WO2021155006A1 - Inhibiteurs de kinases dépendantes des cyclines et leurs utilisations - Google Patents

Inhibiteurs de kinases dépendantes des cyclines et leurs utilisations Download PDF

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Publication number
WO2021155006A1
WO2021155006A1 PCT/US2021/015505 US2021015505W WO2021155006A1 WO 2021155006 A1 WO2021155006 A1 WO 2021155006A1 US 2021015505 W US2021015505 W US 2021015505W WO 2021155006 A1 WO2021155006 A1 WO 2021155006A1
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compound
pharmaceutically acceptable
acceptable salt
och
phenyl
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PCT/US2021/015505
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English (en)
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Zenon D. Konteatis
Mingzong Li
Zhihua Sui
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Les Laboratoires Servier Sas
Servier Pharmaceuticals, Llc
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Publication of WO2021155006A1 publication Critical patent/WO2021155006A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • CDKs Cyclin-dependent kinases
  • CDKs are the catalytic subunits of a large family of serine/threonine protein kinases that become activated when associated with regulatory proteins, primarily cyclins. CDKs are pivotal for the correct timing of cell cycle progression and are responsible for mediating transcription events.
  • CDK7--CDK13 primarily being linked to transcription and CDK 1, 2, 4, and 6 having principal implications in cell cycle management. Cancers show' direct or indirect deregulation of CDKs, therefore targeting CDKs is an important mode to develop new ' anticancer therapeutics.
  • CDK inhibitor drugs have shown great promise in clinical settings. See e.g., Trends in Molecular Medicine. 8 (4 Supp1): S32-7. Given the continuing medical need for cancer therapeutics, additional CDK inhibitors are needed.
  • the provided compounds can be used alone (i.e., as a monotherapy) or in combination with one or more other therapeutic agent effective for treating any of the indications described herein.
  • Ring A is 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclyl, each of which is substituted with 0-4 occurrences of R a ;
  • R 1 is -NR n2 R 4 and R 2 is -L'-R 3 ; or R 1 is L°-Ring B-L 1 -R 3 and R 2 is hydrogen or C1-C6 alkyl;
  • L 2 is attached to R 3 ;
  • x is 0 or an integer from 1 to 10 included; each instance of m is independently 0 or an integer from 1 to 10 included;
  • n is 0 or an integer from 1 to 15 included;
  • y is 0 or an integer from 1 to 10 included;
  • R o1 is hydrogen, C 1 -C 6 alkyl, or an oxygen protecting group.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • tautomers or “tautomeric” refers to two or more interconvertible compounds/ substituents resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).
  • exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
  • the present teachings encompass compounds in the form of tautomers, which includes forms not depicted structurally.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C 1-10 alkyl”).
  • Ci- 6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., «-propyl, isopropyl), butyl (C4)
  • C5 e.g., «-butyl, tert-butyl, sec-butyl, iso-butyl
  • pentyl C5
  • pentyl C5
  • hexyl C 6
  • hexyl e.g., «-hexyl
  • halo or halogen refers to fluorine, chlorine, bromine, or iodine.
  • 5- or 6-membered heterocyclyl or “ 5- or 6-membered heterocyclic” refers to a radical of a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • heterocyclyl groups include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dine, dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, piperidinyl, dithianyl, dioxanyl, triazinanyl, and the like.
  • 5- or 6-membered heteroaryl refers to a 5- or 6-membered monocyclic and unfused 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Exemplary monocyclic 5- or 6- membered heteroaryl groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl.
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the active agent is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (cupric and cuprous), ferric, ferrous, lithium, magnesium, manganese (manganic and manganous), potassium, sodium, zinc and the like salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
  • organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N’,N’- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylameine, trimethylamine, tripropylamine, tromethamine and the like.
  • ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N’,N’- dibenzylethylenediamine, diethylamine, 2-
  • composition and “formulation” are used interchangeably.
  • the term "patient” or “subject” refers to a human in need of treatment with a compound described herein for any purpose, in particular a human in need of such a treatment to treat cancer, or a precancerous condition or lesion.
  • the term “patient” or “subject” can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others, that are in need of treatment with a compound described herein.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing, either partially or completely, the growth of tumors, tumor metastases, or other cancer-causing or neoplastic cells in a patient.
  • treatment refers to the act of treating.
  • a “method of treating cancer” refers to a procedure or course of action that is designed to reduce or eliminate the number of cancer cells in an animal, or to alleviate the symptoms of a cancer.
  • condition “disease,” and “disorder” are used interchangeably.
  • an effective amount means the amount of a compound described herein or a compound described herein in combination with another drug that will elicit the biological or medical response of a tissue, system or animal e.g. human that is being sought.
  • the response is inhibition of tumor volume or the rate of increase in tumor volume over time, for example, static volume or decreased volume.
  • an effective amount is the amount of a disclosed compound that reduces the number of cancer cells or that reduces the rate of increase in number of cancer cells.
  • an effective amount is the amount of a disclosed compound sufficient to cause differentiation of at least a portion of the cancer cells, for example, in hematological tumors the conversion of undifferentiated blast cells to functional neutrophils.
  • a therapeutically effective amount does not necessarily mean that the cancer cells will be entirely eliminated or that the number of cells will be reduced to zero or undetectable, or that the symptoms of the cancer will completely be alleviated.
  • the effective amount is from 0.001 to 100 mg/kg of body weight per day or per week in single or divided doses, or by continuous infusion.
  • a compound Formula I or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.
  • the compound of Formula I is of Formula II: or a pharmaceutically acceptable salt thereof , wherein the remaining variables are as described above for Formula I.
  • the compound of Formula I is of Formula Il-a: or a pharmaceutically acceptable salt thereof , wherein the remaining variables are as described above for Formula I.
  • the compound of Formula I is of Formula Il-b: or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I.
  • the compound of Formula I is of Formula II-c: or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I.
  • the compound of Formula I is of Formula Il-d: or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I.
