, cabozantinib, foretinib), and MET antibodies (emibetuzumab); mitotic kinase inhibitors (CDK4/6 inhibitors such as palbociclib, ribociclib, abemacicilb, lerociclib, trilaciclib, dalpiciclib, birociclib, BPI-16350 and pharmaceutically acceptable salts of each of these); anti-angiogenic agents such as bevacizumab, nintedanib; apoptosis inducers such as Bcl-2 inhibitors e.g., venetoclax, obatoclax, navitoclax, and Mcl-1 inhibitors e
  • the additional anticancer agent is palbociclib (e.g., ibrance®), ribociclib, abemacicilb, tamoxifen, letrozole, olaparib (e.g., Lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g., xeloda®), regorafenib (e.g., stivarga®), afatinib (e.g., gilotrif®), osimertinib (e.g., tagrisso®), gefitinib (e.g., iressa®), erlotinib (e.g., tarceva®), ramucirumab (e.g., cyramza
  • palbociclib e
  • the EGFR inhibitor may be afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02, alflutinib (AST 2818), aumolertinib (formerly almonertinib) (HS10296), BBT-176, BI- 4020, BPI-361175, BPI-D0316, CH7233163, gilitertinib, icotinib, JND-3229, lazertinib, tonicib (EGF 816), avitinib, PCC-0208027, rezivertinib (BRI-77G1), TQB3804, zorifertinib (AZ-3759), or DZD9008; an EGFR antibody such as cetuximab, panitumumab, necitumuma
  • the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered in combination with a CDK4/6 inhibitor. Accordingly, described herein are the products set out below.
  • kits comprising (i) a unit dosage form comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a compound selected from Table 1 or a pharmaceutically acceptable salt thereof, and, separately, (ii) a unit dosage form comprising a CDK4/6 inhibitor.
  • each unit dosage form is a pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients.
  • the unit dosage forms are present in a single package. In some embodiments, the unit dosage forms are present in separate packages.
  • described herein is a method of treating cancer in a subject in need thereof using the combination or kit described above.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a compound selected from Table 1 or a pharmaceutically acceptable salt thereof together with instructions to use the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the compound selected from Table 1 or pharmaceutically acceptable salt thereof, in combination with a CDK4/6 inhibitor.
  • the instructions specify use of the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the compound selected from Table 1 or pharmaceutically acceptable salt thereof, in combination with the CDK4/6 inhibitor for the treatment of a disorder (e.g., cancer).
  • the instructions specify simultaneous, separate, or sequential use of the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the compound selected from Table 1 or pharmaceutically acceptable salt thereof, and the CDK4/6 inhibitor.
  • the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the compound selected from Table 1 or pharmaceutically acceptable salt thereof is in a unit dosage form.
  • the unit dosage form is a pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients.
  • CDK4/6 inhibitor together with instructions to use the
  • the instructions specify use of the CDK4/6 inhibitor in combination with the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the compound selected from Table 1 or pharmaceutically acceptable salt thereof, for the treatment of a disorder (e.g., cancer).
  • the instructions specify simultaneous, separate, or sequential use of the CDK4/6 inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the compound selected from Table 1 or pharmaceutically acceptable salt thereof.
  • the CDK4/6 inhibitor is in a unit dosage form.
  • the unit dosage form is a pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients.
  • the instructions may be of the kind that are provided to a doctor, for example on a drug product label, or they may be of the kind that is provided to a patient, for example by a doctor.
  • C1-6 alkyl is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, Ci- 4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
  • Compounds that are described as being “optionally substituted” may be substituted with one or more specifically described groups or may be unsubstituted. In some embodiments, compounds that are described as being “optionally substituted” are unsubstituted.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group.
  • an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”).
  • an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”).
  • an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”).
  • an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”).
  • an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”).
  • an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”).
  • C1-6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl- 2-butanyl (C5), tertiary amyl (C5), and n-hexyl (Ce).
  • Additional examples of alkyl groups include n- heptyl (C7), n-octyl (Cs), and the like.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having one or more carbon-carbon double bonds.
  • an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”).
  • an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1- butenyl).
  • Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like.
  • Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds).
  • an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”).
  • an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2- butynyl) or terminal (such as in 1-butynyl).
  • C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.
  • Examples of C2-6 alkynyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like.
  • Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like.
  • cycloalkyl refers to a radical of a saturated or partially unsaturated cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C3-12 cycloalkyl”) and zero heteroatoms in the ring system.
  • a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”).
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”).
  • Exemplary C3-6 cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), bicyclo [1.1.
  • C5 cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like.
  • Exemplary C3-8 cycloalkyl groups include, without limitation, the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like.
  • Exemplary C3-10 cycloalkyl groups include, without limitation, the aforementioned C3-8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like.
  • the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contains a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) or tricyclic system (“tricyclic cycloalkyl”).
  • “Cycloalkyl” includes ring systems wherein the cycloalkyl ring as defined above is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the cycloalkyl ring or the one or more aryl or heteroaryl groups, and in such instances, the number of carbons continues to designate the number of carbons in the cycloalkyl ring system.
  • heterocyclyl refers to a radical of a saturated or partially unsaturated 3 to 10-membered ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3 to 10 membered heterocyclyl”).
  • heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”).
  • heterocyclyl in heterocyclyl bicyclic ring systems, the one or more heteroatoms can be present in one ring or both rings.
  • “Heterocyclyl” includes ring systems wherein the heterocyclyl ring as defined above is fused with one or more cycloalkyl groups wherein the point of attachment is either on the heterocyclyl ring or the one or more cycloalkyl groups, and ring systems wherein the heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring or the one or more aryl or heteroaryl groups, and in such instances, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system.
  • a heterocyclyl group is a 5 to 10 membered saturated or partially unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 10 membered heterocyclyl”).
  • a heterocyclyl group is a 5 to 8 membered saturated or partially unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 8 membered heterocyclyl”).
  • a heterocyclyl group is a 5 to 6 membered saturated or partially unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 6 membered heterocyclyl”).
  • the 5 to 6 membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5 to 6 membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5 to 6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3 -membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl- 2, 5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8- membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl.
  • Exemplary 5 -membered heterocyclyl groups fused to a Ce aryl ring include, without limitation, indolinyl, isoindo linyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 it electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce- 14 aryl”).
  • an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl).
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.
  • Particularly aryl groups include pheny
  • heteroaryl refers to a radical of a 5 to 10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 it electrons shared in a cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5 to 10 membered heteroaryl”).
  • heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • the one or more heteroatoms can be present in one or both rings.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring as defined above is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroatom e.g., 2-indolyl
  • a heteroatom e.g., 5-indolyl
  • a heteroaryl group is a 5 to 10 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 10 membered heteroaryl”).
  • a heteroaryl group is a 5 to 8 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 8 membered heteroaryl”).
  • a heteroaryl group is a monocyclic 5 to 6 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 6 membered heteroaryl”).
  • the 5 to 6 membered heteroaryl has 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the 5 to 6 membered heteroaryl has 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the 5 to 6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • a heteroaryl group is a monocyclic 5 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-membered heteroaryl”).
  • a heteroaryl group is a monocyclic 6 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“6-membered heteroaryl”).
  • a heteroaryl group is a 5 to 10 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“5 to 10 membered heteroaryl”).
  • a heteroaryl group is a 5 to 8 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“5 to 8 membered heteroaryl”).
  • a heteroaryl group is a monocyclic 5 to 6 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“5 to 6 membered heteroaryl”).
  • the 5 to 6 membered heteroaryl has 1 to 3 ring heteroatoms that are independently nitrogen or oxygen.
  • the 5 to 6 membered heteroaryl has 1 to 2 ring heteroatoms that are independently nitrogen or oxygen.
  • the 5 to 6 membered heteroaryl has 1 ring heteroatom that is independently nitrogen or oxygen.
  • a heteroaryl group is a monocyclic 5 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“5 -membered heteroaryl”).
  • a heteroaryl group is a monocyclic 6 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“6- membered heteroaryl”).
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5 -membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • alkoxy refers to the group -OR 100 where R 100 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • Other exemplary alkoxy groups are lower alkoxy groups, i.e. alkoxy groups with between 1 and 6 carbon atoms. In some embodiments, alkoxy groups have between 1 and 4 carbon atoms.
  • halogen refers to F, Cl, Br, or I.
  • haloalkyl refers to an alkyl group substituted with one or more halogen atoms, e.g., one or more F atoms.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms, e.g., one or more F atoms.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge el al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (Ci-4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys and rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms “human,” “patient,” and “subject” are used interchangeably herein.
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition.
  • the present disclosure contemplates administration of the compounds described herein as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition.
  • the “effective amount” of a compound as used herein refers to an amount sufficient to elicit the desired biological response.
  • the effective amount of a compound of the present disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.
  • a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (z.e., as (+) or (-)- isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • Isomers e.g., stereoisomers
  • HPLC high pressure liquid chromatography
  • preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L.
  • the present disclosure additionally encompasses compounds and pharmaceutically acceptable salts described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
  • the compounds and pharmaceutically acceptable salts described herein can be administered as the sole active agent, or they can be administered in combination with other active agents.
  • the present invention provides a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration.
  • the present disclosure in an alternative embodiment, also embraces isotopically labeled compounds and pharmaceutically acceptable salts which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • the compounds and pharmaceutically acceptable salts of the present disclosure may have one or more, or all H atoms replaced with deuterium.
  • Scheme A provides a specific exemplary synthetic strategy for the preparation of a compound of Formula A where substituted halogenated-oxadiazole AB is comprised of any suitable substituent which provides a compound of Formula A.
  • Formula A is an alternative depiction of Formula (I).
  • Compounds of Formula A may be prepared by coupling AT and AB via a SnAr reaction, for example by treatment with a base such as DIPEA (diisopropylethylamine) in a solvent such as N.N- dimethylacetamide. The reaction may be performed at an elevated temperature such as 100-110 degrees Celsius.
  • DIPEA diisopropylethylamine
  • An aryl primary amine AU where Hal is a suitable halogen atom (e.g., Br) may be converted into AV using any suitable conjugated addition reaction conditions.
  • the specific groups R 1 , R 2 , R 3 , and R 4 are selected on the basis of the desired groups in the compound of Formula A.
  • the desired compound AV can be prepared using a,P-unsaturated amides reagents such as acrylamide.
  • a solvent such as acetic acid may be used.
  • the reaction may be performed at elevated temperatures, such as 110 degrees Celsius.
  • AV may be converted into AW by a cyclization reaction using appropriate reagents, such as di(l/f-imidazol-l-yl)methanone, in the presence of a base such as triethylamine.
  • a solvent such as A'A'-dimcthyl formamide may be used.
  • the reaction may be performed at an elevated temperature, such as 80-120 degrees Celsius.
  • AW may be converted into AZ by a Buchwald-Hartwig reaction of a secondary amine of formula AF.
  • AZ may be prepared under an inert atmosphere using palladium catalysts such as PEPPSI- IHetp Cl and RuPhos Pd G3 in the presence of a base such as caesium carbonate.
  • a solvent such as dioxane may be used. The reaction may be performed at 100 degrees Celsius.
  • AW may be converted into AZ by a photochemical reaction using an appropriate catalytic system, such as [Ir(dtbbpy)(ppy)2]PFe and Nickel(II) bromide ethylene glycol dimethyl ether complex, in the presence of a base, such as l,4-diazabicyclo[2.2.2]octane.
  • a catalytic system such as [Ir(dtbbpy)(ppy)2]PFe and Nickel(II) bromide ethylene glycol dimethyl ether complex
  • a base such as l,4-diazabicyclo[2.2.2]octane.
  • An appropriate source of irradiation for example at 455 nm, must be used.
  • a solvent such as A'A'-dimcthylacctamidc may be used.
  • the reaction may be performed at 25 degrees Celsius.
  • Scheme C provides a general synthetic approach to the preparation of compounds of formula AB which may be used as starting material AB in Scheme A.
  • An appropriate carboxylic acid BA may be converted into compound BB, where PG is any suitable protecting group such as tert- butoxycarbonyl group.
  • Appropriate reagents such as Zcrt-butyl A'-aminocarbamatc and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, may be used.
  • a solvent such as dichloromethane may be used.
  • the reaction may be performed at 25 degrees Celsius.
  • Any appropriate acid reagent such as trifluoroacetic acid may be used.
  • a solvent such as dichloromethane may be used.
  • the reaction may be performed at an elevated temperature such as 25 degrees Celsius.
  • BC may be converted into intermediate BD using appropriate reagents, such as di(l/f-imidazol-l-yl)methanimine or cyanic bromide.
  • a solvent or a mixture of solvents such as tetrahydrofuran, methanol or dioxane/water may be used.
  • the reaction may be performed at 25-65 degrees Celsius.
  • AB may be prepared from BD using an appropriate Cu(I) or Cu(II) salt (e.g., CuBr or CuBr2) in the presence of tert-butyl nitrite.
  • a solvent such as acetonitrile may be used.
  • the reaction may be performed at 60-80 degrees Celsius.
  • Scheme D provides an alternative general synthetic approach to the preparation of compounds of formula AB which may be used as starting material AB in Scheme A.
  • An appropriate carboxylic acid BA may be converted into BE, where R B is any suitable group such as methyl or ethyl.
  • Appropriate reagents such as thionyl chloride, may be used.
  • the reaction may be performed at 25-60 degrees Celsius.
  • BC may be prepared from BE by treatment with an appropriate reagent such as hydrazine hydrate.
  • a solvent such as methanol or ethanol may be used.
  • the reaction may be performed at 60-80 degrees Celsius.
  • BC may be converted into intermediate BD using appropriate reagents, such as di( I //-imidazol-l -yljmcthaniminc or cyanic bromide.
  • appropriate reagents such as di( I //-imidazol-l -yljmcthaniminc or cyanic bromide.
  • a solvent or a mixture of solvents such as tetrahydrofuran, methanol or dioxane/water may be used.
  • the reaction may be performed at 25-65 degrees Celsius.
  • AB may be prepared from BD using an appropriate Cu(I) or Cu(II) salt (e.g., CuBr or CuBr2) in the presence of tert-butyl nitrite.
  • a solvent such as acetonitrile may be used.
  • the reaction may be performed at 60-80 degrees Celsius.
  • Scheme E provides a specific exemplary synthetic strategy for the preparation of a compound of Formula B where substituted halogenated-oxadiazole AB is comprised of any suitable substituent which provides a compound of Formula B.
  • Formula B is equivalent to Formula A with a glutarimide ring replacing the dihydrouracil ring, and encompasses the compounds provided in Table 1.
  • Compounds of Formula B may be prepared by coupling AA and AB via a SnAr reaction.
  • a SnAr reaction For example, by treatment with a base such as DIPEA (diisopropylethylamine) in a solvent such as N.N- dimethylacetamide.
  • the reaction may be performed at an elevated temperature such as 100-110 degrees Celsius.
  • a general synthetic strategy that may be used to prepare starting materials of general structure AA is depicted in Scheme F.
  • An aryl halide AC where Hal is a suitable halogen atom (e.g., I) and Hal' is a suitable halogen atom (e.g., Br) may be coupled with boronic acid AD, where PG isa suitable protecting group (for example, benzyl), using any suitable metal catalyzed coupling conditions.
  • the specific groups R 1 , R 2 , R 3 , and R 4 are selected on the basis of the desired groups in the compound of Formula B.
  • Compounds of general structure AE can be prepared using a Suzuki coupling reaction with palladium catalyst complex such as palladium catalyst (Pd(PPhs)4 or Pd(dppf)C12) in the presence of a base such as potassium carbonate.
  • a base such as potassium carbonate.
  • a solvent mixture such as dioxane and water may be used.
  • the reaction may be performed at an elevated temperature, such as 90-100 degrees Celsius.
  • AE may be converted into AG by a Buchwald-Hartwig reaction of a secondary amine of formula AF, where PG' is a suitable protecting group (for example, ZcrZ-butoxycarbonyl).
  • the compound can be prepared under an inert atmosphere using palladium catalysts such as PEPPSI-IHetp Cl and RuPhos Pd G3 in the presence of a base such as caesium carbonate.
  • a solvent such as dioxane may be used.
  • the reaction may be performed at 100 degrees Celsius.
  • a solvent such as dioxane can be used.
  • the reaction may be performed at 30-50 degrees Celsius.
  • Scheme G provides an alternative exemplary synthetic procedure for the preparation of starting material AA used in Scheme E.
  • An aryl primary amine Al may be halogenated to AL, where Hal is a suitable halogen atom (e.g., Br), using any suitable halogenating reagent conditions.
  • the specific groups R 1 , R 2 , R 3 , and R 4 are selected on the basis of the desired groups in AA.
  • the desired compound AL can be prepared by a halogenation reaction with reagents such as A-bromo-succinimide. A solvent such as acetonitrile may be used. The reaction may be performed at 20-25 degrees Celsius.
  • AL may be converted into AJ by a Suzuki reaction of boronate AD, where PG is a suitable protecting group (e.g., a benzyl group), with palladium catalyst complexes such as Pd(PPh 3 ) 4 in the presence of a base such as potassium carbonate.
  • PG is a suitable protecting group (e.g., a benzyl group)
  • palladium catalyst complexes such as Pd(PPh 3 ) 4
  • a solvent mixture such as dioxane and water may be used.
  • the reaction may be performed at an elevated temperature, such as 90-100 degrees Celsius.
  • Compound AE where Hal' is a suitable halogen atom (e.g., Br) may be prepared from AJ via a Sandmeyer reaction using appropriate reagents such as CuBr and ZcrZ-butyl nitrite. A solvent such as acetonitrile may be used. The reaction may be performed at 60 degrees Celsius.
  • AE may be converted into AG by a Buchwald-Hartwig reaction of a secondary amine of formula AF, where PG' is a suitable protecting group (e.g., tert-butoxycarbonyl).
  • AE can be prepared under an inert atmosphere using palladium catalysts such as PEPPSI-IHetp Cl and RuPhos Pd G3 in the presence of a base such as caesium carbonate.
  • a base such as caesium carbonate.
  • a solvent such as dioxane may be used. The reaction may be performed at 100 degrees Celsius.
  • a solvent such as dioxane can be used.
  • the reaction may be performed at 30-50 degrees Celsius.
  • Scheme H provides a general synthetic approach to the preparation of compounds of general structure AD which may be used as starting material in Schemes F and G.
  • Compound AK where Hal is any suitable halogen atom (e.g., Cl) may be converted into compound AM, where PG is any suitable protecting group such as a benzyl group.
  • a solvent such as tetrahydrofuran may be used. The reaction may be performed at 20-70 degrees Celsius.
  • Compound AN where Hal' is any suitable halogen atom (e.g., Br) may be prepared from compound AM by a halogenation reaction.
  • Appropriate reagents such as A-bromo -succinimide may be used.
  • a solvent such as acetonitrile may be used.
  • the reaction may be performed at an elevated temperature such as 80 degrees Celsius.
  • Compound AN may be converted into intermediate AD by a borylation reaction.
  • Appropriated reagents, such as triisopropylborate and n -butyllithium, may be used.
  • a solvent such as tetrahydrofuran may be used.
  • the reaction may be performed at low temperature such as minus 78 degrees Celsius.
  • Scheme I provides an alternative exemplary synthetic procedure for the preparation of starting material AA used in Scheme E.
  • a substituted toluene AO where Hal is a suitable halogen atom (e.g., Br) may be converted into AP, where Hal' is a suitable halogen atom (e.g., Br), using any suitable halogenating reagent conditions.
  • the specific groups R 1 , R 2 , R 3 , and R 4 are selected on the basis of the desired groups in the compound of Formula B.
  • AP can be prepared using a halogenating reagent such as A-bromosuccinimide in combination with a reagent such as benzoic peroxyanhydride or AIBN (azobisisobutyronitrile).
  • a solvent such as carbon tetrachloride may be used.
  • the reaction may be performed at elevated temperatures, such as 80 degrees Celsius.
  • AP may be converted into AQ using appropriate reagents, such as potassium cyanide or trimethylsilyl cyanide in combination with tetrabutylammonium fluoride.
  • appropriate reagents such as potassium cyanide or trimethylsilyl cyanide in combination with tetrabutylammonium fluoride.
  • a solvent such as acetonitrile, or a mixture of solvents, such as ethanol/water, may be used.
  • the reaction may be performed at a temperature such as 20 or 80 degrees Celsius.
  • Compounds of general structure AR may be prepared from AQ by a conjugated addition using an appropriate reagent, such as tert-butyl acrylate or methyl acrylate, in the presence of a base, such as sodium methoxide.
  • a base such as sodium methoxide.
  • a solvent such as tetrahydrofuran may be used.
  • the reaction may be performed at 0 to 20 degrees Celsius.
  • AR may be converted into AS by treatment in an appropriate acidic medium such as a mixture of acetic acid and sulfuric acid. The reaction may be performed at elevated temperatures such as 90 degrees Celsius.
  • AS may be converted into AH by a Buchwald-Hartwig reaction of a secondary amine of formula AF.
  • AS can be prepared under an inert atmosphere using palladium catalysts such as PEPPSI- IHetp Cl and RuPhos Pd G3 in the presence of a base such as caesium carbonate.
  • a solvent such as dioxane may be used.
  • the reaction may be performed at elevated temperatures such as 100 degrees Celsius.
  • each of R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, halogen, CN, C1-6 alkyl, and C1-6 alkoxy;
  • ring A is selected from the group consisting of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl, wherein each of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more occurrences of R 5 ; each occurrence of R 5 is independently selected from the group consisting of halogen, Ci- 6 alkyl, C1-6 alkoxy, C3-12 monocyclic
  • R 7 The compound or pharmaceutically acceptable salt of embodiment 11, wherein The compound or pharmaceutically acceptable salt of any one of embodiments 1-13, wherein each of R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, halogen, CN, C1-3 alkyl, and C1-3 alkoxy.
  • each of R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, halogen, and C1-6 alkyl (e.g., C1-3 alkyl).
  • the compound or pharmaceutically acceptable salt of embodiment 16 wherein each of R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, F, Cl, and CH3.
  • the compound or pharmaceutically acceptable salt of any one of embodiments 1-19 wherein
  • ring A is selected from the group consisting of C3-6 monocyclic cycloalkyl, C3-6 bicyclic cycloalkyl, Ce or C10 aryl (e.g., phenyl), and 5 or 6 membered heteroaryl, wherein each of C3-6 monocyclic cycloalkyl, C3-6 bicyclic cycloalkyl, Ce or C10 aryl (or phenyl), and 5 or 6 membered heteroaryl is optionally substituted with one or more occurrences of R 5 .
  • R 5 R 5 from the group consisting of:
  • ring A is selected from the group consisting of: i-k HO-
  • each occurrence of R 5 is independently selected from the group consisting of halogen, C1-6 alkyl (e.g., C1-3 alkyl), C1-6 alkoxy, C3-12 monocyclic cycloalkyl (e.g., C3-6 monocyclic cycloalkyl), and Ce or C10 aryl (e.g., phenyl), wherein each of C1-6 alkyl (or C1-3 alkyl), C1-6 alkoxy, and C3-12 monocyclic cycloalkyl (or C3-6 monocyclic cycloalkyl) is optionally substituted with one or more occurrences of R 6 .
  • C1-6 alkyl e.g., C1-3 alkyl
  • C1-6 alkoxy e.g., C3-6 monocyclic cycloalkyl
  • Ce or C10 aryl e.g., phenyl
  • each occurrence of R 5 is independently selected from the group consisting of F, CH3, CHF2, CF2CH3, CF3,
  • the compound or pharmaceutically acceptable salt of embodiment 38 wherein each occurrence of R 5 is independently selected from the group consisting of F, CH 3 , CHF 2 , CF 3 , CH 2 OCH 3
  • the compound or pharmaceutically acceptable salt of any one of embodiments 1-36 wherein each occurrence of R 5 is C1-6 alkyl (e.g., C1-3 alkyl (e.g., CH3)) that is optionally substituted with one or more occurrences of R 6 .
  • each occurrence of R 6 is independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 alkoxy, and OH.
  • the compound or pharmaceutically acceptable salt of embodiment 41, wherein each occurrence of R 6 is independently selected from the group consisting of F, CH3, OCH3, and OH.
  • the compound or pharmaceutically acceptable salt of any one of embodiments 1-40, wherein each occurrence of R 6 is halogen (e.g., F).
  • n is 0 or 2.
  • a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one of embodiments 1-53 and one or more pharmaceutically acceptable excipients.
  • a combination comprising the compound or pharmaceutically acceptable salt of any one of embodiments 1-53 and a CDK4/6 inhibitor.
  • kits comprising (i) a unit dosage form comprising the compound or pharmaceutically acceptable salt of any one of embodiments 1-53, and, separately, (ii) a unit dosage form comprising a CDK4/6 inhibitor.
  • the method of claim 58, wherein the cancer is breast cancer.
  • the method of claim 59, wherein the breast cancer is HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of embodiments 1-53 or the pharmaceutical composition of embodiment 54.
  • the solid tumor is at least one of the group consisting of: uterine cancer (such as uterine carcinosarcoma and uterine corpus endometrial carcinoma), endometrial cancer, breast cancer (such as breast invasive carcinoma and triple negative breast cancer, ER+ HER2- breast cancer, and HER2+ breast cancer), ovarian cancer (such as ovarian serous cystadenocarcinoma), stomach cancer (such as stomach adenocarcinoma), gastric cancer (such as gastrointestinal stromal cancer), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (such as B-cell lymphoma), sarcoma, esophageal cancer (such as esophageal carcinoma), bladder cancer (such as bladder urothelial carcinoma), lung cancer (such as lung squamous carcinoma and non-small cell lung cancer including EGFRm+ (epidermal growth factor receptor mutant positive) non-small cell lung cancer including EG
  • any one of embodiments 61-63 wherein the cancer is selected from the group consisting of: ovarian cancer, endometrial cancer, gastric cancer, esophaegeal cancer, breast cancer (such as triple negative breast cancer), and lung adenosarcoma.
  • the method of embodiment 64 wherein the cancer is breast cancer.
  • the method of embodiment 65 wherein the breast cancer is HR+ (hormone receptor positive) breast cancer.
  • the method of embodiment 65 or embodiment 66, wherein the breast cancer is ER+ (estrogen receptor positive) breast cancer.
  • the method of embodiment 66, wherein the breast cancer is HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer.
  • the method of embodiment 67 wherein the breast cancer is ER+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer.
  • the method of embodiment 65 wherein the breast cancer is triple negative breast cancer.
  • the method of embodiment 61, wherein the cancer comprises a liquid tumor.
  • the liquid tumor is at least one of the group consisting of: diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia/lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS- related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell/histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma
  • DLBCL diffuse large B
  • any one of embodiments 58-72 wherein the method further comprises administering to the subject an additional therapeutic agent.
  • the method of embodiment 73 wherein the additional therapeutic agent is carboplatin, ribociclib or a pharmaceutically acceptable salt thereof, fulvestrant, or a combination thereof.
  • the method of embodiment 79, wherein the endocrine therapy is an estrogen receptor antagonist such as fulvestrant, or an aromatase inhibitor such as letrozole.
  • the method of embodiment 80, wherein the endocrine therapy is fulvestrant.
  • the method of embodiment 81, wherein the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof, or palbociclib or a pharmaceutically acceptable salt, for example wherein the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.
  • 83 The method of any one of embodiments 58-82, wherein the subject is a treatment-naive subject.
  • the compounds provided herein can be prepared from readily available starting materials using the following methods and procedures. It will be appreciated that where typical or preferred process conditions (z.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by a person of ordinary skill in the art by routine optimization.
  • PEPPSI-IPr [l,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride; PSI: pounds per square inch; quin: quintet; RuPhos Pd G3: (2-Dicyclohexylphosphino-2',6'- diisopropoxy-l,l'-biphenyl)[2-(2'-amino-l,l'-biphenyl)]palladium(II) methanesulfonate; sat. sol.: saturated solution; t: triplet; td: triplet of doublet; TFA: trifluoro acetic acid; tt: triplet of triplet.
  • the solid was purified by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: carbon dioxide/ethyl alcohol; B%:25%, isocratic elution mode) and concentrated under reduced pressure to afford the two separate enantiomers.
  • Step 1 To a solution of phenylmethanol (456 g, 4.22 mol, 439 mL, 2.50 eq.) in tetrahydrofuran (2.50 L) was added potassium lerLbutoxide (473 g, 4.22 mol, 2.50 eq.). The reaction was stirred at 70°C for 1 h. Then 2,6-dichloropyridine (250 g, 1.69 mol, 1.00 eq.) was added at 20°C and the reaction was stirred at 70°C for 12 h. The mixture was diluted with NH4CI sat. sol. (2000 mL) and extracted with ethyl acetate (3 x 1000 mL).
  • Step 2 To a solution of 2,6-bis(benzyloxy)pyridine (200 g, 686 mmol, 1.00 eq.) in acetonitrile (2000 mL) was added A-bromosuccinimidc (134 g, 755 mmol, 1.10 eq.). The reaction was stirred at 80°C for 3 h, then concentrated under reduced pressure to give a residue. The residue was diluted with sodium carbonate (2000 mL) and extracted with ethyl acetate (3 x 1000 mL). The combined organic layers were washed with brine (2000 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.
  • A-bromosuccinimidc 134 g, 755 mmol, 1.10 eq.
  • Step 3 To a solution of 2,6-dibenzyloxy-3-bromo-pyridine (200 g, 540 mmol, 1.00 eq.) and triisopropyl borate (254 g, 1.35 mol, 310 mL, 2.50 eq.) in tetrahydrofuran (2000 mL) was added n- butyllithium (2.50 M, 389 mL, 1.80 eq.) at -78°C under nitrogen atmosphere. The mixture was stirred at 20°C for 12 h. The reaction was quenched by addition of NH4CI sat. sol. (2000 mL). The mixture was extracted with ethyl acetate (3 x 1000 mL).
  • Step 4 Starting from Intermediate E3 according to General Procedure 3 with Pd(PPhs)4, Intermediate F3 was obtained as a yellow oil (690 mg, 1.35 mmol, 31% yield).
  • Step 5 Starting from Intermediate F3 and tert-butyl i(2/?.3.S)-2-mcthylazctidin-3- yl)carbamate according to General Procedure 4 Variant 2, Intermediate G3 was obtained as a yellow oil (750 mg, 1.21 mmol, 90% yield).
  • Step 6 Starting from Intermediate G3 according to General Procedure 5 (no LiCl), Intermediate A3 was obtained as a violet oil (50.0 mg, 114 ⁇ mol, 88% yield).
  • Step 4 Starting from Intermediate E7 according to General Procedure 3 with Pd(PPhs)4, Intermediate F7 was obtained as a white solid (1.90 g, 3.81 mmol, 22% yield).
  • Step 5 Starting from Intermediate F7 and tert-butyl i(2/?.3.S)-2-mcthylazctidin-3- yl)carbamate according to General Procedure 4 Variant 2, Intermediate G7 was obtained as a yellow oil (1.00 g, 1.66 mmol, 83% yield).
