FENG JUN (US)
VERNIER JEAN-MICHAEL (US)
ISLEY NICHOLAS (US)
CHEN PING (US)
WO2022066805A1 | 2022-03-31 | |||
WO2020239123A1 | 2020-12-03 | |||
WO2021041671A1 | 2021-03-04 | |||
WO2019213516A1 | 2019-11-07 |
CLAIMS What is claimed is: 1. A compound of Formula (I) or pharmaceutically acceptable salt thereof: wherein: each R1 is independently methyl or cyanomethyl; n is an integer from 0 to 2; X is -CCF3 or -C-halogen; Ar1 is aryl or heteroaryl, optionally substituted with one or more alkyl, halogen, hydroxy or amino; and Ar2 is a C-linked aryl or heteroaryl, optionally substituted with alkyl or halogen. 2. The compound of claim 1, wherein Ar1 is phenyl optionally substituted with one or more halogens. 3. The compound of claim 1 or 2, wherein X is -CC1 or -CCF3. 4. The compound of any one of claims 1 to 3, wherein Ar1 is a phenyl substituted with one or more halogens. 5. The compound of any one of claims 1 to 4, wherein n is 2 and each R1 is methyl. 6. The compound of any one of claims 1 to 5, wherein Ar2 is selected from: are optionally substituted with halogen. 7. The compound of any one of claims 1 to 5, wherein the compounds is selected from: pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 7 in a pharmaceutically acceptable carrier. method of treating a subject with cancer comprising administering to the subject a compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, or a pharmaceutical composition thereof. . The method of claim 9, wherein the cancer comprises a K-Ras G12 mutation. . The method of claim 10, wherein the G12 mutation is G12C. . The method of any one of claims 9 to 11, wherein the cancer is one or more of pancreatic, lung, and colorectal cancer. . The method of claim 12, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). . The method of any one of claims 9 to 13, wherein the cancer is a CNS cancer. . The method of claim 14, wherein the CNS cancer is a primary cancer. . The method of claim 15, wherein the primary cancer comprises one or more of a glioma, meningioma, medulloblastoma, ganblioglioma, schwannoma, and craniopharyngioma. . The method of claim 16, wherein the glioma comprises one or more of an astrocytoma, a glioblastoma, an oligodendroglioma, and a ependymoma. . The method of claim 14, wherein the CNS cancer comprises a metastatic or secondary cancer. . The method of claim 18, wherein the CN S cancer comprises a cancer metastasized from one or more of melanoma, breast cancer, colon cancer, kidney cancer, nasopharyngeal cancer, leukemia, lymphoma, myeloma, and other of unknown primary site. . Use of a compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7 in the treatment of cancer. . The use of claim 20, wherein the cancer is one or more of pancreatic, lung and colorectal cancer. . The use of claim 20, wherein the cancer is a CNS cancer. . The use of claim 22, wherein the CNS cancer comprises a primary cancer. . The use of claim 23, wherein the primary cancer comprises one or more of a glioma, meningioma, medulloblastoma, ganblioglioma, schwannoma, and craniopharyngioma. . The use of claim 24, wherein the glioma comprises one or more of an astrocytoma, a glioblastoma, an oligodendroglioma, and an ependymoma. . The use of claim 22, wherein the CNS cancer comprises a metastatic or secondary cancer. . The use of claim 26, wherein the CNS cancer comprises a cancer metastasized from one or more of melanoma, breast cancer, colon cancer, kidney cancer, nasopharyngeal cancer, leukemia, lymphoma, myeloma, and other of unknown primary site. . The use of claim 22, wherein the CNS cancer comprises a RAS associated cancer.. A method of preventing or reducing the spread of cancer via CN S pathways comprising administering to the subject a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.. Use of a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 7 or pharmaceutical composition thereof in the manufacture of a medicament for preventing or reducing the spread of cancer via CNS pathways. |
; any of which are optionally substituted with halogen. [0131] In embodiments, there are provided further compounds:
or a pharmaceutically acceptable salt thereof. IV. GENERAL SYNTHETIC METHODS FOR PREPARING COMPOUNDS [0132] The following schemes can be used to practice the various embodiments disclosed herein. It will be understood that these schemes are merely exemplary and that they provide ready access to core structures with variable functionality. V. MODES OF ADMINISTRATION [0133] While it may be possible for the compounds disclosed herein to be administered as the raw chemical, it is also possible to present them as a pharmaceutical composition (i.e., as a formulation). Accordingly, provided herein are pharmaceutical compositions which comprise one or more of the compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic ingredients. The carrier(s) should be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. [0134] The pharmaceutical compositions may include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The pharmaceutical composition may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound disclosed herein or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof (“active ingredient”) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. [0135] Pharmaceutical compositions of the various embodiments disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. [0136] Pharmaceutical compositions that can be used orally include tablets. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. [0137] The compounds disclosed herein may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [0138] Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Dosage [0139] The compounds disclosed herein may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day. A common dose range for adult humans is generally from 5 mg to 2 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. [0140] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. [0141] The compounds disclosed herein can be administered in various modes, e.g. orally, topically, or by injection. The precise amount of compound administered to a subject will be the responsibility of the attendant physician. The specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. Also, the route of administration may vary depending on the condition and its severity. [0142] In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer a In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit. [0143] In any case, the multiple therapeutic agents (at least one of which is a compound of the various embodiments disclosed herein) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks. VI. METHODS OF TREATMENT [0144] In an aspect, embodiments herein provide a method of treating a subject with cancer comprising administering to the subject an amount of a compound of the various embodiments disclosed herein or pharmaceutically acceptable salt thereof. In embodiments, the cancer comprises a K-Ras G12 mutation. In embodiments, the G12 mutatoin is G12C. In embodiments, the cancer is one or more of pancreatic, lung, and colorectal cancer. In embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In further embodiments, the cancer is a CNS cancer. In embodiments, the CNS cancer is a primary cancer. In embodiments, the primary cancer comprises one or more of a glioma, meningioma, medulloblastoma, ganblioglioma, schwannoma, and craniopharyngioma. In embodiments, the glioma comprises one or more of an astrocytoma, a glioblastoma, an oligodendroglioma, and a ependymoma. In embodiments, the CNS cancer comprises a metastatic or secondary cancer. In further embodiments, the CNS cancer comprises a cancer metastasized from one or more of melanoma, breast cancer, colon cancer, kidney cancer, nasopharyngeal cancer, leukemia, lymphoma, myeloma, and other of unknown primary site. [0145] In another aspect, embodiments herein provide methods for treating K-RAS- mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound of the various embodiments disclosed herein effective to reduce or prevent said disorder in the subject optionally in combination with at least one additional agent for the treatment of said disorder that is known in the art. In a related aspect, the various embodiments disclosed herein provides therapeutic compositions comprising at least one compound of the various embodiments disclosed herein in combination with one or more additional agents for the treatment of K- RAS-mediated disorders. In some such embodiments, the K-RAS-mediated disease is cancer and the K-RAS presents in an oncogenic mutated form. [0146] Compounds disclosed herein may be useful in treating K-RAS-mediated disease, disorders and conditions. In some embodiments, the compounds disclosed herein may be used in treating cancer, as disclosed hereinabove. In some such embodiments, the type of cancer may depend on presentation of a particular type of oncogenic mutation of K-RAS. For example, in some embodiments oncogenic K-RAS mutations may be tied to human cancer of the pancreas, lung, and/or colon. 1. Combination Therapies [0147] Compounds disclosed herein may be used in combination therapies. For example, the compounds disclosed herein may be used in combination with inhibitors of mammalian target of rapamycin (mTOR), insulin growth factor 1 receptor (IGF1R), and combinations thereof. Such combination therapies may be particularly suited to certain cancer types such as lung cancer. See Molinas-Arcas et al. Sci. Trans. Med.18 Sep.2019 11:510 eaaw7999 at stm.sciencemag.org/content/11/510/eaaw7999. Compounds disclosed herein may be combined with modulators the ULK family of proteins, which regulate autophagy. Other compounds of interest in combination therapy include inhibitors of SHP2. Other SHP2 inhibitors include those disclosed in WO2016/203404, WO2018/136264, WO2018/057884, WO2019/067843, WO2019/183367, WO2016/203405, WO2019/051084, WO2018/081091, WO2019/165073, WO2017/216706, WO2018/218133, WO2019/183364, WO 2020061103, and WO2020061101. All references and patent applications, including compositions, methods of using, and methods of making compounds disclosed therein are incorporated herein by reference in their entirety. [0148] In embodiments, compounds disclosed herein may be combined with an EGFR inihibitor. In embodiments, the EGFR inhibitor is selective for a mutant EGFR, including, without limitation, C797X, L718Q, G724S, S768I, G719X, L792X, G796X, T263P, A289D/V, G598V, and EGFRvIII high expression. In embodiments, the combination therapy with EGFR agents tracked by mutation and indication are shown in Table CT-1 below. Table 1 Mutation Indication EGFR agent mEGFR NSCLC osimertinib mEGFR NSCLC afatinib mEGFR NSCLC erlotinib mEGFR NSCLC gefitinib mEGFR NSCLC lazertinib mEGFR NSCLC nazartinib mEGFR NSCLC dacomitinib mEGFR NSCLC BLU-945 mEGFR NSCLC icotinib wtEGFR Esophageal/CRC cetuximab wtEGFR CRC paninitumab wtEGFR NSCLC amivantamab wtHER2/wtEGFR Breast cancer lapatinib wtHER2/wtEGFR Breast cancer neratinib wtEGFR NSCLC zorifertinib mEGFR NSCLC mobicertinib [0149] EGFR inhibitors include those disclosed in US Pat. Nos. 5,747,498, 8,946,235, and 9,732,058, WO2002030926, US 20040048880, US20050165035, and WO2019067543. All patents and applications, including compositions, methods of using, and methods of making compounds disclosed therein are incorporated herein by reference in their entirety. [0150] Other combination therapies based on target biomarkers are shown below in Table CT-2. Table 2. Biomarker(s) Cancer Target Combination Agent Type KRAS G12C Solid KRAS G12C AMG 510 tumors KRAS G12C Solid KRAS G12C MRTX849 tumors KRAS G12C Solid KRAS G12C GDC-6036 tumors BRAF V600E CRC / BRAF V600E encorafenib NSCLC BRAF V600E CRC / BRAF V600E dabrafenib NSCLC BRAF V600E CRC / BRAF V600E and encorafenib and NSCLC MEK binimetinib BRAF V600E CRC / BRAF V600E and dabrafenib and NSCLC MEK trametinib RB1 functional Solid CDK4 and CDK6 palbociclib tumors RB1 functional Solid CDK4 and CDK6 abemaciclib tumors RB1 functional Solid CDK4 and CDK6 ribociclib tumors RTK and/or RAS Driven Solid SHP2 TNO155 tumors RTK and/or RAS Driven Solid SHP2 RMC-4630 tumors RTK and/or RAS Driven Solid SHP2 JAB-3068 tumors RTK and/or RAS Driven Solid SHP2 JAB-3312 tumors RTK and/or RAS Driven Solid SHP2 RLY-1971 tumors RTK, RAS, BRAF, and/or Solid ERK ulixertinib MEK driven tumors Biomarker(s) Cancer Target Combination Agent Type RTK, RAS, BRAF, and/or Solid ERK ASN007 MEK driven tumors RTK, RAS, BRAF, and/or Solid ERK LY3214996 MEK driven tumors RTK, RAS, BRAF, and/or Solid ERK LTT462 MEK driven tumors RTK, RAS, and/or BRAF Solid MEK trametinib tumors RTK, RAS, and/or BRAF Solid MEK binimetinib tumors RTK, RAS, and/or BRAF Solid MEK cobimetinib tumors RTK, RAS, and/or BRAF Solid MEK selumetinib tumors MET-driven Solid MET capmatinib tumors MET-driven Solid MET crizotinib tumors MET-driven Solid MET savolitinib tumors [0151] The second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compounds disclosed herein such that they do not adversely affect each other. The compounds may be administered together in a unitary pharmaceutical composition or separately. In one embodiment a compound or a pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat proliferative diseases and cancer. [0152] The term “co-administering” refers to either simultaneous administration, or any manner of separate sequential administration, of a compound disclosed herein or a salt thereof, and a further active pharmaceutical ingredient or ingredients, including cytotoxic agents and radiation treatment. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally. [0153] Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this disclosure in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another. [0154] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound disclosed herein may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a compound of Formula I, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. [0155] The amount of both thecompound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. In certain embodiments, compositions of this disclosure are formulated such that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive can be administered. [0156] Typically, any agent that has activity against a disease or condition being treated may be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved. [0157] In one embodiment, the treatment method includes the co-administration of a compound disclosed herein or a pharmaceutically acceptable salt thereof and at least one cytotoxic agent. The term “cytotoxic agent” as used herein refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu); chemotherapeutic agents; growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof. [0158] Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signalling inhibitors; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.