  • the compound of Formula I is of Formula III: or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I.
  • the compound of Formula I is of Formula Ill-a: or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I.
  • the compound of Formula I is of Formula Ill-b: or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I.
  • R 3 in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, III, III- a, and Illb, or a pharmaceutically acceptable salt thereof, is of formula i: wherein the remaining variables are as described above for
  • R 3 in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, III, III- a, and Illb, or a pharmaceutically acceptable salt thereof, is of formula ii: wherein the remaining variables are as described above for
  • Ring A in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, and III, or a pharmaceutically acceptable salt thereof is pyrazolyl, pyridinyl, or pyridinyl-2- one, each of which is substituted with 0-4 occurrences of R a , wherein the remaining variables are as described above for Formula I or the ninth or tenth embodiments.
  • Ring A in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, and III, or a pharmaceutically acceptable salt thereof is pyrazolyl, pyridinyl, or pyridinyl-2-one, each of which is unsubstituted, wherein the remaining variables are as described above for Formula I or the ninth or tenth embodiments.
  • a -(CH 2 ) x - [ (CH 2 ) m O] n -(CH 2 ) y - in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, III, Ill-a, and Illb, or a pharmaceutically acceptable salt thereof is (CH 2 )zi-(CH 2 OCH 2 )z2- or i '-(OCH 2 CH 2 )zi-(CH 2 )z2; wherein each instance of zl and z2 is independently 0 or an integer from 1 to 10 included, wherein the remaining variables are as described above for Formula I or the ninth, tenth, or eleventh embodiments.
  • a -(CH 2 ) x - [ (CH 2 ) m O] n - (CH 2 ) y - in any one of Formulae I, II, II- a, Il-b, II-c, Il-d, III, Ill-a, and Illb, or a pharmaceutically acceptable salt thereof is selected from one of the following formulae: a -(CH 2 ) 2 OCH 2 -, a -(CH 2 ) 3 OCH 2 -, a - (CH 2 ) 4 OCH 2 -, a -(CH 2 O) 2 CH 2 -, a -(CH 2 O) 3 CH 2 -, a -(CH 2 O) 4 CH 2 -, a -(CH 2 O) 5 CH 2 -, a - (CH 2 O) 6 CH 2 -, a -(CH 2 O) 3 (CH 2 )2-, a -(CH 2 O)
  • R 4 in any one of Formulae I, II, Il-a, Il-b, II-c, and Il-d, or a pharmaceutically acceptable salt thereof is CH 3 , C 2 H 5 , or benzyl, wherein the remaining variables are as described above for Formula I or the ninth, tenth, eleventh, or twelfth embodiments.
  • Ring B in any one of Formulae I, Ill-a and Ill-b, or a pharmaceutically acceptable salt thereof, is pyrazolyl or phenyl, each of which is substituted with 0- 1 occurrences of R b , wherein the remaining variables are as described above for Formula I or the ninth, tenth, eleventh, twelfth, or thirteenth embodiments.
  • Ring B in any one of Formulae I, Ill-a and Ill-b, or a pharmaceutically acceptable salt thereof is pyrazolyl or phenyl, each of which is unsubstituted, wherein the remaining variables are as described above for Formula I or the ninth, tenth, eleventh, twelfth, or thirteenth embodiments.
  • R o1 in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, III, Ill-a, and Illb, or a pharmaceutically acceptable salt thereof is hydrogen or CH 3 , wherein the remaining variables are as described above for Formula I or the tenth, eleventh, twelfth, thirteenth, or fourteenth embodiments.
  • R nl in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, III, Ill-a, and Illb, or a pharmaceutically acceptable salt thereof is hydrogen or CH3, wherein the remaining variables are as described above for Formula I or the ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiments.
  • R n2 in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d is hydrogen or CH3, wherein the remaining variables are as described above for Formula I or the ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiments.
  • R n2 in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d is hydrogen or CH3, wherein the remaining variables are as described above for Formula I or the ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiments.
  • Ill-a, and Illb is hydrogen or CH3, wherein the remaining variables are as described above for Formula I or the ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiments.
  • R n3 in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, III, Ill-a, and Illb, or a pharmaceutically acceptable salt thereof is hydrogen or CH3, wherein the remaining variables are as described above for Formula I or the ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiments.
  • the invention is any one of the compounds from Table 1 and in the Examples, or a pharmaceutical acceptable salt thereof.
  • a compound described herein may have an IC50 of CDK12 (see Example
  • A refers to an IC50 less than 0.300 mM
  • B refers to an IC50 from 0.301 pM to 0.800 pM
  • C refers to an IC50 greater than 0.800 pM.
  • E3 ligase engagement assay Cell VHL (mM) or Cell CRBN (pM)
  • AA refers to an AC50 less than or equal to 1 pM
  • BB refers to an AC50 more than 1 pM.
  • NA means not available.
  • Best- fit IC 50 “+++” refers to an IC50 less than 0.500 pM; “++” refers to an IC50 from 0.501 pM to 1.0 pM, and “+” refers to an IC50 greater than 1.0 pM.
  • Best-fit max (%degradation): “***” refers to 100%- 50%; refers to 49%-20%, refers to “0-19%”.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and
  • compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • parenteral includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • tablets containing a compound described herein, and optionally with another active agent are combined with any of various excipients such as, for example, micro-crystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, along with various disintegrants such as starch (such as com, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinyl pyrrolidone, sucrose, gelatin and acacia.
  • excipients such as, for example, micro-crystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine
  • disintegrants such as starch (such as com, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinyl pyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting purposes.
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules; particular materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the inhibitor may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions in either sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions comprising the active agent or a corresponding water-soluble salt thereof.
  • sterile aqueous solutions may be suitably buffered, and also may be rendered isotonic, e.g., with sufficient saline or glucose.
  • the preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • Any parenteral formulation selected for administration of proteinaceous inhibitors should be selected so as to avoid denaturation and loss of biological activity of the inhibitor.
  • compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor, such as e.g., 0.1 - 100 mg/kg body weight/day, can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound described herein in the composition will also depend upon the particular compound in the composition.
  • compounds and compositions described herein are useful in treating diseases and/or disorders associated with CDK and/or expression of a mutant form of CDK.
  • the disease responsive to a compound or composition described herein is a cancer.
  • methods for treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a compound described herein, or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject comprising a compound described herein, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject.
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject.
  • cancer in a mammal refers to the presence of cells possessing characteristics typical of cancers, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features.
  • the term cancer and tumor is used herein interchangeably.
  • cancer cells will be in the form of a solid tumor, but such cells may exist alone within an animal, or may circulate in the blood stream as independent cells, such as leukemic cells.
  • the cancer cell can be any tissue type, for example, cholangiocarcinoma, pancreatic, lung, bladder, breast, esophageal, colon, ovarian.
  • cancer is selected from the group consisting of glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myelogenous leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinomas and angioimmunoblastic lymphoma.
  • glioblastoma glioma
  • MDS myelodysplastic syndrome
  • MPN myeloproliferative neoplasm
  • AML acute myelogenous leukemia
  • sarcoma melanoma
  • non-small cell lung cancer chondrosarcoma
  • cholangiocarcinomas cholangiocarcinomas
  • angioimmunoblastic lymphoma angioimmunoblastic lymphoma.
  • the cancer is glioma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myelogenous leukemia (AML), melanoma, chondrosarcoma, or angioimmunoblastic non-Hodgkin’s lymphoma (NHL).
  • MDS myelodysplastic syndrome
  • MPN myeloproliferative neoplasm
  • AML acute myelogenous leukemia
  • melanoma chondrosarcoma
  • angioimmunoblastic non-Hodgkin’s lymphoma NHL.
  • the cancer is any cancer treatable, either partially or completely, by administration of a CDK12 inhibitor.
  • the cancer may be, for example, lung cancer, non-small cell lung (NSCL) cancer, bronchioloalviolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma,
  • the precancerous condition or lesion includes, for example, the group consisting of oral leukoplakia, actinic keratosis (solar keratosis), precancerous polyps of the colon or rectum, gastric epithelial dysplasia, adenomatous dysplasia, hereditary nonpolyposis colon cancer syndrome (HNPCC), Barrett's esophagus, bladder dysplasia, and precancerous cervical conditions.
  • the cancer is glioblastoma multiforme.
  • the cancer is breast cancer.
  • the cancer is bladder cancer.
  • the cancer is prostate cancer.
  • the cancer is melanoma.
  • the cancer is endometrial carcinoma.
  • a disclosed compound may be administered in combination with cytotoxic, chemotherapeutic or anti-cancer agents, including for example: alkylating agents or agents with an alkylating action, such as cyclophosphamide (CTX; e.g. CYTOXAN®), chlorambucil (CHL; e.g. LEUKERAN®), cisplatin (CisP; e.g. PLATINOL®) busulfan (e.g. MYLERAN®), melphalan, carmustine (BCNU), streptozotocin, triethylenemelamine (TEM), mitomycin C, and the like; antibiotics, such as actinomycin D, doxorubicin (DXR; e.g.
  • ADRIAMYCIN® daunorubicin (daunomycin), bleomycin, mithramycin and the like
  • alkaloids such as vinca alkaloids such as vincristine (VCR), vinblastine, and the like
  • antitumor agents such as paclitaxel (e.g. TAXOL®) and paclitaxel derivatives, the cytostatic agents, glucocorticoids such as dexamethasone (DEX; e.g.
  • DECADRON® corticosteroids
  • corticosteroids such as prednisone, nucleoside enzyme inhibitors such as hydroxyurea, amino acid depleting enzymes such as asparaginase, leucovorin and other folic acid derivatives, and similar, diverse antitumor agents.
  • the following agents may also be used as additional agents: amifostine (e.g. ETHYOL®), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, lomustine (CCNU), doxorubicin lipo (e.g. DOXIL®), gemcitabine (e.g. GEMZAR®), daunorubicin lipo (e.g.
  • DAUNOXOME® procarbazine, mitomycin, docetaxel (e.g. TAXOTERE®), aldesleukin, carboplatin, oxaliplatin, cladribine, camptothecin, CPT 11 (irinotecan), 10-hydroxy 7-ethyl-camptothecin (SN38), floxuridine, fludarabine, ifosfamide, idarubicin, mesna, interferon beta, interferon alpha, mitoxantrone, topotecan, leuprolide, megestrol, melphalan, mercaptopurine, plicamycin, mitotane, pegaspargase, pentostatin, pipobroman, plicamycin, tamoxifen, teniposide, testolactone, thioguanine, thiotepa, uracil mustard, vinorelbine, chlorambucil.
  • the present disclosure further provides methods for treating tumors in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and in addition, simultaneously or sequentially, one or more anti-hormonal agents.
  • anti-hormonal agent includes natural or synthetic organic or peptidic compounds that act to regulate or inhibit hormone action on tumors.
  • Antihormonal agents include, for example: steroid receptor antagonists, anti-estrogens such as tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, other aromatase inhibitors, 42-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (e.g.
  • FARESTON® anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above; agonists and/or antagonists of glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH) and LHRH (leuteinizing hormone-releasing hormone); the LHRH agonist goserelin acetate, commercially available as ZOLADEX® (AstraZeneca); the LHRH antagonist D-alaninamide N-acetyl-3-(2-naphthalenyl)-D-alanyl-4- chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-N6-(3-pyridinylcarbonyl)-L-lysyl- N6-(3-pyridinylcarbony
  • VDR VDR, and the like.
  • the use of the cytotoxic and other anticancer agents described above in chemotherapeutic regimens is generally well characterized in the cancer therapy arts, and their use herein falls under the same considerations for monitoring tolerance and effectiveness and for controlling administration routes and dosages, with some adjustments.