  • Step 6 Starting from Intermediate G7 according to General Procedure 5 (with LiCl), Intermediate A7 was obtained as a white solid (300 mg, 704 ⁇ mol, 64% yield).
  • Step 4 Starting from Intermediate E9,23 according to General Procedure 3 with Pd(PPhs)4, Intermediate F9,23 was obtained as a brown solid (666 mg, 1.35 mmol, 22% yield).
  • Step 5 Starting from Intermediate F9 and tert-butyl azetidin-3-ylcarbamate according to General Procedure 4 Variant 1, Intermediate G9,23 was obtained as a yellow solid (570 mg, 994 ⁇ mol, 72% yield).
  • Step 6 Starting from Intermediate G9,23 according to General Procedure 5 (no LiCl), Intermediate A9 was obtained as a purple solid (550 mg, 1.34 mmol, 31% yield).
  • Step 4 Starting from Intermediate E15 according to General Procedure 3 with Pd(PPhs)4, Intermediate F15 was obtained as a yellow solid (1.00 g, 2.10 mmol, 66% yield).
  • Step 5 Starting from Intermediate F15 and tert-butyl i(2/?.3.S')-2-mcthylazctidin-3- yl)carbamate according to General Procedure 4 Variant 2, Intermediate G15 was obtained as a yellow solid (1.09 g, 1.87 mmol, 89% yield).
  • Step 6 Starting from Intermediate G5 according to General Procedure 5 (no LiCl), Intermediate A15 was obtained as ayellow solid (1.00 g, crude).
  • Step 7 Starting from Intermediate A9 according to General Procedure 6, Intermediate A23 was obtained as a white solid (100 mg, 228 ⁇ mol, 45% yield).
  • Step 4 Starting from Intermediate E25 according to General Procedure 3 with Pd(PPhs)4, Intermediate F25 was obtained as a yellow oil (1.35 g, 2.80 mmol, 44% yield).
  • Step 5 Starting from Intermediate F25 and tert-butyl i(2/?.3.S)-2-mcthylazctidin-3- yl)carbamate according to General Procedure 4 Variant 2, Intermediate G25 was obtained as a yellow oil (1.42 g, 2.42 mmol, 86% yield).
  • Step 6 Starting from Intermediate G25 according to General Procedure 5 (with LiCl), Intermediate A25 was obtained as a red oil (420 mg, 1.03 mmol, 50% yield).
  • Step 2 Starting from Intermediate 14 (commercially available) according to General Procedure 3 with Pd(dppf)C12, Intermediate J4 was obtained as a yellow oil (2.00 g, 4.65 mmol, 68% yield).
  • Step 3 Starting from Intermediate J4 according to General Procedure 8, Intermediate K4 was obtained as a yellow oil (660 mg, 1.34 mmol, 29% yield).
  • Step 4 Starting from Intermediate K4 according to General Procedure 4 Variant 2 with Zc/7-butyl ((27?,3S)-2-methylazetidin-3-yl)carbamate, Intermediate L4 was obtained as a colourless oil (570 mg, 951 ⁇ mol, 85% yield).
  • Step 5 Starting from Intermediate L4 according to General Procedure 5 (no LiCl), Intermediate A4 was obtained as a white solid (320 mg, 759 ⁇ mol, 80% yield).
  • Step 2 Starting from Intermediate 111,26 (commercially available) according to General Procedure 3 with Pd(dppf)C12, Intermediate Jll,26 was obtained as a yellow oil (7.80 g, 19.1 mmol, 75% yield).
  • Step 3 Starting from Intermediate Jll,26 according to General Procedure 8, Intermediate Kll,26 was obtained as a yellow solid (480 mg, 1.02 mmol, 34% yield).
  • Step 4 Starting from Intermediate KI 1,26 according to General Procedure 4 Variant
  • Step 5 Starting from Intermediate Lil according to General Procedure 5 (no LiCl, 2 h reaction time), Intermediate All was obtained as a yellow solid (420 mg, 1.05 mmol, 96% yield).
  • Step 2 Starting from Intermediate 113 (commercially available) according to General Procedure 3 with Pd(dppf)C12, Intermediate J13 was obtained as a white solid (2. 16 g, 5.08 mmol, 72% yield).
  • Step 3 Starting from Intermediate J13 according to General Procedure 8, Intermediate K13 was obtained as a yellow solid (1.00 g, 2.04 mmol, 40% yield).
  • Step 4 Starting from Intermediate KI 3 according to General Procedure 4 Variant 2 with tert-butyl ((27?,3S)-2-methylazetidin-3-yl)carbamate, Intermediate L13 was obtained as a yellow solid (560 mg, 941 ⁇ mol, 92% yield).
  • Step 5 Starting from Intermediate L13 according to General Procedure 5 (no LiCl), Intermediate A13 was obtained as a white solid (320 mg, 768 ⁇ mol, 81% yield).
  • Step 1 Starting from 2-amino-6-chlorobenzonitrile according to General Procedure 7, Intermediate 118 was obtained as a white solid (1.46 g, 6.31 mmol, 96% yield).
  • Step 2 Starting from Intermediate 118 according to General Procedure 3 with Pd(dppf)C12, Intermediate J18 was obtained as ayellow oil (2.13 g, 4.82 mmol, 76% yield).
  • Step 3 Starting from Intermediate J18 according to General Procedure 8, Intermediate K18 was obtained as a white solid (1.05 g, 2.08 mmol, 43% yield).
  • Step 4 Starting from Intermediate K18 according to General Procedure 4 Variant 2 with tert-butyl ((27?,3S)-2-methylazetidin-3-yl)carbamate, Intermediate L18 was obtained as ayellow solid (0.36 g, 589 ⁇ mol, 28% yield).
  • Step 5 Starting from Intermediate L18 according to General Procedure 5 (with LiCl), Intermediate A18 was obtained as a white solid (0.41 g, 947 ⁇ mol, 88% yield).
  • Step 4 Starting from Intermediate KI 1,26 according to General Procedure 4 Variant
  • Step 5 Starting from Intermediate L26 according to General Procedure 5 (no LiCl, 2 h reaction time), Intermediate A26 was obtained as a yellow oil (430 mg, 1.06 mmol, 97% yield).
  • Step 1 Starting from 4-bromo-3-methyl-aniline according to General Procedure 9, Intermediate M20 was obtained as a yellow oil (1.30 g, 5.06 mmol, 47% yield).
  • Step 2 Starting from Intermediate M20 according to General Procedure 10, Intermediate N20 was obtained as a yellow solid (590 mg, 2.08 mmol, 41% yield).
  • Step 3 Starting from Intermediate N20 according to General Procedure 4 Variant 1, Intermediate A20 was obtained as a yellow solid (500 mg, 1.29 mmol, 62% yield).
  • Step 1 Starting from 4-bromo-3-chloroaniline according to General Procedure 9, Intermediate M21 was obtained as a yellow solid (3.00 g, 10.8 mmol, 45% yield).
  • Step 2 Starting from Intermediate M21 according to General Procedure 10, Intermediate N21 was obtained as a yellow solid (1.00 g, 3.29 mmol, 38% yield).
  • Step 3 Starting from Intermediate N21 according to General Procedure 11, Intermediate A21 was obtained as a yellow solid (210 mg, 514 ⁇ mol, 19% yield).
  • Step 6 According to General Procedure 6 [00242] To a solution of Intermediate A5 (200 mg, 488 ⁇ mol, 1.00 eq.) in A'jV-dimcthyl formamide (2 mL) was added NCS (59 mg, 440 ⁇ mol, 0.90 eq.). The reaction was stirred at 50°C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (Cl 8 column, eluting with water (formic acid) and an acetonitrile gradient 35% - 65%) to afford Intermediate A16 (323 mg, 728 ⁇ mol, 74% yield) as a white solid.
  • Step 5 Starting from Intermediate R5,6,16,22 according to General Procedure 4 Variant 1 with ZcrZ-butyl (3-methylazetidin-3-yl)carbamate, Intermediate A6 was obtained as a yellow solid (140 mg, 342 ⁇ mol, 58% yield).
  • Step 1 Starting from l-bromo-3-chloro-2-methoxy-4-methyl-benzene according to General Procedure 12 (with AIBN), Intermediate O10 was obtained as a transparent oil (2.70 g, 8.59 mmol, 51% yield).
  • Step 2 Starting from Intermediate O10 according to General Procedure 13 Variant 1, Intermediate P10 was obtained as a transparent oil (2.22 g, 8.55 mmol, 98% yield).
  • Step 3 Starting from Intermediate P10 according to General Procedure 14, Intermediate Q10 was obtained as a transparent oil (2.90 g, 8.37 mmol, 97% yield).
  • Step 4 Starting from Intermediate Q10 according to General Procedure 15, Intermediate R10 was obtained as a white solid (1.49 g, 4.48 mmol, 54% yield).
  • Step 5 Starting from Intermediate R10 according to General Procedure 4 Variant 1 with terAbutyl ((27?,3S)-2-methylazetidin-3-yl)carbamate*HCl, Intermediate A10 was obtained as a white solid (380 mg, 868 ⁇ mol, 58% yield).
  • Step 1 Starting from of 5-bromo-l,3-dichloro-2-methylbenzene according to General Procedure 12 (with benzoic peroxyanhydride), Intermediate 012 was obtained as a colourless oil (33.0 g, 98.3 mmol, 94% yield).
  • Step 2 Starting from Intermediate 012 according to General Procedure 13 Variant 1, Intermediate P12 was obtained as a white solid (24.7 g, 88.6 mmol, 86% yield).
  • Step 3 Starting from Intermediate P12 according to General Procedure 14, Intermediate Q12 was obtained as a yellow oil (38.0 g, 91.8 mmol, 99% yield).
  • Step 4 Starting from Intermediate Q12 according to General Procedure 15, Intermediate R12 was obtained as a white solid (33.0 g, 93.0 mmol, 96% yield).
  • Step 5 Starting from Intermediate R12 according to General Procedure 4 Variant 1 with tert-butyl ((27?,3S)-2-methylazetidin-3-yl)carbamate*HCl, Intermediate A12 was obtained as a yellow solid (200 mg, 452 ⁇ mol, 38% yield).
  • Step 3 Starting from 2-(4-bromo-2-fluorophenyl)acetonitrile according to General Procedure 14, Intermediate Q14 was obtained as a white solid (8.40 g, 27.9 mmol, 59% yield).
  • Step 4 Starting from Intermediate Q14 according to General Procedure 15, Intermediate R14 was obtained as a white solid (7.00 g, 24.4 mmol, 99% yield).
  • Step 5 Starting from Intermediate R14 according to General Procedure 4 Variant 1 with tert-butyl ((27?,3S)-2-methylazetidin-3-yl)carbamate*HCl, Intermediate A14 was obtained as a yellow solid (240 mg, 613 ⁇ mol, 58% yield).
  • Step 6 Starting from Intermediate A6 according to General Procedure 6, Intermediate A22 was obtained as a white solid (127 mg, 286 ⁇ mol, 58% yield).
  • Step 5 Starting from 3-(4-bromophenyl)piperidine-2, 6-dione according to General Procedure 4 Variant 1 with tert-butyl (3-methylazetidin-3-yl)carbamate, Intermediate S24 was obtained as a yellow solid (460 mg, 1.23 mmol, 33% yield).
  • Step 6 Starting from Intermediate S24 according to General Procedure 6, Intermediate A24 was obtained as a purple solid (250 mg, 613 ⁇ mol, 54% yield).
  • Step 1 To a solution of Intermediate A5 (1.20 g, 2.93 mmol, 1.00 eq.) in N,N- dimethylform amide (12.0 mL) was added /V-iodo-succinimide (659 mg, 2.93 mmol, 1.00 eq.). The reaction was stirred at 50°C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate T1 (1.00 g, 1.87 mmol, 64% yield) as a yellow solid.
  • Step 1 To a solution of 5 -bromo- 1, 3 -difluoro-2-m ethylbenzene (21.0 g, 101 mmol, 1.00 eq.) in tetrahydrofuran (210 mL) was added lithium diisopropyl amide (2.00 M, 60.9 mL, 1.20 eq.). The mixture was stirred at -70 °C for 0.5 h. Then triethyl borate (22.2 g, 152 mmol, 25.9 mL, 1.50 eq.) was added, and the reaction was stirred at -70 °C for 1 h.
  • Step 2 (6-bromo-2,4-difluoro-3-methylphenyl)boronic acid (5.90 g, 23.5 mmol, 1.00 eq.) was added to a mixture of deuterium oxide (5.40 mL) and pyridine (54.6 mL). The reaction was stirred at 100 °C for 8 h. The pH was adjusted to ⁇ 5 with hydrochloric acid (IM, 100 mL), and the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.
  • IM hydrochloric acid
  • Step 4 - see General Procedure 13, Variant 1.
  • Step 7 - see General Procedure 4.
  • Step 1 Starting from 2-methoxy-6-m ethylnicotinic acid according to General Procedure 16, Intermediate U2 was obtained as a white solid (7.70 g, 27. 1 mmol, 94% yield).
  • Step 2 Starting from Intermediate U2 according to General Procedure 17, Intermediate V2 was obtained as a yellow gum (10.2 g, 25.9 mmol, 94% yield).
  • Step 3 Starting from Intermediate V2 according to General Procedure 18 Variant 1, Intermediate W2 was obtained as a yellow solid (5.20 g, 12.6 mmol, 48% yield).
  • Step 4 Starting from Intermediate W2 according to General Procedure 19 (with CuBr2), Intermediate C2 was obtained as a white solid (300 mg, 966 ⁇ mol, 20% yield). Intermediate C7
  • Step 1 Starting from 4-m ethoxybenzoic acid according to General Procedure 16, Intermediate U7 was obtained as a white solid (5.00 g, 18.8 mmol, 95% yield).
  • Step 2 Starting from Intermediate U7 according to General Procedure 17, Intermediate V7 was obtained as a white solid (2.00 g, 7.14 mmol, 95% yield).
  • Step 3 Starting from Intermediate V7 according to General Procedure 18 Variant 1, Intermediate W7 was obtained as a white solid (1.10 g, 5.75 mmol, 95% yield).
  • Step 4 Starting from Intermediate W7 according to General Procedure 19 (with CuBr2), Intermediate C7 was obtained as a white solid (270 mg, 1.06 mmol, 40% yield).
  • Step 1 Starting from 6-(difluorom ethoxy) nicotinic acid according to General Procedure 16, Intermediate U9 was obtained as a white solid (2.93 g, 9.57 mmol, 90% yield).
  • Step 2 Starting from Intermediate U9 according to General Procedure 17, Intermediate V9 was obtained as a white solid.
  • Step 3 Starting from Intermediate V9 according to General Procedure 18 Variant 2, Intermediate W9 was obtained as a yellow solid (2.95 g, crude).
  • Step 4 Starting from Intermediate W9 according to General Procedure 19 (with CuBr2), Intermediate C9 was obtained as a white solid (637 mg, 2.09 mmol, 42% yield).
  • Step 1 Starting from 2-fluoro-4-methylbenzoic acid according to General Procedure 16, Intermediate U10 was obtained as a white solid (1.60 g, 5.96 mmol, 92% yield).
  • Step 2 Starting from Intermediate U10 according to General Procedure 17, Intermediate VI 0 was obtained as a yellow solid (1.00 g, 5.95 mmol, 99% yield).
  • Step 3 Starting from Intermediate V10 according to General Procedure 18 Variant 2, Intermediate W10 was obtained as a white solid (980 mg, 3.91 mmol, 66% yield).
  • Step 4 Starting from Intermediate W10 according to General Procedure 19 (with CuBr), Intermediate CIO was obtained as a white solid (250 mg, 973 ⁇ mol, 21% yield).
  • Step 1 Starting from 2,2-difluoro-3-methylbicyclo[l.l.l]pentane-l-carboxylic acid according to General Procedure 16, Intermediate Ull was obtained as a white solid (500 mg, 1.81 mmol, 98% yield).
  • Step 2 Starting from Intermediate Ull according to General Procedure 17, Intermediate VI 1 was obtained as a yellow oil (400 mg, crude).
  • Step 3 Starting from Intermediate Vll according to General Procedure 18 Variant 2, Intermediate Wil was obtained as a yellow solid (270 mg, crude).
  • Step 4 Starting from Intermediate Wil according to General Procedure 19 (with
  • Step 1 Starting from 4-cyclopropoxybenzoic acid according to General Procedure 16, Intermediate U12 was obtained as a white solid (1.50 g, 5.13 mmol, 91% yield).
  • Step 2 Starting from Intermediate U12 according to General Procedure 17, Intermediate VI 2 was obtained as a white solid (1.50 g, 4.90 mmol, 95% yield).
  • Step 3 Starting from Intermediate V12 according to General Procedure 18 Variant 1, Intermediate W12 was obtained as a white solid (0.980 g, 4.51 mmol, 92% yield).
  • Step 4 Starting from Intermediate W12 according to General Procedure 19 (with CuBr), Intermediate C12 was obtained as a white solid (360 mg, 1.28 mmol, 31% yield).
  • Step 1 Starting from 5 -cyclobutylisoxazole-3 -carboxylic acid according to General Procedure 16, Intermediate U13 was obtained as a white solid (500 mg, 1.78 mmol, 99% yield).
  • Step 2 Starting from Intermediate U13 according to General Procedure 17, Intermediate VI 3 was obtained as a brown oil (550 mg, crude).
  • Step 3 Starting from Intermediate V13 according to General Procedure 18 Variant 1, Intermediate W13 was obtained as a white solid (280 mg, 1.36 mmol, 73% yield).
  • Step 4 Starting from Intermediate W13 according to General Procedure 19 (with CuBr 2 ), Intermediate C13 was obtained as a yellow solid (100 mg, 370 ⁇ mol, 27% yield).
  • Step 1 Starting from 3-methylbicyclo[l.l.l]pentane-l-carboxylic acid according to General Procedure 16, Intermediate U14 was obtained as a white solid (950 mg, 3.95 mmol, 99% yield).
  • Step 2 Starting from Intermediate U14 according to General Procedure 17, Intermediate VI 4 was obtained as a yellow oil (925 mg, crude).
  • Step 3 Starting from Intermediate V14 according to General Procedure 18 Variant 2, Intermediate W14 was obtained as a yellow solid (730 mg, 4.42 mmol, 85% yield).
  • Step 4 Starting from Intermediate W14 according to General Procedure 19 (with
  • Step 1 Starting from 3 -cyclopropylbicyclo[l.l.l]pentane-l -carboxylic acid according to General Procedure 16, Intermediate U18 was obtained as a white solid (1.20 g, 4.51 mmol, 98% yield).
  • Step 2 Starting from Intermediate U18 according to General Procedure 17, Intermediate VI 8 was obtained as a white solid (380 mg, 2.29 mmol, 51% yield).
  • Step 3 Starting from Intermediate V18 according to General Procedure 18 Variant 2, Intermediate W18 was obtained as a white solid (250 mg, 1.31 mmol, 99% yield).
  • Step 4 Starting from Intermediate W18 according to General Procedure 19 (with
  • Step 1 Starting from 3 -phenylbicyclo [l.l.l]pentane-l -carboxy lie acid according to General Procedure 16, Intermediate U19 was obtained as a white solid (717 mg, crude).
  • Step 2 Starting from Intermediate U19 according to General Procedure 17, Intermediate VI 9 was obtained as a white solid (480 mg, crude).
  • Step 3 Starting from Intermediate V19 according to General Procedure 18 Variant 2, Intermediate W19 was obtained as a yellow solid (420 mg, 1.85 mmol, 79% yield).
  • Step 4 Starting from Intermediate W19 according to General Procedure 19 (with CuBr 2 ), Intermediate C19 was obtained as a white solid (250 mg, 859 ⁇ mol, 61% yield).
  • Step 1 Starting from 3-(2-hydroxypropan-2-yl)bicyclo[l.l.l]pentane-l-carboxylic acid according to General Procedure 16, Intermediate U22 was obtained as a transparent oil (300 mg, 1.06 mmol, 60% yield).
  • Step 2 Starting from Intermediate U22 according to General Procedure 17, Intermediate V22 was obtained as a transparent oil (300 mg, crude).
  • Step 3 Starting from Intermediate V22 according to General Procedure 18 Variant 2, Intermediate W22 was obtained as a transparent oil (300 mg, crude).
  • Step 4 Starting from Intermediate W22 according to General Procedure 19 (with CuBr2), Intermediate C22 was obtained as a white solid (45.0 mg, 165 ⁇ mol, 16% yield).
  • Step 1 Starting from 3 -(methoxymethyl)bicyclo[l.l.l]pentane-l -carboxylic acid according to General Procedure 16, Intermediate U23 was obtained as a white solid (480 mg, 1.78 mmol, 92% yield).
  • Step 2 Starting from Intermediate U23 according to General Procedure 17, Intermediate V23 was obtained as a transparent oil (500 mg, crude).
  • Step 3 Starting from Intermediate V23 according to General Procedure 18 Variant 2, Intermediate W23 was obtained as a transparent oil (340 mg, crude).
  • Step 4 Starting from Intermediate W23 according to General Procedure 19 (with
  • Step 1 Starting from 3 -cyclobutylbicyclo[l.l.l]pentane-l -carboxy lie acid according to General Procedure 16, Intermediate U24 was obtained as a white solid (470 mg, 1.70 mmol, 94% yield).
  • Step 2 Starting from Intermediate U24 according to General Procedure 17 and following purification via Purification Method 2, Intermediate V24 was obtained as a white solid (190 mg, 1.05 mmol, 54% yield).
  • Step 3 Starting from Intermediate V24 according to General Procedure 18 Variant 2, Intermediate W24 was obtained as a white solid (210 mg, crude).
  • Step 4 Starting from Intermediate W24 according to General Procedure 19 (with CuBr2), Intermediate C24 was obtained as a transparent oil (140 mg, 520 ⁇ mol, 51% yield).
  • Step 2 Starting from methyl 4-methylbenzoate according to General Procedure 21, Intermediate Y3 was obtained as a white solid (1.90 g, 12.6 mmol, 95% yield).
  • Step 3 Starting from Intermediate Y3 according to General Procedure 18 Variant 2, Intermediate Z3 was obtained as a white solid (1 g, crude).
  • Step 4 Starting from Intermediate Z3 according to General Procedure 19 (with CuBr2), Intermediate C3 was obtained as a white solid (600 mg, 2.51 mmol, 49% yield).
  • Step 2 Starting from Intermediate X4 according to General Procedure 21, Intermediate Y4 was obtained as a white solid (400 mg, 2.09 mmol, 98% yield).
  • Step 3 Starting from Intermediate Y4 according to General Procedure 18 Variant 2, Intermediate Z4 was obtained as a white solid (650 mg, crude).
  • Step 4 Starting from Intermediate Z4 according to General Procedure 19 (with CuBr), Intermediate C4 was obtained as a white solid (150 mg, 535 ⁇ mol, 39% yield).
  • Step 1 Starting from 4-(trifluoromethoxy)benzoic acid according to General Procedure 20, Intermediate X5 was obtained as a white solid (2.6 g, crude).
  • Step 2 Starting from Intermediate X5 according to General Procedure 21, Intermediate Y5 was obtained as a white solid (1.95 g, 8.24 mmol, 69% yield).
  • Step 3 Starting from Intermediate Y5 according to General Procedure 18 Variant 2, Intermediate Z5 was obtained as a white solid (800 mg, 3.23 mmol, 59% yield).
  • Step 4 Starting from Intermediate Z5 according to General Procedure 19 (with CuBr), Intermediate C5 was obtained as a white solid (400 mg, 1.23 mmol, 37% yield).
  • Step 1 A mixture of methyl 3 -formylbicyclo[l.l. l]pentane-l -carboxylate (100 mg, 649 ⁇ mol, 1.00 eq.) and DAST (257 pL. 1.95 mmol, 3.00 eq.) in dichloromethane (2.00 mL) was cooled to - 78°C and purged with nitrogen 3 times, then the reaction was stirred at -78°C for 6 h under nitrogen. The mixture was diluted with saturated sodium bicarbonate solution (10 mL) at -78°C, and the aqueous layer was extracted with dichloromethane (3 x 8 mL).
  • Step 2 Starting from Intermediate X8 according to General Procedure 21, Intermediate Y8 was obtained as a yellow oil (160 mg, crude).
  • Step 3 Starting from Intermediate Y8 according to General Procedure 18 Variant 2, Intermediate Z8 was obtained as a yellow oil (200 mg, crude).
  • Step 4 Starting from Intermediate Z8 according to General Procedure 19 (with CuBr), Intermediate C8 was obtained as a yellow solid (30.0 mg, 113 ⁇ mol, 11% yield).
  • Step la To a solution of l-(l-methylcyclopropyl)ethan-l-one (1.00 g, 10.2 mmol, 1.12 mL, 1.00 eq.) in tetrahydrofuran (10.0 mL) was added sodium hydride 60% dispersion in mineral oil (611 mg, 15.3 mmol, 1.50 eq.). Then diethyl oxalate (1.39 mL, 10.2 mmol, 1.00 eq.) was added. The reaction was stirred at 65°C for 2 h. The mixture was quenched with NH4CI sat. sol.
  • Step lb To a solution of ethyl (Z)-4-hydroxy-4-(l-methylcyclopropyl)-2-oxobut-3- enoate (1.30 g, 6.56 mmol, 1.00 eq.) in ethanol (13.0 mL) was added hydroxylammonium chloride (547 mg, 7.87 mmol, 1.20 eq.). The reaction was stirred at 80°C for 2 h. The mixture was concentrated under reduced pressure to give a residue.
  • Step 2 Starting from Intermediate X15 according to General Procedure 21, Intermediate Y15 was obtained as a white solid (510 mg, 2.81 mmol, 99% yield).
  • Step 3 Starting from Intermediate Y15 according to General Procedure 18 Variant 2, Intermediate Z15 was obtained as a white solid (350 mg, 1.70 mmol, 60 % yield).
  • Step 4 Starting from Intermediate Z15 according to General Procedure 19 (with CuBr2), Intermediate C15 was obtained as a colourless oil (145 mg, 537 ⁇ mol, 32% yield).
  • Step la To a solution of 3, 3 -difluorocyclobutane- 1-carbaldehyde (100 mg, 833 ⁇ mol, 1.00 eq.) in methanol (1.00 mL) and water (1.00 mL) was added hydroxylammonium chloride (60.8 mg, 874 ⁇ mol, 1.05 eq.) and sodium carbonate (92.7 mg, 874 ⁇ mol, 1.05 eq.). The reaction was stirred at 50°C for 12 h. The mixture was concentrated under reduced pressure to give a residue.
  • Step lb To a solution of 3,3-difluorocyclobutane-l-carbaldehyde oxime (200 mg, 1.48 mmol, 1.00 eq.) in tetrahydrofuran (2.00 mL) was added ethyl propiolate (145 mg, 1.48 mmol, 145 pL, 1.00 eq.) and sodium hypochlorite 10% (5.21 mL, 8.44 mmol, 5.70 eq.) at 0°C. The reaction was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue.
  • Step 2 Starting from Intermediate X16 according to General Procedure 21, Intermediate Y16 was obtained as a yellow oil (40.0 mg, crude).
  • Step 3 Starting from Intermediate Y16 according to General Procedure 18 Variant 2, Intermediate Z16 was obtained as a yellow solid (40.0 mg, crude).
  • Step 4 Starting from Intermediate Z16 according to General Procedure 19 (with CuBr2), Intermediate C16 was obtained as a white solid (10.0 mg, 32.7 ⁇ mol, 20% yield).
  • Step 2 Starting from Intermediate X17 according to General Procedure 21, Intermediate Y17 was obtained as a white solid (350 mg, 1.93 mmol, 99% yield).
  • Step 3 Starting from Intermediate Y17 according to General Procedure 18 Variant 2, Intermediate Z17 was obtained as a yellow solid (310 mg, 1.50 mmol, 78% yield).
  • Step 4 Starting from Intermediate Z17 according to General Procedure 19 (with
  • Step 1 To a solution of diethylzinc (2.00 M, 31.7 mL, 3.00 eq.) in dichloromethane (15.0 mL) was added trifluoro acetic acid (4.70 mL, 63.3 mmol, 3.00 eq.) dropwise at 0°C. The suspension was stirred for 30 min at 0°C, then diiodomethane (5.11 mL, 63.3 mmol, 3.00 eq.) was added.
  • Step 2 Starting from Intermediate X20 according to General Procedure 21, Intermediate Y20 was obtained as a white solid (1.70 g, 12.0 mmol, 62% yield).
  • Step 3 Starting from Intermediate Y20 according to General Procedure 18 Variant 2, Intermediate Z20 was obtained as a yellow solid (3.00 g, crude).
  • Step 4 Starting from Intermediate Z20 according to General Procedure 19 (with CuBr), Intermediate C20 was obtained as a yellow oil (500 mg, 2.16 mmol, 12% yield).
  • Step 2 Starting from Intermediate X21 according to General Procedure 21, Intermediate Y21 was obtained as a white solid (710 mg, crude).
  • Step 3 Starting from Intermediate Y21 according to General Procedure 18 Variant 2, Intermediate Z21 was obtained as a white solid (584 mg, crude).
  • Step 4 Starting from Intermediate Z21 according to General Procedure 19 (with CuBr2), Intermediate C21 was obtained as a yellow solid (58 mg, 175 ⁇ mol, 16% yield).
  • Step 1 To a solution of 3 -(methoxycarbonyl)bicyclo[l.l.l]pentane-l -carboxylic acid (2.50 g, 14.7 mmol, 1.00 eq.) in dichloromethane (30.0 mL) were added l-ethyl-3-(3-dimethylamino- propyl)-carbodiimide hydrochloride (2.87 g, 15.0 mmol, 1.02 eq.) and A'.O-dimcthyl hydroxylamine hydrochloride (1.48 g, 15.1 mmol, 1.03 eq.). The reaction was stirred at 25 °C for 12 h.
  • Step 2 To a solution of methyl 3-(methoxy(methyl)carbamoyl)bicyclo[l.l.l]pentane-l- carboxylate (2.00 g, 9.38 mmol, 1.00 eq.) in tetrahydrofuran (50.0 mL) was added methylmagnesium bromide (3.00 M, 12.5 mL, 4.00 eq.) at -70°C. Then the reaction was stirred at -70°C for 2 h, then it was quenched by addition of methanol (5 mL) and diluted with water (10 mL). The aqueous layer was extracted with ethyl acetate (3 x 20 mL).
  • Step 3 To a solution of methyl 3-acetylbicyclo[l.l. l]pentane-l-carboxylate (0.40 g, 2.38 mmol, 1.00 eq.) in dichloromethane (5.00 mL) was added diethylamino-sulfur trifluoride (1.15 g, 7.13 mmol, 943 pL, 3.00 eq.). The reaction was stirred at 25°C for 10 h, then it was concentrated under reduced pressure to afford Intermediate X25 (0.9 g, crude) as yellow solid.
  • Step 4 Starting from Intermediate X25 according to General Procedure 21, Intermediate Y25 was obtained as a white solid (600 mg, 3.15 mmol, 67% yield).