[0159] “Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram , epigallocatechin gallate , salinosporamide A, carfilzomib, 17-AAG(geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®., Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5 -fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin y II and calicheamicin toll (Angew Chem. Inti. Ed. Engl. 1994 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN ® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK ® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE ® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE ® (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR ® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE ® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA ® ); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above. [0160] Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX ® ; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene , 4- hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON ® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE ® (megestrol acetate), AROMASIN ® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR ® (vorozole), FEMARA ® (letrozole; Novartis), and ARIMIDEX ® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME ® ) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN ® , LEUVECTIN ® , and VAXID ® ; PROLEUKIN ® , rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN ® ; ABARELIX ® rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above. [0161] Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the disclosure include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti–interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories) which is a recombinant exclusively human-sequence, full-length IgG 1 g IU[QJVL_ OMUM[QKISS_ TVLQNQML [V YMKVOUQ`M QU[MYSM\RQU&*+ W-) WYV[MQU' [0162] Chemotherapeutic agent also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.” Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, US Patent No.4,943, 533, Mendelsohn et al.) and variants thereof, such as chimerized 225 (C225 or Cetuximab; ERBUTIX ´ ) and reshaped human 225 (H225) (see, WO 96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (US Patent No.5,212,290); humanized and chimeric antibodies that bind EGFR as described in US Patent No.5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen); EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem.279(29):30375- 30384 (2004)). The anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: WO98/14451, WO98/50038, WO99/09016, and WO99/24037. Particular small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA ´ Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2- propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)pr opoxy]-6- quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’-Chloro- 4’-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazo line, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3- chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimid o[5,4-d]pyrimidine-2,8- diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H- pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1- phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3- bromophenyl)amino]-6-quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4- fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimeth ylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3 fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]ami no]methyl]-2-furanyl]-4- quinazolinamine). [0163] Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo- SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf- 1 signaling; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD 153035,4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules (e.g. those that bind to HER-encoding nucleic acid); quinoxalines (US Patent No.5,804,396); tryphostins (US Patent No.5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinib mesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®); or as described in any of the following patent publications: US Patent No.5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca). [0164] Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa- 2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof. [0165] Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNFa) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra (Kineret), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); Interleukin 13 (IL- 13) blockers such as lebrikizumab; Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-Ml prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTal/β2 blockers such as Anti- lymphotoxin alpha (LTa); radioactive isotopes (e.g., At 211 , 1 131 , 1 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu); miscellaneous investigational agents such as thioplatin, PS-341, phenylbutyrate, ET-18- OCH 3 , or famesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9- tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CCI-779; tipifamib (R11577); orafenib, ABT510; Bel- 2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone; famesyltransferase inhibitors such as lonafamib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN™) combined with 5-FU and leucovorin.
[0166] Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic. [0167] In certain embodiments, chemotherapeutic agents include, but are not limited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, interferons, platinum derivatives, taxanes (e.g., paclitaxel, docetaxel), vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxorubicin), epipodophyllotoxins (e.g., etoposide), cisplatin, an mTOR inhibitor (e.g., a rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (e.g., chlorambucil), 5-fluorouracil, campthothecin, cisplatin, metronidazole, and imatinib mesylate, among others. In other embodiments, a compound disclosed herein is administered in combination with a biologic agent, such as bevacizumab or panitumumab. [0168] In certain embodiments, compounds disclosed herein, or a pharmaceutically acceptable composition thereof, are administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, BCG live, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, camptothecin, carboplatin, carmustine, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin hydrochloride, dromostanolone propionate, epirubicin, epoetin alfa, elotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargramostim, sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine, 6- TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate, or zoledronic acid. [0169] Chemotherapeutic agents also include treatments for Alzheimer's Disease such as donepezil hydrochloride and rivastigmine; treatments for Parkinson's Disease such as L- DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating multiple sclerosis (MS) such as beta interferon (e.g., Avonex ® and Rebif ® ), glatiramer acetate, and mitoxantrone; treatments for asthma such as albuterol and montelukast sodium; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin. [0170] Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, described herein, as well as combinations of two or more of them. VII. EXAMPLES [0171] The following Examples are provided to illustrate exemplary embodiments of the compounds disclosed herein and their preparation. [0172] Various starting materials and other reagents were purchased from commercial suppliers, such as Aldrich Chemical Company, and used without further purification, unless indicated otherwise. Compounds are prepared according to the exemplary procedures provided herein and modifications thereof known to those of skill in the art. The following abbreviations are used throughout the Examples: “Ac” means acetyl, “AcO” or “OAc” means acetoxy, “ACN” means acetonitrile, “aq” means aqueous, “atm” means atmosphere(s), “BOC”, “Boc” or “boc” means N-tert-butoxycarbonyl, “Bn” means benzyl, “Bu” means butyl, “nBu” means normal-butyl, “tBu” means tert-butyl, “Cbz” means benzyloxycarbonyl, “DBU” means 1,8-diazabicyclo[5.4.0]undec-7-ene, “DCM” (CH 2 Cl 2 ) means methylene chloride/dichloromethane, “de” means diastereomeric excess, “DEA” means diethylamine, “DIPEA” means diisopropylethyl amine, “DMA” means N,N-dimethylacetamide, “DMAP” means 4-dimethylaminopyridine, “DMF” means N,N- dimethyl formamide, “DMSO” means dimethylsulfoxide, “DPPP” means 1,3- bis(diphenylphosphino)propane, “ee” means enantiomeric excess, “Et” means ethyl, “EtOAc” means ethyl acetate, “EtOH” means ethanol, “HATU” means 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridi nium 3-oxid hexafluorophosphate, “HOAc” or “AcOH” means acetic acid, “i-Pr” means isopropyl, “IPA” means isopropyl alcohol, “LDA” means lithium diisopropylamide, “LiHMDS” or “LHMDS” means lithium hexamethyldisilazide, “Me” means methyl, “MeOH” means methanol, “MgSO4” means magnesium sulphate, “MS” means mass spectrometry, “MTBE” means methyl tert-butyl ether, Na 2 SO 4 ” means sodium sulphate, “NMP” means 1-methyl 2-pyrrolidinone, “Ph” means phenyl, “sat.” means saturated, “SFC” means supercritical fluid chromatography, “TBME” or “MTBE” means tert-butyl methyl ether, “TEA” means triethyl amine, “TFA” means trifluoroacetic acid, “THF” means tetrahydrofuran, “TLC” means thin layer chromatography, “Rf” means retention fraction, “about” means approximately, “rt” means retention time, “RT” means room temperature, “h” means hours, “min” means minutes, “N” means Normal, “M” means molar, “mL” means milliliter, “mmol” means millimoles, “µmol” means micromoles, “eq.” means equivalent, “ºC.” means degrees Celsius, and “Pa” means pascals. 1 H-NMR spectra are reported in ppm, and were obtained as CDCl 3 solutions (7.25 ppm), DMSO-D 6 solutions (2.50 ppm), or CD 3 OD solutions (3.4 ppm and 4.8 ppm), any may have used internal tetramethylsilane (0.00 ppm) as an internal standard when appropriate. Other NMR solvents were used as needed. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).
2. Preparation of compound 2 [0173] To a solution of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (2.68 g, 10 mmol, 1.0 eq.) in DMF (27 mL) was added DIPEA (6.45 g, 50 mmol, 10 eq.) ,NH 4 Cl (3.20 g, 60 mmol, 6 eq.) and HATU (7.6 g, 20 mmol, 2 eq.) under N2 atmosphere at RT. Then the reaction mixture was stirred for 2 hours, diluted with MTBE (100 mL), washed with 0.5N HCl aq. (50 mL), brine (50 mL)and dried over Na 2 SO 4 . The organic layer was concentrated in vacuo. The residue obtained was purified by a chromatography (0– 50% EtOAc/petroleum ether) to provide the product 2 as a yellow solid (2.3 g, yield: 86%). LC-MS: [M+H] + = 267 3. Preparation of compound 3 [0174] To a solution of 2-amino-4-bromo-5-chloro-3-fluorobenzamide (2.67 g, 10 mmol, 1.0 eq.) in CF 3 COOH (27 mL) was added hydrogen peroxide (5.7 g, 50 mmol, 5 eq,) . The reaction was stirred at 50º for 0.5 hour. Them diluted with MTBE (150Ml), washed with water (100mL), brine"100mL), and then dried over Na 2 SO 4 . The organic layer was concentrated in vacuo, the residue obtained was purified by a chromatography (0-100% EtOAc/petroleum ether) to provide the product 3 as a yellow solid (1.8g, yield: 60%). LC-MS: [M+H] + = 297
4. Preparation of compound 5
[0175] To a solution of 4-bromo-5-chloro-3-fluoro-2-nitrobenzamide (3.0 g, 10 mmol, 1.0 eq) in EtOH (30 ml) and water (6mL) was added 2-((tert- butyldiphenylsilyl)oxy)ethane-1-thiol (3.2 g, 10 mmol, 1.0 eq), potassium carbonate (4.2 g, 30 mmol, 3.0 eq). Then the reaction mixture was stirred at 50 °C for 2 hours. The solvent was removed to afford 6.5 g of the crude product which was used in the subsequent step without further purification. LC-MS: [M+H] + = 593
5. Preparation of compound 6
[0176] To a solution of compound 5 (6.5 g crude, 10 mmol, 1.0 eq.) in CH3COOH (120 mL) was added Iron powder (2.8 g, 50 mmol, 5eq.). The reaction mixture was stirred at 50 °C for 2h. After filtration, the collected solid was washed with EtOAc (500 mL). The organic phase was washed with water 300 mL, brine 300 mL and concentrated in vacuo. The residue obtained was purified by a chromatography (0-100% EtOAc/petroleum ether) to provide the product 6 as a yellow solid (2.8g, yield: 50%). LC-MS: [M+H] + = 563
6. Preparation of compound 7
[0177] To a solution of compound 6 (5.6 g, 10 mmol, 1.0 eq.) in DCM (110 mL) was added DIPEA (2.6 g, 20 mmol, 2 eq.), CDI (4.9 g, 30 mmol, 3.0 eq.) at rt. The reaction mixture was stirred for 16 hours. After filtration, the filter cake was washed with petroleum ether (50 mL) and dried to afford the product 7 as an off-white solid (4.7 g, yield: 80%). LC-MS: [M+H] + = 589
7. Preparation of compound 8
[0178] To a solution of compound 7 (5.9 g, 10 mmol, 1.0 eq.) in THE (60 mL) was added tetrabutylammonium fluoride (10 mL, 10 mmol, 1.0 eq.). The reaction mixture was stirred for 3 hours. After diluted with EtOAc (150 mL), washed with H2O (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give the crude product 8 as an off-white solid (3.16g, yield: 90%).