  • the actual dosages of the cytotoxic agents may vary depending upon the patient's cultured cell response determined by using histoculture methods. Generally, the dosage will be reduced compared to the amount used in the absence of additional other agents. Typical dosages of an effective cytotoxic agent can be in the ranges recommended by the manufacturer, and where indicated by in vitro responses or responses in animal models, can be reduced by up to about one order of magnitude concentration or amount.
  • the actual dosage will depend upon the judgment of the physician, the condition of the patient, and the effectiveness of the therapeutic method based on the in vitro responsiveness of the primary cultured malignant cells or histocultured tissue sample, or the responses observed in the appropriate animal models.
  • the present disclosure further provides methods for treating tumors or tumor metastases in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and in addition, simultaneously or sequentially, one or more angiogenesis inhibitors.
  • Anti- angiogenic agents include, for example: VEGFR inhibitors, such as SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, Calif., USA), or as described in, for example International Application Nos.
  • WO 99/24440 WO 99/62890, WO 95/21613, WO 99/61422, WO 98/50356, WO 99/10349, WO 97/32856, WO 97/22596, WO 98/54093, WO 98/02438, WO 99/16755, and WO 98/02437, and U.S. Patent Nos. 5,883,113, 5,886,020, 5,792,783, 5,834,504 and 6,235,764; VEGF inhibitors such as IM862 (Cytran Inc.
  • VEGF vascular endothelial growth factor
  • angiozyme a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.)
  • antibodies to VEGF such as bevacizumab (e.g. AVASTINTM, Genentech, South San Francisco, CA), a recombinant humanized antibody to VEGF; integrin receptor antagonists and integrin antagonists, such as to a v ⁇ 3, ⁇ v ⁇ 5 and ⁇ v ⁇ 6 integrins, and subtypes thereof, e.g.
  • cilengitide EMD 121974
  • anti-integrin antibodies such as for example a n ⁇ 3 specific humanized antibodies (e.g. VITAXIN®); factors such as IFN-alpha (U.S. Patent Nos. 41530,901, 4,503,035, and 5,231,176); angiostatin and plasminogen fragments (e.g. kringle 1-4, kringle 5, kringle 1-3 (O'Reilly, M. S. et al. (1994) Cell 79:315- 328; Cao et al. (1996) J. Biol. Chem. 271: 29461-29467; Cao et al. (1997) J. Biol. Chem.
  • PF4 platelet factor 4
  • plasminogen activator/urokinase inhibitors plasminogen activator/urokinase inhibitors
  • urokinase receptor antagonists heparinases
  • fumagillin analogs such as TNP-4701
  • suramin and suramin analogs angiostatic steroids
  • bFGF antagonists flk-1 and fit- 1 antagonists
  • anti- angiogenesis agents such as MMP-2 (matrix-metalloproteinase 2) inhibitors and MMP-9 (matrix-metalloproteinase 9) inhibitors.
  • MMP-2 matrix-metalloproteinase 2 inhibitors
  • MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1.
  • MMP-2 and/or MMP-9 are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP- 8, MMP-10, MMP-11, MMP-12, and MMP-13).
  • MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP- 8, MMP-10, MMP-11, MMP-12, and MMP-13 are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP- 8, MMP-10, MMP-11, MMP-12, and MMP-13).
  • the present disclosure further provides methods for treating tumors or tumor metastases in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and in addition, simultaneously or sequentially, one or more tumor cell pro-apoptotic or apoptosis- stimulating agents.
  • the present disclosure further provides methods for treating tumors or tumor metastases in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and in addition, simultaneously or sequentially, one or more signal transduction inhibitors.
  • Signal transduction inhibitors include, for example: erbB2 receptor inhibitors, such as organic molecules, or antibodies that bind to the erbB2 receptor, for example, trastuzumab (e.g. HERCEPTIN®); inhibitors of other protein tyrosine-kinases, e.g. imitinib (e.g. GLEEVEC®); ras inhibitors; raf inhibitors (e.g. BAY 43-9006, Onyx Pharmaceuticals/Bayer Pharmaceuticals); MEK inhibitors; mTOR inhibitors; cyclin dependent kinase inhibitors; protein kinase C inhibitors; and PDK-1 inhibitors (see Dancey, J. and Sausville, E.A. (2003) Nature Rev. Drug Discovery 2:92-313, for a description of several examples of such inhibitors, and their use in clinical trials for the treatment of cancer).
  • trastuzumab e.g. HERCEPTIN®
  • ErbB2 receptor inhibitors include, for example: ErbB2 receptor inhibitors, such as GW- 282974 (Glaxo Wellcome pic), monoclonal antibodies such as AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Tex., USA) and 2B-1 (Chiron), and erbB2 inhibitors such as those described in International Publication Nos. WO 98/02434, WO 99/35146, WO 99/35132, WO 98/02437, WO 97/13760, and WO 95/19970, and U.S. Patent Nos. 5,587,458, 5,877,305, 6,465,449 and 6,541,481.
  • GW- 282974 Gaxo Wellcome pic
  • monoclonal antibodies such as AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Tex., USA) and 2B-1 (Chiron)
  • erbB2 inhibitors such as those described in International Publication Nos. WO 98/02
  • the present disclosure further provides methods for treating tumors or tumor metastases in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and in addition, simultaneously or sequentially, one or more additional anti-proliferative agents.
  • Additional antiproliferative agents include, for example: Inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFR, including the compounds disclosed and claimed in U.S. patent Nos. 6,080,769, 6,194,438, 6,258,824, 6,586,447, 6,071,935, 6,495,564, 6,150,377, 6,596,735 and 6,479,513, and International Patent Publication WO 01/40217.
  • the present disclosure further provides methods for treating tumors or tumor metastases in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and in addition, simultaneously or sequentially, treatment with radiation or a radiopharmaceutical.
  • the source of radiation can be either external or internal to the patient being treated.
  • the therapy is known as external beam radiation therapy (EBRT).