  • Step 5 Starting from Intermediate Y25 according to General Procedure 18 Variant 2, Intermediate Z25 was obtained as a white solid (680 mg, crude).
  • Step 6 Starting from Intermediate Z25 according to General Procedure 19 (with CuBr2), Intermediate C25 was obtained as a yellow solid (600 mg, 2.15 mmol, 68% yield).
  • Step 1 To a solution of Intermediate Cl (500 mg, 1.77 mmol, 1.00 eq.) in N,N- dimethylacetamide (6.00 mL) were added A'jV-diisopropylcthylaminc (769 pL, 4.42 mmol, 2.50 eq.) and Intermediate B5 (546 mg, 1.77 mmol, 1.00 eq.). The reaction was stirred at 110 °C for 1 h, then it was filtered and concentrated under reduced pressure to give a residue.
  • A'jV-diisopropylcthylaminc 769 pL, 4.42 mmol, 2.50 eq.
  • Intermediate B5 546 mg, 1.77 mmol, 1.00 eq.
  • Step 2 To a solution of 3-(2,6-difluoro-4-((27?,3S)-2-methyl-3-((5-(3- (trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)-l,3,4-oxadiazol-2-yl)amino)azetidin-l-yl)phenyl)piperidine- 2,6-dione (300 mg, 0.59 mmol, 1 eq.) in DMF (20 V) was added NCS (173 mg, 1.30 mmol, 2.2 eq.). The reaction was stirred at 50 °C for 8 h, then it was poured into water (20 V).
  • Step 1 To a solution of 3 -(trifluoromethyl)bicyclo[l.l.l]pentane-l -carboxylic acid (0.90 g, 5.00 mmol, 1.00 eq.) in methanol (1.00 mL) was added thionyl chloride (1.19 g, 9.99 mmol, 726 pL. 2.00 eq.) at 0 °C. The reaction was stirred at 25 °C for 12 h, then it was concentrated to afford methyl 3- (trifluoromethyl)bicyclo[l. l.l]pentane-l -carboxylate (970 mg, 5.00 mmol, 99% yield) as a yellow oil.
  • Step 2 To a solution of methyl 3 -(trifluoromethyl)bicyclo[l.l.l]pentane-l -carboxylate (970 mg, 5.00 mmol, 1.00 eq.) in methanol (9.00 mL) was added hydrazine hydrate (4.41 g, 74.9 mmol, 4.28 mL, 85% purity, 15.0 eq.). The reaction was stirred at 60 °C for 2 h, then it was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL).
  • Step 3 To a solution of 3 -(trifluoromethyl)bicyclo[ 1.1.1 ]pentane-l -carbohydrazide (3.23 g, 16.6 mmol, 1.00 eq.) in methanol (30.0 mL) was added cyanogen bromide (2.11 g, 20.0 mmol, 1.47 mL, 1.20 eq.). The reaction was stirred at 65 °C for 3 h, then it was quenched by addition of water (30 mL). The aqueous layer was extracted with ethyl acetate (3 x 40 mL).
  • Step 4 To a solution of 5-(3-(trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)-l,3,4-oxadiazol- 2-amine (2.20 g, 10.0 mmol, 1.00 eq.) in acetonitrile (22.0 mL) were added tert-butyl nitrite (2.07 g, 20.1 mmol, 2.39 mL, 2.00 eq.) and copper(I) bromide (2.88 g, 20.1 mmol, 2.00 eq.). The reaction was stirred at 80 °C for 2 h, then it was filtered and concentrated under reduced pressure to give a residue.
  • Step 5 To a solution of 5-bromo-l,3-difluoro-2-methylbenzene (10.0 g, 48.3 mmol, 1.00 eq.) in tetrachloromethane (100 mL) were added A'-bromo succinimide (8.60 g, 48.3 mmol, 1.00 eq.) and (E)-3,3'-(diazene-l,2-diyl)bis(2 -methylpropanenitrile) (397 mg, 2.42 mmol, 0.05 eq.). The reaction was stirred at 80 °C for 2 h, then it was filtered and concentrated under reduced pressure to give a residue.
  • Step 6 To a solution of 5-bromo-2-(bromomethyl)-l,3-difluorobenzene (12.0 g, 41.9 mmol, 1.00 eq.) in ethanol (90.0 mL) and water (30.0 mL) was added potassium cyanide (3.01 g, 46.1 mmol, 1.98 mL, 1.10 eq.). The reaction was stirred at 60 °C for 2 h, then it was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.
  • Step 7 To a solution of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (7.00 g, 30.1 mmol, 1.00 eq.) and methyl acrylate (2.60 g, 30.1 mmol, 2.72 mL, 1.00 eq.) in tetrahydrofuran (70.0 mL) was added sodium methoxide (163 mg, 3.02 mmol, 0.10 eq.) at 0 °C. The reaction was stirred at 20 °C for 1 h, then it was quenched with saturated ammonium chloride aqueous solution (150 mL).
  • Step 8 To a solution of methyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoate (8.60 g, 27.0 mmol, 1.00 eq.) in acetic acid (80.0 mL) was added sulfuric acid (8.00 mL). The reaction was stirred at 90 °C for 2 h, then it was poured into ice water (50 mL) and the resulting precipitate was filtered. The precipitate was lyophilized to afford 3-(4-bromo-2,6-difluorophenyl)piperidine-2, 6-dione (6.00 g, 19.7 mmol, 72% yield) as a white solid.
  • Step 9 To a solution of 3-(4-bromo-2,6-difluorophenyl)piperidine-2, 6-dione (1.37 g, 4.49 mmol, 1.00 eq.) in dioxane (8.00 mL) were added tert-butyl ((27?,3S)-2-methylazetidin-3-yl)carbamate (1.00 g, 4.49 mmol, 1.00 eq., hydrochloride), caesium carbonate (4.39 g, 13.5 mmol, 3.00 eq.) and 1,3- bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro-2Z7-imidazol-l-ium-2-ide;3- chloropyridine;dichloropalladium (218 mg, 225 ⁇ mol, 0.05 eq.) under nitrogen atmosphere.
  • Step 10 A solution of tert-butyl ((27?,3S)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-2-methylazetidin-3-yl) carbamate (1.50 g, 3.66 mmol, 1.00 eq.) in trifluoroacetic acid (15.0 mL) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue.
  • Step 11 To a solution of 3-(4-((27?,3N)-3-amino-2-methylazetidin-l-yl)-2,6- difluorophenyl)piperidine-2, 6-dione (3.10 g, 8.72 mmol, 1.00 eq.) in A'jV-dimcthylacctamidc (30.0 mL) were added A'.A'-diisopropylcthylaminc (5.64 g, 43.6 mmol, 7.60 mL, 5.00 eq.) and 2-bromo-5-(3- (trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)-l,3,4-oxadiazole (2.47 g, 8.72 mmol, 1.00 eq.).
  • Step 12 To a solution of 3-(2,6-difluoro-4-((27?,3S)-2-methyl-3-((5-(3- (trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)-l,3,4-oxadiazol-2-yl)amino)azetidin-l-yl)phenyl)piperidine-
  • CDK2-HiBiT luminescence live-cell abundance measurements were performed using a genetically modified HEK293 clonal cell line containing a C-terminal HiBiT tag knock-in on the CDK2 endogenous locus and stably expressing LgBiT protein. This was obtained from Promega (Madison, WI).
  • Cells were plated in 384-well white bottom plates (Coming, 3570) using a Biotek MultiFlo FX (BioTek) at 5000 cells per well in 25 pl DMEM without phenol red (ThermoFisher Scientific, 21063029) supplemented with 10% FBS (Coming, 35-016-CV), 1% Penicillin/Streptomycin (ThermoFisher Scientific, 15140-163), and 0.5% Nano-Glo Endurazine Live Cell Substrate (Promega, N2571). Cells were incubated for 16 hours at 37°C and 5% CO2.
  • Sinf is the fitted activity level at infinite concentration of test sample ("infinite activity").
  • n is the Hill coefficient for the curve, i.e. the measure of the slope at AC50.
  • DC50 is the concentration at which the activity reaches 50% of its maximum level.
  • EC50 half maximal effective concentration
  • IC50 half maximal inhibitory concentration
  • EC50 implies activation (increasing curves)
  • IC50 is used for inhibition (decreasing curves). It is a measure of potency where low values indicate high potency.
  • C is the concentration in logarithmic units corresponding to the values on the x-axis of the dose-response curve plot.
  • n was restricted to between 0.5 and 2.
  • the span (So - Sint) was restricted to between 25% and 125%. If the span was less than 25%, a constant fit was applied to the curve.
  • the span (So - Smf, i.e. the difference between the top and bottom plateaus on the dose response curve) is also referred to herein as the D span . It represents the maximal percentage decrease in the amount of CDK2 over the doses tested at the measured time-point. A greater D span value therefore indicates that the compound mediates greater levels of protein degradation.
  • CDK2 except that 1) a genetically modified HEK293 pooled cell line with a N-terminal HiBiT tag knock-in on GSPT1 endogenous locus and stably expressing LgBiT protein was used instead of the genetically modified HEK293 clonal cell line containing a C-terminal HiBiT tag knock-in on the CDK2 endogenous locus and stably expressing LgBiT protein, 2) the Nano-Gio Endurazine Live Cell Substrate was used at 0.2% instead of 0.5%, and 3) 2000 cells/well were seeded instead of 5000 as for CDK2.
  • the compounds provided herein are effective in mediating the degradation of CDK2.
  • the compounds provided herein can selectively mediate the degradation of CDK2 over GSPT1.
  • the phenyl -glutarimide ring system of the compounds provided in Table 1 is known to be present in certain compounds that mediate the degradation of GSPT1.
  • the compounds provided herein cause little or no degradation of GSPT1.
  • Example 5 In vitro effect of Compound 36 in MDA-MB-157 breast, Kuramochi ovarian and
  • the MDA-MB-157 breast cancer cell line was acquired from ATCC and maintained by Monte Rosa in vitro as monolayer culture in Leibovitz's L-15 Medium supplemented with 10% heat inactivated fetal bovine serum and at 37 °C in CO?- free air.
  • the Kuramochi ovarian cancer cell line and the MKN1 gastric cancer cell lines were acquired from JCRB and maintained by Monte Rosa in vitro as monolayer culture in RPMI 1640 medium supplemented with 10% heat inactivated fetal bovine serum at 37°C in 5% CO2 in air.
  • 24h treatment resulted in a dose dependent accumulation of cells in the G1 phase, from 64.2% in the DMSO treated conditions to 91% at the 1000 nM concentration of Compound 36 in MDA-MB-157 cells and respectively, 63% for DMSO and 88.6% for 1000 nM treatment with Compound 36 in Kuramochi cells.
  • Example 6 In vivo PK/PD study to evaluate Compound 36 in combination with ribociclib in human breast cancer xenograft model MCF7
  • a cell line-derived xenograft model of human hormone-receptor positive/HER2 -negative breast cancer, MCF7 was used to assess the PK/PD effect of Compound 36 alone and the combinatorial PK/PD effect of Compound 36 with the CDK4/6 inhibitor ribociclib (Medchem Express).
  • the MCF7 tumor cell line was obtained from American Type Culture Collection (ATCC) and was expanded in vitro as a monolayer culture in DMEM medium supplemented with 15% heat inactivated fetal bovine serum at 37 °C in an atmosphere of 5% CO2 in air. Cells growing in an exponential growth phase were harvested, counted, and used for tumor inoculation.
  • Plasma samples were collected at Oh, Ih, 2h, 8h and 24h post first dose on day 5 and were analyzed for drug levels using the AB API6500 + LC/MS/MS instrument (AB Sciex). Tumor samples were collected at 8h and 24h post first dose on day 5.
  • CDK2 protein levels were determined by Western blot analysis from lysed tumor samples and relative levels calculated by normalization to CDK2 protein levels in vehicle treated samples. The following antibodies were used for PD analysis: Table 9.

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Abstract

Described herein are compounds that mediate the degradation of cyclin-dependent kinase 2 (CDK2) and are therefore useful in the treatment of various disorders, such as cancer.

Description

COMPOUNDS THAT MEDIATE PROTEIN DEGRADATION AND METHODS OF USE
THEREOF
BACKGROUND
[001] The ubiquitin proteasome system can be manipulated with different small molecules to trigger targeted degradation of specific proteins of interest. Promoting the targeted degradation of pathogenic proteins using small molecule degraders is emerging as a new modality in the treatment of diseases. One such modality relies on redirecting the activity of E3 ligases such as cereblon (a phenomenon known as E3 reprogramming) using low molecular weight compounds, which have been termed molecular glues, to promote the poly-ubiquitination and ultimately proteasomal degradation of new protein substrates involved in the development of diseases. The molecular glues bind to both the E3 ligase and the target protein, thereby mediating an alteration of the ligase surface and enabling an interaction with the target protein.
[002] WO 2023/069700, WO 2023/069720, and PCT/US2023/077781 describe compounds that mediate the degradation of cyclin-dependent kinase 2 (CDK2) and are thus useful in treating diseases. There exists a need for further therapeutics that mediate the degradation of CDK2.
SUMMARY
[003] Described herein are novel compounds that modulate cereblon to mediate the targeted degradation of the protein CDK2 and are therefore useful in the treatment of various disorders, such as cancer.
[004] The inventors prepared a novel series of CDK2 degraders, which are provided in Table 1 herein. Therefore, described herein is a compound selected from Table 1 or a pharmaceutically acceptable salt thereof.
[005] The inventors discovered that the glutarimide ring of these compounds can be replaced with a dihydrouracil ring, leading to further CDK2 degraders. Therefore, also described herein is a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (I): wherein: each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, halogen, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl (e.g., CF3), and C1-6 haloalkoxy (e.g., OCF3); ring A is selected from the group consisting of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl, wherein each of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more occurrences of R5; each occurrence of R5 is independently selected from the group consisting of halogen, NH2, S(O)2NH2, C1-6 alkyl, C1-6 alkoxy, C3-12 monocyclic cycloalkyl, aryl, and heteroaryl, wherein each of C1-6 alkyl, C1-6 alkoxy, and C3-12 monocyclic cycloalkyl is optionally substituted with one or more occurrences of R6; each occurrence of R6 is independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, and OH; each occurrence of R7 is H or C1-6 alkyl; and n is an integer selected from the group consisting of 0, 1, 2, and 3.
[006] Thus, in a first aspect, described herein is a novel CDK2 degrader, i.e. a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: i. a compound of Formula (I): wherein each variable is as defined above; or ii. a compound selected from Table 1.
[007] In a second aspect, described herein is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt described herein and one or more pharmaceutically acceptable excipients. [008] In a third aspect, described herein is a method of treating cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein.
BRIEF DESCRIPTION OF FIGURES
[009] FIG. 1 shows results from an in vitro experiment to evaluate the effect of Compound 36 on proliferation of MDA-MB-157 breast, Kuramochi ovarian and MKN1 gastric cancer cells.
[0010] FIG. 2 shows results from an in vitro experiment to evaluate the effect of Compound 36 on the cell cycle of MDA-MB-157 breast, Kuramochi ovarian and MKN1 gastric cancer cells.
[0011] FIG. 3 shows results from an in vivo experiment to evaluate the pharmacokinetic effects of Compound 36 alone and in combination with ribociclib in a human hormone-receptor positive/HER2- negative breast cancer model.
[0012] FIG. 4 shows results from an in vivo experiment to evaluate the pharmacodynamic effects of Compound 36 alone and in combination with ribociclib in a human hormone-receptor positive/HER2- negative breast cancer model.
DETAILED DESCRIPTION
[0013] The features and other details of the disclosure will now be more particularly described.
Certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.
Compounds
[0014] In one aspect, described herein is a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: i. a compound of Formula (I): wherein: each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, halogen, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl (e.g., CF3), and C1-6 haloalkoxy (e.g., OCF3); ring A is selected from the group consisting of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl, wherein each of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more occurrences of R5; each occurrence of R5 is independently selected from the group consisting of halogen, NH2, S(O)2NH2, CI-6 alkyl, C1-6 alkoxy, C3-12 monocyclic cycloalkyl, aryl, and heteroaryl, wherein each of C1-6 alkyl, C1-6 alkoxy, and C3-12 monocyclic cycloalkyl is optionally substituted with one or more occurrences of R6; each occurrence of R6 is independently selected from the group consisting of halogen, Ci-6 alkyl, C1-6 alkoxy, and OH; each occurrence of R7 is H or C1-6 alkyl; and n is an integer selected from the group consisting of 0, 1, 2, and 3; or ii. a compound selected from Table 1 below.
[0015] In one aspect, described herein is a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: i. a compound of Formula (I): wherein: each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, halogen, CN, C1-6 alkyl, and C1-6 alkoxy; ring A is selected from the group consisting of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl, wherein each of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more occurrences of R5; each occurrence of R5 is independently selected from the group consisting of halogen, Ci- 6 alkyl, C1-6 alkoxy, C3-12 monocyclic cycloalkyl, and aryl, wherein each of C1-6 alkyl, C1-6 alkoxy, and C3-12 monocyclic cycloalkyl is optionally substituted with one or more occurrences of R6; each occurrence of R6 is independently selected from the group consisting of halogen, Ci- 6 alkyl, C1-6 alkoxy, and OH; each occurrence of R7 is H or C1-6 alkyl; and n is an integer selected from the group consisting of 0, 1, 2, and 3; or ii. a compound selected from Table 1 below.
Tables 1 and 2. Exemplary Compounds
[0016] Tables 1 and 2 below include the compound number of each compound in accordance with the contents of the present specification.
Table 1
Table 2
[0017] In some embodiments, the compound is a compound of Formula (I).
[0018] In some embodiments, each occurrence of R7 is H or C1-3 alkyl. In some embodiments, each occurrence of R7 is H or CH3. [0020] In some embodiments, the compound of Formula (I) is a compound of Formula (II):
[0021] In some embodiments, each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, halogen, and C1-6 alkyl. In some embodiments, each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, halogen, and C1-3 alkyl. In some embodiments, each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, F, Cl, and CH3.
[0023] In some embodiments, ring A is C3-12 bicyclic cycloalkyl that is optionally substituted with one or more occurrences of R5. In some embodiments, ring A is C3-6 bicyclic cycloalkyl that is optionally substituted with one or more occurrences of R5. In some embodiments, ring A is bicyclo [l.l.l]pentyl that is optionally substituted with one or more occurrences of R5. In some embodiments, ring A is In some embodiments, ring A is . In some embodiments, ring
[0024] In some embodiments, each occurrence of R5 is C1-6 alkyl that is optionally substituted with one or more occurrences of R6. In some embodiments, each occurrence of R5 is C1-3 alkyl that is optionally substituted with one or more occurrences of R6. In some embodiments, each occurrence of R5 is CH3.
[0025] In some embodiments, each occurrence of R6 is halogen. In some embodiments, each occurrence of R6 is F.
[0026] In some embodiments, n is 0.
[0027] In some embodiments, the compound of Formula (I) is a compound of Formula (IA): compound of Formula (I) is a compound of Formula (ID):
[0028] In some embodiments, the compound of Formula (I) is selected from the group consisting some embodiments, the compound of Formula (I) is selected
[0029] In some embodiments, the compound is a compound selected from Table 1.
[0030] In some embodiments, the compound is a compound selected from Table 3. Table 3
[0031] In some embodiments, the compound is selected from Table 1 and is not a compound of
Table 3.
[0032] In some embodiments, the compound is Compound 36. In some embodiments, the compound is Compound 78. In some embodiments, the compound is Compound 79.
Pharmaceutical Compositions
[0033] In one aspect, described herein is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt described herein and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound or pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound or pharmaceutically acceptable salt.
[0034] The pharmaceutical compositions described herein may be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. Advantageously, the compounds of the invention are suitable for oral administration. [0035] Compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. In some embodiments, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.
Methods of Treatment and Uses
[0036] The compounds described herein can be used to degrade CDK2.
[0037] In some embodiments of the disclosure, a compound described herein is used to degrade
CDK2 in an ex vivo or in vitro system. In some embodiments, a compound described herein is used to degrade CDK2 in an ex vivo system. In some embodiments, a compound described herein is used to degrade CDK2 in an in vitro system.
[0038] Described herein is a method of degrading CDK2 comprising combining CDK2 and cereblon with a compound described herein in an ex vivo system or in vitro system. In some embodiments, the method comprises combining CDK2 and cereblon with a compound described herein in an ex vivo system. In some embodiments, the method comprises combining CDK2 and cereblon with a compound described herein in an in vitro system.
[0039] Cyclin dependent kinases (CDKs) are a family of closely related kinases that regulate progression through the cell cycle. CDK activity is further modulated by levels of specific cyclins; for example, cyclin El activates cyclin dependent kinase 2 (CDK2). Mechanisms activating CDK2 in tumors are (i) amplification of cyclin El or cyclin E2, and (ii) loss of the AMBRA1 gene. Elimination of CDK2 is contemplated to treat such disorders.
[0040] Accordingly, the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein are contemplated as useful in the treatment or prevention of disorders in subjects in need thereof. In some embodiments, a compound or pharmaceutical composition described herein is used to degrade CDK2 in a subject. In some embodiments, a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein is used to degrade CDK2 for the treatment or prevention of a disorder. Where methods for treatment of the human or animal body by surgery or therapy, or diagnostic methods practiced on the human or animal body, are described herein, this corresponds to the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein for use in such methods.
[0041] In one aspect, described herein is a method of treating or preventing a disorder in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein. In some embodiments, the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered to degrade CDK2 in the subject.
[0042] In one aspect, described herein is a method of degrading CDK2 in a subject suffering from a disorder, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition described herein. In some embodiments, the compound binds to cereblon and a CDK2 protein to induce ubiquitination and subsequent proteasomal degradation of the CDK2 protein.
[0043] Exemplary disorders that can be treated or prevented by the methods of the present disclosure include, but are not limited to, cancer of the bladder, bone, brain, breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, upper aerodigestive tract (including nasal cavity and paranasal sinuses, nasopharynx or cavum, oral cavity, oropharynx, larynx, hypopharynx, and salivary glands), neck, ovaries, pancreas, prostate, rectum, skin, stomach, testis, throat, and uterus. Other exemplary disorders include, but are not limited to, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, e.g., neuroendocrine prostate cancer such as castration-resistant neuroendocrine prostate cancer (NEPC) and lung neuroendocrine tumors (Lu- NETs), rectal adenocarcinoma, colorectal cancer, including stage 3 and stage 4 colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy -insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma; and blood bourne (liquid) or hematological cancers, including but not limited to leukemias, lymphomas, and myelomas, such as diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia/lymphoma, adult T- cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell/histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (for example, DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus-type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM).
[0044] In some embodiments, the disorder is cancer.
[0045] In some embodiments, the disorder is cancer that comprises a solid tumor. In some embodiments, the solid tumor is at least one of the group consisting of: uterine cancer (such as uterine carcinosarcoma and uterine corpus endometrial carcinoma), endometrial cancer, breast cancer, (such as breast invasive carcinoma and triple negative breast cancer, ER+ HER2- breast cancer, and HER2+ breast cancer), ovarian cancer (such as ovarian serous cystadenocarcinoma), stomach cancer (such as stomach adenocarcinoma), gastric cancer (such as gastrointestinal stromal cancer), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (such as B-cell lymphoma), sarcoma, esophageal cancer (such as esophageal carcinoma), bladder cancer (such as bladder urothelial carcinoma), lung cancer (such as lung squamous carcinoma and non-small cell lung cancer including EGFRm+ (epidermal growth factor receptor mutant positive) non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, mesothelioma, and malignant melanoma. In some embodiments, the solid tumor is at least one of the group consisting of: prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, and melanoma.
[0046] In some embodiments, the disorder is cancer that is selected from the group consisting of: ovarian cancer, endometrial cancer, gastric cancer, esophaegeal cancer, breast cancer (such as triple negative breast cancer), and lung adenosarcoma. In some embodiments, the disorder is breast cancer, gastric cancer, or ovarian cancer. In some embodiments, the disorder is breast cancer or ovarian cancer. In some embodiments, the disorder is ovarian cancer.
[0047] In some embodiments, the disorder is breast cancer. In some embodiments, the breast cancer is HR+ (hormone receptor positive) breast cancer. In some embodiments, the breast cancer is ER+ (estrogen receptor positive) breast cancer. In some embodiments, the breast cancer is HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer. In some embodiments, the breast cancer is ER+ HER2- breast cancer. In some embodiments, the cancer is triple negative breast cancer.
[0048] In some embodiments, the disorder is cancer that comprises a liquid tumor. In some embodiments, the liquid tumor is at least one of the group consisting of: diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia/lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell/histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (for example, DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T -cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus- type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM). In some embodiments, the liquid tumor is at least one of the group consisting of: acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (such as follicular lymphoma, including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, and multiple myeloma.
[0049] In one aspect, described herein is a method of treating cancer (e.g., a cancer described herein) in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein. [0050] In one aspect, described herein is a method of degrading CDK2 in a subject suffering from cancer (e.g., a cancer described herein), wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein.
[0051] In one aspect, described herein is a method of treating a solid tumor (e.g., a solid tumor described herein) in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein.
[0052] In one aspect, described herein is a method of treating a liquid tumor (e.g., a liquid tumor described herein) in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein. In some embodiments, the liquid tumor is that of a haematological cancer (e.g., a haematological cancer described herein).
[0053] In some embodiments, the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered as a first-line therapy. In some embodiments, the subject to which the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered is a treatment-naive subject, i.e. a subject that has not yet been treated with the standard of care.
Combinations
[0054] The compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein can be administered as single agents or in combination with one or more additional therapeutic agents such as additional anticancer agents, in particular standard of care agents appropriate for the particular disorder (e.g., the particular cancer) to be treated. Therefore, in some embodiments, the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered in combination with an additional therapeutic agent, for example an additional anticancer agent. In other words, the compounds, salts, or compositions of the invention may be for use in therapy in combination with an additional therapeutic agent, for example an additional anticancer agent. Similarly, a therapeutic agent, for example an anticancer agent, may be for use in therapy with the compounds, salts, or compositions of the invention.
[0055] The additional therapeutic agent may be administered at the same time or at a different time (for example, sequentially) to the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein. [0056] Additional anticancer agents that can be administered in the methods of the present disclosure include anticancer agents of the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and/or serine/threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immuno -oncology agents, and the like.
[0057] Alternatively, the additional anticancer agent may be an anticancer agent of one of the following classes: endocrine agents, PIK3CA inhibitors, antibody-drug conjugates, PLK1 inhibitors, Estrogen PROTAC, anti-angiogenesis agents, signal transduction inhibitors such as kinase inhibitors and cell cycle inhibitors, classical antineoplastic agents such as hormonal modulators, epigenetic modulators, immunomodulatory agents, and EGFR inhibitors.
[0058] In some embodiments, the additional therapeutic agent is a CDK4/6 inhibitor such as palbociclib, ribociclib, abemaciclib, lerociclib, trilaciclib, dalpiciclib, birociclib,BPI-16350, or in each case a pharmaceutically acceptable salt thereof. In some embodiments, CDK4/6 inhibitor is palbociclib, ribociclib, abemaciclib, or in each case a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4/6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof, or ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4/6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof such as ribociclib succinate. In some embodiments, the CDK4/6 inhibitor is abemaciclib or a pharmaceutically acceptable salt thereof. These additional therapeutic agents are particularly suitable when the disorder to be treated is breast cancer (such as HR+ breast cancer, ER+ breast cancer, HR+ HER2- breast cancer, or ER+ HER2- breast cancer). In some embodiments, the breast cancer has progressed despite treatment with a CDK4/6 inhibitor. In some embodiments, the breast cancer is resistant to treatment with a CDK4/6 inhibitor. In some embodiments, the subject with breast cancer is a treatment-naive subject. In some embodiments, the CDK4/6 inhibitor is administered in combination with endocrine therapy. In some embodiments, the CDK4/6 inhibitor is administered in combination with endocrine therapy and the endocrine therapy is administered in combination with a luteinising hormone- releasing hormone (LHRH) agonist. In some embodiments, the endocrine therapy is an estrogen receptor antagonist such as fulvestrant, or an aromatase inhibitor such as letrozole. In some embodiments, the endocrine therapy is fulvestrant. In some embodiments, the CDK4/6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof, or ribociclib or a pharmaceutically acceptable salt thereof, and is administered in combination with fulvestrant. In some embodiments, the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof and is administered in combination with fulvestrant. In any of the preceding embodiments, the CDK4/6 inhibitor may be present in the form of a pharmaceutically acceptable salt. For example, ribociclib, if present, may be in the form of a succinate salt, i.e. as ribociclib succinate. In some embodiments, the compound is Compound 36 and the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound 78 and the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound 79 and the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof.
[0059] In some embodiments, the additional anticancer agent is an endocrine agent such as an aromatase inhibitor, a SERD (Selective Estrogen-Receptor Downregulators), or a SERM (Selective Estrogen Receptor Modulator). Examples of aromatase inhibitors include exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), and formestane. Examples of SERDs include fulvestrant, SZ102, G1T48, RADI 901, elacestrant, GDC-9545, giredestrant, SAR439859, amcenestrant, AZD9833, camizestrant, LY3484356, Zn-c5, and D-0502. Examples of SERMs include tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF 4227 (Cheisi).
[0060] In some embodiments, the additional anticancer agent is a PIK3CA inhibitor such as alpelisib (PIQRAY), BEBT-908, BPI-21668, bupalisib, inavolisib, TQB-3525, RLY-2608, miransertib, MEN-1611, LOXO-783, HS-10352, HH-CYH33, gedatolisib, or fimepinostat.
[0061] In some embodiments, the additional anticancer agent is an antibody-drug conjugate such as Trastuzumab deruxtecan (Enhertu), Trastuzumab duocarmazine, Trastuzumab emtansine (Kadcyla), Upifitamab rilsodotin, mirvetuximab soravtansine, Tisotumab vedotin (Tivdak), Praluzatamab ravtansine, Sacituzumab govitecan or Sacituzumab Govitecan-hziy (Trodelvy), Datopotamab deruxtecan, Ladiratuzumab vedotin, Patritumab deruxtecan, STRO-002, MORab-202, DS-6000, Anetumab, avtansine, XMT-2056, or Disitamab Vedotin (RC48-ADC, Aidexi).
[0062] In some embodiments, the additional anticancer agent is a PLK1 inhibitor such as onvansertib, B12536, BI6727, GSK461364A, TAK960, or rigosertib.
[0063] In some embodiments, the additional anticancer agent is Estrogen PROTAC (ARV-471,
H3B-5942).
[0064] In some embodiments, the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered in combination with a standard of care agent. In some embodiments, the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered in combination with endocrine therapy, for example, an agent such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole. In some embodiments, the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered in combination with a chemotherapeutic agent, for example, docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, vinorelbine, or liposomal doxorubicin. In some embodiments, the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered in combination with an anti-HER2 agent, for example, trastuzumab or pertuzumab.
[0065] In some embodiments, the additional therapeutic agent is carboplatin, ribociclib or a pharmaceutically acceptable salt thereof, fulvestrant, or a combination thereof.