8. Preparation of compound 9
[0179] To a solution of 7-bromo-6-chloro-8-((2-hydroxyethyl)thio)quinazoline-2,4-dio l (3.5 g, 10 mmol, 1.0 eq.) in THF (100 mL) was added PPI13 (4.5 g, 17 mmol, 1.7 eq.), then DEAD (3.0 g, 17 mmol, 1.7 eq.) at - 10~0 °C. The reaction mixture was stirred for 1 hour. After diluted with EtOAc (100 mL), washed with water ( 100 mL), brine ( 100 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue obtained was diluted with DCM (100 mL) and stirred for 2 hours. After filtration, the filter cake was washed with DCM (50mL) and dried to give the product 9 as an off-white solid (1.5g, yield: 45%). LC-MS: [M+H]+ = 333. [0180] Compounds of the present disclosure having a substituted, fused 7-membered ring can be prepared in a similar manner. Examples [0181] Example 100a and 100b: (3S,11S)-8-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-( pyridin-4-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-6-one (example 100a)and (3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5 -chloro-2,4- difluorophenyl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-di hydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one (example 100b) [0182] Step 1: 2,4,7-Trichloro-8-iodo-6-(trifluoromethyl)quinazoline [0183] To a mixture of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(1H,3H)- dione (5.1 mmol) in N,N-diisopropylethylamine (17.9 mmol) was added phosphoryl trichloride (12 mL). The mixture was stirred at 110 °C for 12 hours and the reaction mixture was concentrated under reduced pressure to afford a residue that was taken up in cold water and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude material was purified by silica gel chromatography (0-15% ethyl acetate in petroleum ether) to afford the title compound in 44% yield as a white solid. MS (ESI) m/z: 427.0 [M+1]+. [0184] Step 2: tert-Butyl (2S,6R)-4-(2,7-dichloro-8-iodo-6-(trifluoromethyl)quinazolin - 4-yl)-2,6-dimethylpiperazine-1-carboxylate [0185] To a solution of 2,4,7-trichloro-8-iodo-6-(trifluoromethyl)quinazoline (2.04 mmol) and triethylamine (6.11 mmol) in dichloromethane (10 mL) was added tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate (1.83 mmol) at 0 °C. The mixture was stirred at room temperature for 1 hour and the volatiles were removed under reduced pressure. The residue was purified by silica gel column chromatography (5-15% ethyl acetate in petroleum ether) to afford the title compound in 82% yield as white solid. MS (ESI) m/z: 605.2 [M+1]+. [0186] Step 3: tert-Butyl (2S,6R)-4-(7-chloro-8-iodo-2-oxo-6-(trifluoromethyl)-1,2- dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxylate [0187] To a solution of tert-butyl (2S,6R)-4-(2,7-dichloro-8-iodo-6- (trifluoromethyl)quinazolin-4-yl)-2,6-dimethylpiperazine-1-c arboxylate (1.73 mmol) in acetonitrile (50 mL) was added 2-(methylsulfonyl)ethan-1-ol (3.47 mmol), cesium carbonate (3.47 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.17 mmol). The mixture was stirred at 80 °C for 2 hours and the volatiles were removed under reduced pressure to afford a solid that was redissolved in dichloromethane, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was triturated with a 10:1 mixture of tert-butylmethylether and ethyl acetate (60 mL). The yellow solid was filtered and dried under vacuum to afford the title compound in 88% yield. MS (ESI) m/z: 587.2 [M+l]+.
[0188] Step 4: 2-(Pyridin-4-yl)propane-1,3-diol
[0189] A mixture of 4-methylpyridine (430 mmol) in 37% formaldehyde (1.72 mol) was stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (1-10% methanol in ethyl acetate). The title compound was isolated in 88% yield as a colorless oil. 1H NMR (400 MHz, methanol-d4) 8 ppm 2.99 (q, J = 6.4 Hz, 1H) 3.77-3.91 (m, 4 H) 7.29-7.47 (m, 2 H) 8.33-8.54 (m, 2 H).
[0190] Step 5: 3-Hydroxy-2-(pyridin-4-yl)propyl 4-methylbenzenesulfonate
[0191] To a 0 °C solution of 2-(pyridin-4-yl)propane-l,3-diol (65.3 mmol) in dichloromethane (100 mL) was added p-toluensulfony Ichloride (65.3 mmol), N,N- dimethylaminopyridine (6.53 mmol) and pyridine (65.3 mmol). The mixture was stirred at 25 °C for 3 hours, quenched with water and extracted with ethyl acetate three times. The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a residue that was used into the next step without further purification.
[0192] Step 6: 5'-(3-Hydroxy-2-(pyridin-4-yl)propyl) ethanethioate
[0193] To a solution of 3-hydroxy-2-(pyridin-4-yl)propyl 4-methylbenzenesulfonate
(55.3 mmol) in dimethyl formamide (150 mL) was added potassium thioacetate (81.9 mmol). The mixture was stirred at 50 °C for 2 hours , quenched with water and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (50-100 % ethyl acetate in petroleum ether). The title compound was isolated in 15% yield as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.35 (s, 3 H) 2.99 (quin, J= 6.4 Hz, 1 H) 3.15-3.24 (m, 1 H), 3.37 (dd, J= 14.0, 7.2 Hz, 1H) 3.79-3.90 (m, 2 H) 7.14-7.24 (m, 2 H), 8.48-8.59 (m, 2H).
[0194] Step 7: tert-butyl (2S,6R)-4-(7-chloro-8-((3-hydroxy-2-(pyridin-4- yl)propyl)thio)-2-oxo-6-(tri fluoromethyl)- 1 ,2-dihydroquinazolin-4-yl)-2, 6- dimethylpiperazine-1-carboxylate
[0195] To a solution of S-(3-hydroxy-2-(pyridin-4-yl)propyl) ethanethioate (0.95 mmol) and tert-butyl (2S,6R)-4-(7-chloro-8-iodo-2-oxo-6-(trifluoromethyl)- 1,2- dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-l -carboxylate (1.42 mmol) in 1,2- ethanediol (2 mL) and isopropanol (2 mL), was added potassium carbonate (2.84 mmol) and cuprous iodide (0.47 mmol). The mixture was stirred at 85 °C for 2 hours, quenched with water and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a residue that was purified by preparative TLC. The title compound was isolated in 65% yield as a yellow solid. MS (ESI) m/z: 627.9 [M+l]+.
[0196] Step 8: tert-Butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-4-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate (Int-la) and tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo- 3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4 ]thiazepino[2,3,4- ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (Int-lb)
[0197] To a 0 °C solution of tert-butyl (2S,6R)-4-(7-chloro-8-((3-hydroxy-2-(pyridin-4- yl)propyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydroquinazo lin-4-yl)-2,6- dimethylpiperazine-1-carboxylate (2.11 mmol) in tetrahydrofuran (100 mL) was added triphenylphosphine (10.6 mmol). The mixture was stirred at 0 °C for 30 minutes and diethyl azodicarboxylate (10.6 mmol) was added. After 12 hours, the volatiles were removed under reduced pressure to afford a residue that was purified by silica gel chromatography (0-10 % methanol in ethyl acetate). Compounds Int-1a and Int-1b were isolated as a 1:1 mixture of diastereomers in 65% yield. Pure diastereomers Int-1a and Int-1b were obtained by purification of the aforementioned mixture by SFC (Daicel Chiralcel OD 250mmx30mm,10um using as mobile phase 50% methanol in CO 2 ) and characterized by SFC (Chiracel OD-3, 50x4.6 mm, 3 um using as mobile phase 40% methanol (containing 0.05% diethylamine) in CO 2 at 3 mL/min.) [0198] Int-1a: SFC Rt= 1.03 min; MS (ESI) m/z: 609.9 [M+1] + [0199] Int-1b: SFC Rt= 1.40 min; MS (ESI) m/z: 609.9 [M+1] + [0200] Step 9: tert-Butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3- (pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]t hiazepino[2,3,4- ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate
[0201] To a solution of tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate (0.46 mmol) and (5-chloro-2,4-difluoro-phenyl)boronic acid (1.84 mmol) in dioxane (5 mL) and water (0.1 mL) was added potassium phosphate (1.38 mmol) and Ruphos Pd G4 (0.05 mmol). The mixture was stirred at 80 °C for 30 minutes and the reaction mixture was filtered and concentrated under reduced pressure to afford a residue that was purified by preparative TLC and semi-preparative reverse phase- HPLC. The title compound was isolated in 33% yield as a yellow solid. MS (ESI) m/z: 722.1 [M+1]+. [0202] Step 10: (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5- dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl )-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one [0203] To a solution of tert-butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6- oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4- ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (0.17 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) at 0 °C. The mixture was stirred at 0 °C for 30 minutes followed by evaporation of volatiles under reduced pressure. The title compound was isolated in 87% yield as a yellow oil and used in the next step without further purification. MS (ESI) m/z: 622.0 [M+l]+.
[0204] Step 11: (3S, 11 S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-l-yl)-11-(5- chloro-2,4-difluorophenyl)-3-(pyridin-4-yl)-10-(trifIuoromet hyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6 -one (example 100a)and (3S)-8-((3S,5R)-4-acryloyl- 3,5-dimethylpiperazin- 1 -yl)- 11 -(5-chloro-2,4-difluorophenyl)-3-(pyridin-4-yl)- 10- (trifluoromethyl)-3,4-dihydro-2H,6H-[ 1 ,4]thiazepino[2,3,4-ij]quinazolin-6-one (example
[0205] To a 0 °C solution of (35)-11-(5-chloro-2,4-difluorophenyl)-8-((35,5R)-3,5- dimethylpiperazin- 1 -yl)-3-(pyridin-4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one (0.16 mmol) in dichloromethane (3 mL) was added triethylamine (0.05 mmol) and prop-2-enoyl chloride (0.32 mmol). The mixture was stirred at 0 °C for 30 minutes and the volatiles were removed under reduced pressure to afford a residue that was purified by preparative TLC. Compounds la and lb were isolated as a 1:1 mixture of diastereomers in 54% yield. Pure diastereomers la and lb were obtained by purification of the aforementioned mixture by SFC (Daicel Chiralpak AD 250mmx30mm, lOum, using as mobile phase 50% isopropanol in CO2) and characterized by SFC (Chiralpak AD-3, 50x4.6mm, 3 um. Using as mobile phase: 5-40% isopropanol (containing 0.05% diethylamine) in CO2 at 3 mL/min.)