  • EBRT external beam radiation therapy
  • BT brachytherapy
  • Radioactive atoms for use in the context of this invention can be selected from the group including, but not limited to, radium, cesium-137, iridium-192, americium-241, gold-198, cobalt-57, copper-67, technetium-99, iodine-123, iodine-131, and indium-111.
  • the CDK12 inhibitor according to this invention is an antibody
  • Radiation therapy is a standard treatment for controlling unresectable or inoperable tumors and/or tumor metastases. Improved results have been seen when radiation therapy has been combined with chemotherapy.
  • Radiation therapy is based on the principle that high-dose radiation delivered to a target area will result in the death of reproductive cells in both tumor and normal tissues.
  • the radiation dosage regimen is generally defined in terms of radiation absorbed dose (Gy), time and fractionation, and must be carefully defined by the oncologist.
  • the amount of radiation a patient receives will depend on various considerations, but the two most important are the location of the tumor in relation to other critical structures or organs of the body, and the extent to which the tumor has spread.
  • a typical course of treatment for a patient undergoing radiation therapy will be a treatment schedule over a 1 to 6 week period, with a total dose of between 10 and 80 Gy administered to the patient in a single daily fraction of about 1.8 to 2.0 Gy, 5 days a week.
  • the inhibition of tumor growth by means of the agents comprising the combination of the invention is enhanced when combined with radiation, optionally with additional chemotherapeutic or anticancer agents.
  • Parameters of adjuvant radiation therapies are, for example, contained in International Patent Publication WO 99/60023.
  • the present disclosure further provides methods for treating tumors or tumor metastases in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and in addition, simultaneously or sequentially, treatment with one or more agents capable of enhancing antitumor immune responses.
  • CTLA4 cytotoxic lymphocyte antigen 4 antibodies
  • MDX-CTLA4 cytotoxic lymphocyte antigen 4 antibodies
  • Specific CTLA4 antibodies that can be used in the present invention include those described in U.S. Patent No.
  • the chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company), and used without further purification. Flash chromatography was performed on a CombiFlashRf 150 (ISCO) via column with silica gel particles of 200-300 mesh. Analytical and preparative thin layer chromatography plates (TLC) were HSGF 254 (0.15-0.2mm thickness, Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR) spectra were recorded using Bruker. AMX-400 NMR (Bruker, VARIAN) at around 20 - 30°C unless otherwise specified.
  • ISCO CombiFlashRf 150
  • TLC Analytical and preparative thin layer chromatography plates
  • NMR Nuclear magnetic resonance
  • Preparative HPLC unless otherwise described, the compounds were purified using a GILSON GX-281 system equipped with a Phenomenex Gemini NX-C18 Column (5 pm, 110A, 150 x 30 mm) or equivalent and the following solvent system: 3 ⁇ 4O, AcCN, and 1% ammonia in H2O. Specific elution gradients were based on the retention times obtained with an analytical LC-MS, however, in general all elution gradients of H2O and MeCN were run over a 12 minute run time with a flow rate of 30 mL/min.
  • Analytical LC-MS (Acid condition) analytical LC-MS was performed on a Agilent 1200 Series HPLC& single quadmpole MSD and ELSD instrument equipped with a Waters Xbridge-C18 column (50x2mm, 5pm ), a column temperature of 40 °C or 50°C and using the following solvent system: Solvent A: 0.04 % TFA in H2O; and Solvent B: 0.02 % TFA in ACN. All compounds were run using 4.5min gradient methods with a flow rate of 0.6 mL/min or 0.8mL/min. Actual gradient will depend on the polarity of compound.
  • Preparative Chiral SFC Separation stereoisomer mixtures were separated using a Berger MultiGram SFC/ Waters Thar 80 instrument on one of the following columns: ChiralPak AS-H (30 x 250 mm), eluting with either 0.1 % NH3H2O in MeOH / CO 2 , or 0.1 % 0.1 % NH3H2O in EtOH / CO2 or 0.1 %0.1 % NH3H2O in isopropanol / CO2 with a flow rate of 50-80 mL/min and a column temperature of 38°C.
  • Analytical Chiral SFC Separation stereoisomer mixtures or single enantiomers were analyzed using a Waters UPC2 or Agilent analytical SFC instrument on one of the following columns: ChiralPak AS-3 (4.6 x 150 mm), eluting with either 0.1 % diethylamine in MeOH / CO2, or 0.1 % diethylamine in EtOH / CO2 or 0.1 % diethylamine in isopropanol / CO2, with a flow rate of 2.5 imL/min and a column temperature of 35°C.
  • Step A Synthesis of ethyl 2-(2-(4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)-lH-pyrazol-l-yl)ethoxy)acetate.
  • Step B Synthesis of 2-(2-(4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)-lH-pyrazol-l-yl)ethoxy)acetic acid.
  • Step C Synthesis of (2S,4R)-l-((S)-2-(2-(2-(4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin- 2-yl)amino)cyclohexyl)ureido)phenyl)-lH-pyrazol-l-yl)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide.
  • reaction mixture was concentrated under reduced pressure to remove solvent.
  • the residue was diluted with saturated NaHCCL (15 mL) and extracted with ethyl acetate (30 mL *3).
  • the organic layer was washed with brine (20 ml), dried over Na 2 SO 4 , filtered and evaporated to give a crude product.
  • Example 1 The procedure set forth above in Example 1 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.
  • Step A Synthesis of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4- (l-(2-(2-(2-(2-(2-(l,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethyl)-lH-pyrazol-4- yl)phenyl)urea.
  • Step B Synthesis of l-(4-(l-(2-(2-(2-(2-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-lH-pyrazol-4- yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)urea.
  • Step C Synthesis of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4- (l-(2-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)ethyl)-lH-pyrazol-4-yl)phenyl)urea.
  • Example 2 The procedure set forth above in Example 2 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.