[0066] In some embodiments, the additional anticancer agent is an anti-angiogenesis agent such as an anti-angiogenesis agent selected from the group consisting of: VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, PKCb inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha- v/beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (matrix-metalloproteinase 9) inhibitors. Preferred anti-angiogenesis agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG 13736), SU 14813 (Pfizer), and AG 13958 (Pfizer). Further antiangiogenesis agents include vatalanib (CGP 79787), Sorafenib (Nexavar™), pegaptanib octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE 941), tetrathiomolybdate (Coprexa™), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352), and CP-868,596 (Pfizer). Yet further anti-angiogenesis agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex™), and UCN 01 (Kyowa Hakko). Yet further anti-angiogenesis agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC 59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP 751 (invedus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia™). Yet further antiangiogenesis agents include exisulind (Aptosyn™), salsalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Yet further anti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat™), and PCK 3145 (Procyon). Yet further anti-angiogenesis agents (including VEGFR / PDGFR inhibitors) include ponatinib (Iclusig), BT1718, anlotinib, lenvatinib (Lenvima), tivozanib (Fotivda), dovitinib, brolucizumab (Beovu), aflibercept (Eylea), and faricimab. Yet further antiangiogenesis agents include acitretin (Neotigason™), plitidepsin (aplidine™), cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4 HPR), halofuginone (Tempostatin™), Panzem™ (2~methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukrain™ (NSC 631570), Vitaxin™ (MED1522), and zoledronic acid (Zometa™).
[0067] In some embodiments, the additional anticancer agent is a signal transduction inhibitor
(an agent that inhibits how regulatory molecules that govern the fundamental processes of cell growth, differentiation, and survival communicate within the cell). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors also include kinase inhibitors (such as tyrosine kinase inhibitors and serine/threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signal transduction inhibitors include famesyl protein transferase inhibitors, EGF inhibitors, ErbB-1 (EGER), ErbB-2, pan erb, IGF 1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, inhibitors of the WNT pathway, and multitargeted kinase inhibitors. Examples of signal transduction inhibitors include BMS 214662 (Bristol- Myers Squibb), lonafamib (Sarasar™), pelitrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCiM h-R3™), panitumumab (Vectibix™), Vandetanib (Zactima™), pazopanib (SB 786034), ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer Ingelheim), and Cervene™ (TP 38). Other examples of signal transduction inhibitors include gefitinib (Iressa™), cetuximab (Erbitux™), erlotinib (Tarceva™), trastuzumab (Herceptin™), sunitinib (Sutent™), imatinib (Gleevec™), crizotinib (Pfizer), lorlatinib (Pfizer), dacomitinib (Pfizer), bosutinib (Pfizer), gedatolisib (Pfizer), canertinib (Cl 1033), pertuzumab (Omnitarg™), lapatinib (Tycerb™), pelitinib (EKB 569), miltefosine (Miltefosin™), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM 1), mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), ARRY 142886 (Array Biopharm), everolimus (Certican™), zotarolimus (Endeavor™), temsirolimus (Torisel™), AP 23573 (ARIAD), and VX 680 (Vertex), XL 647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University), and GI-4000 (Globelmmune). Further examples of signal transduction inhibitors include ABT 751 (Abbott), alvocidib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 112 (One Bio), BMS 387032 (Bristol-Myers Squibb), palbociclib (Pfizer), and AG 024322 (Pfizer).
[0068] In some embodiments, the additional anticancer agent is a classical antineoplastic agent.
Classical antineoplastic agents include hormonal modulators such as hormonal, anti-hormonal, androgen agonist, androgen antagonist and anti-estrogen therapeutic agents, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing agents or gene activating agents, ribonucleases, proteosomics, Topoisomerase I inhibitors, Camptothecin derivatives, Topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (P ARP-1) inhibitors (such as talazoparib, olapariv, rucaparib, niraparib, iniparib, veliparib), microtubulin inhibitors, antibiotics, plant derived spindle inhibitors, platinum-coordinated compounds, gene therapeutic agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins. Examples of classical antineoplastic agents include glucocorticoids such as dexamethasone, prednisone, prednisolone, methyl prednisolone, hydrocortisone, and progestins such as medroxyprogesterone, megestrol acetate (Megace), mifepristone (RU-486), Selective Estrogen Receptor Modulators (SERMs, such as tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF 4227 (Cheisi)), Selective Estrogen-Receptor Downregulators (SERDs, such as fulvestrant, SZ102, G1T48, RADI 901, elacestrant, GDC-9545, giredestrant, SAR439859, amcenestrant, AZD9833, camizestrant, LY3484356, Zn-c5, D-0502), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), formestane; gonadotropin-releasing hormone (GnRH, also commonly referred to as luteinizing hormone-releasing hormone [LHRH]) agonists such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar), abarelix (Plenaxis), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandron), and osaterone, dutasteride, epristeride, finasteride, Serenoa repens, PHL 00801, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide; antiandrogen agents, such as enzalutamide, abiraterone acetate, bicalutamide (Casodex); and combinations thereof. Further examples of classical antineoplastic agents include suberolanilide hydroxamic acid (SAHA, Merck Inc./Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M- 777, MS-275, pivaloyloxymethyl butyrate and PXD-101; Onconase (ranpimase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, irinotecan HC1 (Camptosar), lurtotecan, Orathecin (rubitecan, Supergen), SN-38, topotecan, camptothecin, 10-hydroxy camptothecin, 9-aminoearaptothecin, irinotecan, SN-38, edotecarin, topotecan, aclarubicin, adriamycin, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxycarbamide, nemorubicin, novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylating compounds such as cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi), streptozocin, satrplatin, and combinations thereof. Yet further examples of classical antineoplastic cytotoxic agents include Abraxane (Abraxis Bio Science, Inc.), Batabulin (Amgen), EPO 906 (Novartis), Vinflunine (Bristol-Myers Squibb Company), actinomycin D, bleomycin, mitomycin C, neocarzinostatin (Zinostatin), vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxei (Taxotere), Ortataxel, paclitaxel (including Taxoprexin, a DHA/paciltaxel conjugate), cisplatin, carboplatin, Nedaplatin, oxaliplatin (Eloxatin), Satraplatin, Camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), Taxotere alitretinoin, Canfosfamide (Telcyta™), DMXAA (Antisoma), ibandronic acid, L-asparaginase, pegaspargase (Oncaspar™), Efaproxiral (Efaproxyn™ - radiation therapy), bexarotene (Targretin™), Tesmilifene (DPPE - enhances efficacy of cytotoxics), Theratope™ (Biomira), Tretinoin (Vesanoid™), tirapazamine (Trizaone™), motexafin gadolinium (Xcytrin™), Cotara™ (mAb), NBI-3001 (Protox Therapeutics), polyglutamatepaclitaxel (Xyotax™), and combinations thereof. Yet further examples of classical antineoplastic agents include Advexin (ING 201), TNFerade (GeneVec, a compound which expresses TNF alpha in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Oblimersen, Genta), Combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, Pfizer Inc.), Provastatin (Pravachol, Bristol-Myers Squibb), Lovastatin (Mevacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin, Niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, and combinations thereof.
[0069] In some embodiments, the additional anticancer agent is an epigenetic modulator such as an inhibitor of EZH2, SMARCA4, PBRM1, ARID1A, ARID2, ARID IB, DNMT3A, TET2, MLL1/2/3, NSD1/2, SETD2, BRD4, DOTIL, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1/2, or BCL6.
[0070] In some embodiments, the additional anticancer agent is an immunomodulatory agent such as an inhibitor of CTLA-4 (for example, ipilimumab), PD-1 or PD-L1 (for example, pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab, or dosterlimab), LAG-3 (for example, relatlimab), TIM-3, TIGIT, 4-1BB, 0X40, GITR, or CD40, or a CAR-T-cell therapy.
[0071] In some embodiments, the additional anticancer agent is an EGFR inhibitor such as afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, or gefitinib, or an EGFR antibody such as cetuximab, panitumumab, or necitumumab.
[0072] In some embodiments, the additional anticancer agent is an anticancer agent that is not an
EGFR inhibitor, for example selected from MEK, including mutant MEK, inhibitors (trametinib, cobimetinib, binimetinib, selumetinib, refametinib); c-MET, including mutant c-Met, inhibitors (savolitinib, cabozantinib, foretinib), and MET antibodies (emibetuzumab); mitotic kinase inhibitors (CDK4/6 inhibitors such as palbociclib, ribociclib, abemacicilb, lerociclib, trilaciclib, dalpiciclib, birociclib, BPI-16350 and pharmaceutically acceptable salts of each of these); anti-angiogenic agents such as bevacizumab, nintedanib; apoptosis inducers such as Bcl-2 inhibitors e.g., venetoclax, obatoclax, navitoclax, and Mcl-1 inhibitors e.g., AZD-5991, AMG-176, S-64315; and mTOR inhibitors such as rapamycin, temsirolimus, everolimus, ridoforolimus.
[0073] In some embodiments, the additional anticancer agent is palbociclib (e.g., ibrance®), ribociclib, abemacicilb, tamoxifen, letrozole, olaparib (e.g., Lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g., xeloda®), regorafenib (e.g., stivarga®), afatinib (e.g., gilotrif®), osimertinib (e.g., tagrisso®), gefitinib (e.g., iressa®), erlotinib (e.g., tarceva®), ramucirumab (e.g., cyramza®), an EGFR inhibitor, pralsetinib, ABT- 263 (navitoclax), MK-1775 (adavosertib), BAY-1895344, berzosertib, ceralasertib, SRA-737, LY2603618 (rabusertib), and trastuzumab (e.g., herceptin®), or combinations thereof. The EGFR inhibitor may be afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02, alflutinib (AST 2818), aumolertinib (formerly almonertinib) (HS10296), BBT-176, BI- 4020, BPI-361175, BPI-D0316, CH7233163, gilitertinib, icotinib, JND-3229, lazertinib, nazartinib (EGF 816), avitinib, PCC-0208027, rezivertinib (BRI-77G1), TQB3804, zorifertinib (AZ-3759), or DZD9008; an EGFR antibody such as cetuximab, panitumumab, necitumumab, HLX07, or JMT101; or a bispecific EGFR and MET antibody (e.g., amivantamab (JNJ-61186372, JNJ-372)).
Combinations with CDK4/6 inhibitors
[0074] As discussed above, in some embodiments, the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered in combination with a CDK4/6 inhibitor. Accordingly, described herein are the products set out below.
[0075] In one aspect, described herein is a combination comprising:
(i) a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a compound selected from Table 1 or a pharmaceutically acceptable salt thereof; and
(ii) a CDK4/6 inhibitor.
[0076] In one aspect, described herein is a kit comprising (i) a unit dosage form comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a compound selected from Table 1 or a pharmaceutically acceptable salt thereof, and, separately, (ii) a unit dosage form comprising a CDK4/6 inhibitor. In some embodiments, each unit dosage form is a pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients. In some embodiments, the unit dosage forms are present in a single package. In some embodiments, the unit dosage forms are present in separate packages.
[0077] In one aspect, described herein is a method of treating cancer in a subject in need thereof using the combination or kit described above.
[0078] In one aspect, described herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a compound selected from Table 1 or a pharmaceutically acceptable salt thereof, together with instructions to use the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the compound selected from Table 1 or pharmaceutically acceptable salt thereof, in combination with a CDK4/6 inhibitor. In some embodiments, the instructions specify use of the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the compound selected from Table 1 or pharmaceutically acceptable salt thereof, in combination with the CDK4/6 inhibitor for the treatment of a disorder (e.g., cancer). In some embodiments, the instructions specify simultaneous, separate, or sequential use of the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the compound selected from Table 1 or pharmaceutically acceptable salt thereof, and the CDK4/6 inhibitor. In some embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the compound selected from Table 1 or pharmaceutically acceptable salt thereof, is in a unit dosage form. In some embodiments, the unit dosage form is a pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients.
[0079] In one aspect, described herein is a CDK4/6 inhibitor together with instructions to use the
CDK4/6 inhibitor in combination with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a compound selected from Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the instructions specify use of the CDK4/6 inhibitor in combination with the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the compound selected from Table 1 or pharmaceutically acceptable salt thereof, for the treatment of a disorder (e.g., cancer). In some embodiments, the instructions specify simultaneous, separate, or sequential use of the CDK4/6 inhibitor and the compound of Formula (I) or pharmaceutically acceptable salt thereof, or the compound selected from Table 1 or pharmaceutically acceptable salt thereof. In some embodiments, the CDK4/6 inhibitor is in a unit dosage form. In some embodiments, the unit dosage form is a pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients. [0080] In either of the preceding two aspects, the instructions may be of the kind that are provided to a doctor, for example on a drug product label, or they may be of the kind that is provided to a patient, for example by a doctor.
Definitions
[0081] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.
[0082] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C1-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-6, C1-5, Ci- 4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
[0083] Compounds that are described as being “optionally substituted” may be substituted with one or more specifically described groups or may be unsubstituted. In some embodiments, compounds that are described as being “optionally substituted” are unsubstituted.
[0084] The term “alkyl” as used herein refers to a radical of a straight-chain or branched saturated hydrocarbon group. In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl- 2-butanyl (C5), tertiary amyl (C5), and n-hexyl (Ce). Additional examples of alkyl groups include n- heptyl (C7), n-octyl (Cs), and the like. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), and i-Bu (-CH2CH(CH3)2).
[0085] The term “alkenyl” as used herein refers to a radical of a straight-chain or branched hydrocarbon group having one or more carbon-carbon double bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1- butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like.
[0086] The term “alkynyl” as used herein refers to a radical of a straight-chain or branched hydrocarbon group having one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2- butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkynyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. [0087] The term “cycloalkyl” as used herein refers to a radical of a saturated or partially unsaturated cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C3-12 cycloalkyl”) and zero heteroatoms in the ring system. In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Exemplary C3-6 cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), bicyclo [1.1. l]pentyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 cycloalkyl groups include, without limitation, the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 cycloalkyl groups include, without limitation, the aforementioned C3-8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. In some embodiments, the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contains a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) or tricyclic system (“tricyclic cycloalkyl”). “Cycloalkyl” includes ring systems wherein the cycloalkyl ring as defined above is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the cycloalkyl ring or the one or more aryl or heteroaryl groups, and in such instances, the number of carbons continues to designate the number of carbons in the cycloalkyl ring system.
[0088] The term “heterocyclyl” as used herein refers to a radical of a saturated or partially unsaturated 3 to 10-membered ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3 to 10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”). In heterocyclyl bicyclic ring systems, the one or more heteroatoms can be present in one ring or both rings. “Heterocyclyl” includes ring systems wherein the heterocyclyl ring as defined above is fused with one or more cycloalkyl groups wherein the point of attachment is either on the heterocyclyl ring or the one or more cycloalkyl groups, and ring systems wherein the heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring or the one or more aryl or heteroaryl groups, and in such instances, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system.
[0089] In some embodiments, a heterocyclyl group is a 5 to 10 membered saturated or partially unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5 to 8 membered saturated or partially unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5 to 6 membered saturated or partially unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 6 membered heterocyclyl”). In some embodiments, the 5 to 6 membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5 to 6 membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5 to 6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
[0090] Exemplary 3 -membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl- 2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8- membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary 5 -membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, without limitation, indolinyl, isoindo linyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
[0091] The term “aryl” as used herein refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 it electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce- 14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
[0092] The term “heteroaryl” as used herein refers to a radical of a 5 to 10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 it electrons shared in a cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5 to 10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. In heteroaryl bicyclic ring systems, the one or more heteroatoms can be present in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring as defined above is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. In bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
[0093] As explained above, in some embodiments a heteroaryl group is a 5 to 10 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5 to 8 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 8 membered heteroaryl”). In some embodiments, a heteroaryl group is a monocyclic 5 to 6 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5 to 6 membered heteroaryl”). In some embodiments, the 5 to 6 membered heteroaryl has 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5 to 6 membered heteroaryl has 1 to 2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5 to 6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl group is a monocyclic 5 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-membered heteroaryl”). In some embodiments, a heteroaryl group is a monocyclic 6 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“6-membered heteroaryl”).
[0094] In some embodiments, a heteroaryl group is a 5 to 10 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“5 to 10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5 to 8 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“5 to 8 membered heteroaryl”). In some embodiments, a heteroaryl group is a monocyclic 5 to 6 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“5 to 6 membered heteroaryl”). In some embodiments, the 5 to 6 membered heteroaryl has 1 to 3 ring heteroatoms that are independently nitrogen or oxygen. In some embodiments, the 5 to 6 membered heteroaryl has 1 to 2 ring heteroatoms that are independently nitrogen or oxygen. In some embodiments, the 5 to 6 membered heteroaryl has 1 ring heteroatom that is independently nitrogen or oxygen. In some embodiments, a heteroaryl group is a monocyclic 5 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“5 -membered heteroaryl”). In some embodiments, a heteroaryl group is a monocyclic 6 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently nitrogen or oxygen (“6- membered heteroaryl”).
[0095] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5 -membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
[0096] The term “alkoxy” as used herein refers to the group -OR100 where R100is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Other exemplary alkoxy groups are lower alkoxy groups, i.e. alkoxy groups with between 1 and 6 carbon atoms. In some embodiments, alkoxy groups have between 1 and 4 carbon atoms.
[0097] The term “halogen” as used herein refers to F, Cl, Br, or I.
[0098] The term “haloalkyl” as used herein refers to an alkyl group substituted with one or more halogen atoms, e.g., one or more F atoms.
[0099] The term “haloalkoxy” as used herein refers to an alkoxy group substituted with one or more halogen atoms, e.g., one or more F atoms.
[00100] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge el al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
[00101] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys and rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.
[00102] The terms “disease,” “disorder,” and “condition” are used interchangeably herein.
[00103] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition. In some embodiments, the present disclosure contemplates administration of the compounds described herein as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition.
[00104] In general, the “effective amount” of a compound as used herein refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the present disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.
[00105] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
[00106] It is to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (z.e., as (+) or (-)- isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
[00107] Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds and pharmaceutically acceptable salts described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [00108] The compounds and pharmaceutically acceptable salts described herein can be administered as the sole active agent, or they can be administered in combination with other active agents. In some embodiments, the present invention provides a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration.
[00109] The present disclosure, in an alternative embodiment, also embraces isotopically labeled compounds and pharmaceutically acceptable salts which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 170, 31P, 32P, 35S, 18F, and 36C1, respectively. For example, the compounds and pharmaceutically acceptable salts of the present disclosure may have one or more, or all H atoms replaced with deuterium.
Preparation of compounds
Scheme A
[00110] Scheme A provides a specific exemplary synthetic strategy for the preparation of a compound of Formula A where substituted halogenated-oxadiazole AB is comprised of any suitable substituent which provides a compound of Formula A. Formula A is an alternative depiction of Formula (I). [00111] Compounds of Formula A may be prepared by coupling AT and AB via a SnAr reaction, for example by treatment with a base such as DIPEA (diisopropylethylamine) in a solvent such as N.N- dimethylacetamide. The reaction may be performed at an elevated temperature such as 100-110 degrees Celsius.
Scheme B
[00112] A general synthetic strategy that may be used to prepare compounds of formula AT, which may be used as starting material AT in Scheme A, is depicted in Scheme B. An aryl primary amine AU where Hal is a suitable halogen atom (e.g., Br) may be converted into AV using any suitable conjugated addition reaction conditions. The specific groups R1, R2, R3, and R4 are selected on the basis of the desired groups in the compound of Formula A. The desired compound AV can be prepared using a,P-unsaturated amides reagents such as acrylamide. A solvent such as acetic acid may be used. The reaction may be performed at elevated temperatures, such as 110 degrees Celsius.
[00113] AV may be converted into AW by a cyclization reaction using appropriate reagents, such as di(l/f-imidazol-l-yl)methanone, in the presence of a base such as triethylamine. A solvent such as A'A'-dimcthyl formamide may be used. The reaction may be performed at an elevated temperature, such as 80-120 degrees Celsius.
[00114] AW may be converted into AZ by a Buchwald-Hartwig reaction of a secondary amine of formula AF. AZ may be prepared under an inert atmosphere using palladium catalysts such as PEPPSI- IHetp Cl and RuPhos Pd G3 in the presence of a base such as caesium carbonate. A solvent such as dioxane may be used. The reaction may be performed at 100 degrees Celsius. Alternatively, AW may be converted into AZ by a photochemical reaction using an appropriate catalytic system, such as [Ir(dtbbpy)(ppy)2]PFe and Nickel(II) bromide ethylene glycol dimethyl ether complex, in the presence of a base, such as l,4-diazabicyclo[2.2.2]octane. An appropriate source of irradiation, for example at 455 nm, must be used. A solvent such as A'A'-dimcthylacctamidc may be used.
[00115] AT may be prepared by removal of PG' (assuming PG' = tert-butoxycarbonyl) from AZ in the presence of an appropriate acid such as trifluoro acetic acid. The reaction may be performed at 25 degrees Celsius.
Scheme C
[00116] Scheme C provides a general synthetic approach to the preparation of compounds of formula AB which may be used as starting material AB in Scheme A. An appropriate carboxylic acid BA may be converted into compound BB, where PG is any suitable protecting group such as tert- butoxycarbonyl group. Appropriate reagents, such as Zcrt-butyl A'-aminocarbamatc and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, may be used. A solvent such as dichloromethane may be used. The reaction may be performed at 25 degrees Celsius. BC may be prepared from BB by removal of PG, assuming PG = Zcrt-butoxycarbony I. Any appropriate acid reagent such as trifluoroacetic acid may be used. A solvent such as dichloromethane may be used. The reaction may be performed at an elevated temperature such as 25 degrees Celsius. BC may be converted into intermediate BD using appropriate reagents, such as di(l/f-imidazol-l-yl)methanimine or cyanic bromide. A solvent or a mixture of solvents such as tetrahydrofuran, methanol or dioxane/water may be used. The reaction may be performed at 25-65 degrees Celsius. AB may be prepared from BD using an appropriate Cu(I) or Cu(II) salt (e.g., CuBr or CuBr2) in the presence of tert-butyl nitrite. A solvent such as acetonitrile may be used. The reaction may be performed at 60-80 degrees Celsius.
Scheme D
[00117] Scheme D provides an alternative general synthetic approach to the preparation of compounds of formula AB which may be used as starting material AB in Scheme A. An appropriate carboxylic acid BA may be converted into BE, where RB is any suitable group such as methyl or ethyl. Appropriate reagents, such as thionyl chloride, may be used. A solvent, such as methanol or ethanol (corresponding to RB = methyl and RB = ethyl respectively), may be used. The reaction may be performed at 25-60 degrees Celsius. BC may be prepared from BE by treatment with an appropriate reagent such as hydrazine hydrate. A solvent such as methanol or ethanol may be used. The reaction may be performed at 60-80 degrees Celsius. BC may be converted into intermediate BD using appropriate reagents, such as di( I //-imidazol-l -yljmcthaniminc or cyanic bromide. A solvent or a mixture of solvents such as tetrahydrofuran, methanol or dioxane/water may be used. The reaction may be performed at 25-65 degrees Celsius. AB may be prepared from BD using an appropriate Cu(I) or Cu(II) salt (e.g., CuBr or CuBr2) in the presence of tert-butyl nitrite. A solvent such as acetonitrile may be used. The reaction may be performed at 60-80 degrees Celsius.
Scheme E
AA Formula B
[00118] Scheme E provides a specific exemplary synthetic strategy for the preparation of a compound of Formula B where substituted halogenated-oxadiazole AB is comprised of any suitable substituent which provides a compound of Formula B. Formula B is equivalent to Formula A with a glutarimide ring replacing the dihydrouracil ring, and encompasses the compounds provided in Table 1.
[00119] Compounds of Formula B may be prepared by coupling AA and AB via a SnAr reaction. For example, by treatment with a base such as DIPEA (diisopropylethylamine) in a solvent such as N.N- dimethylacetamide. The reaction may be performed at an elevated temperature such as 100-110 degrees Celsius.
Scheme F
[00120] A general synthetic strategy that may be used to prepare starting materials of general structure AA is depicted in Scheme F. An aryl halide AC, where Hal is a suitable halogen atom (e.g., I) and Hal' is a suitable halogen atom (e.g., Br) may be coupled with boronic acid AD, where PG isa suitable protecting group (for example, benzyl), using any suitable metal catalyzed coupling conditions. The specific groups R1, R2, R3, and R4 are selected on the basis of the desired groups in the compound of Formula B. Compounds of general structure AE can be prepared using a Suzuki coupling reaction with palladium catalyst complex such as palladium catalyst (Pd(PPhs)4 or Pd(dppf)C12) in the presence of a base such as potassium carbonate. A solvent mixture such as dioxane and water may be used. The reaction may be performed at an elevated temperature, such as 90-100 degrees Celsius.
[00121] AE may be converted into AG by a Buchwald-Hartwig reaction of a secondary amine of formula AF, where PG' is a suitable protecting group (for example, ZcrZ-butoxycarbonyl). The compound can be prepared under an inert atmosphere using palladium catalysts such as PEPPSI-IHetp Cl and RuPhos Pd G3 in the presence of a base such as caesium carbonate. A solvent such as dioxane may be used. The reaction may be performed at 100 degrees Celsius.
[00122] Compounds of general structure AH may be prepared from AG by removal of PG using hydrogen in the presence of a metal catalyst such as palladium on carbon, assuming PG = benzyl. A solvent such as dioxane can be used. The reaction may be performed at 30-50 degrees Celsius. AA can be prepared by removal of PG' from AH in the presence of an appropriate acid such as trifluoroacetic acid, assuming PG'= ZcrZ-butoxycarbonyl. The reaction may be performed at 25 degrees Celsius.
Scheme G
[00123] Scheme G provides an alternative exemplary synthetic procedure for the preparation of starting material AA used in Scheme E. An aryl primary amine Al may be halogenated to AL, where Hal is a suitable halogen atom (e.g., Br), using any suitable halogenating reagent conditions. The specific groups R1, R2, R3, and R4 are selected on the basis of the desired groups in AA. The desired compound AL can be prepared by a halogenation reaction with reagents such as A-bromo-succinimide. A solvent such as acetonitrile may be used. The reaction may be performed at 20-25 degrees Celsius.
[00124] AL may be converted into AJ by a Suzuki reaction of boronate AD, where PG is a suitable protecting group (e.g., a benzyl group), with palladium catalyst complexes such as Pd(PPh3)4 in the presence of a base such as potassium carbonate. A solvent mixture such as dioxane and water may be used. The reaction may be performed at an elevated temperature, such as 90-100 degrees Celsius.
[00125] Compound AE, where Hal' is a suitable halogen atom (e.g., Br) may be prepared from AJ via a Sandmeyer reaction using appropriate reagents such as CuBr and ZcrZ-butyl nitrite. A solvent such as acetonitrile may be used. The reaction may be performed at 60 degrees Celsius. [00126] AE may be converted into AG by a Buchwald-Hartwig reaction of a secondary amine of formula AF, where PG' is a suitable protecting group (e.g., tert-butoxycarbonyl). AE can be prepared under an inert atmosphere using palladium catalysts such as PEPPSI-IHetp Cl and RuPhos Pd G3 in the presence of a base such as caesium carbonate. A solvent such as dioxane may be used. The reaction may be performed at 100 degrees Celsius.
[00127] Intermediate AH may be prepared from AG by removal of PG using hydrogen in the presence of a metal catalyst such as palladium on carbon, assuming PG = benzyl. A solvent such as dioxane can be used. The reaction may be performed at 30-50 degrees Celsius. AA can be prepared by removal of PG' from AH in the presence of an appropriate acid such as trifluoroacetic acid, assuming PG'= ZcrZ-butoxycarbonyl. The reaction may be performed at 25 degrees Celsius.
Scheme H
[00128] Scheme H provides a general synthetic approach to the preparation of compounds of general structure AD which may be used as starting material in Schemes F and G. Compound AK, where Hal is any suitable halogen atom (e.g., Cl) may be converted into compound AM, where PG is any suitable protecting group such as a benzyl group. An appropriate alcohol, such as phenylmethanol for PG = benzyl group, may be used in the presence of an appropriate base, such as potassium tert-butoxide. A solvent such as tetrahydrofuran may be used. The reaction may be performed at 20-70 degrees Celsius. Compound AN, where Hal' is any suitable halogen atom (e.g., Br) may be prepared from compound AM by a halogenation reaction. Appropriate reagents such as A-bromo -succinimide may be used. A solvent such as acetonitrile may be used. The reaction may be performed at an elevated temperature such as 80 degrees Celsius. Compound AN may be converted into intermediate AD by a borylation reaction. Appropriated reagents, such as triisopropylborate and n -butyllithium, may be used. A solvent such as tetrahydrofuran may be used. The reaction may be performed at low temperature such as minus 78 degrees Celsius.
Scheme I
[00129] Scheme I provides an alternative exemplary synthetic procedure for the preparation of starting material AA used in Scheme E. A substituted toluene AO where Hal is a suitable halogen atom (e.g., Br) may be converted into AP, where Hal' is a suitable halogen atom (e.g., Br), using any suitable halogenating reagent conditions. The specific groups R1, R2, R3, and R4 are selected on the basis of the desired groups in the compound of Formula B. AP can be prepared using a halogenating reagent such as A-bromosuccinimide in combination with a reagent such as benzoic peroxyanhydride or AIBN (azobisisobutyronitrile). A solvent such as carbon tetrachloride may be used. The reaction may be performed at elevated temperatures, such as 80 degrees Celsius.
[00130] AP may be converted into AQ using appropriate reagents, such as potassium cyanide or trimethylsilyl cyanide in combination with tetrabutylammonium fluoride. A solvent, such as acetonitrile, or a mixture of solvents, such as ethanol/water, may be used. The reaction may be performed at a temperature such as 20 or 80 degrees Celsius.
[00131] Compounds of general structure AR may be prepared from AQ by a conjugated addition using an appropriate reagent, such as tert-butyl acrylate or methyl acrylate, in the presence of a base, such as sodium methoxide. A solvent such as tetrahydrofuran may be used. The reaction may be performed at 0 to 20 degrees Celsius. [00132] AR may be converted into AS by treatment in an appropriate acidic medium such as a mixture of acetic acid and sulfuric acid. The reaction may be performed at elevated temperatures such as 90 degrees Celsius.
[00133] AS may be converted into AH by a Buchwald-Hartwig reaction of a secondary amine of formula AF. AS can be prepared under an inert atmosphere using palladium catalysts such as PEPPSI- IHetp Cl and RuPhos Pd G3 in the presence of a base such as caesium carbonate. A solvent such as dioxane may be used. The reaction may be performed at elevated temperatures such as 100 degrees Celsius.
[00134] AA can be prepared by removal of PG' from AH in the presence of an appropriate acid, assuming PG'= ZcrZ-butoxycarbonyl. such as trifluoroacetic acid. The reaction may be performed at 25 degrees Celsius.
EXEMPLARY EMBODIMENTS
[00135] Various exemplary embodiments are set out below.
1. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: i. a compound of Formula (I): wherein: each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, halogen, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; ring A is selected from the group consisting of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl, wherein each of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more occurrences of R5; each occurrence of R5 is independently selected from the group consisting of halogen, NH2, S(O)2NH2, C1-6 alkyl, C1-6 alkoxy, 63-12 monocyclic cycloalkyl, aryl, and heteroaryl wherein each of C1-6 alkyl, C1-6 alkoxy, and C3-12 monocyclic cycloalkyl is optionally substituted with one or more occurrences of R6; each occurrence of R6 is independently selected from the group consisting of halogen, Ci- 6 alkyl, C1-6 alkoxy, and OH; each occurrence of R7 is H or C1-6 alkyl; and n is an integer selected from the group consisting of 0, 1, 2, and 3; or ii. a compound selected from Table 1. The compound or pharmaceutically acceptable salt of embodiment 1, wherein the compound is a compound of Formula (I). The compound or pharmaceutically acceptable salt of embodiment 1 or embodiment 2, wherein: each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, halogen, CN, C1-6 alkyl, and C1-6 alkoxy; ring A is selected from the group consisting of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl, wherein each of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more occurrences of R5; each occurrence of R5 is independently selected from the group consisting of halogen, Ci- 6 alkyl, C1-6 alkoxy, C3-12 monocyclic cycloalkyl, and aryl, wherein each of C1-6 alkyl, C1-6 alkoxy, and C3-12 monocyclic cycloalkyl is optionally substituted with one or more occurrences of R6; each occurrence of R6 is independently selected from the group consisting of halogen, Ci- e alkyl, C1-6 alkoxy, and OH; each occurrence of R7 is H or C1-6 alkyl; and n is an integer selected from the group consisting of 0, 1, 2, and 3. The compound or pharmaceutically acceptable salt of any one of embodiments 1-3, wherein each occurrence of R7 is H or C1-3 alkyl. The compound or pharmaceutically acceptable salt of embodiment 4, wherein each occurrence of R7 is H or CH3. The compound or pharmaceutically acceptable salt of any one of embodiments 1-5, wherein
R7
The compound or pharmaceutically acceptable salt of embodiment 6, wherein
R7
The compound or pharmaceutically acceptable salt of embodiment 6, wherein The compound or pharmaceutically acceptable salt of any one of embodiments 1-5, wherein
The compound or pharmaceutically acceptable salt of embodiment 10, wherein The compound or pharmaceutically acceptable salt of embodiment 10, wherein
R7 The compound or pharmaceutically acceptable salt of embodiment 11, wherein The compound or pharmaceutically acceptable salt of any one of embodiments 1-13, wherein each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, halogen, CN, C1-3 alkyl, and C1-3 alkoxy. The compound or pharmaceutically acceptable salt of embodiment 14, wherein each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, F, Cl, CN, CH3, and OCH3. The compound or pharmaceutically acceptable salt of any one of embodiments 1-13, wherein each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, halogen, and C1-6 alkyl (e.g., C1-3 alkyl). The compound or pharmaceutically acceptable salt of embodiment 16, wherein each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, F, Cl, and CH3. The compound or pharmaceutically acceptable salt of embodiment 17, wherein each of R1, R2, R3, and R4 is independently selected from hydrogen and F. The compound or pharmaceutically acceptable salt of any one of embodiments 1-18, wherein any one of R1, R2, R3, and R4 is deuterium. The compound or pharmaceutically acceptable salt of any one of embodiments 1-19, wherein
21. The compound or pharmaceutically acceptable salt of any one of embodiments 1-19, wherein , and wherein none of R1, R2, R3, and R4 are hydrogen.
22. The compound or pharmaceutically acceptable salt of embodiment 20 or embodiment 21, wherein
23. The compound or pharmaceutically acceptable salt of embodiment 22, wherein The compound or pharmaceutically acceptable salt of embodiment 24, wherein The compound or pharmaceutically acceptable salt of embodiment 25, wherein The compound or pharmaceutically acceptable salt of any one of embodiments 1-26, wherein ring A is selected from the group consisting of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, aryl, and heteroaryl, wherein each of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more occurrences of R5. The compound or pharmaceutically acceptable salt of embodiment 27, wherein ring A is selected from the group consisting of C3-6 monocyclic cycloalkyl, C3-6 bicyclic cycloalkyl, Ce or C10 aryl (e.g., phenyl), and 5 or 6 membered heteroaryl, wherein each of C3-6 monocyclic cycloalkyl, C3-6 bicyclic cycloalkyl, Ce or C10 aryl (or phenyl), and 5 or 6 membered heteroaryl is optionally substituted with one or more occurrences of R5. The compound or pharmaceutically acceptable salt of embodiment 28, wherein ring A is selected from the group consisting of cyclopropyl, bicyclo [1.1. l]pentyl, phenyl, isoxazole, and pyridine, wherein each of cyclopropyl, bicyclo [1.1. l]pentyl, phenyl, isoxazole, and pyridine is optionally substituted with one or more occurrences of R5. The compound or pharmaceutically acceptable salt of embodiment 29, wherein ring A is selected
R5 R5 from the group consisting of:
31. The compound or pharmaceutically acceptable salt of embodiment 30, wherein ring A is selected
32. The compound or pharmaceutically acceptable salt of embodiment 31, wherein ring A is selected from the group consisting of:
The compound or pharmaceutically acceptable salt of embodiment 32, wherein ring A is selected from the group consisting of: i-k HO- The compound or pharmaceutically acceptable salt of any one of embodiments 1-26, wherein ring A is C3 -12 bicyclic cycloalkyl (e.g., C3-6 bicyclic cycloalkyl) that is optionally substituted with one or more occurrences of R5. The compound or pharmaceutically acceptable salt of embodiment 34, wherein ring A is bicyclo [1.1. l]pentyl that is optionally substituted with one or more occurrences of R5 (e.g., wherein ring The compound or pharmaceutically acceptable salt of embodiment 35, wherein ring A is The compound or pharmaceutically acceptable salt of any one of embodiments 1-36, wherein each occurrence of R5 is independently selected from the group consisting of halogen, C1-6 alkyl (e.g., C1-3 alkyl), C1-6 alkoxy, C3-12 monocyclic cycloalkyl (e.g., C3-6 monocyclic cycloalkyl), and Ce or C10 aryl (e.g., phenyl), wherein each of C1-6 alkyl (or C1-3 alkyl), C1-6 alkoxy, and C3-12 monocyclic cycloalkyl (or C3-6 monocyclic cycloalkyl) is optionally substituted with one or more occurrences of R6. The compound or pharmaceutically acceptable salt of embodiment 37, wherein each occurrence of R5 is independently selected from the group consisting of F, CH3, CHF2, CF2CH3, CF3, The compound or pharmaceutically acceptable salt of embodiment 38, wherein each occurrence of R5 is independently selected from the group consisting of F, CH3, CHF2, CF3, CH2OCH3, The compound or pharmaceutically acceptable salt of any one of embodiments 1-36, wherein each occurrence of R5 is C1-6 alkyl (e.g., C1-3 alkyl (e.g., CH3)) that is optionally substituted with one or more occurrences of R6. The compound or pharmaceutically acceptable salt of any one of embodiments 1-40, wherein each occurrence of R6 is independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 alkoxy, and OH. The compound or pharmaceutically acceptable salt of embodiment 41, wherein each occurrence of R6 is independently selected from the group consisting of F, CH3, OCH3, and OH. The compound or pharmaceutically acceptable salt of any one of embodiments 1-40, wherein each occurrence of R6 is halogen (e.g., F). The compound or pharmaceutically acceptable salt of any one of embodiments 1-43, wherein n is 0 or 2. The compound or pharmaceutically acceptable salt of embodiment 44, wherein if n is 2, ring A is cyclopropyl that is optionally substituted with one or more occurrences of R5 (e.g., wherein ring The compound or pharmaceutically acceptable salt of embodiment 45, wherein R5 is C1-6 alkyl (e.g., C1-3 alkyl (e.g., CH3)). The compound or pharmaceutically acceptable salt of any one of embodiments 1-43, wherein n is 0. The compound or pharmaceutically acceptable salt of any one of embodiments 1-19, wherein the compound of Formula (I) is a compound of Formula (IA):
The compound or pharmaceutically acceptable salt of embodiment 48, wherein the compound of Formula (I) is a compound of Formula (IB): The compound or pharmaceutically acceptable salt of embodiment 49, wherein the compound of Formula (I) is a compound of Formula (IB): The compound or pharmaceutically acceptable salt of any one of embodiments 1-50, wherein the The compound or pharmaceutically acceptable salt of embodiment 51, wherein the compound of The compound or pharmaceutically acceptable salt of embodiment 1, wherein the compound is a compound selected from T able 1. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one of embodiments 1-53 and one or more pharmaceutically acceptable excipients. A combination comprising the compound or pharmaceutically acceptable salt of any one of embodiments 1-53 and a CDK4/6 inhibitor. A kit comprising (i) a unit dosage form comprising the compound or pharmaceutically acceptable salt of any one of embodiments 1-53, and, separately, (ii) a unit dosage form comprising a CDK4/6 inhibitor. The kit of embodiment 56, wherein each unit dosage form is a pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients. A method of treating cancer in a subject in need thereof using the combination or kit of any one of embodiments 55-57. The method of claim 58, wherein the cancer is breast cancer. The method of claim 59, wherein the breast cancer is HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer. A method of treating cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of embodiments 1-53 or the pharmaceutical composition of embodiment 54. The method of embodiment 61, wherein the cancer comprises a solid tumor. The method of embodiment 62, wherein the solid tumor is at least one of the group consisting of: uterine cancer (such as uterine carcinosarcoma and uterine corpus endometrial carcinoma), endometrial cancer, breast cancer (such as breast invasive carcinoma and triple negative breast cancer, ER+ HER2- breast cancer, and HER2+ breast cancer), ovarian cancer (such as ovarian serous cystadenocarcinoma), stomach cancer (such as stomach adenocarcinoma), gastric cancer (such as gastrointestinal stromal cancer), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (such as B-cell lymphoma), sarcoma, esophageal cancer (such as esophageal carcinoma), bladder cancer (such as bladder urothelial carcinoma), lung cancer (such as lung squamous carcinoma and non-small cell lung cancer including EGFRm+ (epidermal growth factor receptor mutant positive) non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, mesothelioma, and malignant melanoma. The method of any one of embodiments 61-63, wherein the cancer is selected from the group consisting of: ovarian cancer, endometrial cancer, gastric cancer, esophaegeal cancer, breast cancer (such as triple negative breast cancer), and lung adenosarcoma. The method of embodiment 64, wherein the cancer is breast cancer. The method of embodiment 65, wherein the breast cancer is HR+ (hormone receptor positive) breast cancer. The method of embodiment 65 or embodiment 66, wherein the breast cancer is ER+ (estrogen receptor positive) breast cancer. The method of embodiment 66, wherein the breast cancer is HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer. The method of embodiment 67, wherein the breast cancer is ER+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer. The method of embodiment 65, wherein the breast cancer is triple negative breast cancer. The method of embodiment 61, wherein the cancer comprises a liquid tumor. The method of embodiment 71, wherein the liquid tumor is at least one of the group consisting of: diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia/lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS- related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell/histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (e.g., DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T -cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus-type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM). The method of any one of embodiments 58-72, wherein the method further comprises administering to the subject an additional therapeutic agent. The method of embodiment 73, wherein the additional therapeutic agent is carboplatin, ribociclib or a pharmaceutically acceptable salt thereof, fulvestrant, or a combination thereof. The method of any one of embodiments 65-70, wherein the method further comprises administering to the subject a CDK4/6 inhibitor. The method of any one of embodiments 58-60 or 75, wherein the CDK4/6 inhibitor is palbociclib, ribociclib, abemaciclib, lerociclib, trilaciclib, dalpiciclib, birociclib, BPI-16350, or in each case a pharmaceutically acceptable salt thereof. The method of embodiment 76, wherein the CDK4/6 inhibitor is ribociclib, palbociclib, abemaciclib, or in each case a pharmaceutically acceptable salt thereof. The method of embodiment 77, wherein the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof, or palbociclib or a pharmaceutically acceptable salt, for example wherein the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. The method of any one of embodiments 58-60 or 75-78, wherein the CDK4/6 inhibitor is administered in combination with endocrine therapy, optionally wherein the endocrine therapy is administered in combination with a luteinising hormone-releasing hormone (LHRH) agonist. The method of embodiment 79, wherein the endocrine therapy is an estrogen receptor antagonist such as fulvestrant, or an aromatase inhibitor such as letrozole. The method of embodiment 80, wherein the endocrine therapy is fulvestrant. The method of embodiment 81, wherein the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof, or palbociclib or a pharmaceutically acceptable salt, for example wherein the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. 83. The method of any one of embodiments 58-82, wherein the subject is a treatment-naive subject.
84. The combination or kit of any one of embodiments 55-57, or the method of any one of embodiments 58-60 or 75-82, wherein the CDK4/6 inhibitor is in the form of a pharmaceutically acceptable salt.
EXAMPLES
Example 1. Synthesis of Exemplary Compounds
[00136] The compounds provided herein can be prepared from readily available starting materials using the following methods and procedures. It will be appreciated that where typical or preferred process conditions (z.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by a person of ordinary skill in the art by routine optimization.
[00137] Abbreviations: AIBN: 2,2-azobis(2-methylpropionitrile); Boc: ZcrZ-butyloxycarbonyl: brd: broad doublet; brdd: broad doublet of doublet; brs: broad singlet; brt: broad triplet; eq: equivalents; CuBr: copper bromide; CuBr2: copper(II) bromide; d: doublet; dd: doublet of doublet; ddd: doublet of doublet of doublet; DAST: (diethylamino)sulfur trifluoride; DCM: dichloromethane; DIPEA: diisopropy ethylamine; DMSO: dimethyl sulfoxide; DPPA: diphenylphosphoryl azide; ESI: electrospray ionization; EtOAc: ethyl acetate; EtOH: ethanol; h: hours; HC1: hydrochloric acid; HPLC: high- performance liquid chromatography; [Ir(dtbbpy)(ppy)2]PFe: |4.4'-/Ls( l . l -dimcthylcthyl)-2.2'-bipyridinc- A'l .A'd '|A/.s|2-(2-pyridinyl-Ajphcnyl-C|iridium([[[) hexafluorophosphate; K2CO3: potassium carbonate; LED: light-emitting diode; LiCl: lithium chloride; m: multiplet; MeOH: methanol; MS: mass spectrometry; MsOH: methanesulfonic acid; NCS: A'-chlorosuccinimidc: NH4CI: ammonium chloride; NMR: nuclear magnetic resonance; q: quartet; s: singlet; Pd(dppf)C12: [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0); Pd| Pf Bu), I2: bis(tri-tert-butylphosphine)palladium(0);
PEPPSI-IPr: [l,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride; PSI: pounds per square inch; quin: quintet; RuPhos Pd G3: (2-Dicyclohexylphosphino-2',6'- diisopropoxy-l,l'-biphenyl)[2-(2'-amino-l,l'-biphenyl)]palladium(II) methanesulfonate; sat. sol.: saturated solution; t: triplet; td: triplet of doublet; TFA: trifluoro acetic acid; tt: triplet of triplet.
[00138] The compounds in Tables 1 and 2 were prepared via the following reactions.
Examples 1-82
Scheme 1. Preparation of Compounds 1-82
General purification methods
Purification Method 1:
[00139] Upon reaction completion, the solvents were removed in vacuo and the residue was purified by column chromatography or prep-TLC (eluting with an appropriate mixture of Petroleum ether and Ethyl acetate) to afford the desired products.
Purification Method 2:
[00140] Upon reaction completion, the solvents were removed in vacuo and the residue was purified by /Vcp-HPLC with a Cl 8 column (type: Phenomen ex luna, YMC-Actus Triart, or Welch Xtimate) of the appropriate size. A mobile phase containing a mixture of water (formic acid condition) [Solvent A] and acetonitrile [Solvent B] was used. An appropriate gradient ranging from 0 to 80% of solvent B was applied. The pure compounds were then lyophilized.
Purification Method 3: Chiral SFC
[00141] The solid was purified by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: carbon dioxide/ethyl alcohol; B%:25%, isocratic elution mode) and concentrated under reduced pressure to afford the two separate enantiomers.
General procedures
[00142] Intermediates Bl-27 were synthesized from the corresponding Intermediates Al-27, respectively, as follows:
Step 1 - General Procedure 1:
Variant 1: [00143] Intermediate A (1.00 eq.) was dissolved in TFA (0.25 M relative to Intermediate A), and the reaction was stirred at room temperature (25 - 30°C) until reaction completion (1 - 2 h). The reaction mixture was concentrated under reduced pressure to afford Intermediate B. It was either used directly in the next step or purified using Purification Method 2.
Variant 2:
[00144] Intermediate A (1.00 eq.) was dissolved in DCM (0.13 M relative to Intermediate A) and TFA (19.5 eq.) was added. The mixture was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to afford Intermediate B. It was used directly without further purification.
Variant 3:
[00145] Intermediate A (1.00 eq.) was dissolved in MsOH (0.3 M relative to Intermediate A), and the reaction was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue, which was purified using Purification Method 2 to afford Intermediate B.
Variant 4:
[00146] Intermediate A (1.00 eq.) was dissolved in DCM (0.05 - 0.2 M relative to Intermediate A) and MsOH (3 - 4 eq.) was added. The mixture was stirred at 25 °C until reaction completion (1 - 2 h). It was concentrated under reduced pressure to afford Intermediate B.
Variant 5:
[00147] Intermediate A (1.00 eq.) was dissolved in HFIP (0.24 M relative to Intermediate A) and the reaction was stirred at 200 °C for 5 min. It was concentrated under reduced pressure to afford Intermediate B.
Step 2 - General Procedure 2:
Variant 1:
[00148] Intermediate B (1.00 eq.) was dissolved in A' A'-dimcthylacctamidc (0.05 - 0.2 M relative to Intermediate B). DIPEA (3.00 eq.) and Intermediate C (1.10 eq.) were added. The reaction was stirred at 100 - 110°C until reaction completion (1 - 3 h). In some cases, a workup was performed: the mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. In most cases, the reaction mixture was concentrated under reduced pressure directly to give a residue. The residue was purified using Purification Method 1 or Purification Method 2 to afford the pure exemplary compounds.
Variant 2: [00149] Intermediate B (1.00 eq.) was dissolved in DMSO (0. 13 M relative to Intermediate B). DIPEA (3.00 eq.), K2CO3 (1.00 eq.) and Intermediate C (2.00 eq.) were added. The reaction was stirred at 80°C until reaction completion (2 h). The mixture was concentrated under reduced pressure to give a residue. The residue was purified using Purification Method 2 to afford the pure exemplary compounds.
Table 4. Intermediates Al-27, Bl-27, and Cl-25
Representative example: Compound 1
Step 1. According to General Procedure 1, Variant 1:
[00150] To a solution of Intermediate Al (100 mg, 245 μmol, 1.00 eq.) was added trifluoroacetic acid (1.00 mL). The mixture was stirred at 25°C for 1 h, then concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (Cl 8 column; gradient: 3%-33% solvent B over 10 min) and lyophilized to afford Intermediate Bl (38.0 mg, 122 μmol, 49% yield) as a yellow solid.
Step 2. According to General Procedure 2, Variant 1:
[00151] To a solution of Intermediate Bl (38.0 mg, 123 μmol, 1.00 eq.) \n N.N- dimethylacetamide (0.50 mL) was added A'.A'-diisopropylcthylaminc (47.9 mg, 370 μmol, 64.5 pL, 3.00 eq.) and Intermediate Cl (35.0 mg, 123 μmol, 1.00 eq.). The reaction was stirred at 110°C for 1 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by /Vcp-HPLC (C18 column; gradient: 43%-73% solvent B over 10 min) and lyophilized to afford Compound 1 (22.52 mg, 43.72 μmol, 35% yield) as a white solid.
[00152] 1H NMR (400 MHz, DMSO-d6) δ = 10.81 (s, 1H), 8.22 (d, J= 7.0 Hz, 1H), 7.17 (s, 1H), 7.05 (dd, J= 2.0, 8.4 Hz, 1H), 6.78 - 6.65 (m, 1H), 4.58 (t, J= 7.4 Hz, 1H), 4.07 (t, J= 5.8 Hz, 1H), 4.03 - 3.95 (m, 1H), 3.77 (dd, J= 4.6, 12.0 Hz, 1H), 3.48 (t, J= 7.0 Hz, 1H), 2.70 - 2.60 (m, 1H), 2.47 (br t, J = 3.6 Hz, 1H), 2.39 (s, 6H), 2.19 (dq, J= 4.2, 12.4 Hz, 1H), 1.98 (td, J= 4.2, 8.6 Hz, 1H), 1.38 (d, J= 6.0 Hz, 3H)
[00153] MS (ESI) m/z 510.3 [M+H]+
[00154] The other Compounds 2-82 were synthesized in analogy to the above example and general methods. Details are provided in Table 5.
Table 5. Synthesis of Compounds 2-82 from Intermediates B and C
Synthesis of Intermediates Al-27: General Schemes and Procedures
Synthesis of Intermediates Al, A3, A7, A9, A15, A23, A25
Intermediates Intermediates A3, A7, A9, A15, A25 A1, A23 H1 : R1'2’3'5 = H, R4 = Me
Scheme 2: Synthesis of Intermediates Al, A3, A7, A9, Al 5, A23, A25
[00155] Step 1. To a solution of phenylmethanol (456 g, 4.22 mol, 439 mL, 2.50 eq.) in tetrahydrofuran (2.50 L) was added potassium lerLbutoxide (473 g, 4.22 mol, 2.50 eq.). The reaction was stirred at 70°C for 1 h. Then 2,6-dichloropyridine (250 g, 1.69 mol, 1.00 eq.) was added at 20°C and the reaction was stirred at 70°C for 12 h. The mixture was diluted with NH4CI sat. sol. (2000 mL) and extracted with ethyl acetate (3 x 1000 mL). The combined organic layers were washed with brine (2000 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (250 mL) at 20°C for 0.5 h to afford 2,6- bis(benzyloxy)pyridine (445 g, 1.53 mol, 90% yield) as a white solid.
[00156] Step 2. To a solution of 2,6-bis(benzyloxy)pyridine (200 g, 686 mmol, 1.00 eq.) in acetonitrile (2000 mL) was added A-bromosuccinimidc (134 g, 755 mmol, 1.10 eq.). The reaction was stirred at 80°C for 3 h, then concentrated under reduced pressure to give a residue. The residue was diluted with sodium carbonate (2000 mL) and extracted with ethyl acetate (3 x 1000 mL). The combined organic layers were washed with brine (2000 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (400 mL) at 20°C for 0.5 h to afford 2,6-bis(benzyloxy)-3-bromopyridine (151 g, 407 mmol, 59% yield) as a white solid. MS (ESI) m/z 369.9 [M+H]+
[00157] Step 3. To a solution of 2,6-dibenzyloxy-3-bromo-pyridine (200 g, 540 mmol, 1.00 eq.) and triisopropyl borate (254 g, 1.35 mol, 310 mL, 2.50 eq.) in tetrahydrofuran (2000 mL) was added n- butyllithium (2.50 M, 389 mL, 1.80 eq.) at -78°C under nitrogen atmosphere. The mixture was stirred at 20°C for 12 h. The reaction was quenched by addition of NH4CI sat. sol. (2000 mL). The mixture was extracted with ethyl acetate (3 x 1000 mL). The combined organic layers were washed with brine (2000 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (400 mL) at 20°C for 0.5 h to afford (2,6-bis(benzyloxy)pyridin- 3-yl)boronic acid Intermediate DI (83.0 g, 230 mmol, 45% yield) as a white solid. MS (ESI) m/z 336.0 [M+H]+
Step 4 - General Procedure 3:
[00158] A mixture of Intermediate E (1.00 eq.), Intermediate DI (1.00 - 1.05 eq.), palladium catalyst (Pd(PPh3)4 or Pd(dppf)C12) (0.04 - 0.10 eq.) and potassium carbonate (2.00 - 3.00 eq.) in dioxane/water 4/1 (0.15 - 0.5 M relative to Intermediate E) was degassed by purging with nitrogen 3 times. The reaction was stirred under nitrogen at 90 - 100°C until reaction completion (8 - 12 h). The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 7 or 2 to afford Intermediate F.
Step 5 - General procedure 4:
Variant 1:
[00159] A mixture of Intermediate F (1.00 eq.), the appropriate Boc-protected azetidin-3 -amine (1.00 eq.), Pd-PEPPSI-IHetp Cl (0.01 - 0.10 eq.) and caesium carbonate (3.00 eq.) in dioxane (0.2 - 0.4 M relative to Intermediate F) was degassed by purging with nitrogen 3 times. The reaction was stirred at 100°C until reaction completion (1 - 12 h) under nitrogen. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was used without purification, or it was purified via Purification Method 1 or Purification Method 2 to afford Intermediate G.
Variant 2:
[00160] Intermediate F (1.00 eq.) and the appropriate Boc-protected azetidin-3-amine (1.00 eq.) were dissolved in dioxane (0.05 - 0.2 M relative to Intermediate F). RuPhos Pd G3 (0.10 eq.) and caesium carbonate (3.00 eq.) were added, and the mixture was degassed by purging with nitrogen 3 times. The reaction was stirred at 100°C under nitrogen until reaction completion (1 - 12 h). The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate G.
Step 6 - General procedure 5:
[00161] Intermediate G (1.00 eq.) was dissolved in dioxane (0.05 - 0.2 M relative to Intermediate G) and palladium on carbon (10% purity, 0.50 eq.) was added. If Intermediate G contained a chloroaryl bond, lithium chloride (15.0 eq.) was also added. The mixture was purged with hydrogen 3 times, and then stirred under hydrogen atmosphere (15 psi) at 30 - 50°C until reaction completion (2 - 12 h). The reaction mixture was filtered and concentrated under reduced pressure to afford Intermediate A (or Intermediate H). It was either used directly in the next reaction or purified with Purification Method 1 or Purification Method 2.
Step 7 - General Procedure 6:
[00162] Intermediate H (1.00 eq.) was dissolved in A'.A'-dimcthyl formamide (0.25 - 0.3 M reaction relative to Intermediate H) and NCS (0.80 - 1.00 eq.) was added. The reaction was stirred at 30 - 50°C for 2 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford the corresponding 2-chlorinated Intermediate A.
Representative example: Intermediate Al
Step 4: According to General Procedure 3
[00163] A mixture of Intermediate El (20.0 g, 70.7 mmol, 1.00 eq.), Intermediate DI (23.7 g, 70.7 mmol, 1.00 eq.), Pd(PPhs)4 (3.27 g, 2.83 mmol, 0.04 eq.) and potassium carbonate (24.4 g, 177 mmol, 2.50 eq.) in dioxane/water 4/1 (200 mL) was purged with nitrogen 3 times, then stirred at 90°C for 12 h under nitrogen. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate=l/0 to 5/1) to afford Intermediate Fl (21.1 g, 47.3 mmol, 67% yield) as a white solid.
Step 5: According to General Procedure 4 [00164] A mixture of Intermediate Fl (0.300 g, 672 μmol, 1.00 eq.), Zc/7-butyl ((2R,3S)-2- methylazetidin-3-yl)carbamate (150 mg, 672 μmol, 1.00 eq., hydrochloride), caesium carbonate (657 mg, 2.02 mmol, 3.00 eq.) and RuPhos Pd G3 (56.2 mg, 67.2 μmol, 0.10 eq.) in dioxane (3.00 mL) was purged with nitrogen 3 times, then stirred at 100°C for 1 h under nitrogen. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate=l/O to 0/1) to afford Intermediate G1 (590 mg, crude) as a yellow solid.
Step 6: According to General Procedure 5
[00165] To a solution of Intermediate G1 (590 mg, 1.07 mmol, 1.00 eq.) in dioxane (6.00 mL) was added palladium on activated carbon (569 mg, 535 μmol, 10% purity, 0.50 eq.) under nitrogen. The mixture was purged with hydrogen 3 times, then stirred at 50°C for 2 h under hydrogen atmosphere (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to afford Intermediate Hl (360 mg, 964 μmol, 90% yield) as a white solid.
Step 7: According to General Procedure 6
[00166] To a solution of Intermediate Hl (220 mg, 589 μmol, 1.00 eq.) in A'.A'-dimcthyl formamide (2.00 mL) was added NCS (62.9 mg, 471 μmol, 0.80 eq.). The reaction was stirred at 30°C for 2 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by /Vcp-HPLC (C18 column; mobile phase: [water(formic acid)-acetonitrile]; gradient: 43%- 73% B over 10 min) and lyophilized to afford Intermediate Al (100 mg, 245 μmol, 41% yield) as a pink solid.
[00167] Intermediates A3, A7, A9, A15, A23 and A25 were synthesized in analogy to the above reactions using the general procedures.
Intermediate A3
Intermediate E3
[00168] To a solution of l-bromo-3,5-difluoro-2-methoxybenzene (2.00 g, 8.97 mmol, 1.00 eq.) in tetrahydrofuran (20.0 mL) was added lithium diisopropylamide (2.00 M, 4.93 mL, 1.10 eq.) at -78°C. The mixture was stirred at -78°C for 1 h. Then iodine (2.50 g, 9.86 mmol, 1.99 mL, 1.10 eq.) in tetrahydrofuran (10.0 mL) was added. The reaction was stirred at 25°C for 2 h, then it was quenched with hydrochloric acid (1 M, 20 mL), extracted with ethyl acetate (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Intermediate E3 (3.40 g, crude) as a yellow solid.
[00169] Step 4: Starting from Intermediate E3 according to General Procedure 3 with Pd(PPhs)4, Intermediate F3 was obtained as a yellow oil (690 mg, 1.35 mmol, 31% yield).
[00170] Step 5: Starting from Intermediate F3 and tert-butyl i(2/?.3.S)-2-mcthylazctidin-3- yl)carbamate according to General Procedure 4 Variant 2, Intermediate G3 was obtained as a yellow oil (750 mg, 1.21 mmol, 90% yield).
[00171] Step 6: Starting from Intermediate G3 according to General Procedure 5 (no LiCl), Intermediate A3 was obtained as a violet oil (50.0 mg, 114 μmol, 88% yield).
Intermediate A7
[00172] Step 4: Starting from Intermediate E7 according to General Procedure 3 with Pd(PPhs)4, Intermediate F7 was obtained as a white solid (1.90 g, 3.81 mmol, 22% yield).
[00173] Step 5: Starting from Intermediate F7 and tert-butyl i(2/?.3.S)-2-mcthylazctidin-3- yl)carbamate according to General Procedure 4 Variant 2, Intermediate G7 was obtained as a yellow oil (1.00 g, 1.66 mmol, 83% yield).
[00174] Step 6: Starting from Intermediate G7 according to General Procedure 5 (with LiCl), Intermediate A7 was obtained as a white solid (300 mg, 704 μmol, 64% yield).
Intermediate A9
[00175] Step 4: Starting from Intermediate E9,23 according to General Procedure 3 with Pd(PPhs)4, Intermediate F9,23 was obtained as a brown solid (666 mg, 1.35 mmol, 22% yield).