[0206] Compound 100a: SFC Rt= 1.79 min; MS (ESI) m/z: 676.0 [M+l]+. NMR (400 MHz, CDC13) δ ppm 1.51 - 1.59 (m, 6 H) 3.15 (br d, J= 13.6 Hz, 1 H) 3.41 (td, J = 12.8, 4.8 Hz, 2 H) 3.70 - 3.87 (m, 2 H) 4.12 - 4.27 (m, 2 H) 4.53 - 4.91 (m, 4 H) 5.80 (dd, J = 10.4, 2.0 Hz, 1 H) 6.43 (dd, J= 16.8, 2.0 Hz, 1 H) 6.64 (dd, J= 16.4, 10.4 Hz, 1 H) 7.06 (t, J= 8.8 Hz, 1 H) 7.28 - 7.34 (m, 3 H) 8.14 (s, 1 H) 8.49 - 8.67 (m, 2 H). [0207] Compound 100b: SFC Rt= 3.30 min; MS (ESI) m/z: 676.0 [M+l]+. 1H NMR (400 MHz, CDC13) 5 ppm 1.53 (br d, J = 6.8Hz, 6 H) 3.06 - 3.27 (m, 1 H) 3.41 (ddd, J = 17.6, 13.2, 4.4 Hz, 2 H) 3.61 - 3.83 (m, 2 H) 4.14 - 4.23 (m, 2 H) 4.53 - 4.90 (m, 4 H) 5.80 (dd, J = 10.4, 2.0 Hz, 1 H) 6.43 (dd, J = 16.8, 1.6 Hz, 1 H) 6.64 (dd, J = 16.8, 10.4 Hz, 1 H) 7.10 (t, J - 8.8 Hz, 1 H) 7.23 - 7.27 (m, 1 H) 7.30 (br d, J = 5.2 Hz, 2 H) 8.15 (s, 1 H) 8.59 (d, J = 6.0 Hz, 2 H).
[0208] Example 101a and 101b: (3R)-8-((3S,5R )-4-acryloyl-3,5-dimethylpiperazin-l- yl)-11-(5-chloro-2,4-difluorophenyl)-3-(pyridin-4-yl)-10-(tr ifluoromethyl)-3,4-dihvdro- 2H,6H-[1,4]thiazepino[2,3,4-ii]quinazolin-6-one (101a) and (3R ,11S)-8-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin-l-yl)-11-(5-chloro-2,4-difluo rophenyl)-3-((S)-3,4- dihydropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H- [1,4]thiazepinor2,3,4-
[0209] Step 1: tert-Butyl (2S,6R)-4-((3R)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-
(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1, 4]thiazepino[2,3,4- ij]quinazolin-8-yl)-2,6-dimethylpiperazine- 1 -carboxylate [0210] Potassium phosphate (1.18 mmol) and Ruphos Pd G4 (0.04 mmol) were added to a solution of tert-butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-4-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate (0.39 mmol) and (5-chloro-2,4-difluoro-phenyl)boronic acid (1.57 mmol) in dioxane (5 mL) and water (0.1 mL). The mixture was stirred at 80 °C for 30 minutes, cooled down to room temperature and the insoluble materials were filtered. Evaporation of volatiles under reduced pressure afforded a residue that was purified by preparative TLC. The title compound was isolated in 61% yield as a yellow solid. MS (ESI) m/z: 722.1 [M+1]+. [0211] Step 2: (3R)-11-(5-Chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5- dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl )-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one [0212] Trifluoroacetic acid (1 mL) was added to a 0 °C solution of tert-butyl (2S,6R)-4- ((3R)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl )-10-(trifluoromethyl)-3,4- dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1- carboxylate (0.25 mmol) in dichloromethane (3 mL). The reaction was stirred at 0 °C for 30 minutes and the volatiles were removed under reduced pressure to afford the title compound in 97% yield as a yellow oil. MS (ESI) m/z: 622.0 [M+1]+. [0213] Step 3: (3R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5 -chloro-2,4- difluorophenyl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-di hydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one (101a) and (3R,11S)-8-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-( (S)-3,4-dihydropyridin-4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-6-one (101b)
[0214] To a 0 °C solution of (3R)- 1 l-(5-Chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5- dimethylpiperazin-1-yl)-3-(pyridin-4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one (0.16 mmol) in dichloromethane (3 mL) was added triethylamine (0.05 mmol) and prop-2-enoyl chloride (0.32 mmol). The mixture was stirred at 0 °C for 30 minutes and the volatiles were removed under reduced pressure to afford a residue that was purified by preparative TLC. Compounds 101a and 101b were isolated as a 1 : 1 mixture of diastereomers in 94% yield.
[0215] Pure diastereomers 101a and 101b were obtained by purification of the aforementioned mixture by SFC (column: Daicel Chiralpak IG 250mmx30mm, lOum using as mobile phase 55% isopropanol/acetonitrile (4: 1) in CO2). Each individual diastereomer was analyzed by SFC (Chiralpak AD-3, 50x4.6 mm, 3 um, using as mobile phase 40% isopropanol (containing 0.05% diethylamine) in CO2 at 3 mL/min).
[0216] Compound 101a: SFC Rt= 1.25 min; MS (ESI) m/z: 676.0 [M+l]+. 1H NMR (400 MHz, CDC13) δ ppm- 1.50 - 1.61 (m, 6 H) 3.16 (br d, J = 12.8 Hz, 1 H) 3.41 (td, J = 12.4, 4.8 Hz, 2 H) 3.67 - 3.95 (m, 2 H) 4.12 - 4.25 (m, 2 H) 4.42 - 5.05 (m, 4 H) 5.72 - 5.90 (m, 1 H) 6.43 (dd, J = 16.8, 1.6 Hz, 1 H) 6.56 - 6.72 (m, 1 H) 7.06 (t, J = 8.8 Hz, 1 H) 7.31 (t, J = 7.6 Hz, 1 H) 7.38 (d, J = 6.0 Hz, 2 H) 8. 14 (s, 1 H) 8.62 (d, J = 6.0 Hz, 2 H).
[0217] Compound 101b: SFC Rt= 2.23 min; MS (ESI) m/z: 676.0 [M+l]+. 1H NMR (400 MHz, CDC13) δ ppm- 1.48 - 1.61 (m, 6 H) 2.99 - 3.24 (m, 1 H) 3.41 (ddd, J = 17.6, 13.2, 4.6 Hz, 2 H) 3.57 - 3.89 (m, 2 H) 4.19 (br dd, J = 13.2, 5.6 Hz, 2 H) 4.46 - 5.00 (m, 4 H) 5.80 (dd, J = 10.4, 1.6 Hz, 1 H) 6.43 (dd, J = 16.8, 1.6 Hz, 1 H) 6.64 (dd, J = 16.8, 10.4 Hz, 1 H) 7.10 (t, J = 8.8 Hz, 1 H) 7.25 (s, 1 H) 7.31 (br d, J = 5.6 Hz, 2 H) 8.15 (s, 1 H) 8.52 - 8.67 (m, 2 H). [0218] Example 102: (3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5 - bromo-2,4-difluorophenyl)-3-(pyridin-4-yl)-10-(trifluorometh yl)-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one [0219] Step 1: tert-butyl (2S,6R)-4-((3S)-11-(5-amino-2,4-difluorophenyl)-6-oxo-3- (pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]t hiazepino[2,3,4- ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [0220] The title compound was prepared analogously to Example 100, step 9, where (5- chloro-2,4-difluoro-phenyl)boronic acid was replaced with 2,4-difluoro-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. The title compound was isolated in 78% yield as a yellow solid. MS (ESI) m/z: 703.2 [M+1]+. [0221] Step 2: tert-butyl (2S,6R)-4-((3S)-11-(5-bromo-2,4-difluorophenyl)-6-oxo-3- (pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]t hiazepino[2,3,4- ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate
[0222] To a solution of copper bromide (0.14 mmol) and tert-butyl nitrite (0.17 mmol) in acetonitrile (1 mL) was added tert-butyl (2R,6S)-4-[(125)-8-(5-amino-2,4-difluoro- phenyl)-2-oxo- 12-(4-pyridyl)-7-(trifluoromethyl)- 10-thia- 1 ,3- diazatricyclo[7.4.1.05,14]tetradeca-3,5,7,9(14)-tetraen-4-yl ]-2,6-dimethyl-piperazine-1- carboxylate (0.11 mmol) in acetonitrile (1 mL) and the reaction was stirred at 60 °C for 30 minutes. The reaction mixture was filtered and concentrated under reduced pressure to afford a residue that was purified by preparative TLC followed by semi-preparative reverse phase-HPLC. The title compound was isolated in 40% yield as a yellow solid. MS (ESI) m/z: 768.2 [M+l]+.
[0223] Step 3: (3S)- 11-(5-Bromo-2,4-difluorophenyl)-8-((3S,5R)-3,5- dimethylpiperazin-1-yl)-3-(pyridin-4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one
[0224] The title compound was prepared analogously to Example 100, step 10, where tert-butyl (25,6R)-4-((35)-11-(5-chl oro-2, 4-difluorophenyl)-6-oxo-3-(pyridin-4- yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((3S)-11-(5- bromo-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluo romethyl)-3,4-dihydro- 2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethyl piperazine-1-carboxylate.
The title compound was isolated in 99% yield as a yellow oil. MS (ESI) m/z: 668.1 [M+l]+.
[0225] Step 4: (3S)-8-((3S,5R)-4-Acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5 -bromo-
2,4-difluorophenyl)-3-(pyridin-4-yl)-10-(trifluoromethyl) -3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one
[0226] The title compound was prepared analogously to Example 100, step 11 , where (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethy lpiperazin-1-yl)-3-(pyridin- 4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-6-one was replaced with (35)- 1 l-(5-Bromo-2,4-difluorophenyl)-8-((3S,5R)-3,5- dimethylpiperazin-1-yl)-3-(pyridin-4-yl)-10-(trifluoromethyl )-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 97% yield as a yellow oil. MS (ESI) m/z: 722.1 [M+l]+. 1H NMR (400 MHz, CDC13) δ ppm 1.54 (br d, J = 6.8 Hz, 6 H) 3.04 - 3.25 (m, 1 H) 3.34 - 3.46 (m, 2 H) 3.57 - 3.89 (m, 2 H) 4.19 (br dd, J = 13.6, 6.8 Hz, 2 H) 4.50 - 4.93 (m, 4 H) 5.80 (dd, J = 10.4, 1.6 Hz, 1 H) 6.38 - 6.49 (m, 1 H) 6.56 - 6.71 (m, 1 H) 6.99 - 7.15 (m, 1 H) 7.31 (br dd, J = 4.4, 2.0 Hz, 2 H) 7.43 (dt, J = 14.4, 7.2 Hz, 1 H) 8.14 (d, J = 3.6 Hz, 1 H) 8.51 - 8.68 (m, 2 H).
[0227] Example 104a and 104b: (3S,11R)-8-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-( pyridin-3-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ii ]quinazolin-6-one (example 104a) and (3S,1 lS)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5- chloro-2,4- difluorophenyl)-3 -(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H- [1,4]thiazenino[2,3,4-ii]quinazolin-6-one (example 104b)
Example 104a Example 104b
[0228] Step 1: 2-(pyridin-3-yl)prop-2-en-1-ol
[0229] A mixture of pyridin-3-ylboronic acid (41 mmol), 2-bromoprop-2-en-1-ol (49 mmol), potassium phosphate (122 mmol) and XPhosPd G2 (1.0 mmol) in THF (50mL) and water (50 mL) was stirred at 60 °C for 12 hours. The reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (35-80% ethyl acetate in hexanes). The title compound was isolated in 53% yield as colorless oil. MS (ESI) m/z: 136.1 [M+H]+.
[0230] Step 2: 2-(pyridin-3-yl)propane-l,3-diol
[0231] A 10M THF solution of borane dimethyl sulfide complex (8.6 mL) was added over a 0 °C solution of 2-(pyridin-3-yl)prop-2-en-1-ol (22 mmol) in THF (30 mL). After 5 minutes, a IM aqueous solution of NaOH (6.5 mL) was added dropwise, followed by a 35% aqueous solution of hydrogen peroxide (86 mmol). After 2 hours, methanol (50 mL) was added and the resulting reaction was stirred at 70 °C for 12 hours. The reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (0-20% methanol in ethyl acetate). The title compound was isolated in 73% yield as colorless oil. 1H NMR (400 MHz, CDC13) δ 8.58 - 8.48 (m, 2H), 7.68 - 7.59 (m, 1H), 7.32 - 7.28 (m, 1H), 4.10 - 3.96 (m, 4H), 3.16 - 3.07 (m, 1H).