  • Step B Synthesis of l-(4-(6-(2-aminoethoxy)pyridin-3-yl)phenyl)-3-benzyl-l-((lr,4r)-4- ((5-cyanopyridin-2-yl)amino)cyclohexyl)urea.
  • Step C Synthesis of N-(2-((5-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethyl)-2-((2-(2,6-dioxopiperidin-3- yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide.
  • Example 3 The procedure set forth above in Example 3 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.
  • Step A Synthesis of l-(4-(6-(2-(4-aminobutoxy)ethoxy)pyridin-3-yl)phenyl)-3-benzyl-l- ((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)urea.
  • reaction mixture was heated to 75°C under nitrogen and stirred at 75°C for 16hrs.
  • EtOAc 50 mL was added into the reaction mixture and the result mixture was washed with water (15 mL), saturated brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Step B Synthesis of N-(4-(2-((5-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethoxy)butyl)-2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide.
  • Example 4 The procedure set forth above in Example 4 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.
  • Step B Synthesis of 2-(2-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4- (l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)methyl)-lH-pyrazol-l- yl)ethoxy)acetic acid.
  • Step C Synthesis of (2S,4R)-l-((S)-2-(2-(2-(4-((3-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)methyl)-lH-pyrazol-l-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.
  • Example 5 The procedure set forth above in Example 5 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.
  • Step A Synthesis of tert-butyl (2-((4-bromopyridin-2-yl)oxy)ethyl)carbamate.
  • tert-butyl N-(2-hydroxyethyl)carbamate (1.83 g, 11.36 mmol, 1.76 mL)
  • 4- bromo-2-fluoro-pyridine (1 g, 5.68 mmol)
  • THF 10 mL
  • NaH 341 mg, 8.52 mmol, 60% purity
  • reaction mixture was cooled to 0°C and quenched by saturated NH4CI (25 mL).
  • the result mixture was extracted with EtOAc (4 x 15 mL).
  • the combined organic layer was washed with saturated brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Step B Synthesis of tert-butyl (2-((4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethyl)carbamate.
  • reaction mixture was heated to 75°C under nitrogen and stirred at 75°C for 16hrs.
  • EtOAc 50 mL was added into the reaction mixture and the result mixture was washed with water (15 mL) and saturated brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Step C Synthesis of l-(4-(2-(2-aminoethoxy)pyridin-4-yl)phenyl)-3-benzyl-l-((lr,4r)-4- ((5-cyanopyridin-2-yl)amino)cyclohexyl)urea.
  • reaction mixture was stirred at 20°C for lhr.
  • the combined organic lays were washed with saturated brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated to dry.
  • the residue was purified by column chromatography on silica gel (Petroleum ether:
  • Example 6 The procedure set forth above in Example 6 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.
  • Step A Synthesis of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4- (2-fluoropyridin-4-yl)phenyl)urea.
  • reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with saturated NaCl (30 mL * 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 ,
  • Step C Synthesis of l-(4-(2-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)pyridin-4-yl)phenyl)- 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)urea.
  • Step D Synthesis of N-(3-(2-(2-((4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethoxy)ethoxy)propyl)-2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide.
  • Example 7 2.06 - 2.15 (m, 3 H), 1.98 (br d, 2 H), 1.85 (quin, 2 H), 1.27 - 1.44 (m, 4 H).
  • the procedure set forth above in Example 7 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.
  • Step A Synthesis of tert-butyl (4-(4-((3-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)methyl)phenoxy)butyl)carbamate.
  • Step B Synthesis of 3-(4-(4-aminobutoxy)benzyl)-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea.
  • Step C Synthesis of N-(4-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3- (4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)methyl)phenoxy)butyl)-2-((2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide.
  • Example 8 The procedure set forth above in Example 8 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.
  • Step A Synthesis of tert-butyl (3-(4-((3-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)methyl)phenoxy)propyl)carbamate.
  • Step B 3-(4-(3-aminopropoxy)benzyl)-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea.
  • Step C N-(3-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l-methyl- 6-oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)methyl)phenoxy)propyl)-2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide.
  • reaction mixture was stirred at 20°C for 16 hrs.
  • the reaction mixture was filtered and the filtrate was purified by prep-HPLC, Prep-HPLC: column: Boston Prime C18 150*30mm*5um; mobile phase: [water(0.04% NH3H2O + lOmM NH 4 HCO 3 )-ACN];
  • Example 9 The procedure set forth above in Example 9 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.
  • Step A Synthesis of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4- (6-(2-hydroxyethyl)pyridin-3-yl)phenyl)urea.
  • reaction mixture was heated to 75°C under nitrogen and stirred at 75°C for 16 hrs.
  • EtOAc 50 mL was added into the result mixture and the result mixture was washed with water (15 mL), saturated brine (15 mL), dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Step B 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(6-(2-((2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)ethyl)pyridin-3-yl)phenyl)urea.
  • Example 10 The procedure set forth above in Example 10 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary
  • Step A Synthesis of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4- (6-fluoropyridin-3-yl)phenyl)urea.
  • Step B Synthesis of 3-benzyl-l-((lr, 4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4- (6-(2-hydroxyethoxy)pyridin-3-yl)phenyl)urea.
  • Step C Synthesis of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4- (6-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)ethoxy)pyridin-3- yl)phenyl)urea.
  • reaction mixture was submitted to prep_HPLC purification directly without any work-up (column: Boston Prime C18 150*30mm*5um;mobile phase: [water (0.04%NH 3 H 2 O + lOmM NH 4 HCO 3 )-ACN]; B%: 50%-80%,8min) to give the desired product 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)ethoxy)pyridin-3-yl)phenyl)urea.
  • Example 11 The procedure set forth above in Example 11 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary
  • Example 12 l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(4-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)butoxy)benzyl)-l-(4-(l-methyl-6-oxo- l,6-dihydropyridin-3-yl)phenyl)urea
  • Step A Synthesis of 3-(4-(4-((tert-butyldimethylsilyl)oxy)butoxy)benzyl)-l-((lr,4r)-4- ((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)urea.