[00176] Step 5: Starting from Intermediate F9 and tert-butyl azetidin-3-ylcarbamate according to General Procedure 4 Variant 1, Intermediate G9,23 was obtained as a yellow solid (570 mg, 994 μmol, 72% yield).
[00177] Step 6: Starting from Intermediate G9,23 according to General Procedure 5 (no LiCl), Intermediate A9 was obtained as a purple solid (550 mg, 1.34 mmol, 31% yield).
Intermediate Al 5
[00178] Step 4: Starting from Intermediate E15 according to General Procedure 3 with Pd(PPhs)4, Intermediate F15 was obtained as a yellow solid (1.00 g, 2.10 mmol, 66% yield). [00179] Step 5: Starting from Intermediate F15 and tert-butyl i(2/?.3.S')-2-mcthylazctidin-3- yl)carbamate according to General Procedure 4 Variant 2, Intermediate G15 was obtained as a yellow solid (1.09 g, 1.87 mmol, 89% yield).
[00180] Step 6: Starting from Intermediate G5 according to General Procedure 5 (no LiCl), Intermediate A15 was obtained as ayellow solid (1.00 g, crude).
Intermediate A23
[00181] Step 7: Starting from Intermediate A9 according to General Procedure 6, Intermediate A23 was obtained as a white solid (100 mg, 228 μmol, 45% yield).
Intermediate A25
[00182] Step 4: Starting from Intermediate E25 according to General Procedure 3 with Pd(PPhs)4, Intermediate F25 was obtained as a yellow oil (1.35 g, 2.80 mmol, 44% yield).
[00183] Step 5: Starting from Intermediate F25 and tert-butyl i(2/?.3.S)-2-mcthylazctidin-3- yl)carbamate according to General Procedure 4 Variant 2, Intermediate G25 was obtained as a yellow oil (1.42 g, 2.42 mmol, 86% yield).
[00184] Step 6: Starting from Intermediate G25 according to General Procedure 5 (with LiCl), Intermediate A25 was obtained as a red oil (420 mg, 1.03 mmol, 50% yield).
Intermediates A4, A8, All, A13, A18, and A26
Intermediate K Intermediate L Intermediates
K4: R1 = H, R2 = F, R3 = OMe L4: R1’5 = H, R2 = F, R3 = OMe, R4 = Me A4, A8, A11, A13, A18, A26 K8: R1 = H, R2 = F, R3 = CN L8: R1 ,5 = H, R2 = F, R3 = CN, R4 = Me K11,26: R1 2 = H, R3 = CN L11 : R1 ,2 = H, R3 = CN
K13: R1 = F, R2 = H, R3 = CN L13: R1 = F, R2’5 = H, R3 = CN, R4 = Me K18: R1 = H, R2 = Cl, R3 = CN K18: R1 ,5 = H, R2 = Cl, R3 = CN, R4 = Me
L26: R1’2’4 = H, R3 = CN, R5 = Me
Scheme 3: Synthesis of Intermediates A4, A8, All, Al 3, Al 8, andA26
Step 1 - General Procedure 7:
[00185] When bromide Intermediate I was not commercially available, it was synthesized as follows.
[00186] The appropriate aniline (1.00 eq.) and A'-bromosuccinimidc (1.00 eq.) were dissolved in acetonitrile (0.6 - 0.7 M reaction relative to aniline) and the reaction was stirred at 20 - 25°C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate I.
[00187] Step 2 - see General Procedure 3 [00188] Step 3 - General Procedure 8:
[00189] Intermediate J (1.00 eq.) was dissolved in acetonitrile (0.15 - 0.3 M relative to Intermediate J) and CuBr (1.00 - 2.00 eq.) was added, followed by tert-butyl nitrite (1.50 - 2.00 eq.). The reaction was stirred at 60°C for 1 h, then concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate K.
[00190] Step 4 - see General Procedure 4
[00191] Step 5 - see General Procedure 5
Representative example: Intermediate A8
Step 1: according to General Procedure 7
[00192] To a solution of 2-amino-6-fluorobenzonitrile (500 mg, 3.67 mmol, 1.00 eq.) in acetonitrile (5.00 mL) was added A'-bromosuccinimidc (654 mg, 3.67 mmol, 1.00 eq.). The mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 0/1) to afford Intermediate 18 (670 mg, 3.12 mmol, 85% yield) as a white solid.
Step 2: according to General Procedure 3
[00193] A mixture of Intermediate 18 (670 mg, 3.12 mmol, 1.00 eq.), Intermediate DI (1.10 g, 3.27 mmol, 1.05 eq.), Pd(dppf)C12 (228 mg, 312 μmol, 0.100 eq.) and potassium carbonate (1.29 g, 9.35 mmol, 3.00 eq.) in dioxane/water 4/1 (15.0 mL) was purged with nitrogen 3 times, then stirred at 90°C for 12 h under nitrogen. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 0/1) to afford Intermediate J8 (980 mg, 2.30 mmol, 74% yield) as a yellow solid.
Step 3: according to General Procedure 8
[00194] To a solution of Intermediate J8 (980 mg, 2.30 mmol, 1.00 eq.) in acetonitrile (15.0 mL) was added copper bromide (566 mg, 2.53 mmol, 119 pL, 1.10 eq.) and tert-butyl nitrite (356 mg, 3.46 mmol, 411 pL. 1.50 eq.). The reaction was stirred at 60°C for 1 h, then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 0/1) to afford Intermediate K8 (950 mg, 1.15 mmol, 50% yield) as a yellow oil.
Step 4: according to General Procedure 4, Variant 2
[00195] A mixture of Intermediate K8 (550 mg, 1.12 mmol, 1.00 eq.), tert-butyl ((2R,3S)-2- methylazetidin-3-yl)carbamate (263 mg, 1.18 mmol, 1.05 eq.), RuPhos Pd G3 (94.0 mg, 112 μmol, 0.10 eq.) and caesium carbonate (1.10 g, 3.37 mmol, 3.00 eq.) in dioxane (7.00 mL) was purged with nitrogen
3 times, then stirred at 100°C for 1 h under nitrogen. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 0/1) to afford Intermediate L8 (350 mg, 589 μmol, 52% yield) as a colourless oil.
Step 5: according to General Procedure 5
[00196] To a solution of Intermediate L8 (350 mg, 589 μmol, 1.00 eq.) in dioxane (5.00 mL) was added palladium on carbon (313 mg, 294 μmol, 10% purity, 0.50 eq.). The reaction was stirred under hydrogen atmosphere (15 psi) at 50°C for 12 h. The mixture was filtered and concentrated under reduced pressure to afford Intermediate A8 (300 mg, crude) as colourless oil.
[00197] Intermediates A4, All, A13, A18 and A26 were synthesized in analogy to the above reactions using the general procedures.
Intermediate A4
[00198] Step 2: Starting from Intermediate 14 (commercially available) according to General Procedure 3 with Pd(dppf)C12, Intermediate J4 was obtained as a yellow oil (2.00 g, 4.65 mmol, 68% yield).
[00199] Step 3: Starting from Intermediate J4 according to General Procedure 8, Intermediate K4 was obtained as a yellow oil (660 mg, 1.34 mmol, 29% yield).
[00200] Step 4: Starting from Intermediate K4 according to General Procedure 4 Variant 2 with Zc/7-butyl ((27?,3S)-2-methylazetidin-3-yl)carbamate, Intermediate L4 was obtained as a colourless oil (570 mg, 951 μmol, 85% yield).
[00201] Step 5: Starting from Intermediate L4 according to General Procedure 5 (no LiCl), Intermediate A4 was obtained as a white solid (320 mg, 759 μmol, 80% yield).
Intermediate All
[00202] Step 2: Starting from Intermediate 111,26 (commercially available) according to General Procedure 3 with Pd(dppf)C12, Intermediate Jll,26 was obtained as a yellow oil (7.80 g, 19.1 mmol, 75% yield).
[00203] Step 3: Starting from Intermediate Jll,26 according to General Procedure 8, Intermediate Kll,26 was obtained as a yellow solid (480 mg, 1.02 mmol, 34% yield). [00204] Step 4: Starting from Intermediate KI 1,26 according to General Procedure 4 Variant
2 with tert-butyl ((27?,3S)-2-methylazetidin-3-yl)carbamate, Intermediate Lil was obtained as a yellow solid (630 mg, crude).
[00205] Step 5: Starting from Intermediate Lil according to General Procedure 5 (no LiCl, 2 h reaction time), Intermediate All was obtained as a yellow solid (420 mg, 1.05 mmol, 96% yield).
Intermediate Al 3
[00206] Step 2: Starting from Intermediate 113 (commercially available) according to General Procedure 3 with Pd(dppf)C12, Intermediate J13 was obtained as a white solid (2. 16 g, 5.08 mmol, 72% yield).
[00207] Step 3: Starting from Intermediate J13 according to General Procedure 8, Intermediate K13 was obtained as a yellow solid (1.00 g, 2.04 mmol, 40% yield).
[00208] Step 4: Starting from Intermediate KI 3 according to General Procedure 4 Variant 2 with tert-butyl ((27?,3S)-2-methylazetidin-3-yl)carbamate, Intermediate L13 was obtained as a yellow solid (560 mg, 941 μmol, 92% yield).
[00209] Step 5: Starting from Intermediate L13 according to General Procedure 5 (no LiCl), Intermediate A13 was obtained as a white solid (320 mg, 768 μmol, 81% yield).
Intermediate Al 8
[00210] Step 1: Starting from 2-amino-6-chlorobenzonitrile according to General Procedure 7, Intermediate 118 was obtained as a white solid (1.46 g, 6.31 mmol, 96% yield).
[00211] Step 2: Starting from Intermediate 118 according to General Procedure 3 with Pd(dppf)C12, Intermediate J18 was obtained as ayellow oil (2.13 g, 4.82 mmol, 76% yield).
[00212] Step 3: Starting from Intermediate J18 according to General Procedure 8, Intermediate K18 was obtained as a white solid (1.05 g, 2.08 mmol, 43% yield).
[00213] Step 4: Starting from Intermediate K18 according to General Procedure 4 Variant 2 with tert-butyl ((27?,3S)-2-methylazetidin-3-yl)carbamate, Intermediate L18 was obtained as ayellow solid (0.36 g, 589 μmol, 28% yield).
[00214] Step 5: Starting from Intermediate L18 according to General Procedure 5 (with LiCl), Intermediate A18 was obtained as a white solid (0.41 g, 947 μmol, 88% yield).
Intermediate A26 [00215] Step 4: Starting from Intermediate KI 1,26 according to General Procedure 4 Variant
2 with tert-butyl (3-methylazetidin-3-yl) carbamate, Intermediate L26 was obtained as a yellow solid (500 mg, 867 μmol, 82% yield).
[00216] Step 5: Starting from Intermediate L26 according to General Procedure 5 (no LiCl, 2 h reaction time), Intermediate A26 was obtained as a yellow oil (430 mg, 1.06 mmol, 97% yield).
Intermediates A17, A20, A21
Intermediate M Intermediate N
Intermediates
A17, A20, A21
Scheme 4: Synthesis of Intermediates Al 7, A20 and A21
Step 1 - General Procedure 9:
[00217] To a solution of the appropriate 4-bromoaniline (1.00 eq.) in acetic acid (0.48 - 0.53 M relative to bromoaniline) was added acrylamide (1.00 - 2.00 eq.). The reaction was stirred at 110°C until reaction completion (2 - 12 h). The reaction was quenched with water, and the aqueous layer was extracted with ethyl acetate (3 *). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate M.
Step 2 - General Procedure 10:
[00218] Intermediate M (1.00 eq.) was dissolved in 2V,2V-dimethyl formamide. Triethylamine (2.00 eq.) and di(177-imidazol-l-yl)methanone (5.00 eq.) were added. The reaction was stirred at 80 - 120°C until reaction completion (6 - 12 h). The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate N.
Step 3 - General Procedure 4 or General Procedure 11:
[00219] A mixture of Intermediate N (1.00 eq.), tert-butyl((27?,3S)-2-methylazetidin-3- yl)carbamate*HCl (2.00 eq.), [Ir(dtbbpy)(ppy)2]PFe (48.2 mg, 52.7 μmol, 0.02 eq.), Nickel(II) bromide ethylene glycol dimethyl ether complex (0.05 eq.) and l,4-diazabicyclo[2.2.2]octane (1.80 eq.) in N.N- dimethylacetamide (0.18 M relative to Intermediate N) was purged with argon, then irradiated at 455 nm (blue LED) for 16 h at 25°C. The reaction was quenched by addition of water, and the aqueous layer was extracted with ethyl acetate (3 x). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford the corresponding Intermediate A.
Representative example: Intermediate A17
Step 1. According to General Procedure 9:
[00220] To a solution of 4-bromo-2,6-difluoroaniline (1.00 g, 4.81 mmol, 1.00 eq.) in acetic acid (10.0 mL) was added acrylamide (663 pL, 9.62 mmol, 2.00 eq.). The reaction was stirred at 110°C for 12 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 0/1) to afford Intermediate M17 (271 mg, 971 μmol, 20% yield) as a pink solid.
Step 2. According to General Procedure 10:
[00221] To a solution of Intermediate M17 (271 mg, 971 μmol, 1.00 eq.) in A'jV-dimcthyl formamide (2.00 mL) were added triethylamine (270 pL, 1.94 mmol, 2 eq.) and di(l/7-imidazol-l- yl)methanone (787 mg, 4.86 mmol, 5.00 eq.). The reaction was stirred at 80°C for 12 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 0/1) to afford Intermediate N17 (107 mg, 350 μmol, 36% yield) as a yellow solid.
Step 3. According to General Procedure 4, Variant 1:
[00222] A mixture of Intermediate N17 (130 mg, 426 μmol, 1.00 eq.), tert-butyl ((27?,3S)-2- methylazetidin-3-yl)carbamate*HCl (79.4 mg, 356 μmol, 1.00 eq.), Pd PEPPSLIHetp Cl (20.7 mg, 21.3 μmol, 0.05 eq.), and caesium carbonate (417 mg, 1.28 mmol, 3.00 eq.) in dioxane (1.00 mL) was purged with nitrogen 3 times, then the reaction was stirred at 100°C for 12 h under nitrogen. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 0/1) to afford Intermediate A17 (75.0 mg, 108 μmol, 44% yield) as a yellow solid. [00223] Intermediates A20 and A21 were synthesized in analogy to the above reactions using the general procedures.
Intermediate A20
[00224] Step 1: Starting from 4-bromo-3-methyl-aniline according to General Procedure 9, Intermediate M20 was obtained as a yellow oil (1.30 g, 5.06 mmol, 47% yield).
[00225] Step 2: Starting from Intermediate M20 according to General Procedure 10, Intermediate N20 was obtained as a yellow solid (590 mg, 2.08 mmol, 41% yield).
[00226] Step 3: Starting from Intermediate N20 according to General Procedure 4 Variant 1, Intermediate A20 was obtained as a yellow solid (500 mg, 1.29 mmol, 62% yield).
Intermediate A21
[00227] Step 1: Starting from 4-bromo-3-chloroaniline according to General Procedure 9, Intermediate M21 was obtained as a yellow solid (3.00 g, 10.8 mmol, 45% yield).
[00228] Step 2: Starting from Intermediate M21 according to General Procedure 10, Intermediate N21 was obtained as a yellow solid (1.00 g, 3.29 mmol, 38% yield).
[00229] Step 3: Starting from Intermediate N21 according to General Procedure 11, Intermediate A21 was obtained as a yellow solid (210 mg, 514 μmol, 19% yield).
Intermediates A5, A6, A10, A12, A14, A16, A22, and A24
Intermediates Intermediates R5, 6, 16,22: R1 2 = F, R3 = H A16, A22, A24 A5, A6, A10, A12, A14
R10: R1 = H, R2 = Cl, R3 = OMe S24: R1'2'3'4 = H, R5 = Me R12: R1’2 = Cl, R3 = H
R14: R1 = F, R2’3 = H
Scheme 5: Synthesis of Intermediates A 5, A6, A10, A12, A14, A16, A22, A24
Step 1 - General Procedure 12:
[00230] To a solution of the appropriate 4-bromotoluene (1.00 eq.) in carbon tetrachloride or acetonitrile (0.4 - 0.5 M relative to 5 -bromo -2 -methylbenzene) were added A'-bromosuccinimidc (1.00 eq.) and benzoic peroxyanhydride (0.10 eq.) or AIBN (0.05 - 0.10 eq.). The reaction was stirred at 80°C under nitrogen until reaction completion (2 - 12 h). The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate O.
Step 2 - General Procedure 13:
Variant 1
[00231] Intermediate O (1.00 eq.) was dissolved in acetonitrile (0.3 - 1.7 M relative to Intermediate O) and trimethylsilyl cyanide (1.50 - 3.00 eq.) was added. The mixture was cooled to 0°C and tetrabutylammonium fluoride (I M tetrahydrofuran, 1.50 - 3.00 eq.) was added slowly. The reaction was stirred at 20°C until reaction completion (15 min - 2 h). The mixture was either concentrated directly to give a residue, or it was worked up by quenching with water and extracting the aqueous layer with ethyl acetate (3 x). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate P.
Variant 2
[00232] To a solution of Intermediate O (1.00 eq.) in ethanol/water 3/1 (0.37 M relative to Intermediate O) was added potassium cyanide (1.20 eq.). The reaction was stirred at 60°C for 2 h. The mixture was diluted with water and extracted with ethyl acetate (3 x). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate P.
Step 3 - General Procedure 14:
[00233] Intermediate P (1.00 eq.) was dissolved in tetrahydrofuran (0.44 - 0.46 M relative to Intermediate P) and cooled to 0°C. tert-butyl acrylate or methyl acrylate (1.00 - 7.10 eq.) and sodium methoxide (0.10 - 0.20 eq.) were added. The reaction was stirred at 20°C until reaction completion (1 - 2 h). The mixture was either concentrated directly to give a residue, or it was worked up by quenching with NH4CI sat. sol. and extracting the aqueous layer with ethyl acetate (3 x). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate Q.
Step 4 - General Procedure 15:
[00234] Intermediate Q (1.00 eq.) was dissolved in acetic acid/sulfuric acid 10/1 (0.25 - 0.32 M relative to Intermediate Q). The reaction was stirred at 90°C for 2h, then poured into ice water. The resulting precipitate was filtered and washed with water, then lyophilized to afford Intermediate R.
[00235] Step 5 - see General Procedure 4.
[00236] Step 6 - see General Procedure 6.
Representative examples: Intermediates A5 and A16
Step 1. According to General Procedure 12:
[00237] To a solution of 5-bromo-l,3-difluoro-2-methylbenzene (19.3 g, 93.1 mmol, 1.00 eq.) in tetrachloromethane (190 mL) was added /V-bromosuccinimide (16.6 g, 93.1 mmol, 1.00 eq.) and (E)-3,3'- (diazene-l,2-diyl)bis(2 -methylpropanenitrile) (764 mg, 4.65 mmol, 0.05 eq.). The reaction was stirred at 80 °C for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with 100% petroleum ether) to afford Intermediate 05,6,16,22 (21.2 g, 74.2 mmol, 80% yield) as yellow oil. Step 2. According to General Procedure 13, Variant 2:
[00238] To a solution of Intermediate 05,6,16,22 (21.2 g, 74.2 mmol, 1.00 eq.) in ethanol (150 mL) and water (50.0 mL) was added potassium cyanide (5.79 g, 89.0 mmol, 3.81 mL, 1.20 eq.). The reaction was stirred at 60°C for 2 h. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 * 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 20/1) to afford Intermediate P5,6,16,22 (12.2 g, 52.6 mmol, 71% yield) as a white solid.
Step 3. According to General Procedure 14:
[00239] To a solution of Intermediate P5,6,16,22 (12.2 g, 52.6 mmol, 1.00 eq.), methyl acrylate (4.73 mL, 52.6 mmol, 1.00 eq.) in tetrahydrofuran (120 mL) was added sodium methoxide (284.06 mg, 5.26 mmol, 0. 10 eq.) at 0°C. The reaction was stirred at 20°C for 1 h. The mixture was quenched with NH4CI sat. sol. (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 10/1) to afford Intermediate Q5,6,16,22 (13.5 g, 42.4 mmol, 81% yield) as yellow oil.
Step 4. According to General Procedure 15:
[00240] To a solution of Intermediate Q5,6,16,22 (13.5 g, 42.4 mmol, 1.00 eq.) in acetic acid (135 mL) was added sulfuric acid (13.5 mL, 253 mmol, 5.97 eq.). The reaction was stirred at 90°C for 2 h. The mixture was poured into ice water (400 mL) and the precipitate was filtered. The precipitate was lyophilized to afford Intermediate R5,6,16,22 (15.0 g, crude) as a white solid.
Step 5. According to General Procedure 4, Variant 1:
[00241] A mixture of Intermediate R5,6,16,22 (900 mg, 2.96 mmol, 1 eq.), Zc/7-butyl ((27?,3S)-2- methylazetidin-3-yl)carbamate*HCl (659 mg, 2.96 mmol, 1.00 eq.), Pd-PEPPSI-IHetp Cl (144 mg, 148 μmol, 0.05 eq.) and caesium carbonate (2.89 g, 8.88 mmol, 3.00 eq.) in dioxane (9 mL) was purged with nitrogen 3 times, then stirred at 100°C for 1 h under nitrogen. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 3/1) to afford Intermediate A5 (900 mg, 2.20 mmol, 74% yield) as a white solid.
Step 6. According to General Procedure 6 [00242] To a solution of Intermediate A5 (200 mg, 488 μmol, 1.00 eq.) in A'jV-dimcthyl formamide (2 mL) was added NCS (59 mg, 440 μmol, 0.90 eq.). The reaction was stirred at 50°C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (Cl 8 column, eluting with water (formic acid) and an acetonitrile gradient 35% - 65%) to afford Intermediate A16 (323 mg, 728 μmol, 74% yield) as a white solid.
[00243] 'H NMR (400 MHz, DMSCMs) 8 = 10.94 (s, 1H), 7.43 (br d, J= 6.8 Hz, 1H), 6.47 (br d, J= 12.0 Hz, 1H), 4.54 (t, J= 7.8 Hz, 1H), 4.14 (br dd, J= 5.2, 12.8 Hz, 1H), 4.02 (s, 1H), 3.97 - 3.84 (m, 1H), 3.55 (br t, J= 7.2 Hz, 1H), 2.84 - 2.68 (m, 1H), 2.54 - 2.54 (m, 1H), 2.16 - 2.04 (m, 1H), 2.00 (br s, 1H), 1.39 (s, 9H), 1.33 (br d, J= 5.4 Hz, 3H)
[00244] Intermediates A6, A10, A12, A14, A22 and A24 were synthesized in analogy to the above reactions using the general procedures.
Intermediate A6
[00245] Step 5: Starting from Intermediate R5,6,16,22 according to General Procedure 4 Variant 1 with ZcrZ-butyl (3-methylazetidin-3-yl)carbamate, Intermediate A6 was obtained as a yellow solid (140 mg, 342 μmol, 58% yield).
Intermediate A10
[00246] Step 1: Starting from l-bromo-3-chloro-2-methoxy-4-methyl-benzene according to General Procedure 12 (with AIBN), Intermediate O10 was obtained as a transparent oil (2.70 g, 8.59 mmol, 51% yield).
[00247] Step 2: Starting from Intermediate O10 according to General Procedure 13 Variant 1, Intermediate P10 was obtained as a transparent oil (2.22 g, 8.55 mmol, 98% yield).
[00248] Step 3: Starting from Intermediate P10 according to General Procedure 14, Intermediate Q10 was obtained as a transparent oil (2.90 g, 8.37 mmol, 97% yield).
[00249] Step 4: Starting from Intermediate Q10 according to General Procedure 15, Intermediate R10 was obtained as a white solid (1.49 g, 4.48 mmol, 54% yield).
[00250] Step 5: Starting from Intermediate R10 according to General Procedure 4 Variant 1 with terAbutyl ((27?,3S)-2-methylazetidin-3-yl)carbamate*HCl, Intermediate A10 was obtained as a white solid (380 mg, 868 μmol, 58% yield).
Intermediate Al 2 [00251] Step 1: Starting from of 5-bromo-l,3-dichloro-2-methylbenzene according to General Procedure 12 (with benzoic peroxyanhydride), Intermediate 012 was obtained as a colourless oil (33.0 g, 98.3 mmol, 94% yield).
[00252] Step 2: Starting from Intermediate 012 according to General Procedure 13 Variant 1, Intermediate P12 was obtained as a white solid (24.7 g, 88.6 mmol, 86% yield).
[00253] Step 3: Starting from Intermediate P12 according to General Procedure 14, Intermediate Q12 was obtained as a yellow oil (38.0 g, 91.8 mmol, 99% yield).
[00254] Step 4: Starting from Intermediate Q12 according to General Procedure 15, Intermediate R12 was obtained as a white solid (33.0 g, 93.0 mmol, 96% yield).
[00255] Step 5: Starting from Intermediate R12 according to General Procedure 4 Variant 1 with tert-butyl ((27?,3S)-2-methylazetidin-3-yl)carbamate*HCl, Intermediate A12 was obtained as a yellow solid (200 mg, 452 μmol, 38% yield).
Intermediate Al 4
[00256] Step 3: Starting from 2-(4-bromo-2-fluorophenyl)acetonitrile according to General Procedure 14, Intermediate Q14 was obtained as a white solid (8.40 g, 27.9 mmol, 59% yield).
[00257] Step 4: Starting from Intermediate Q14 according to General Procedure 15, Intermediate R14 was obtained as a white solid (7.00 g, 24.4 mmol, 99% yield).
[00258] Step 5: Starting from Intermediate R14 according to General Procedure 4 Variant 1 with tert-butyl ((27?,3S)-2-methylazetidin-3-yl)carbamate*HCl, Intermediate A14 was obtained as a yellow solid (240 mg, 613 μmol, 58% yield).
Intermediate A22
[00259] Step 6: Starting from Intermediate A6 according to General Procedure 6, Intermediate A22 was obtained as a white solid (127 mg, 286 μmol, 58% yield).
Intermediate A24
[00260] Step 5: Starting from 3-(4-bromophenyl)piperidine-2, 6-dione according to General Procedure 4 Variant 1 with tert-butyl (3-methylazetidin-3-yl)carbamate, Intermediate S24 was obtained as a yellow solid (460 mg, 1.23 mmol, 33% yield).
[00261] Step 6: Starting from Intermediate S24 according to General Procedure 6, Intermediate A24 was obtained as a purple solid (250 mg, 613 μmol, 54% yield).
Intermediates A2, A19
Scheme 6: Synthesis of Intermediate A2
[00262] Step 1. To a solution of Intermediate A5 (1.20 g, 2.93 mmol, 1.00 eq.) in N,N- dimethylform amide (12.0 mL) was added /V-iodo-succinimide (659 mg, 2.93 mmol, 1.00 eq.). The reaction was stirred at 50°C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 2 to afford Intermediate T1 (1.00 g, 1.87 mmol, 64% yield) as a yellow solid.
[00263] Step 2. A mixture of Intermediate T1 (1.00 g, 1.87 mmol, 1.00 eq.) and cuprous cyanide (335 mg, 3.74 mmol, 816 pL. 2.00 eq.) in A'.A'-dimcthylform amide (10.0 mL) was purged with nitrogen 3 times, then stirred at 130°C for 12 h under nitrogen. The mixture was diluted with water (20 mL), and the aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 0/1) to afford Intermediate A2 (250 mg, 576 μmol, 31% yield) as yellow oil. 19
Scheme 7: Synthesis of Intermediate Al 9 [00264] Step 1. Starting from Intermediate Lil according to General Procedure 5 (no LiCl, 12 h reaction time), Intermediate A19 was obtained as a white solid (150 mg, 387 μmol, 15% yield).
Intermediate A27
Scheme 8: Synthesis of Intermediate A27
[00265] Step 1. To a solution of 5 -bromo- 1, 3 -difluoro-2-m ethylbenzene (21.0 g, 101 mmol, 1.00 eq.) in tetrahydrofuran (210 mL) was added lithium diisopropyl amide (2.00 M, 60.9 mL, 1.20 eq.). The mixture was stirred at -70 °C for 0.5 h. Then triethyl borate (22.2 g, 152 mmol, 25.9 mL, 1.50 eq.) was added, and the reaction was stirred at -70 °C for 1 h. The reaction was quenched with hydrochloric acid (IM, 100 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate = 1/0 to 0/1) to afford (6- bromo-2,4-difluoro-3-methylphenyl)boronic acid (11.8 g, 47.0 mmol, 46% yield) as a white solid.
[00266] Step 2. (6-bromo-2,4-difluoro-3-methylphenyl)boronic acid (5.90 g, 23.5 mmol, 1.00 eq.) was added to a mixture of deuterium oxide (5.40 mL) and pyridine (54.6 mL). The reaction was stirred at 100 °C for 8 h. The pH was adjusted to ~5 with hydrochloric acid (IM, 100 mL), and the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate = 1/0 to 10/1) to afford 5-bromo-l,3-difluoro- 2-methylbenzene-<7 (5.00 g, 24.0 mmol, 51% yield) as colourless oil. [00267] Step 3 - see General Procedure 12.
[00268] Step 4 - see General Procedure 13, Variant 1.
[00269] Step 5 - see General Procedure 14.
[00270] Step 6 - see General Procedure 15.
[00271] Step 7 - see General Procedure 4.
Synthesis of Intermediates C1-C24: General Schemes and Procedures
U19, V19, W19 U22, V22, W22 U23, V23, W23 U24, V24, W24
Scheme 9: Synthesis of Intermediates C2, C6, C7, C9, CIO, Cll, C12, C13, C14, C18, C19, C22, C23, C24
Step 1 - General Procedure 16:
[00272] The appropriate carboxylic acid (1.00 eq.) was dissolved in dichloromethane (0.35 - 0.7 M relative to the carboxylic acid) and tert-butyl 2V-aminocarbamate (1.03 - 1.30 eq.) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.02 - 1.20 eq.) were added. The reaction was stirred at 25°C until reaction completion (1 - 12 h). The mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate (3 x). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Intermediate U. If necessary, it was purified via Purification Method 1. Step 2 - General Procedure 17:
[00273] Intermediate U (1.00 eq.) was dissolved in dichloromethane (0.3 - 0.6 M relative to Intermediate U) and trifluoroacetic acid (5 - 8 eq.) was added. The reaction was stirred at 25°C until reaction completion (1 - 2 h). The mixture was concentrated under reduced pressure to afford Intermediate V. If necessary, Intermediate V was suspended in water and lyophilized to remove remaining trifluoroacetic acid. If necessary, it was purified via Purification Method 1 or Purification Method 2.
Step 3 - General Procedure 18:
Variant 1:
[00274] Intermediate V (1.00 eq.) was dissolved in tetrahydrofuran (0.3 - 0.5 M relative to Intermediate V) and di(lZ7-imidazol-l-yl)methanimine (1.00 - 1.10 eq.) was added. The reaction was stirred at 60°C until reaction completion (1 - 2 h). The mixture was concentrated under reduced pressure to give a residue. The residue was triturated with water or ethyl acetate, then filtered to afford Intermediate W.