[0232] Step 3: 3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propan-1-ol
[0233] 2-(Pyridin-3-yl)propane-l,3-diol (13.0 mmol) was added to a 0 °C suspension of NaH (13.1 mmol) in THF (20 mL). The reaction was stirred at room temperature for 30 minutes, cooled down to 0 °C and a solution of TBDPSC1 (10.4 mmol) in THF (20 mL) was added. After 30 minutes, the reaction was stopped by the addition of a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (20-50% ethyl acetate in hexanes). The title compound was isolated in 47% yield as a colorless oil. 1H NMR (400 MHz, CDC13) δ 8.49 (d, J = 4.4 Hz, 1H), 8.45 (s, 1H), 7.61 (dd, J = 7.6, 11.2 Hz, 4H), 7.54 (d, J = 8.0 Hz, 1H), 7.49 - 7.33 (m, 6H), 7.21 (dd, J = 4.8, 7.6 Hz, 1H), 4.11 - 4.05 (m, 1H), 3.99 - 3.89 (m, 3H), 3.08 (quin, J = 6.0 Hz, 1H), 2.14 (s, 1H), 1.05 (s, 9H).
[0234] Step 4: S-(3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3-yl)propyl) ethanethioate
[0235] A solution of triphenylphosphine (8.20 mmol) and DIAD (8.17 mmol) in THF (50 mL) was stirred at 0°C for 30 minutes. 3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3- yl)propan-1-ol (4.09 mmol) and ethanethioic S-acid (9.81 mmol) were added and the mixture was stirred at room temperature for one hour. Evaporation of volatiles under reduced pressure afforded a residue that was purified by silica gel chromatography (10- 25% ethyl acetate in hexanes). The title compound was isolated in 98% yield as a colorless oil. MS (ESI) m/z: 450.1 [M+H]+.
[0236] Step 5: tert-butyl (2S,6R)-4-(8-((3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3 - yl)propyl)thio)-7-chloro-2-oxo-6-(trifluoromethyl)-l,2-dihyd roquinazolin-4-yl)-2,6- dimethylpiperazine-1-carboxylate
[0237] The title compound was prepared analogously to Example 100, step 7 where S- (3-hydroxy-2-(pyridin-4-yl)propyl) ethanethioate was replaced with S-(3-((tert- butyldiphenylsilyl)oxy)-2-(pyri din-3 -yl)propyl) ethanethioate. The title compound was isolated in 97% yield as a brown solid. MS (ESI) m/z: 866.3 [M+H]+.
[0238] Step 6: tert-butyl (2S,6R)-4-(7-chloro-8-((3-hydroxy-2-(pyridin-3- yl)propyl)thio)-2-oxo-6-(tri fluoromethyl)- l,2-dihydroquinazolin-4-yl)-2, 6- dimethylpiperazine-1-carboxylate
[0239] A IM solution of TBAF in THF (4.4 mL) was added over a solution of tert-butyl (2S,6R)-4-(8-((3-((tert-butyldiphenylsilyl)oxy)-2-(pyridin-3 -yl)propyl)thio)-7-chloro-2- oxo-6-(trifluoromethyl)- 1 ,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1- carboxylate (3.69 mmol) in THF (50 mL). After 2 hours the reaction mixture was diluted with water, extracted with ethyl acetate three times and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a residue that was purified by silica gel chromatography (20% methanol in ethyl acetate). The title compound was isolated in 80% yield as brown solid. MS (ESI) m/z: 628.2 [M+H]+. [0240] Step 7: tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-3-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate and tert-butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3- (pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]t hiazepino[2,3,4- ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate
[0241] The title compounds were prepared analogously to Example 100, step 8 where tert-butyl (2S,6R)-4-(7-chloro-8-((3-hydroxy-2-(pyridin-4-yl)propyl)thi o)-2-oxo-6- (trifluoromethyl)- 1 ,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1-carboxyl ate was replaced with tert-butyl (2S,6R)-4-(7-chloro-8-((3-hydroxy-2-(pyridin-3-yl)propyl)thi o)-2- oxo-6-(trifluoromethyl)- 1 ,2-dihydroquinazolin-4-yl)-2,6-dimethylpiperazine-1- carboxylate. The title compounds were isolated in 98% yield as a 1:1 mixture of diastereomers. Each individual diastereomer was isolated by purification of the aforementioned mixture by SFC (Chiracel Chiralpak AD 250x30mm, 10 um using 40% methanol in CO2 as mobile phase). Each individual diastereomer was characterized by analytical SFC (Chiralpak AD-3, 50x4.6mm, 3um using as mobile phase 5-40% ethanol (containing 0.05% of diethylamine) in CO2 at 3 mL/min.)
[0242] tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-3-yl)- 10-(trifluoromethyl)- 3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)- 2,6-dimethylpiperazine-1- carboxylate: Rt= 1.94 min. MS (ESI) m/z: 610.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 9.38 - 8.16 (m, 2H), 8.01 (s, 1H), 7.86 (s, 1H), 7.63 - 7.25 (m, 1H), 4.85 - 4.40 (m, 2H), 4.32 - 4.16 (m, 2H), 4.04 - 3.95 (m, 3H), 3.68 (br s, 2H), 3.17 (dt, J = 4.0, 12.4 Hz, 2H), 1.44 (s, 9H), 1.42 - 1.26 (m, 6H).
[0243] tert-butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-3-yl)-10-(trifluor omethyl)- 3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)- 2,6-dimethylpiperazine-1- carboxylate: Rt= 2.42 min. MS (ESI) m/z: 610.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) 5 8.63 (d, J = 7.6 Hz, 1H), 8.01 (s, 1H), 7.87 (d, J = 3.2 Hz, 1H), 7.64 - 7.29 (m, 1H), 5.01 - 4.42 (m, 2H), 4.29 - 4.16 (m, 2H), 4.05 - 3.99 (m, 3H), 3.94 - 3.59 (m, 2H), 3.17 (dt, J = 4.0, 12.4 Hz, 2H), 1.44 (s, 9H), 1.41 - 1.26 (m, 6H).
[0244] Step 8: tert-butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3- (pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]t hiazepino[2,3,4- ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate
[0245] The title compound was prepared analogously to Example 100, step 9, where tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluor omethyl)-3,4- dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1- carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-3-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate. The title compound was isolated in 52% yield as a white solid. MS (ESI) m/z: 722.1 [M+H]+.
[0246] Step 9: (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethy lpiperazin- 1 -yl)-3-(pyridin-3-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 - ij]quinazolin-6-one [0247] The title compound was prepared analogously to Example 100, step 10 where tert-butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(py ridin-4-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((3S)-11-(5- chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-3-yl)-10-(triflu oromethyl)-3,4-dihydro- 2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethyl piperazine-1-carboxylate. The title compound was isolated in 99% yield as a yellow oil. MS (ESI) m/z: 622.1 [M+H]+.
[0248] Step 10: (3S,l lR)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5- chloro-2,4-difluorophenyl)-3-(pyridin-3-yl)-10-(trifluoromet hyl)-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one (example 104a) and (3S,1 lS)-8-((3S,5R)-4- acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluo rophenyl)-3-(pyridin-3-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-6-one (Example 104b)
Example 104a Example 104b
[0249] The title compounds were prepared analogously to Example 100, step 11 where (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethy lpiperazin-1-yl)-3-(pyridin- 4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-6-one was replaced with (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5- dimethylpiperazin-1-yl)-3-(pyridin-3-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compounds were isolated in 66% yield as a white solid and as a 1: 1 mixture of diastereomers. Each individual diastereomer was obtained by purification of the aforementioned mixture by SFC (Chiracel Chiralpak IC 250x30mm, 10 um using 65% methanol in CO2 as mobile phase). Each individual diastereomer was characterized by analytical SFC (Chiralpak IC-3, 50x4.6mm, 3um using as mobile phase 60% methanol (containing 0.05% of diethylamine) in CO2 at 3 mL/min. [0250] (3 S, 1 lR)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5- chloro-2,4- difIuorophenyl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-di hydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one (Example 104a): Rt= 2.98 min. MS (ESI) m/z: 676.0 [M+H]+. 1H NMR (400 MHz, CDC13) δ 8.87 - 8.39 (m, 2H), 8.15 (s, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.40 - 7.28 (m, 2H), 7.10 (t, J = 8.8 Hz, 1H), 6.64 (dd, J = 10.4, 16.4 Hz, 1H), 6.43 (dd, J = 2.0, 16.4 Hz, 1H), 5.83 - 5.76 (m, 1H), 5.11 - 4.48 (m, 4H), 4.19 (d, J = 13.2 Hz, 2H), 3.89 - 3.58 (m, 2H), 3.46 - 3.36 (m, 2H), 3.27 - 3.00 (m, 1H), 1.61 - 1.53 (m, 6H).
[0251] (3S,l lS)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5- chloro-2,4- difluorophenyl)-3-(pyridin-3-yl)-10-(trifluoromethyl)-3,4-di hydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one (Example 104b): Rt= 3.62 min. MS (ESI) m/z: 676.0 [M+H]+. 1H NMR (400 MHz, CDC13) δ 8.91 - 8.30 (m, 2H), 8.14 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.10 - 7.02 (m, 1H), 6.70 - 6.58 (m, 1H), 6.47 - 6.39 (m, 1H), 5.83 - 5.76 (m, 1H), 4.91 - 4.54 (m, 4H), 4.23 - 4.15 (m, 2H), 3.91 - 3.72 (m, 2H), 3.40 (dt, J = 4.4, 13.2 Hz, 2H), 3.22 - 3.03 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H), 1.54 (d, J = 6.8 Hz, 3H).
[0252] Example 106: (R)-8-((3S.5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4- fIuorophenyl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihv dro-2H,6H- [1,4]thiazepino[2,3,4-ii]quinazolin-6-one
[0253] Step 1: tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-2-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate and tert-butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3- (pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]t hiazepino[2,3,4- ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate
[0254] The title compounds were prepared analogously to Example 100, where 4- methylpyridine was replaced with 2-methylpyridine in step 4. The title compounds were isolated as a 1:1 mixture of diastereomers. Each individual diastereomer was obtained by purification of the aforementioned mixture by SFC (Chiracel Chiralpak AS, 250x50mm, 10 um using 40% methanol in CO2 as mobile phase) and characterized by analytical SFC (Chiralpak IC-3, 50x4.6mm, 3um using as mobile phase 5-40% methanol (containing 0.05% of diethylamine) in CO2 at 3 mL/min.)
[0255] tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-2-yl)- 10-(trifluoromethyl)- 3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)- 2,6-dimethylpiperazine-1- carboxylate: Rt= 1.12 minutes. MS (ESI) m/z: 610.2 [M+H]+.
[0256] tert-butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-2-yl)-10-(trifluor omethyl)- 3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)- 2,6-dimethylpiperazine-1- carboxylate: Rt= 1.39 minutes. MS (ESI) m/z: 610.2 [M+H]+.
[0257] Step 2: tert-butyl (2S,6R)-4-((R)-11-(4-fluorophenyl)-6-oxo-3-(pyridin-2-yl)-10 - (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate
[0258] The title compound was prepared analogously to Example 100, step 9, where tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluor omethyl)-3,4- dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1- carboxylate was replaced with tert-butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-2-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate. The title compound was isolated in 91% yield as a yellow solid. MS (ESI) m/z: 670.2 [M+H]+.