  • Step B Synthesis of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(4- hydroxybutoxy)benzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea.
  • Step C Synthesis of 4-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l- methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)methyl)phenoxy)butyl 4- methylbenzenesulfonate.
  • Step D Synthesis of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(4-((2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)butoxy)benzyl)-l-(4-(l-methyl-6- oxo-1, 6-dihydropyridin-3-yl)phenyl)urea.
  • the mixture was stirred at 80 °C for 2 hrs.
  • the reaction mixture was concentrated under reduced pressure to remove solvent.
  • the mixture was diluted with brine (15 mL) and extracted with DCM (60 mL *3).
  • the organic layer was washed with brine (20 ml), dried over Na 2 SO 4 , filtered and evaporated to give a crude product.
  • the crude product was purified by prep-HPLC(column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(10mM NH 4 HCO 3 -ACN] ; B%: 32%-62%, 8min) to give the desired compound l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(4-((2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)butoxy)benzyl)-l-(4-(l-methyl-6- oxo-l,6-dihydropyridin-3-yl)phenyl)urea (24 mg).
  • Example 12 The procedure set forth above in Example 12 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary
  • reaction mixture was stirred at 80°C for 16 hrs.
  • the reaction mixtuer was poured into saturated NH4CI (30 mL).
  • the result mixture was extracted with EtOAc (4 * 15 mL).
  • the combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Step B Synthesis of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(3- hydroxypropoxy)benzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea.
  • Step C Synthesis of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(3-((2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)propoxy)benzyl)-l-(4-(l-methyl-6- oxo-1, 6-dihydropyridin-3-yl)phenyl)urea To a solution of l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-3-(4-(3-hydroxypropoxy)benzyl)-l-(4-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)phenyl)urea (0.1 g, 165 umol), 2-(2,6-dioxo
  • reaction mixture was stirred at 40°C for 16 hrs.
  • DCM 50 mL was added into the reaction mixture and result mixture was washed with water (20 mL), brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated to dryness.
  • Step A Synthesis of l-(4-(lH-pyrazol-4-yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)urea.
  • the reaction mixture was concentrated under reduced pressure to remove solvent.
  • the mixture was diluted with saturated brine (35 mL) and extracted with ethyl acetate (100 mL *3).
  • the organic layer was washed with brine (20 ml), dried over Na 2 SO 4 , filtered and evaporated to give a crude product.
  • the crude product was purified by prep-HPLC (column: Boston Prime C18 150*30mm 5um; mobile phase: [water(0.04% NH3H2O + lOmM NH 4 HCO 3 )-ACN]; B%: 35%-65%,8min) to give the desired compound l-(4-(lH-pyrazol-4-yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)urea (1.39 g).
  • Step A Synthesis of tert-butyl ((lr,4r)-4-((4-bromophenyl)amino)cyclohexyl)carbamate.
  • the reaction mixture was concentrated under reduced pressure to remove solvent.
  • the mixture was diluted with saturated brine (50 ruL) and extracted with ethyl acetate (200 ruL *3).
  • the organic layer was washed with brine (30 ml), dried over Na 2 SO 4 , filtered and evaporated to give a crude product.
  • Step C Synthesis of 4-cyano-N,N-dimethyl-lH-pyrazole-l-sulfonamide.
  • TEA 815 mg, 8.06 mmol
  • N,N-dimethylsulfamoyl chloride 848 mg, 5.91 mmol
  • the mixture was stirred at 50 °C for 15 hrs.
  • the mixture was quenched with saturated brine (10 mL) and extracted with ethyl acetate (20 mL *3).
  • Step D Synthesis of 4-(aminomethyl)-N,N-dimethyl-lH-pyrazole-l-sulfonamide.
  • 4-cyano-N,N-dimethyl-lH-pyrazole- 1-sulfonamide 8.9 g, 44.45 mmol
  • NH3.H2O 18.20 g, 20 mL
  • MeOH 200 mL
  • Raney Ni 800 mg, 44.45 mmol
  • the mixture was stirred under 3 ⁇ 4 (50 psi.) at 25 °C for 15 hrs.
  • the mixture was filtered and concentrated in vacuum to give a crude product.
  • Step E Synthesis of 4-nitrophenyl ((l-(N,N-dimethylsulfamoyl)-lH-pyrazol-4- yl)methyl)carbamate.
  • NMM N-methyl methyl
  • 4-(aminomethyl)-N,N- dimethyl-pyrazole- 1 -sulfonamide 4.7 g, 23.01 mmol.
  • the mixture was stirred at 0 °C for 2 hrs.
  • the mixture was diluted with saturated brine (10 mL) and extracted with DCM (20 mL *3).
  • Step F Synthesis of tert-butyl ((lr,4r)-4-(3-((l-(N,N-dimethylsulfamoyl)-lH-pyrazol-4- yl)methyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)cyclohexyl)carbamate.
  • Step H Synthesis of 3-((lH-pyrazol-4-yl)methyl)-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea.
  • Example 16 Synthesis of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4- hydroxybenzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea Step A. Synthesis of tert-butyl ((lr,4r)-4-(3-(4-methoxybenzyl)-l-(4-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)phenyl)ureido)cyclohexyl)carbamate.
  • Step B Synthesis of l-((lr,4r)-4-aminocyclohexyl)-3-(4-methoxybenzyl)-l-(4-(l-methyl- 6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea.
  • Step C Synthesis of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4- methoxybenzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea.
  • Step D Synthesis of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4- hydroxybenzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea.
  • reaction mixture was quenched by addition saturated NaHCO 3 solution (50 ml) at 0 °C, and the reaction mixture was extracted with DCM 300 mL (lOOmL * 3). The combined organic layers were concentrated under reduced pressure to give desired product l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-hydroxybenzyl)- l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea (1.15 g, crude).