Variant 2:
[00275] Intermediate V (1.00 eq.) was dissolved in methanol or dioxane/water 1/1 (0.2 - 0.7 M relative to Intermediate V) and cyanic bromide (1.00 - 2.15 eq.) was added. The reaction was stirred at 25 - 65°C until reaction completion (1 - 8 h). The mixture was concentrated under reduced pressure to afford Intermediate W. If necessary, the residue was triturated with water or ethyl acetate, then filtered to afford Intermediate W.
Step 4 - General Procedure 19:
[00276] Intermediate W (1.00 eq.) was dissolved in acetonitrile (0.2 - 0.5 M relative to Intermediate W) and Cu(I) or Cu(II) salt (CuBr or CuBr2) (1.10 - 2.00 eq.) followed by tert-butyl nitrite (1.50 - 2.00 eq.) were added. The reaction was stirred at 60 - 80°C until reaction completion (1 - 2 h). The mixture was concentrated under reduced pressure to give a residue. The residue was purified via Purification Method 1 to afford Intermediate C.
Representative example: Intermediate C6
Step 1. According to General Procedure 16:
[00277] To a solution of 4-(trifluoromethyl)benzoic acid (1.00 g, 5.26 mmol, 1.00 eq.) in dichloromethane (10.0 mL) was added tert-butyl A'-aminocarbamatc (716 mg, 5.42 mmol, 1.03 eq.) and 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (1.03 g, 5.37 mmol, 1.02 eq.). The reaction was stirred at 25°C for 12 h. The mixture was quenched by addition of water (30 mL), and the aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford Intermediate U6 (1.30 g, 4.27 mmol, 81% yield) as a white solid.
Step 2. According to General Procedure 17:
[00278] Intermediate U6 (1.30 g, 4.27 mmol, 1.00 eq.) was dissolved in dichloromethane (10.0 mL) and trifluoroacetic acid (2.00 mL, 26.9 mmol, 6.30 eq.) was added. The reaction was stirred at 25°C for 2 h. The volatiles were removed under reduced pressure to afford Intermediate V6 (1.30 g, crude) as a white solid.
Step 3. According to General Procedure 18, Variant 1:
[00279] To a solution of Intermediate V6 (1.30 g, 6.37 mmol, 1.00 eq.) in tetrahydrofuran (13.0 mL) was added di(lZ7-imidazol-l-yl)methanimine (1.03 g, 6.37 mmol, 1.00 eq.). The reaction was stirred at 60°C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate at 25 °C for 30 min, then the solid was filtered to afford Intermediate W6 (750 mg, 3.27 mmol, 51% yield) as a white solid.
Step 4. According to General Procedure 19:
[00280] To a solution of Intermediate W6 (1.60 g, 6.98 mmol, 1.00 eq.) in acetonitrile (16.0 mL) was added copper(I) bromide (2.00 g, 14.0 mmol, 2.00 eq.) and Zc/7-butyl nitrite (1.25 mL, 10.5 mmol, 1.50 eq.). The reaction was stirred at 60°C for 1 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 5/1) to afford Intermediate C6 (1.40 g, 4.73 mmol, 34% yield) as a yellow solid.
[00281] Intermediates C2, C7, C9, CIO, Cll, C12, C13, C14, C18, C19, C22, C23, and C24 were synthesized in analogy to the above reactions using the general procedures.
Intermediate C2
[00282] Step 1: Starting from 2-methoxy-6-m ethylnicotinic acid according to General Procedure 16, Intermediate U2 was obtained as a white solid (7.70 g, 27. 1 mmol, 94% yield).
[00283] Step 2: Starting from Intermediate U2 according to General Procedure 17, Intermediate V2 was obtained as a yellow gum (10.2 g, 25.9 mmol, 94% yield).
[00284] Step 3: Starting from Intermediate V2 according to General Procedure 18 Variant 1, Intermediate W2 was obtained as a yellow solid (5.20 g, 12.6 mmol, 48% yield).
[00285] Step 4: Starting from Intermediate W2 according to General Procedure 19 (with CuBr2), Intermediate C2 was obtained as a white solid (300 mg, 966 μmol, 20% yield). Intermediate C7
[00286] Step 1: Starting from 4-m ethoxybenzoic acid according to General Procedure 16, Intermediate U7 was obtained as a white solid (5.00 g, 18.8 mmol, 95% yield).
[00287] Step 2: Starting from Intermediate U7 according to General Procedure 17, Intermediate V7 was obtained as a white solid (2.00 g, 7.14 mmol, 95% yield).
[00288] Step 3: Starting from Intermediate V7 according to General Procedure 18 Variant 1, Intermediate W7 was obtained as a white solid (1.10 g, 5.75 mmol, 95% yield).
[00289] Step 4: Starting from Intermediate W7 according to General Procedure 19 (with CuBr2), Intermediate C7 was obtained as a white solid (270 mg, 1.06 mmol, 40% yield).
Intermediate C9
[00290] Step 1: Starting from 6-(difluorom ethoxy) nicotinic acid according to General Procedure 16, Intermediate U9 was obtained as a white solid (2.93 g, 9.57 mmol, 90% yield).
[00291] Step 2: Starting from Intermediate U9 according to General Procedure 17, Intermediate V9 was obtained as a white solid.
[00292] Step 3: Starting from Intermediate V9 according to General Procedure 18 Variant 2, Intermediate W9 was obtained as a yellow solid (2.95 g, crude).
[00293] Step 4: Starting from Intermediate W9 according to General Procedure 19 (with CuBr2), Intermediate C9 was obtained as a white solid (637 mg, 2.09 mmol, 42% yield).
Intermediate CIO
[00294] Step 1: Starting from 2-fluoro-4-methylbenzoic acid according to General Procedure 16, Intermediate U10 was obtained as a white solid (1.60 g, 5.96 mmol, 92% yield).
[00295] Step 2: Starting from Intermediate U10 according to General Procedure 17, Intermediate VI 0 was obtained as a yellow solid (1.00 g, 5.95 mmol, 99% yield).
[00296] Step 3: Starting from Intermediate V10 according to General Procedure 18 Variant 2, Intermediate W10 was obtained as a white solid (980 mg, 3.91 mmol, 66% yield).
[00297] Step 4: Starting from Intermediate W10 according to General Procedure 19 (with CuBr), Intermediate CIO was obtained as a white solid (250 mg, 973 μmol, 21% yield).
Intermediate Cll [00298] Step 1: Starting from 2,2-difluoro-3-methylbicyclo[l.l.l]pentane-l-carboxylic acid according to General Procedure 16, Intermediate Ull was obtained as a white solid (500 mg, 1.81 mmol, 98% yield).
[00299] Step 2: Starting from Intermediate Ull according to General Procedure 17, Intermediate VI 1 was obtained as a yellow oil (400 mg, crude).
[00300] Step 3: Starting from Intermediate Vll according to General Procedure 18 Variant 2, Intermediate Wil was obtained as a yellow solid (270 mg, crude).
[00301] Step 4: Starting from Intermediate Wil according to General Procedure 19 (with
CuBr2), Intermediate Cll was obtained as a white solid (100 mg, 377 μmol, 28% yield).
Intermediate Cl 2
[00302] Step 1: Starting from 4-cyclopropoxybenzoic acid according to General Procedure 16, Intermediate U12 was obtained as a white solid (1.50 g, 5.13 mmol, 91% yield).
[00303] Step 2: Starting from Intermediate U12 according to General Procedure 17, Intermediate VI 2 was obtained as a white solid (1.50 g, 4.90 mmol, 95% yield).
[00304] Step 3: Starting from Intermediate V12 according to General Procedure 18 Variant 1, Intermediate W12 was obtained as a white solid (0.980 g, 4.51 mmol, 92% yield).
[00305] Step 4: Starting from Intermediate W12 according to General Procedure 19 (with CuBr), Intermediate C12 was obtained as a white solid (360 mg, 1.28 mmol, 31% yield).
Intermediate Cl 3
[00306] Step 1: Starting from 5 -cyclobutylisoxazole-3 -carboxylic acid according to General Procedure 16, Intermediate U13 was obtained as a white solid (500 mg, 1.78 mmol, 99% yield).
[00307] Step 2: Starting from Intermediate U13 according to General Procedure 17, Intermediate VI 3 was obtained as a brown oil (550 mg, crude).
[00308] Step 3: Starting from Intermediate V13 according to General Procedure 18 Variant 1, Intermediate W13 was obtained as a white solid (280 mg, 1.36 mmol, 73% yield).
[00309] Step 4: Starting from Intermediate W13 according to General Procedure 19 (with CuBr2), Intermediate C13 was obtained as a yellow solid (100 mg, 370 μmol, 27% yield).
Intermediate Cl 4 [00310] Step 1: Starting from 3-methylbicyclo[l.l.l]pentane-l-carboxylic acid according to General Procedure 16, Intermediate U14 was obtained as a white solid (950 mg, 3.95 mmol, 99% yield).
[00311] Step 2: Starting from Intermediate U14 according to General Procedure 17, Intermediate VI 4 was obtained as a yellow oil (925 mg, crude).
[00312] Step 3: Starting from Intermediate V14 according to General Procedure 18 Variant 2, Intermediate W14 was obtained as a yellow solid (730 mg, 4.42 mmol, 85% yield).
[00313] Step 4: Starting from Intermediate W14 according to General Procedure 19 (with
CuBr2), Intermediate C14 was obtained as a white solid (220 mg, 960 μmol, 22% yield).
Intermediate Cl 8
[00314] Step 1: Starting from 3 -cyclopropylbicyclo[l.l.l]pentane-l -carboxylic acid according to General Procedure 16, Intermediate U18 was obtained as a white solid (1.20 g, 4.51 mmol, 98% yield).
[00315] Step 2: Starting from Intermediate U18 according to General Procedure 17, Intermediate VI 8 was obtained as a white solid (380 mg, 2.29 mmol, 51% yield).
[00316] Step 3: Starting from Intermediate V18 according to General Procedure 18 Variant 2, Intermediate W18 was obtained as a white solid (250 mg, 1.31 mmol, 99% yield).
[00317] Step 4: Starting from Intermediate W18 according to General Procedure 19 (with
CuBr2), Intermediate C18 was obtained as a yellow oil (180 mg, 706 μmol, 54% yield).
Intermediate Cl 9
[00318] Step 1: Starting from 3 -phenylbicyclo [l.l.l]pentane-l -carboxy lie acid according to General Procedure 16, Intermediate U19 was obtained as a white solid (717 mg, crude).
[00319] Step 2: Starting from Intermediate U19 according to General Procedure 17, Intermediate VI 9 was obtained as a white solid (480 mg, crude).
[00320] Step 3: Starting from Intermediate V19 according to General Procedure 18 Variant 2, Intermediate W19 was obtained as a yellow solid (420 mg, 1.85 mmol, 79% yield).
[00321] Step 4: Starting from Intermediate W19 according to General Procedure 19 (with CuBr2), Intermediate C19 was obtained as a white solid (250 mg, 859 μmol, 61% yield).
Intermediate C22 [00322] Step 1: Starting from 3-(2-hydroxypropan-2-yl)bicyclo[l.l.l]pentane-l-carboxylic acid according to General Procedure 16, Intermediate U22 was obtained as a transparent oil (300 mg, 1.06 mmol, 60% yield).
[00323] Step 2: Starting from Intermediate U22 according to General Procedure 17, Intermediate V22 was obtained as a transparent oil (300 mg, crude).
[00324] Step 3: Starting from Intermediate V22 according to General Procedure 18 Variant 2, Intermediate W22 was obtained as a transparent oil (300 mg, crude).
[00325] Step 4: Starting from Intermediate W22 according to General Procedure 19 (with CuBr2), Intermediate C22 was obtained as a white solid (45.0 mg, 165 μmol, 16% yield).
Intermediate C23
[00326] Step 1: Starting from 3 -(methoxymethyl)bicyclo[l.l.l]pentane-l -carboxylic acid according to General Procedure 16, Intermediate U23 was obtained as a white solid (480 mg, 1.78 mmol, 92% yield).
[00327] Step 2: Starting from Intermediate U23 according to General Procedure 17, Intermediate V23 was obtained as a transparent oil (500 mg, crude).
[00328] Step 3: Starting from Intermediate V23 according to General Procedure 18 Variant 2, Intermediate W23 was obtained as a transparent oil (340 mg, crude).
[00329] Step 4: Starting from Intermediate W23 according to General Procedure 19 (with
CuBr2), Intermediate C23 was obtained as a transparent oil (150 mg, 579 μmol, 33% yield).
Intermediate C24
[00330] Step 1: Starting from 3 -cyclobutylbicyclo[l.l.l]pentane-l -carboxy lie acid according to General Procedure 16, Intermediate U24 was obtained as a white solid (470 mg, 1.70 mmol, 94% yield).
[00331] Step 2: Starting from Intermediate U24 according to General Procedure 17 and following purification via Purification Method 2, Intermediate V24 was obtained as a white solid (190 mg, 1.05 mmol, 54% yield).
[00332] Step 3: Starting from Intermediate V24 according to General Procedure 18 Variant 2, Intermediate W24 was obtained as a white solid (210 mg, crude).
[00333] Step 4: Starting from Intermediate W24 according to General Procedure 19 (with CuBr2), Intermediate C24 was obtained as a transparent oil (140 mg, 520 μmol, 51% yield).
Scheme 10: Synthesis of Intermediates Cl, C3, C4, C5, C8, CIS, C16, C17, C20, C21, C25
Step 1 - General Procedure 20:
[00334] The appropriate carboxylic acid (1.00 eq.) was dissolved in methanol (0.5 M relative to the carboxylic acid) and the mixture was cooled to 0°C. Thionyl chloride (1.50 eq.) was added. The reaction was stirred at 25 - 60°C until reaction completion (3 - 12 h). The mixture was concentrated under reduced pressure to afford Intermediate X.
Step 2 - General Procedure 21:
[00335] Intermediate X was dissolved in MeOH or EtOH (0.4 - 0.7 M relative to Intermediate X) and hydrazine hydrate 85% in water (2.00 - 20.00 eq.) was added. The reaction was stirred at 25 - 80°C until reaction completion (2 - 12 h). The mixture was either concentrated under reduced pressure to give Intermediate Y, or it was worked up by diluting the reaction mixture with water and extracting the aqueous layer with ethyl acetate (3 x). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford Intermediate Y. If necessary, it was purified via Purification Method 1 or Purification Method 2.
[00336] Step 3: see General Procedure 18
[00337] Step 4: see General Procedure 19
Representative example: Intermediate Cl
Step 1. According to General Procedure 20:
[00338] 3-(trifluoromethyl)bicyclo[l.l. l]pentane-l-carboxylic acid (0.900 g, 5.00 mmol, 1.00 eq.) was dissolved in methanol (1.00 mL) and cooled to 0°C. Thionyl chloride (726 pL. 9.99 mmol, 2.00 eq.) was added, and the reaction was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure to afford Intermediate XI (970 mg, 5.00 mmol, 99% yield) as yellow oil.
Step 2. According to General Procedure 21:
[00339] Intermediate XI (970 mg, 5.00 mmol, 1.00 eq.) was dissolved in methanol (9.00 mL) and hydrazine hydrate 85% in water (4.28 mL, 74.9 mmol, 15.0 eq.) was added. The reaction was stirred at 60°C for 2 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated to afford Intermediate Y1 (700 mg, 3.61 mmol, 72% yield) as a white solid.
Step 3. According to General Procedure 18, Variant 2:
[00340] Intermediate Y1 (3.23 g, 16.6 mmol, 1.00 eq.) was dissolved in methanol (30.0 mL) and cyanogen bromide (1.47 mL, 20.0 mmol, 1.20 eq.) was added. The reaction was stirred at 65°C for 3 h. The mixture was filtered and concentrated under reduced pressure to afford Intermediate Z1 (1.10 g, 5.02 mmol, 30 % yield) as a white solid.
Step 4. According to General Procedure 19:
[00341] Intermediate Z1 (2.20 g, 10.0 mmol, 1.00 eq.) was dissolved in acetonitrile (22.0 mL) was added tert-butyl nitrite (2.39 mL, 20.1 mmol, 2.00 eq.) and copper(I) bromide (611 pL. 20.1 mmol, 2.00 eq.). The reaction was stirred at 80°C for 2 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5/1) to afford Intermediate Cl (1.10 g, 3.89 mmol, 39% yield) as a white solid.
[00342] Intermediates C3, C4, C5, C8, C15, C16, C17, C20 and C21 were synthesized in analogy to the above reactions using the general procedures.
Intermediate C3
[00343] Step 2: Starting from methyl 4-methylbenzoate according to General Procedure 21, Intermediate Y3 was obtained as a white solid (1.90 g, 12.6 mmol, 95% yield).
[00344] Step 3: Starting from Intermediate Y3 according to General Procedure 18 Variant 2, Intermediate Z3 was obtained as a white solid (1 g, crude).
[00345] Step 4: Starting from Intermediate Z3 according to General Procedure 19 (with CuBr2), Intermediate C3 was obtained as a white solid (600 mg, 2.51 mmol, 49% yield).
Intermediate C4
Intermediate X4
[00346] Step 1: A mixture of methyl 2-chloro-6-methylnicotinate (1.00 g, 5.39 mmol, 1.00 eq.), cyclopropylboronic acid (486 mg, 5.66 mmol, 1.05 eq.), potassium carbonate (2.23 g, 16.2 mmol, 3.00 eq.) and Pd[P( Bu)3]2 (275 mg, 539 μmol, 0.100 eq.) in dioxane/water 4/1 was purged with nitrogen 3 times, then the reaction was stirred at 90°C for 12 h under nitrogen. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 0/1) to afford Intermediate X4 (410 mg, 2.14 mmol, 40% yield) as colourless oil.
[00347] Step 2: Starting from Intermediate X4 according to General Procedure 21, Intermediate Y4 was obtained as a white solid (400 mg, 2.09 mmol, 98% yield).
[00348] Step 3: Starting from Intermediate Y4 according to General Procedure 18 Variant 2, Intermediate Z4 was obtained as a white solid (650 mg, crude).
[00349] Step 4: Starting from Intermediate Z4 according to General Procedure 19 (with CuBr), Intermediate C4 was obtained as a white solid (150 mg, 535 μmol, 39% yield).
Intermediate C5
[00350] Step 1: Starting from 4-(trifluoromethoxy)benzoic acid according to General Procedure 20, Intermediate X5 was obtained as a white solid (2.6 g, crude).
[00351] Step 2: Starting from Intermediate X5 according to General Procedure 21, Intermediate Y5 was obtained as a white solid (1.95 g, 8.24 mmol, 69% yield).
[00352] Step 3: Starting from Intermediate Y5 according to General Procedure 18 Variant 2, Intermediate Z5 was obtained as a white solid (800 mg, 3.23 mmol, 59% yield).
[00353] Step 4: Starting from Intermediate Z5 according to General Procedure 19 (with CuBr), Intermediate C5 was obtained as a white solid (400 mg, 1.23 mmol, 37% yield).
Intermediate C8
Intermediate X8
[00354] Step 1 : A mixture of methyl 3 -formylbicyclo[l.l. l]pentane-l -carboxylate (100 mg, 649 μmol, 1.00 eq.) and DAST (257 pL. 1.95 mmol, 3.00 eq.) in dichloromethane (2.00 mL) was cooled to - 78°C and purged with nitrogen 3 times, then the reaction was stirred at -78°C for 6 h under nitrogen. The mixture was diluted with saturated sodium bicarbonate solution (10 mL) at -78°C, and the aqueous layer was extracted with dichloromethane (3 x 8 mL). The organic layer was washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 0/1) to afford Intermediate X8 (160 mg, crude) as a yellow oil.
[00355] Step 2: Starting from Intermediate X8 according to General Procedure 21, Intermediate Y8 was obtained as a yellow oil (160 mg, crude).
[00356] Step 3: Starting from Intermediate Y8 according to General Procedure 18 Variant 2, Intermediate Z8 was obtained as a yellow oil (200 mg, crude).
[00357] Step 4: Starting from Intermediate Z8 according to General Procedure 19 (with CuBr), Intermediate C8 was obtained as a yellow solid (30.0 mg, 113 μmol, 11% yield).
Intermediate C15
Intermediate X15
[00358] Step la: To a solution of l-(l-methylcyclopropyl)ethan-l-one (1.00 g, 10.2 mmol, 1.12 mL, 1.00 eq.) in tetrahydrofuran (10.0 mL) was added sodium hydride 60% dispersion in mineral oil (611 mg, 15.3 mmol, 1.50 eq.). Then diethyl oxalate (1.39 mL, 10.2 mmol, 1.00 eq.) was added. The reaction was stirred at 65°C for 2 h. The mixture was quenched with NH4CI sat. sol. (20.0 mL) at 10°C, and the aqueous layer was extracted with ethyl acetate (2 x 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 100/1) to afford ethyl (Z)-4-hydroxy-4-(l-methylcyclopropyl)-2-oxobut-3 -enoate (1.30 g, 5.25 mmol, 51% yield) as yellow oil.
[00359] Step lb: To a solution of ethyl (Z)-4-hydroxy-4-(l-methylcyclopropyl)-2-oxobut-3- enoate (1.30 g, 6.56 mmol, 1.00 eq.) in ethanol (13.0 mL) was added hydroxylammonium chloride (547 mg, 7.87 mmol, 1.20 eq.). The reaction was stirred at 80°C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase column chromatography (Cl 8, eluting with water/acetonitrile = 1/0 to 0/1, 0.1% formic acid) and lyophilized to afford Intermediate X15 (900 mg, 4.61 mmol, 70% yield) as yellow oil.
[00360] Step 2: Starting from Intermediate X15 according to General Procedure 21, Intermediate Y15 was obtained as a white solid (510 mg, 2.81 mmol, 99% yield).
[00361] Step 3: Starting from Intermediate Y15 according to General Procedure 18 Variant 2, Intermediate Z15 was obtained as a white solid (350 mg, 1.70 mmol, 60 % yield).
[00362] Step 4: Starting from Intermediate Z15 according to General Procedure 19 (with CuBr2), Intermediate C15 was obtained as a colourless oil (145 mg, 537 μmol, 32% yield).
Intermediate Cl 6
Intermediate X16
[00363] Step la: To a solution of 3, 3 -difluorocyclobutane- 1-carbaldehyde (100 mg, 833 μmol, 1.00 eq.) in methanol (1.00 mL) and water (1.00 mL) was added hydroxylammonium chloride (60.8 mg, 874 μmol, 1.05 eq.) and sodium carbonate (92.7 mg, 874 μmol, 1.05 eq.). The reaction was stirred at 50°C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was adjusted to pH = 5 with hydrochloric acid (1 M, 5 mL), and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3, 3 -difluorocyclobutane- 1-carbaldehyde oxime (70.0 mg, 518 μmol, 62% yield) as yellow oil.
[00364] Step lb: To a solution of 3,3-difluorocyclobutane-l-carbaldehyde oxime (200 mg, 1.48 mmol, 1.00 eq.) in tetrahydrofuran (2.00 mL) was added ethyl propiolate (145 mg, 1.48 mmol, 145 pL, 1.00 eq.) and sodium hypochlorite 10% (5.21 mL, 8.44 mmol, 5.70 eq.) at 0°C. The reaction was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (5 mL), and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 100/1 to 50/1) to afford Intermediate X16 (60.0 mg, 260 μmol, 18% yield) as colourless oil.
[00365] Step 2: Starting from Intermediate X16 according to General Procedure 21, Intermediate Y16 was obtained as a yellow oil (40.0 mg, crude).
[00366] Step 3: Starting from Intermediate Y16 according to General Procedure 18 Variant 2, Intermediate Z16 was obtained as a yellow solid (40.0 mg, crude).
[00367] Step 4: Starting from Intermediate Z16 according to General Procedure 19 (with CuBr2), Intermediate C16 was obtained as a white solid (10.0 mg, 32.7 μmol, 20% yield).
Intermediate Cl 7
Intermediate X17
[00368] Step 1: A mixture of ethyl 5 -bromo-4-methyl-isoxazole-3 -carboxylate (900 mg, 3.85 mmol, 1.00 eq.), cyclopropylboronic acid (330 mg, 3.85 mmol, 1.00 eq.), Pd(dppf)C12 (281 mg, 385 μmol, 0.10 eq.), and potassium carbonate (1.59 g, 11.5 mmol, 3.00 eq.) in dioxane/water 4/1 (10.00 mL) was purged with nitrogen 3 times, then the reaction was stirred at 90°C for 12 hr under nitrogen. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 5/1) to afford Intermediate X17 (387 mg, 1.98 mmol, 52% yield) as colourless oil.
[00369] Step 2: Starting from Intermediate X17 according to General Procedure 21, Intermediate Y17 was obtained as a white solid (350 mg, 1.93 mmol, 99% yield).
[00370] Step 3: Starting from Intermediate Y17 according to General Procedure 18 Variant 2, Intermediate Z17 was obtained as a yellow solid (310 mg, 1.50 mmol, 78% yield). [00371] Step 4: Starting from Intermediate Z17 according to General Procedure 19 (with
CuBr2), Intermediate C17 was obtained as a white solid (146 mg, 541 μmol, 43% yield).
Intermediate C20
Intermediate X20
[00372] Step 1: To a solution of diethylzinc (2.00 M, 31.7 mL, 3.00 eq.) in dichloromethane (15.0 mL) was added trifluoro acetic acid (4.70 mL, 63.3 mmol, 3.00 eq.) dropwise at 0°C. The suspension was stirred for 30 min at 0°C, then diiodomethane (5.11 mL, 63.3 mmol, 3.00 eq.) was added. After an additional 30 min at 0°C, a solution of ethyl 4-methylpent-4-enoate (3.00 g, 21.1 mmol, 1.00 eq.) in dichloromethane (15.0 mL) was added at 0°C. The reaction was stirred at 20°C for 12 h under nitrogen. The mixture was diluted with methanol (20.0 mL) and brine (30.0 mL). After 30 min, the solvent was removed under reduced pressure, and NH4CI sat. sol. (80.0 mL) was added. The aqueous layer was extracted with dichloromethane (3 x 80 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Intermediate X20 (3.00 g, crude) as yellow oil.
[00373] Step 2: Starting from Intermediate X20 according to General Procedure 21, Intermediate Y20 was obtained as a white solid (1.70 g, 12.0 mmol, 62% yield).
[00374] Step 3: Starting from Intermediate Y20 according to General Procedure 18 Variant 2, Intermediate Z20 was obtained as a yellow solid (3.00 g, crude).
[00375] Step 4: Starting from Intermediate Z20 according to General Procedure 19 (with CuBr), Intermediate C20 was obtained as a yellow oil (500 mg, 2.16 mmol, 12% yield).
Intermediate C21 [00376] Step 1: To a solution of methyl 4-hydroxybenzoate (1.00 g, 6.57 mmol, 1.00 eq.) in tetrahydrofuran (10.0 mL) were added triphenylphosphine (2.59 g, 9.86 mmol, 1.50 eq.) and 3,3- difluorocyclobutan-l-ol (710 mg, 6.57 mmol, 1.00 eq.). The reaction mixture was cooled to 0°C and diethyl azodicarboxylate (1.79 mL, 9.86 mmol, 1.50 eq.) was added. The reaction was stirred at 25°C for 16 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with petroleum ether/ethyl acetate = 1/0 to 30/1) to afford Intermediate X21 (517 mg, 2.13 mmol, 16% yield) as a pink solid.
[00377] Step 2: Starting from Intermediate X21 according to General Procedure 21, Intermediate Y21 was obtained as a white solid (710 mg, crude).
[00378] Step 3: Starting from Intermediate Y21 according to General Procedure 18 Variant 2, Intermediate Z21 was obtained as a white solid (584 mg, crude).
[00379] Step 4: Starting from Intermediate Z21 according to General Procedure 19 (with CuBr2), Intermediate C21 was obtained as a yellow solid (58 mg, 175 μmol, 16% yield).
Intermediate C25
Intermediate X25
[00380] Step 1 : To a solution of 3 -(methoxycarbonyl)bicyclo[l.l.l]pentane-l -carboxylic acid (2.50 g, 14.7 mmol, 1.00 eq.) in dichloromethane (30.0 mL) were added l-ethyl-3-(3-dimethylamino- propyl)-carbodiimide hydrochloride (2.87 g, 15.0 mmol, 1.02 eq.) and A'.O-dimcthyl hydroxylamine hydrochloride (1.48 g, 15.1 mmol, 1.03 eq.). The reaction was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate = 1/0 to 0/1) to afford methyl 3- (methoxy(methyl)carbamoyl)bicyclo[l.l.l]pentane-l -carboxylate (5.2 g, 24.4 mmol, 83% yield) as a white solid.
[00381] Step 2 : To a solution of methyl 3-(methoxy(methyl)carbamoyl)bicyclo[l.l.l]pentane-l- carboxylate (2.00 g, 9.38 mmol, 1.00 eq.) in tetrahydrofuran (50.0 mL) was added methylmagnesium bromide (3.00 M, 12.5 mL, 4.00 eq.) at -70°C. Then the reaction was stirred at -70°C for 2 h, then it was quenched by addition of methanol (5 mL) and diluted with water (10 mL). The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate = 3/1) to afford methyl 3- acetylbicyclo[l. l.l]pentane-l -carboxylate (0.60 g, 3.57 mmol, 38% yield) as a white solid.
[00382] Step 3: To a solution of methyl 3-acetylbicyclo[l.l. l]pentane-l-carboxylate (0.40 g, 2.38 mmol, 1.00 eq.) in dichloromethane (5.00 mL) was added diethylamino-sulfur trifluoride (1.15 g, 7.13 mmol, 943 pL, 3.00 eq.). The reaction was stirred at 25°C for 10 h, then it was concentrated under reduced pressure to afford Intermediate X25 (0.9 g, crude) as yellow solid.
[00383] Step 4: Starting from Intermediate X25 according to General Procedure 21, Intermediate Y25 was obtained as a white solid (600 mg, 3.15 mmol, 67% yield).
[00384] Step 5: Starting from Intermediate Y25 according to General Procedure 18 Variant 2, Intermediate Z25 was obtained as a white solid (680 mg, crude).
[00385] Step 6: Starting from Intermediate Z25 according to General Procedure 19 (with CuBr2), Intermediate C25 was obtained as a yellow solid (600 mg, 2.15 mmol, 68% yield).
Synthesis of Compound 77
[00386] Step 1. To a solution of Intermediate Cl (500 mg, 1.77 mmol, 1.00 eq.) in N,N- dimethylacetamide (6.00 mL) were added A'jV-diisopropylcthylaminc (769 pL, 4.42 mmol, 2.50 eq.) and Intermediate B5 (546 mg, 1.77 mmol, 1.00 eq.). The reaction was stirred at 110 °C for 1 h, then it was filtered and concentrated under reduced pressure to give a residue. The residue was purified via purification method 1 to afford 3-(2,6-difluoro-4-((2A,3S)-2-methyl-3-((5-(3-(trifluoromethyl)bicyclo[l.Ll]pentan-l- yl)-l, 3, 4-oxadiazol-2-yl)amino)azetidin-l-yl)phenyl)piperidine-2, 6-dione (497 mg, 963 μmol, 27% yield) as a white solid.