[0259] Step 3: (R)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluoropheny l)-3- (pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]t hiazepino[2,3,4- ij]quinazolin-6-one
[0260] The title compound was prepared analogously to Example 100, step 10 where tert-butyl (2S,6R)-4-((3 S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)- 10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((R)-11-(4- fluorophenyl)-6-oxo-3-(pyridin-2-yl)-10-(trifluoromethyl)-3, 4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpipera zine-1-carboxylate. The title compound was isolated in 95% yield as a yellow solid. MS (ESI) m/z: 570.2 [M+H]+ [0261] Step 4: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3-(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihy dro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one
[0262] The title compound was prepared analogously to Example 100, step 11 where tert-butyl (2S,6R)-4-((3 S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)- 10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate was replaced with (R)-8-((3S,5R)-3,5- dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(pyridin-2-yl) - 10-(trifluoromethyl)-3,4- dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 33% yield as a yellow solid. MS (ESI) m/z: 624.3 [M+H]+.1H NMR (400 MHz, CDC13-d) δ, 8.46 (br d, J = 4.4 Hz, 1H), 8.03 (s, 1H), 7.59 (dt, J = 1.6, 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.17 - 7.06 (m, 5H), 6.57 (dd, J = 10.4, 16.8 Hz, 1H), 6.35 (dd, J = 1.6, 16.8 Hz, 1H), 5.76 - 5.65 (m, 1H), 4.92 (br d, J = 4.4 Hz, 2H), 4.76 - 4.39 (m, 2H), 4.15 - 4.07 (m, 2H), 3.92 - 3.75 (m, 1H), 3.59 - 3.40 (m, 2H), 3.32 - 3.23 (m, 2H), 1.46 (br d, J = 6.8 Hz, 6H).
[0263] Examples 107a and Example 107b: (3R,1 lS)-8-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-bromo-2,4-difluorophenyl)-3-(p yridin-2-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazenino[2,3,4-ii ]quinazolin-6-one and (3R,1 lR)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5- bromo-2,4- difluorophenyl)-3 -(pyridin-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4] thiazepino[2,3,4-ii]quinazolin-6-one
[0264] The title compounds were prepared analogously to Example 102, where tert- butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)- 10-(trifluoromethyl)-3,4-dihydro- 2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethyl piperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((R)-11-chloro-6-oxo-3-(pyridin-2-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate. The title compounds were obtained as a 1:1 mixture of diastereomers. Each individual diastereomer was obtained by purification of the aforementioned mixture by SFC (Chiracel Chiralpak AD, 250x30mm, 10 um using 45% isopropanol (containing 0.1 % of ammonium hydroxide) in CO2 as mobile phase) and characterized by analytical SFC (Chiralpak AD, 50x4.6mm, 3um using as mobile phase 40% isopropanol (containing 0.05% of diethylamine) in CO2 at 3 mL/min.)
[0265] Example 107a: Rt= 0.46 minutes. MS (ESI) m/z: 721.9 [M+H]+. NMR NMR (400 MHz, CDCl 3 -d) δ, 8.57 (br d, J= 4.4 Hz, 1H), 8.12 (s, 1H), 7.73 - 7.64 (m, 1H), 7.42 (t, J= 7.2 Hz, 1H), 7.36 - 7.30 (m, 1H), 7.23 - 7.16 (m, 1H), 7.06 - 6.97 (m, 1H), 6.64 (dd, J= 10.4, 16.8 Hz, 1H), 6.43 (dd, J= 2.0, 16.8 Hz, 1H), 5.79 (dd, J = 2.0, 10.4 Hz, 1H), 5.08 - 4.93 (m, 2H), 4.84 - 4.49 (m, 2H), 4.22 - 4.13 (m, 2H), 4.01 - 3.91 (m, 1H), 3.71 - 3.52 (m, 2H), 3.41 - 3.32 (m, 2H), 1.55 (br d, J= 7.2 Hz, 6H).
[0266] Example 107b: Rt= 0.83 minutes. MS (ESI) m/z: 721.9 [M+H]+. 1H NMR (400 MHz, CDC13-d) δ, 8.47 (br s, 1H), 8.11 - 8.01 (m, 1H), 7.67 - 7.55 (m, 1H), 7.35 (brt, J = 7.2 Hz, 1H), 7.26 (br d, J = 7.2 Hz, 1H), 7.15 - 7.10 (m, 1H), 6.95 (t, J = 8.8 Hz, 1H), 6.56 (dd, J = 10.4, 16.8 Hz, 1H), 6.35 (dd, J = 2.0, 16.8 Hz, 1H), 5.74 - 5.68 (m, 1H), 4.92 (br d, J = 4.4 Hz, 2H), 4.74 - 4.23 (m, 2H), 4.09 (br d, J = 12.8 Hz, 2H), 3.95 - 3.76 (m, 1H), 3.70 - 3.35 (m, 2H), 3.34 - 3.21 (m, 2H), 1.49 (br s, 6H).
[0267] Example 108a and 108b: (3S,l lR)-8-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-bromo-2,4-difluorophenyl)-3-(p yridin-3-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ii ]quinazolin-6-one and
(3S.11S)-8-((3S.5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl )-11-(5-bromo-2,4- difluorophenyl)-3 -(pyridin-3-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-
[0268] The title compounds were prepared analogously to Example 102, where tertbutyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)- 10-(trifluoromethyl)-3,4-dihydro- 2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethyl piperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-3-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate. The title compounds were obtained as a 1: 1 mixture of diastereomers. Each individual diastereomer was obtained by purification of the aforementioned mixture by SFC (Phenomenex cellulose-2, 250x30mm, 10 um using 70% methanol in CO2 as mobile phase) and characterized by analytical SFC (Unichiral OZ-5H, 50x4.6mm, 3um using as mobile phase 60% methanol (containing 0.05% of diethylamine) in CO2 at 3 mL/min).
[0269] Example 108a: Rt= 1.89 minutes. MS (ESI) m/z: 720.0 [M+H]+. 1H NMR (400 MHz, CDC13) δ 9.15 - 8.23 (m, 1H), 8.15 (s, 1H), 7.75 (d, J = 6.8 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.37 - 7.27 (m, 2H), 7.08 (t, J = 8.4 Hz, 1H), 6.70 - 6.58 (m, 1H), 6.43 (dd, J = 2.0, 16.4 Hz, 1H), 5.80 (dd, J = 2.0, 10.4 Hz, 1H), 5.09 - 4.31 (m, 4H), 4.19 (d, J = 12.8 Hz, 2H), 3.97 - 3.54 (m, 2H), 3.46 - 3.34 (m, 2H), 3.29 - 2.97 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H), 1.53 (d, J - 6.8 Hz, 3H).
[0270] Example 108b: Rt= 3.03 minutes. MS (ESI) m/z: 720.0 [M+H]+. J H NMR (400 MHz, CDCl 3 ) δ 9.10 - 8.29 (m, 1H), 8.14 (s, 1H), 7.84 - 7.73 (m, 1H), 7.46 (t, J= 7.0 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.04 (t, J= 8.4 Hz, 1H), 6.64 (dd, J= 10.4, 16.4 Hz, 1H), 6.48 - 6.38 (m, 1H), 5.80 (dd, J= 1.6, 10.4 Hz, 1H), 5.07 - 4.42 (m, 4H), 4.19 (dd, J = 5.2, 13.6 Hz, 2H), 3.98 - 3.71 (m, 2H), 3.45 - 3.36 (m, 2H), 3.17 - 3.09 (m, 1H), 1.59 (d, J= 6.8 Hz, 3H), 1.54 (d, J = 6.8 Hz, 3H).
[0271 ] Example 109: (3S)-8-((3S.5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5 - chloro-2,4-difluorophenyl)-3-(5-fluoropyridin-3-yl)-10-(trif luoromethyl)-3,4-dihvdro- 2H.6H-[1,4]thiazepino[2,3,4-ii]quinazolin-6-one
[0272] Step 1: tert-butyl (2S,6R)-4-((R)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate and tert-butyl (2S,6R)-4-((S)-11-chloro-3-(5- fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2 H,6H-[1,4]thiazepino[2,3,4- ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate
[0273] The title compounds were prepared analogously to Examples 104a and 104b, where pyridin-3-ylboronic acid was replaced with (5-fluoropyridin-3-yl)boronic acid in step 1. The title compounds were obtained as a 1:1 mixture of diastereomers and each individual diastereomer was isolated by purification of the aforementioned mixture by SFC (Chiracel Chiralpak IC 250x30mm, 10 um using 65% ethanol in CO2 as mobile phase) and characterized by analytical SFC (Chiralpak IC-3, 50x4.6mm, 3um using as mobile phase 60% ethanol (containing 0.05% of diethylamine) in CO2 at 3 mL/min). [0274] tert-butyl (2S,6R)-4-((R)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate: Rt= 1.58 minutes. MS (ESI) m/z: 628.1 [M+H]+. [0275] tert-butyl (2S,6R)-4-((S)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate: Rt= 2.87 minutes. MS (ESI) m/z: 628.1 [M+H]+. [0276] Step 2: tert-butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-(5- fIuoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2 H,6H-[1,4]thiazepino[2,3,4- ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate
[0277] The title compound was prepared analogously to Example 100, step 9, where tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluor omethyl)-3,4- dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1- carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-chloro-3-(5-fluoropyridin-3- yl)-6-oxo- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-8- yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 85% yield as a yellow solid. MS (ESI) m/z: 740.0 [M+H]+.
[0278] Step 3: (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethy lpiperazin- l-yl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)-3,4-dihy dro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one
[0279] The title compound was prepared analogously to Example 100, step 10 where tert-butyl (2S,6R)-4-((3 S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)- 10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((3S)-11-(5- chloro-2,4-difluorophenyl)-3-(5-fluoropyridin-3-yl)-6-oxo-10 -(trifluoromethyl)-3,4- dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1- carboxylate. The title compound was isolated in 99% yield as a yellow solid. MS (ESI) m/z: 640.0 [M+H]+.
[0280] Step 4: (3S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5 -chloro-2,4- difluorophenyl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl )-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one
[0281] The title compound was prepared analogously to Example 100, step 11 , where (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethy lpiperazin-1-yl)-3-(pyridin- 4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-6-one was replaced with (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5- dimethylpiperazin-1-yl)-3-(5-fluoropyridin-3-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one. The title compound was isolated in 21% yield as a white solid. MS (ESI) m/z: 694.4 [M+H]+. 1H NMR (400 MHz, CDC13) δ 8.48 (s, 1H), 8.43 (d, J - 2.4 Hz, 1H), 8.14 (s, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.36 - 7.27 (m, 1H), 7.14 - 7.03 (m, 1H), 6.68 - 6.60 (m, 1H), 6.47 - 6.40 (m, 1H), 5.80 (d, J = 11.6 Hz, 1H), 4.97 - 4.54 (m, 4H), 4.19 (dd, J = 5.2, 12.0 Hz, 2H), 3.96 - 3.67 (m, 2H), 3.41 (t, J = 4.4, 12.4 Hz, 2H), 3.20 - 3.04 (m, 1H), 1.59 (d, J = 6.8 Hz, 3H), 1.54 (d, J = 6.8 Hz, 3H).