  • Recombinant CDK12/Cyclin K complex was produced by double infection in the baculovims/SF9 system using one virus for each protein; the complex was purified by an affinity tag on CDK12 followed by size-exclusion chromatography to recover heterodimeric complex exclusively.
  • Compounds were assayed in a reaction buffer containing (50 mM HEPES pH 7.2, 0.05% (w/v) bovine serum albumin, 20 mM MgCl 2 , 1 mM DTT, 0.01% (v/v) Tween-20, 1 mM sodium vanadate, 3% DMSO, 5 uM ATP, 4 uM CDK9tide substrate).
  • VHL and CRBN BRET-based engagement assays were performed with the NanoBRETTM TE In-cell CRBN or VHL kits (PROMEGA Cat# CS1810C140 or CS1810C157 respectively) according to the following steps:
  • HCT116 cells were transduced with NanoLuciferase-CRBN or VHL-NanoLucif erase and were routinely grown in growth medium [RPMI1640 (Corning Cat# 10-041-CV), Tet-Free FBS (Takara Cat# 631101)]. 2. At the day of the assay, medium was removed, and cells were washed and dissociated by trypsinization. Trypsin was neutralized by addition of growth medium and cells were pelleted by centrifugation at 200 x g for 5 minutes.
  • Complete 20X NanoBRETTM Dilution buffer (components included in the NanoBRETTM TE In-cell CRBN or VHL kits) was prepared as follows: a. Prepared 100X solution of NanoBRETTM tracer in pure DMSO (100X solution corresponds to 50uM for CRBN tracer and lOOuM for VHL tracer). b. Mix one part of 100X tracer to 4 parts NanoBRETTM tracer dilution buffer to generate Complete 20X NanoBRETTM Tracer Dilution Buffer (20X solution corresponds to lOuM for CRBN tracer and 20uM for VHL tracer).
  • NanoBRETTM NanoGlo® substrate (components included in the NanoBRETTM TE In-cell CRBN or VHL kits) was prepared immediumtely prior to BRET measurements in Opti-MEM without serum or phenol red as follows: a. Diluted NanoBRETTM NanoGlo® substrate 1:166 and Extracellular NanoLuc Inhibitor 1:500 in Opti-MEM without serum or phenol red. b. Mixed gently by inversion 5-10 times.
  • BRET raw ratio values were calculated by dividing the acceptor emission value (610nm) by the donor emission value (450nm) for each well.
  • Raw BRET values for DMSO treated cells were set to 100 and the raw BRET values of the compound treated were expressed as % of the DMSO control (relative BRET values).
  • Relative BRET values were plotted as a function of the loglO of the concentration of compound and data points were fitted to a non-linear curve using the variable regression model in GraphPad Prism (version 8) from which the concentration leading to 50% max effect (IC50) was calculated.
  • the compounds were evaluated for CDK12 degradation in HCT116 cells engineered to carry homozygous insertion of the HiBit tag (PROMEGA, DNA sequence GTG AGC GGCT GGCGGCT GTT C A AG A AG ATT AGC ) in the C-terminus of the CDK12 gene (HCT116 CDK12-HiBit cells).
  • HiBit tag DNA sequence GTG AGC GGCT GGCGGCT GTT C A AG A AG ATT AGC
  • HCT116 CDK12-HiBit cells C-terminus of the CDK12 gene.
  • Levels of HiBit that directly correspond to CDK12 levels were detected using the NanoGlo® HiBit Lytic Detection System (PROMEGA Cat# N3050) and cell viability was quantitated using the CellTiter-Glo® Luminescent Cell Viability Assay (PROMEGA Cat# G7573) according to the following steps:
  • HCT116 CDK12-HiBit cells were routinely maintained in growth medium
  • Serially diluted compounds were prepared as follows: a. Initial compound stock of lOmM was diluted 9 times in a 3 -fold dilution scheme in DMSO to generate 9 concentrations (10, 3.333333, 1.111111, 0.37037, 0.123457, 0.041152, 0.013717, 0.004572 and 0.001524 mM) of compound that correspond to 1000X stock solutions. b. Each dilution was further diluted to 10X concentration growth medium. A tenth condition of 1% DMSO in growth medium was prepared to act as control.
  • Nano-Glo® HiBit Lytic Detection Reagent and CellTiter-Glo Reagent were prepared as follows: a. Nano-Glo® HiBit Lytic Detection Reagent is prepared by diluting the LgBiT protein 1:100 and the Nano-Glo® HiBiT Lytic Substrate 1:50 in Nano-Glo Lytic Buffer (components included in NanoGlo® HiBit Lytic Detection System). b.
  • CellTiter-Glo® Reagent is prepared by dissolving the CellTiter-Glo® Substrate in CellTiter-Glo® Buffer (components included in CellTiter-Glo® Luminescent Cell Viability Assay). 10. Added lOOul of Nano-Glo® HiBit Lytic Detection Reagent or per well (30 wells each).
  • Luminescence was measured using the GloMAX® Discover plate reader (PROMEGA Cat# GM3000) using the pre-installed Luminesence protocol

Abstract

L'invention concerne de nouveaux composés de formule (I); des sels pharmaceutiquement acceptables de ceux-ci, et des compositions pharmaceutiques de ceux-ci, qui sont utiles dans le traitement de maladies et d'affections médiées par les CDK telles que le cancer.
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CN115286491A (zh) * 2022-08-31 2022-11-04 山东省药学科学院 一种2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯的制备方法
WO2023020209A1 (fr) * 2021-08-16 2023-02-23 中国科学院上海药物研究所 Composé d'urée contenant une substitution du cycle 2-hétéroaromatique, son procédé de préparation et son utilisation

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CN115286491A (zh) * 2022-08-31 2022-11-04 山东省药学科学院 一种2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯的制备方法
CN115286491B (zh) * 2022-08-31 2023-09-15 山东省药学科学院 一种2-[2-(6-溴己氧基)乙氧基甲基]-1,3-二氯苯的制备方法

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