[00387] Step 2. To a solution of 3-(2,6-difluoro-4-((27?,3S)-2-methyl-3-((5-(3- (trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)-l,3,4-oxadiazol-2-yl)amino)azetidin-l-yl)phenyl)piperidine- 2,6-dione (300 mg, 0.59 mmol, 1 eq.) in DMF (20 V) was added NCS (173 mg, 1.30 mmol, 2.2 eq.). The reaction was stirred at 50 °C for 8 h, then it was poured into water (20 V). After stirring for 12 h at 25 °C, the resulting precipitate was filtered. The solid was washed off the filter with ethyl acetate (10 V) and THF (2 V). The mixture was washed with water (3 V) and 20% NaCl solution (3 V), then concentrated under reduced pressure to give a residue. The residue was purified via purification method 1 to afford Compound 77 as a white solid (296 mg, 0.51 mmol, 87% yield).
Representative example: Synthesis of Compound 36
[00388] Step 1. To a solution of 3 -(trifluoromethyl)bicyclo[l.l.l]pentane-l -carboxylic acid (0.90 g, 5.00 mmol, 1.00 eq.) in methanol (1.00 mL) was added thionyl chloride (1.19 g, 9.99 mmol, 726 pL. 2.00 eq.) at 0 °C. The reaction was stirred at 25 °C for 12 h, then it was concentrated to afford methyl 3- (trifluoromethyl)bicyclo[l. l.l]pentane-l -carboxylate (970 mg, 5.00 mmol, 99% yield) as a yellow oil. [00389] Step 2. To a solution of methyl 3 -(trifluoromethyl)bicyclo[l.l.l]pentane-l -carboxylate (970 mg, 5.00 mmol, 1.00 eq.) in methanol (9.00 mL) was added hydrazine hydrate (4.41 g, 74.9 mmol, 4.28 mL, 85% purity, 15.0 eq.). The reaction was stirred at 60 °C for 2 h, then it was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated to afford 3- (trifluoromethyl)bicyclo[l. l.l]pentane-l -carbohydrazide (700 mg, 3.61 mmol, 72% yield) as awhite solid.
[00390] Step 3. To a solution of 3 -(trifluoromethyl)bicyclo[ 1.1.1 ]pentane-l -carbohydrazide (3.23 g, 16.6 mmol, 1.00 eq.) in methanol (30.0 mL) was added cyanogen bromide (2.11 g, 20.0 mmol, 1.47 mL, 1.20 eq.). The reaction was stirred at 65 °C for 3 h, then it was quenched by addition of water (30 mL). The aqueous layer was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 5-(3-(trifhioromethyl)bicyclo[l.l.l]pentan-l-yl)-l,3,4-oxadiazol-2-amine (1.10 g, 5.02 mmol, 30 % yield) as a white solid.
[00391] Step 4. To a solution of 5-(3-(trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)-l,3,4-oxadiazol- 2-amine (2.20 g, 10.0 mmol, 1.00 eq.) in acetonitrile (22.0 mL) were added tert-butyl nitrite (2.07 g, 20.1 mmol, 2.39 mL, 2.00 eq.) and copper(I) bromide (2.88 g, 20.1 mmol, 2.00 eq.). The reaction was stirred at 80 °C for 2 h, then it was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 5/1) to afford 2-bromo-5-(3- (trifluoromethyl)bicyclo[l. l.l]pentan-l-yl)-l,3,4-oxadiazole (1.10 g, 3.89 mmol, 39% yield) as a white solid.
[00392] Step 5. To a solution of 5-bromo-l,3-difluoro-2-methylbenzene (10.0 g, 48.3 mmol, 1.00 eq.) in tetrachloromethane (100 mL) were added A'-bromo succinimide (8.60 g, 48.3 mmol, 1.00 eq.) and (E)-3,3'-(diazene-l,2-diyl)bis(2 -methylpropanenitrile) (397 mg, 2.42 mmol, 0.05 eq.). The reaction was stirred at 80 °C for 2 h, then it was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate = 1/0) to afford 5- bromo-2-(bromomethyl)-l,3-difluorobenzene (12.0 g, 41.9mmol, 86% yield) as a yellow oil.
[00393] Step 6. To a solution of 5-bromo-2-(bromomethyl)-l,3-difluorobenzene (12.0 g, 41.9 mmol, 1.00 eq.) in ethanol (90.0 mL) and water (30.0 mL) was added potassium cyanide (3.01 g, 46.1 mmol, 1.98 mL, 1.10 eq.). The reaction was stirred at 60 °C for 2 h, then it was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate = 1/0 to 20/1) to afford 2-(4-bromo-2,6- difluorophenyl)acetonitrile (7.00 g, 30.1 mmol, 71% yield) as a white solid.
[00394] Step 7. To a solution of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (7.00 g, 30.1 mmol, 1.00 eq.) and methyl acrylate (2.60 g, 30.1 mmol, 2.72 mL, 1.00 eq.) in tetrahydrofuran (70.0 mL) was added sodium methoxide (163 mg, 3.02 mmol, 0.10 eq.) at 0 °C. The reaction was stirred at 20 °C for 1 h, then it was quenched with saturated ammonium chloride aqueous solution (150 mL). The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate = 1/0 to 20/1) to afford methyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoate (8.60 g, 27.0 mmol, 89% yield) as a yellow oil.
[00395] Step 8. To a solution of methyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoate (8.60 g, 27.0 mmol, 1.00 eq.) in acetic acid (80.0 mL) was added sulfuric acid (8.00 mL). The reaction was stirred at 90 °C for 2 h, then it was poured into ice water (50 mL) and the resulting precipitate was filtered. The precipitate was lyophilized to afford 3-(4-bromo-2,6-difluorophenyl)piperidine-2, 6-dione (6.00 g, 19.7 mmol, 72% yield) as a white solid.
[00396] 'H NMR (400 MHz, DMSO-O d = 11.00 (s, 1H), 7.54 - 7.51 (m, 1H), 7.51 - 7.48 (m, 1H), 4.26 (dd, J= 5.2, 12.7 Hz, 1H), 2.82 - 2.80 (m, 1H), 2.57 - 2.51 (m, 1H), 2.13 (br dd, J= 3.9, 13.1 Hz, 1H), 2.06 - 1.99 (m, 1H).
[00397] Step 9. To a solution of 3-(4-bromo-2,6-difluorophenyl)piperidine-2, 6-dione (1.37 g, 4.49 mmol, 1.00 eq.) in dioxane (8.00 mL) were added tert-butyl ((27?,3S)-2-methylazetidin-3-yl)carbamate (1.00 g, 4.49 mmol, 1.00 eq., hydrochloride), caesium carbonate (4.39 g, 13.5 mmol, 3.00 eq.) and 1,3- bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro-2Z7-imidazol-l-ium-2-ide;3- chloropyridine;dichloropalladium (218 mg, 225 μmol, 0.05 eq.) under nitrogen atmosphere. The reaction was stirred at 100 °C for 1 h under nitrogen atmosphere. Two batches were combined, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate = 5/1 to 1/1) to afford tert-butyl ((27?, 3S)-l-(4-(2, 6- dioxopiperidin-3-yl)-3, 5-difluorophenyl)-2-methylazetidin-3-yl) carbamate (3.50 g, 7.61 mmol, 84% yield, 89% purity) as a yellow solid.
[00398] Step 10. A solution of tert-butyl ((27?,3S)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)-2-methylazetidin-3-yl) carbamate (1.50 g, 3.66 mmol, 1.00 eq.) in trifluoroacetic acid (15.0 mL) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase column chromatography (water/acetonitrile = 100/0 to 0/100, 0.1% formic acid) and lyophilized to afford 3-(4-((27?,3S)-3-amino-2-methylazetidin-l-yl)-2,6- difluorophenyl)piperidine-2, 6-dione (1.10 g, 2.52 mmol, 68% yield, 97% purity, trifluoro acetate) as a white solid.
[00399] Step 11. To a solution of 3-(4-((27?,3N)-3-amino-2-methylazetidin-l-yl)-2,6- difluorophenyl)piperidine-2, 6-dione (3.10 g, 8.72 mmol, 1.00 eq.) in A'jV-dimcthylacctamidc (30.0 mL) were added A'.A'-diisopropylcthylaminc (5.64 g, 43.6 mmol, 7.60 mL, 5.00 eq.) and 2-bromo-5-(3- (trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)-l,3,4-oxadiazole (2.47 g, 8.72 mmol, 1.00 eq.). The reaction was stirred at 110 °C for 8 h, then it was quenched with water (30 mL). The aqueous layer was extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine (3 x 60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate = 1/0 to 0/1) to afford 3-(2,6-difluoro-4-((27?,3S)-2-methyl-3-((5-(3-
(trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)-l,3,4-oxadiazol-2-yl)amino)azetidin-l-yl)phenyl)piperidine-
2,6-dione (1.50 g, 2.93 mmol, 34% yield) as a yellow solid.
[00400] 'H NMR (400 MHz, DMSO-</6) 8 = 10.87 (s, 1H), 8.22 (d, J = 7.4 Hz, 1H), 6.22 (d, J = 11.0 Hz, 2H), 4.22 (t, J= 7.6 Hz, 1H), 4.07 - 4.03 (m, 2H), 4.00 - 3.94 (m, 1H), 3.50 (br t, J= 6.8 Hz, 1H), 2.74 (br d, J= 5.4 Hz, 1H), 2.50 - 2.45 (m, 1H), 2.39 (s, 6H), 2.16 - 2.04 (m, 1H), 1.95 - 1.90 (m, 1H), 1.47 (d, J = 6.0 Hz, 3H).
[00401] Step 12. To a solution of 3-(2,6-difluoro-4-((27?,3S)-2-methyl-3-((5-(3- (trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)-l,3,4-oxadiazol-2-yl)amino)azetidin-l-yl)phenyl)piperidine-
2,6-dione (1.92 g, 3.75 mmol, 1.00 eq.) in dimethylformamide (2.00 mL) was added 1-chloropyrrolidine-
2.5-dione (401 mg, 3.00 mmol, 0.80 eq.). The reaction was stirred at 50 °C for 12 h, then it was quenched with water (30 mL). The aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition; column: Waters xbridge 150*25 mm 10 um; mobile phase: [water (ammonium bicarbonate) - acetonitrile]; gradient: 38%-68% B over 10 min) and lyophilized to afford 3-(3-chloro-2,6-difluoro-4-((27?,3S)-2-methyl-3-((5-(3- (trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)-l,3,4-oxadiazol-2-yl)amino)azetidin-l-yl)phenyl)piperidine-
2.6-dione (1.00627 g, 1.81 mmol, 48.17% yield, 98% purity) as an off-white solid.
[00402] 'H NMR (400 MHz, DMSO-</6) 8 = 10.94 (br s, 1H), 8.35 - 8.17 (m, 1H), 6.51 (br d, J = 12.2 Hz, 1H), 4.65 (t, J= 7.8 Hz, 1H), 4.24 - 4.08 (m, 2H), 4.07 - 3.94 (m, 1H), 3.82 - 3.52 (m, 1H), 2.90 - 2.72 (m, 1H), 2.57 - 2.54 (m, 1H), 2.40 (s, 6H), 2.16 - 2.06 (m, 1H), 2.02 - 1.96 (m, 1H), 1.44 - 1.35 (m, 3H)
[00403] MS (ESI) m/z 546.1 [M+H]+
Representative example: Synthesis of Compounds 78 and 79
Compound 36 Compound 78 Compound 79
[00404] 3 -(3 -chloro-2,6-difluoro-4-((2R,3S)-2-methyl-3 -((5 -(3 -
(trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)-l,3,4-oxadiazol-2-yl)amino)azetidin-l-yl)phenyl)piperidine- 2,6-dione (200 mg, 366 μmol, 1.00 eq.) was purified by chiral SFC (column: DAICEL CHIRALCEL OD (250 mm *50 mm, 10 um); mobile phase: [carbon dioxide - isopropanol]; B%: 35%, isocratic elution mode); mobile phase: [carbon dioxide - ethyl alcohol/acetonitrile]; B%: 60%, isocratic elution mode) and concentrated under reduced pressure to give two solids. The absolute configuration was assigned arbitrarily. Compound 78 was the first eluting isomer. Compound 79 was the second eluting isomer.
[00405] Compound 78: Peak 1 (Rt = 1.722 min) (S)-3-(3-chloro-2,6-difluoro-4-((2R,3S)-2- methyl-3 -((5 -(3 -(trifluoromethyl)bicyclo [1.1.1 ]pentan- 1 -yl)- 1 ,3 ,4-oxadiazol-2-yl)amino)azetidin- 1 - yl)phenyl)piperidine-2, 6-dione (68.38 mg, 122.76 μmol, 33.51% yield, 98% purity) as a white solid. 1H NMR (400 MHz, DMSO-O 8 = 10.94 (s, 1H), 8.25 (d, J = 7.0 Hz, 1H), 6.61 - 6.35 (m, 1H), 4.70 - 4.60 (m, 1H), 4.24 - 4.10 (m, 2H), 4.07 - 3.94 (m, 1H), 3.67 (dd, J= 6.4, 8.2 Hz, 1H), 2.86 - 2.73 (m, 1H), 2.55 - 2.53 (m, 1H), 2.40 (s, 6H), 2.16 - 2.04 (m, 1H), 2.03 - 1.95 (m, 1H), 1.39 (d, J = 6.2 Hz, 3H). MS (ESI) m/z 546.1 [M+H]+
[00406] Compound 79: Peak 2 (Rt = 1.805 min) (R)-3-(3-chloro-2,6-difluoro-4-((2R,3S)-2- methyl-3 -((5 -(3 -(trifluoromethyl)bicyclo [1.1.1 ]pentan- 1 -yl)- 1 ,3 ,4-oxadiazol-2-yl)amino)azetidin- 1 - yl)phenyl)piperidine-2, 6-dione (74.94 mg, 133.16 μmol, 36.35% yield, 97% purity) as a white solid. 1H NMR (400 MHz, DMSO-O 8 = 10.95 (s, 1H), 8.26 (d, J = 7.0 Hz, 1H), 6.51 (d, J = 11.0 Hz, 1H), 4.67 -
4.62 (m, 1H), 4.22 - 4.11 (m, 2H), 4.05 - 3.96 (m, 1H), 3.68 (dd, J= 6.4, 8.0 Hz, 1H), 2.87 - 2.73 (m, 1H),
2.62 - 2.53 (m, 1H), 2.40 (s, 6H), 2.16 - 2.06 (m, 1H), 2.00 (br dd, J= 2.2, 5.2 Hz, 1H), 1.39 (d, J= 6.2 Hz, 3H). MS (ESI) m/z 546.1 [M+H]+
Example 2. CDK2 Live-cell HiBiT Assay
[00407] CDK2-HiBiT luminescence live-cell abundance measurements were performed using a genetically modified HEK293 clonal cell line containing a C-terminal HiBiT tag knock-in on the CDK2 endogenous locus and stably expressing LgBiT protein. This was obtained from Promega (Madison, WI). Cells were plated in 384-well white bottom plates (Coming, 3570) using a Biotek MultiFlo FX (BioTek) at 5000 cells per well in 25 pl DMEM without phenol red (ThermoFisher Scientific, 21063029) supplemented with 10% FBS (Coming, 35-016-CV), 1% Penicillin/Streptomycin (ThermoFisher Scientific, 15140-163), and 0.5% Nano-Glo Endurazine Live Cell Substrate (Promega, N2571). Cells were incubated for 16 hours at 37°C and 5% CO2. Compound dosing was performed using a Labcyte Echo 650 acoustic dispenser (Beckman Coulter) as follows: first, 10-point 3-fold serial dilutions of the indicated compounds were pre-prepared in DMSO from a 10 mM stock directly on Echo qualified 384LDV plates (Beckman Coulter) and a fixed volume of 2.5 nL was then transferred to the cells. The cells were subsequently incubated at 37°C and 5% CO2 for 24 hours, after which the HiBiT -LgBiT luminescence signal was directly read on a Pherastar FSX using the “LUM plus” optic module. Two repeats were carried out (n = 2).
[00408] Analysis was performed using Genedata (Genedata, Basel, Switzerland). Luminescence response (R) was calculated using the formula: R = 100 * (S - N) / (P - N) where S is the signal in each well, and N and P are the mean negative and positive control values on the same plate. In other words, the signal in each well was normalized between 100% (DMSO treated cells) and 0% (dead cells or empty wells). Dose response curves in Genedata were fit to the Hill equation (four-parameter logistic equation):
R = So + Sinf - So where:
So is the fitted activity level at zero concentration of test sample ("zero activity").
Sinf is the fitted activity level at infinite concentration of test sample ("infinite activity"). n is the Hill coefficient for the curve, i.e. the measure of the slope at AC50.
DC50 is the concentration at which the activity reaches 50% of its maximum level. Sometimes, the terms EC50 ("half maximal effective concentration") or IC50 ("half maximal inhibitory concentration") are used as well: EC50 implies activation (increasing curves), IC50 is used for inhibition (decreasing curves). It is a measure of potency where low values indicate high potency.
C is the concentration in logarithmic units corresponding to the values on the x-axis of the dose-response curve plot.
[00409] n was restricted to between 0.5 and 2. The span (So - Sint) was restricted to between 25% and 125%. If the span was less than 25%, a constant fit was applied to the curve.
[00410] The span (So - Smf, i.e. the difference between the top and bottom plateaus on the dose response curve) is also referred to herein as the Dspan. It represents the maximal percentage decrease in the amount of CDK2 over the doses tested at the measured time-point. A greater Dspan value therefore indicates that the compound mediates greater levels of protein degradation.
Example 3. GSPT1 Live-cell HiBiT Assay
[00411] HiBiT -GSPT 1 luminescence live-cell abundance measurements were performed as for
CDK2, except that 1) a genetically modified HEK293 pooled cell line with a N-terminal HiBiT tag knock-in on GSPT1 endogenous locus and stably expressing LgBiT protein was used instead of the genetically modified HEK293 clonal cell line containing a C-terminal HiBiT tag knock-in on the CDK2 endogenous locus and stably expressing LgBiT protein, 2) the Nano-Gio Endurazine Live Cell Substrate was used at 0.2% instead of 0.5%, and 3) 2000 cells/well were seeded instead of 5000 as for CDK2.
Example 4. Assay Data
[00412] As can be seen from the data in Table 6, the compounds provided herein are effective in mediating the degradation of CDK2. In addition, the compounds provided herein can selectively mediate the degradation of CDK2 over GSPT1. The phenyl -glutarimide ring system of the compounds provided in Table 1 is known to be present in certain compounds that mediate the degradation of GSPT1. However, it has been discovered by the inventors that the compounds provided herein cause little or no degradation of GSPT1.
Table 6. Assay Data
Example 5. In vitro effect of Compound 36 in MDA-MB-157 breast, Kuramochi ovarian and
MKN1 gastric cancer cells
[00413] The MDA-MB-157 breast cancer cell line was acquired from ATCC and maintained by Monte Rosa in vitro as monolayer culture in Leibovitz's L-15 Medium supplemented with 10% heat inactivated fetal bovine serum and at 37 °C in CO?- free air.
[00414] The Kuramochi ovarian cancer cell line and the MKN1 gastric cancer cell lines were acquired from JCRB and maintained by Monte Rosa in vitro as monolayer culture in RPMI 1640 medium supplemented with 10% heat inactivated fetal bovine serum at 37°C in 5% CO2 in air.
Proliferation assay.
[00415] For each cell line, cells were plated at a density of 500 cells / well in quadruplicate in 96- well plates in the presence of DMSO or under a 9-point dose response curve (DRC) with a starting concentration of 10,000 nM, intermediate concentrations of 3,333 nM, 1,111 nM, 370 nM, 123 nM, 41.15 nM, 13.7 nM, 4.57 nM and a lowest concentration of 1.52 nM of Compound 36. After 7 days, the antiproliferative effect of Compound 36 relative to DO and DMSO treated cells was assessed using a CyQuant assay.
[00416] As shown in FIG. 1, a 7-day treatment with Compound 36 resulted in a strong antiproliferative effect relative to DMSO and DO on MDA-MB-157 cells (Emax = 96%, EC50 = 15 nM). Similarly, a significant antiproliferative effect was also observed in the Kuramochi and MKN1 lines (Emax = ~ 75 %). Bars show mean.
Cell cycle'. [00417] The MDA-MB-157 and Kuramochi cells were maintained in vitro as described above, plated at a density of 3 x 104 cells / well in triplicate in 24-well plates and allowed to settle overnight. The cells were then treated with DMSO or 1 nM, 10 nM, 100 nM or 1000 nM of Compound 36. After a 24- hour treatment, compound effects on the cell cycle were assessed using an EdU incorporation assay for flow cytometry (Click-iT™ EdU Alexa Fluor™ 647 Flow Cytometry Assay Kit), and a DAPI (4 ',6- diamidino-2-phenylindole) counterstain to measure DNA content.
[00418] As shown in FIG. 2, 24h treatment resulted in a dose dependent accumulation of cells in the G1 phase, from 64.2% in the DMSO treated conditions to 91% at the 1000 nM concentration of Compound 36 in MDA-MB-157 cells and respectively, 63% for DMSO and 88.6% for 1000 nM treatment with Compound 36 in Kuramochi cells.
Example 6. In vivo PK/PD study to evaluate Compound 36 in combination with ribociclib in human breast cancer xenograft model MCF7
[00419] A cell line-derived xenograft model of human hormone-receptor positive/HER2 -negative breast cancer, MCF7, was used to assess the PK/PD effect of Compound 36 alone and the combinatorial PK/PD effect of Compound 36 with the CDK4/6 inhibitor ribociclib (Medchem Express). The MCF7 tumor cell line was obtained from American Type Culture Collection (ATCC) and was expanded in vitro as a monolayer culture in DMEM medium supplemented with 15% heat inactivated fetal bovine serum at 37 °C in an atmosphere of 5% CO2 in air. Cells growing in an exponential growth phase were harvested, counted, and used for tumor inoculation. 6-8-week-old female BALB/c nude mice were implanted with 17-beta estradiol tablet (0.5 mg, 90-day release) on the left flank 24 hours prior to tumor cell inoculation. Each mouse was inoculated subcutaneously on the right flank with either MCF7 cells (1.5 x 107) in 0.2 mL of DMEM and Matrigel mixture (1:1 ratio) for tumor development. Tumor size measurements were conducted by caliper and recorded twice a week throughout the study, whereby tumor volume (mm3) was calculated using the formula: TV = a x b2/2, where “a” and “b” are the long and short diameters of a tumor, respectively. Drug treatments started when the mean tumor volume reached approximately 215 mm3. Animals were dosed orally (p.o.) twice daily (BID) for 5 days with Compound 36 alone, or in combination with once daily (Q.D.) oral administration of ribociclib as indicated in Tables 7 and 8. Six animals were used per dose group. The following compounds were used:
Table 7.
[00420] The following groups and treatments were used:
Table 8.
[00421] Plasma samples were collected at Oh, Ih, 2h, 8h and 24h post first dose on day 5 and were analyzed for drug levels using the AB API6500 + LC/MS/MS instrument (AB Sciex). Tumor samples were collected at 8h and 24h post first dose on day 5. CDK2 protein levels were determined by Western blot analysis from lysed tumor samples and relative levels calculated by normalization to CDK2 protein levels in vehicle treated samples. The following antibodies were used for PD analysis: Table 9.
[00422] As shown in FIG. 3, when dosed orally, Compound-36 achieved dose proportional exposure in mice, which was not affected by its combination with ribociclib. As shown in FIG. 4, in the preclinical tumor xenograft model of hormone receptor-positive/HER2 -negative breast cancer, Compound 36 drove dose dependent degradation of CDK2, which was further enhanced by its combination with a CDK4/6 inhibitor (ribociclib).
EQUIVALENTS
[00423] While specific embodiments have been discussed, the above specification is illustrative and not restrictive. Many variations of the embodiments will become apparent to those skilled in the art upon review of this specification. The full scope of what is disclosed should be determined by reference to the claims, along with the full scope of their equivalents, and the specification, along with such variations.

Claims

CLAIMS What is claimed is:
1. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is: i. a compound of Formula (I): wherein: each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, halogen, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl (e.g., CF3), and C1-6 haloalkoxy (e.g., OCF3); ring A is selected from the group consisting of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl, wherein each of C3-12 monocyclic cycloalkyl, C3-12 bicyclic cycloalkyl, 3 to 10 membered heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more occurrences of R5; each occurrence of R5 is independently selected from the group consisting of halogen, NH2, S(O)2NH2, C1-6 alkyl, C1-6 alkoxy, 63-12 monocyclic cycloalkyl, aryl, and heteroaryl, wherein each of 61-6 alkyl, 61-6 alkoxy, and 63-12 monocyclic cycloalkyl is optionally substituted with one or more occurrences of R6; each occurrence of R6 is independently selected from the group consisting of halogen, 61- 6 alkyl, C1-6 alkoxy, and OH; each occurrence of R7 is H or C1-6 alkyl; and n is an integer selected from the group consisting of 0, 1, 2, and 3; or ii. a compound selected from Table 1.
2. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is a compound of Formula (I).
3. The compound or pharmaceutically acceptable salt of claim 1 or claim 2, wherein:
1. each occurrence of R7 is H or C1-3 alkyl, for example wherein each occurrence of R7 is H or CH3;
4. The compound or pharmaceutically acceptable salt of any one of claims 1-3, wherein: i. each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, halogen, and C1-6 alkyl (e.g., C1-3 alkyl), for example wherein each of R1, R2, R3, and R4 is independently selected from the group consisting of hydrogen, F, Cl, and CH3; and/or
5. The compound or pharmaceutically acceptable salt of any one of claims 1-4, wherein: i. ring A is C3-12 bicyclic cycloalkyl (e.g., C3-6 bicyclic cycloalkyl) that is optionally substituted with one or more occurrences of R5, for example wherein ring A is bicyclofl .1. l]pentyl that is optionally substituted with one or more occurrences of R5 (e.g., wherein ring A is ii. each occurrence of R5 is C1-6 alkyl (e.g., C1-3 alkyl (e.g., CH3)) that is optionally substituted with one or more occurrences of R6; in. each occurrence of R6 is halogen (e.g., F); and/or iv. wherein n is 0.
6. The compound or pharmaceutically acceptable salt of any one of claims 1-5, wherein the compound of Formula (I) is a compound of Formula (IA): for example wherein the compound of Formula (I) is a compound of Formula (IB): for example wherein the compound of Formula (I) is selected from the group consisting of:
7. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is a compound selected from T able 1.
8. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one of claims 1-7 and one or more pharmaceutically acceptable excipients.
9. A combination comprising the compound or pharmaceutically acceptable salt of any one of claims 1 -7 and a CDK4/6 inhibitor.
10. A kit comprising (i) a unit dosage form comprising the compound or pharmaceutically acceptable salt of any one of claims 1-7, and, separately, (ii) a unit dosage form comprising a CDK4/6 inhibitor.
11. The kit of claim 10, wherein each unit dosage form is a pharmaceutical composition additionally comprising one or more pharmaceutically acceptable excipients.
12. A method of treating cancer in a subject in need thereof using the combination or kit of any one of claims 9-11.
13. The method of claim 12, wherein the cancer is breast cancer, for example HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer.
14. A method of treating cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-7 or the pharmaceutical composition of claim 8.
15. The method of claim 14, wherein: i. the cancer comprises a solid tumor, for example wherein the solid tumor is at least one of the group consisting of: uterine cancer (such as uterine carcinosarcoma and uterine corpus endometrial carcinoma), endometrial cancer, breast cancer, (such as breast invasive carcinoma and triple negative breast cancer, ER+ HER2- breast cancer, and HER2+ breast cancer), ovarian cancer (such as ovarian serous cystadenocarcinoma), stomach cancer (such as stomach adenocarcinoma), gastric cancer (such as gastrointestinal stromal cancer), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (such as B-cell lymphoma), sarcoma, esophageal cancer (such as esophageal carcinoma), bladder cancer (such as bladder urothelial carcinoma), lung cancer (such as lung squamous carcinoma and non-small cell lung cancer including EGFRm+ (epidermal growth factor receptor mutant positive) non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, mesothelioma, and malignant melanoma; or ii. the cancer comprises a liquid tumor, for example wherein the liquid tumor is at least one of the group consisting of: diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia/lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), nonHodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell/histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B- cell lymphoma, indolent lymphoma (e.g., DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus-type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM).
16. The method of claim 14 or claim 15i., wherein the cancer is selected from the group consisting of: ovarian cancer, endometrial cancer, gastric cancer, esophaegeal cancer, breast cancer (such as triple negative breast cancer), and lung adenosarcoma.
17. The method of claim 16, wherein the cancer is breast cancer, for example wherein the breast cancer is HR+ (hormone receptor positive) breast cancer, ER+ (estrogen receptor positive) breast cancer, HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer, ER+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer, or triple negative breast cancer.
18. The method of any one of claims 12-17, wherein the method further comprises administering to the subject an additional therapeutic agent, for example wherein the additional therapeutic agent is carboplatin, ribociclib or a pharmaceutically acceptable salt thereof, fulvestrant, or a combination thereof.
19. The method of claim 17, wherein the method further comprises administering to the subject a CDK4/6 inhibitor.
20. The method of any one of claims 12, 13, or 19, wherein the CDK4/6 inhibitor is (i) palbociclib, ribociclib, abemaciclib, lerociclib, trilaciclib, dalpiciclib, birociclib, BPI-16350, or in each case a pharmaceutically acceptable salt thereof, (ii) ribociclib, palbociclib, abemaciclib, or in each case a pharmaceutically acceptable salt thereof, (Hi) ribociclib or a pharmaceutically acceptable salt thereof, or palbociclib or a pharmaceutically acceptable salt thereof, or (iv) ribociclib or a pharmaceutically acceptable salt thereof.
21. The method of any one of claims 12, 13, 19, or 20, wherein the CDK4/6 inhibitor is administered in combination with endocrine therapy (for example wherein the endocrine therapy is an estrogen receptor antagonist such as fulvestrant, or an aromatase inhibitor such as letrozole, for example wherein the endocrine therapy is fulvestrant), optionally wherein the endocrine therapy is administered in combination with a luteinizing hormone-releasing hormone (LHRH) agonist.
22. The method of claim 21, wherein the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof, or palbociclib or a pharmaceutically acceptable salt (for example wherein the CDK4/6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof), and is administered in combination with fulvestrant.
23. The method of any one of claims 12-22, wherein the subject is a treatment-naive subject.
24. The combination or kit of any one of claims 9-11, or the method of any one of claims 12, 13, or 19-22, wherein the CDK4/6 inhibitor is in the form of a pharmaceutically acceptable salt.
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