[0282] Example 112a and Example 112b: (3S,1 lS)-8-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(5-chloro-2,4-difluorophenyl)-3-( 3-fluoropyridin-4-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ii ]quinazolin-6-one (112a) and (3S,l lR)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5- chloro-2,4- difluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl )-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ii]quinazolin-6-one (112b)
[0283] Step 1: tert-butyl (2S,6R)-4-((S)-11-chloro-3-(3-fluoropyridin-4-yl)-6-oxo-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate and tert-butyl (2S,6R)-4-((R)-11-chloro-3-(3- fluoropyridin-4-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2 H,6H-[1,4]thiazepino[2,3,4- ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate
[0284] The title compounds were prepared analogously to Example 100, where 4- methylpyridine was replaced with 3-fluoro-4-methyl-pyridine in step 4. These two compounds were obtained as a 1: 1 mixture of diastereomers. Each individual diastereomer was isolated by purification of the aforementioned mixture by SFC (Chiracel Chiralpak IC 250x30mm, 10 um using 60% methanol (containing 0.1% of ammonium hydroxide) in CO2 as mobile phase) and characterized by analytical SFC ((S,S) Whelk-Ol, 50x4.6mm, 1.8 um, with 50% mcthanol/acctonitrile (4:1) (containing 0.05% of diethylamine) in CO2 as mobile phase at 3 mL/min).
[0285] tert-butyl (2S,6R)-4-((S)-11-chloro-3-(3-fluoropyridin-4-yl)-6-oxo-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate: Rt= 1.41 minutes. MS (ESI) m/z: 628.4 [M+H]+ [0286] tert-butyl (2S,6R)-4-((R)-11-chloro-3-(3-fluoropyridin-4-yl)-6-oxo-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate: Rt= 1.81 minutes MS (ESI) m/z: 628.4 [M+H]+ [0287] Step 2: tert-butyl (2S,6R)-4-((3S)-11-(5-chloro-2,4-difluorophenyl)-3-(3- fluoropyridin-4-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2 H,6H-[1,4]thiazepino[2,3,4- ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate [0288] The title compound was prepared analogously to Example 100, step 9, where tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluor omethyl)-3,4- dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1- carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-chloro-3-(3-fluoropyridin-4- yl)-6-oxo- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-8- yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 44% yield as a yellow solid. MS (ESI) m/z: 740.5 [M+H]+.
[0289] Step 2: (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethy lpiperazin- l-yl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)-3,4-dihy dro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one
[0290] The title compound was prepared analogously to Example 100, step 10 where tert-butyl (2S,6R)-4-((3 S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)- 10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((3S)-11-(5- chloro-2,4-difluorophenyl)-3-(3-fluoropyridin-4-yl)-6-oxo-10 -(trifluoromethyl)-3,4- dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1- carboxylate. The title compound was isolated in 98% yield as a yellow solid. MS (ESI) m/z: 640.5 [M+H]+.
[0291] Step 3: (3S,l lS)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5- chloro-2,4-difluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trif luoromethyl)-3,4-dihydro- 2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (example 112a) and (3 S, 1 lR)-8- ((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5-chloro -2,4-difluorophenyl)-3-(3- fIuoropyridin-4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 - ij]quinazolin-6-one (Example 112b)
[0292] The title compounds were prepared analogously to Example 100, step 11 where (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethy lpiperazin-1-yl)-3-(pyridin- 4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-6-one was replaced with (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5- dimethylpiperazin-1-yl)-3-(3-fluoropyridin-4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-
[1.4]thiazepino[2,3,4-ij]quinazolin-6-one. These two compounds were isolated in 51% yield as a 1 : 1 mixture of diastereomers. Each individual diastereomer was isolated by purification of the mixture by SFC (Chiracel OD 250x30mm, 10 um using 50% methanol in CO2 as mobile phase) and characterized by analytical SFC (Chiralpak IC-3, 50x4.6mm, 3um using as mobile phase 60% methanol/acetonitrile (containing 0.05% of diethylamine) in CO2 at 3 mL/min).
[0293] (3S,l lS)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5- chloro-2,4- difluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl )-3,4-dihydro-2H,6H-
[1.4]thiazepino[2,3,4-ij]quinazolin-6-one (112a) (Example 112a): Rt= 0.92 minutes. MS (ESI) m/z: 694.1 [M+H]+. 1H NMR (400 MHz, CDC13) δ ppm 1.54 (d, J = 6.8 Hz, 3 H) 1.59 (d, J = 6.8 Hz, 3 H) 3.02 - 3.23 (m, 1 H) 3.42 (td, J = 12.4, 4.4 Hz, 2 H) 3.65 - 3.86 (m, 1 H) 4.11 - 4.24 (m, 3 H) 4.54 - 5.01 (m, 4 H) 5.74 - 5.84 (m, 1 H) 6.38 - 6.48 (m, 1 H) 6.58 - 6.70 (m, 1 H) 7.05 (t, J = 8.8 Hz, 1 H) 7.30 (t, J = 7.6 Hz, 2 H) 8.14 (s, 1 H) 8.32 - 8.61 (m, 2 H).
[0294] (3 S, 1 lR)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(5- chloro-2,4- difluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl )-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one (example 112b): Rt= 1.37 minutes. MS (ESI) m/z: 694.1 [M+H]+. 1H NMR (400 MHz, CDC13) δ ppm 1.53 (d, J = 6.4 Hz, 3 H) 1.59 (br s, 3 H) 2.97 - 3.27 (m, 1 H) 3.36 - 3.46 (m, 2 H) 3.54 - 3.83 (m, 1 H) 4.05 - 4.26 (m, 3 H) 4.49 - 5.05 (m, 4 H) 5.80 (dd, J = 10.4, 2.0 Hz, 1 H) 6.43 (dd, J = 16.8, 2.0 Hz, 1 H) 6.64 (dd, J = 16.8, 10.4 Hz, 1 H) 7.09 (t, J = 8.8 Hz, 1 H) 7.25 (br s, 1 H) 7.29 (br s, 1 H) 8.14 (s, 1 H), 8.44 (d, 4.8 Hz), 8.47 (s, 1H).
[0295] Example 113: (S)-8-((3S.5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihv dro-2H,6H-[1,4]thiazepino[2,3,4-ii]quinazolin-6-one
[0296] Step 1: tert-butyl (2S,6R)-4-((S)-11-(4-fluorophenyl)-6-oxo-3-(pyridin-4-yl)-10 -
(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate
[0297] The title compound was prepared analogously to Example 100, step 9, where (5- chloro-2,4-difluoro-phenyl)boronic acid was replaced with (4-fluorophenyl)boronic acid. The title compound was isolated in 73% yield as a yellow solid. MS (ESI) m/z: 670.2 [M+l]+.
[0298] Step 2: (S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluoropheny l)-3- (pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]t hiazepino[2,3,4- ij]quinazolin-6-one
[0299] The title compound was prepared analogously to Example 100, step 10, where tert-butyl (25,6R)-4-((3S)-11-(5-chl oro-2, 4-difluorophenyl)-6-oxo-3 -(pyridin-4-yl)- 10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-(4- fluorophenyl)-6-oxo-3-(pyridin-4-yl)-10-(trifluoromethyl)-3, 4-dihydro-2H,6H-
[1.4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpip erazine-1-carboxylate. The title compound was isolated in 99% yield as a yellow solid. MS (ESI) m/z: 570.1 [M+l]+ [0300] Step 3: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3-(pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihy dro-2H,6H-
[1.4]thiazepino[2,3,4-ij]quinazolin-6-one
[0301] The title compound was prepared analogously to Example 100, step 11 , where (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethy lpiperazin-1-yl)-3-(pyridin- 4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-6-one was replaced with (S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluoropheny l)-3- (pyridin-4-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]t hiazepino[2,3,4- ij]quinazolin-6-one. The title compound was isolated in 91% yield as a yellow solid. MS (ESI) m/z: 624.2 [M+l]+. NMR (400 MHz, CDCl 3 ) δ ppm 1.53 (d, J = 7.2 Hz, 3 H) 1.61 (d, J = 6.8 Hz, 3 H) 3.01 - 3.18 (m, 1 H) 3.41 (ddd, J = 17.2, 13.2, 4.0 Hz, 2 H) 3.60 - 3.83 (m, 2 H) 4.20 (dd, J = 12.8, 6.4 Hz, 2 H) 4.56 - 4.95 (m, 4 H) 5.74 - 5.85 (m, 1 H)
6.43 (dd, J = 16.8, 2.0 Hz, 1 H) 6.59 - 6.71 (m, 1 H) 7.17 - 7.26 (m, 4 H) 7.29 - 7.38 (m, 2 H) 8.13 (s, 1 H) 8.49 - 8.71 (m, 2 H).
[0302] Example 114: (S)-8-((3S.5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)- 3,4-dihvdro-2H,6H- [1,4]thiazepino[2,3,4-ii]quinazolin-6-one
[0303] Step 1: tert-butyl (2S,6R)-4-((S)-11-(4-fluorophenyl)-3-(3-fluoropyridin-4-yl)- 6- oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2 ,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate
[0304] The title compound was prepared analogously to Example 100, step 9, where tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluor omethyl)-3,4- dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1- carboxylate and (5-chloro-2,4-difluoro-phenyl)boronic acid were replaced with tert-butyl (2S,6R)-4-((S)-11-chloro-3-(3-fluoropyridin-4-yl)-6-oxo- 10-(trifluoromethyl)-3,4- dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1- carboxylate and (4-fluorophenyl)boronic acid. The title compound was isolated as a yellow solid. MS (ESI) m/z: 688.2 [M+l]+. [0305] Step 2: (S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluoropheny l)-3-(3- fluoropyridin-4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 - ij]quinazolin-6-one
[0306] The title compound was prepared analogously to Example 100, step 10, where tert-butyl (2S,6R)-4-((3 S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)- 10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-(4- fluorophenyl)-3-(3-fluoropyridin-4-yl)-6-oxo-10-(trifluorome thyl)-3,4-dihydro-2H,6H-
[1.4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpip erazine-1-carboxylate. The title compound was isolated in 99% yield as a yellow solid. MS (ESI) m/z: 588.2 [M+l]+. [0307] Step 3: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3-(3-fluoropyridin-4-yl)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H-
[1.4]thiazepino[2,3,4-ij]quinazolin-6-one
[0308] The title compound was prepared analogously to Example 100, step 11 , where (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethy lpiperazin-1-yl)-3-(pyridin- 4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-6-one was replaced with (S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluoropheny l)-3-(3- fluoropyridin-4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 - ij]quinazolin-6-one. The title compound was isolated in 61% yield as a yellow solid. MS (ESI) m/z: 642.2 [M+l]+. NMR (400 MHz, CDC1 3 ) 5 ppm 1.53 (d, J = 6.8 Hz, 3 H) 1.60 (d, J = 6.0 Hz, 3 H) 2.91 - 3.20 (m, 1 H) 3.34 - 3.48 (m, 2 H) 3.53 - 3.81 (m, 1 H) 3.97 - 4.26 (m, 3 H) 4.45 - 5.07 (m, 4 H) 5.73 - 5.85 (m, 1 H) 6.43 (dd, J = 16.8, 2.0 Hz, 1 H) 6.58 - 6.69 (m, 1 H) 7.14 - 7.23 (m, 3 H) 7.25 (br s, 1 H) 7.30 (br s, 1 H) 8.12 (s, 1 H) 8.29 - 8.57 (m, 2 H).
[0309] Example 115: 8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3,11-bis(4 - fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]th iazepino[2,3,4- ii]quinazolin-6-one
[0310] Methyl 2-(4-fluorophenyl)-3-hydroxypropanoate (2)
[0311] To a mixture of methyl 2-(4-fluorophenyl)acetate (5 g, 29.76 mmol) and sodium methanolate (0.08031g, 1.49 mmol) in DMSO (10 mL) was added polyformaidehyde (0.93 g, 31 .25 mmol) at 20 °C for 16 hours. The mixture was quenched with water and neutralized with 2 N hydrochloric acid, and extracted with ethyl acetate (100 mL><3). The combined organic phases was washed with brine (50 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column with petroleum ether/ethyl acetate=5%~40% to afford methyl 2-(4-fluorophenyl)-3- hydroxypropanoate 2 (4.5 g, yield 76%) as a white solid.
[0312] 2-(4-fluorophenyl)propane-l,3-diol (3) [0313] To a solution of methyl 2-(4-fluorophenyl)-3-hydroxypropanoate (11 g, 55.56 mmol) in THF (100 mL) was added 1.0 M DIBAL-H (166.68 mmol, 166.68 mL) at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C under nitrogen atmosphere for 3 hours. After completion, the mixture was quenched with sodium sulfate decahydrate and filtration. The solution was concentrated and the residue was purified by silica gel column (PE/EA = 10%~l 00%) to afford 2-(4-fluorophenyl)propane- 1,3 -diol 3 (5.05 g, yield 53 %) as a yellow oil.
[0314] 2-(4-fluorophenyl)-3-hydroxypropyl 4-methylbenzenesulfonate (4)
[0315] To a mixture of 2-(4-fluorophenyl)propane-l,3-diol (5.0 g, 29.4 mmol) and TEA (5.94 g, 58.82 mmol) in DCM (50 mL) was added Tosyl chloride (3.35 g, 17.6 mmol) at 0 °C. The mixture was stirred at 20°C for 12 hours. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column (PE/EA = 0—2: 1) to afford 2-(4-fluorophenyl)-3-hydroxypropyl 4-methylbenzenesulfonate 4 (3.58 g, yield 38 %) as a white solid.
[0316] S-(2-(4-fluorophenyl)-3-hydroxypropyl) ethanethioate (5)
[0317] To a mixture of 2-(4-fluorophenyl)-3 -hydroxypropyl 4-methylbenzenesulfonate (3.6 g, 11.11 mmol) in acetone (10 mL) was added potassium methanesulfinate (2.53 g, 22.2 mmol) at 20°C. The mixture was stirred at 50 °C for 1 hour. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column (DCM/MeOH = 0-20:1) to afford S-(2-(4-fluorophenyl)-3-hydroxypropyl) ethanethioate 5 (1.7 g, yield 67 %) as a yellow oil.
[0318] 7-chloro-8-((2-(4-fluorophenyl)-3-hydroxypropyl)thio)-4-hydr oxy-6- (trifluoromethyl)quinazolin-2(lH)-one (6)
[0319] To a mixture of S-(2-(4-fluorophenyl)-3-hydroxypropyl) ethanethioate (1.65 g, 7.24 mmol) and 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4(lH,3H)-di one (2.82 g, 7.24 mmol) in ethylene glyol (10 mL) and isopropanol (10 mL) were added Cui (551 mg, 2.90 mmol) and K2CO3 (3 g, 21.72 mmol) at 20°C under N2 atmosphere. The mixture was stirred at 85 °C for 3 hours. After completion, the mixture was extracted with ethyl acetate (100 mL><3). The combined organic phases was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The organic was concentrated under reduced pressure and the residue was purified by silica gel column with DCM/MeOH =0%~20% to afford 7-chloro- 8-((2-(4-fluorophenyl)-3-hydroxypropyl)thio)-4-hydroxy-6-(tr ifluoromethyl)quinazolin- 2(lH)-one 6 (160 mg) as a yellow solid. [0320] 11-chloro-3-(4-fluorophenyl)-8-hydroxy-10-(trifluoromethyl)- 3,4-dihydro- 2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (7)
[0321] To a mixture of 7-chloro-8-((2-(4-fluorophenyl)-3-hydroxypropyl)thio)-4- hydroxy-6-(trifluoromethyl)quinazolin-2(lH)-one (160 mg, 0.36 mmol) and triphenylphosphine (189 mg, 0.72 mmol) in tetrahydro furan (20 mL) was added diethyl azodicarboxylate (125 mg, 0.72 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at 20°C for 1 hour. After completion, the mixture was concentrated under reduced pressure and the residue was purified by the reversed flash to afford 1 l-chloro-3-(4- fluorophenyl)-8-hydroxy- 10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4- ij]quinazolin-6(2H)-one 7 (100 mg, 73% yield) as a yellow solid.
[0322] tert-butyl (2S,6R)-4-(11-chloro-3-(4-fluorophenyl)-6-oxo-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate (8)
[0323] To a mixture of 1 l-chloro-3-(4-fluorophenyl)-8-hydroxy-10-(trifluoromethyl)-
3.4-dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one 7 (100 mg, 0.23 mmol) and potassium carbonate (254 mg, 1.84 mmol) in acetonitrile (10 mL) was added 4- methylbenzenesulfonic anhydride (112 mg, 0.345 mmol) at 0 °C. The mixture was stirred at 30 °C for 4 hours. Then, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (98 mg, 0.46 mmol) was added into the reaction mixture. The reaction mixture was stirred at 30 °C for further 2 hours. After completion, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column (PE/EA = 0%~100%) to afford tert-butyl (2S,6R)-4-(11-chloro-3-(4-fluorophenyl)-6-oxo-10-(trifluorom ethyl)-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpipera zine-1-carboxylate 8 (50 mg, 35% yield)) as a yellow solid.
[0324] tert-butyl (2S,6R)-4-(3,11-bis(4-fluorophenyl)-6-oxo-10-(trifluoromethy l)-
3.4-dihydro-2H,6H- [1,4 ] thiazepino [2,3,4-ij ] quinazolin-8-yl)-2,6-dimethylpiperazine- 1-carboxylate (9)
[0325] To a solution of tert-butyl (2S,6R)-4-(11-chloro-3-(4-fluorophenyl)-6-oxo-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate 8 (50 mg, 0.08 mmol), (4-fluorophenyl)boronic acid (90 mg, 0.64 mmol) and tripotassium phosphate (64 mg, 0.24 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added chloro(2-dicyclohexylphosphino-2', 6'- diisopropoxy- 1,1'- biphenyl)[2-(2'-amino-l,l'-biphenyl)]palladium(II) (12 mg, 0.016 mmol) at 20 °C under N2 atmosphere. The mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column (DCM/MeOH = 0%~20%) to afford tert-butyl (2S,6R)-4- (3,11 -bis(4-fluorophenyl)-6-oxo- 10-(trifluoromethyl)-3,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpipera zine-1-carboxylate 9 (40 mg, yield: 73%) as a yellow solid.
[0326] 8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3,11-bis(4-fluorophen yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-6-one (10) [0327] To a solution of tert-butyl (2S,6R)-4-(3,11-bis(4-fluorophenyl)-6-oxo-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate 9 (40 mg, 0.058 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (5 mL) at 0 °C. The reaction solution was stirred at room temperature for 1 h. After completion, the mixture was concentrated and the residue was purified by silica gel column (dichloromethane/methanol = 0%~20%) to afford the product 10 (20 mg, yield: 59%) as a yellow solid.
[0328] 8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3,11-bis(4 -fluorophenyl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-6-one (11)
[0329] To a mixture of 8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-3,l 1 -bis(4- fluorophenyl)- 10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]qu inazolin-6(2H)- one 10 (20 mg, 0.034 mmol) and triethyl amine (10 mg, 0.102 mmol) in dichloromethane (5 ml) was added acrylic anhydride (9 mg, 0.068 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. After completion, the mixture was concentrated and the residue was purified by Prep-HPLC to afford 8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-3,11- bis(4-fluorophenyl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]th iazepino[2,3,4-ij]quinazolin- 6(2H)-one 11 (7 mg, yield: 32%) as a white solid. ! H NMR (400 MHz, CDCl 3 ) δ 8.11 (s, 1H), 7.35-7.29 (m, 3H), 7.25-7.16 (m, 3H), 7.04-6.99 (m, 2H), 6.67-6.60 (m, 1H), 6.42 (dd, J= 16.8 Hz, 2.0 Hz, 1H), 5.78 (dd, J = 10.8 Hz, 2.4 Hz, 1H), 4.78-4.63 (m, 4H), 4.21- 4.15 (m, 2H), 3.75-3.63 (m, 2H), 3.42-3.33 (m, 2H), 3.06-3.03 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H), 1.51 (d, J= 6.8 Hz, 3H).
[0330] Example 122: (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3-(thiophen-3-yl)-10-(trifluoromethyl)-3,4-dih vdro-[1,4]thiazepinor2,3,4- ii1quinazolin-6(2H)-one (Pl) and Example 123: (S)-8-((3S,5R)-4-acryloyl-3,5- dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-3-yl )-10-(trifluoromethyl)-3,4- dihydro-[1,4]thiazepino[2,3,4-ii]quinazolin-6(2H)-one (P2)
[0331] 3-(thiophen-3-yl)oxetane (2)
[0332] To a mixture of thiophen-3-ylboronic acid (20 g, 101 mmol), Nickel(II) bromide ethylene glycol dimethyl ether complex (3.12 g, 10.1 mol), (1S,2S)-N 1 ,N 2 - dimethylcyclohexane- 1 ,2-diamine (2.15 g, 15.15 mmol) and Potassium tert-butoxide (22.62 g, 202 mmol) in 1,4-dioxane (350 mL) was added 3-iodooxetane (27.88 g, 151.5 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred at 60 °C for 18 hours. After completion, the mixture was poured into ice-water (300 mL) and extracted with ethyl acetate (150 mL x 3). After concentration, the residue was purified by silica gel column with petroleum ether/ ethyl acetate = 20/1 to afford to afford 3-(thiophen-3- yl)oxetane (2) (1.38 g, 10% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.35- 7.33 (m, 1H), 7.20-7.18 (m, 1H), 7.12-7.11 (m,lH), 5.04-5.00 (m, 2H), 4.77-4.74 (m, 2H), 4.35-4.27 (m, 1H).
[0333] 3-bromo-2-(thiophen-3-yl)propan-1-ol (3)
[0334] To a solution of 3-(thiophen-3-yl)oxetane (2) (1.38 g, 9.86 mmol) in dichloromethane (30 mL) was added Boron tribromide (10 mL, 9.86 mmol, IM in dichloromethane) at -78 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 1 hour. After completion, the mixture was poured into ice-water (50 mL) and extracted with ethyl acetate (50 mL x 3), the mixture was concentrated to afford the product 3- bromo-2-(thiophen-3-yl)propan-1-ol (3) (2.1 g, crude) as colorless oil. ' l l NMR (400 MHz, CDCl 3 ) δ 7.26-7.24 (m, 1H), 7.07 (d, J= 2.0 Hz, 1H), 6.94 (d, J= 4.8 Hz, 1H), 3.88-3.81 (m, 2H), 3.68-3.55 (m, 2H), 3.27-3.21 (m, 1H).
[0335] 3-mercapto-2-(thiophen-3-yl)propan-1-ol (4)
[0336] To a solution of 3-bromo-2-(thiophen-3-yl)propan-1-ol (3) (2.1 g 9.54 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydrogensulfide (1.6 g, 28.62 mmol). The mixture was stirred at room temperature for 2 hours. After completion, the mixture was poured into ice-water (50 mL) and extracted with ethyl acetate (50 mL x 3). After concentration, the residue was purified by silica gel column with dichloromethane/methanol 30/1 to afford to afford 3-mercapto-2-(thiophen-3-yl)propan- l-ol (4) (1.42 g, 85% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.35-7.33 (m, 1H), 7.11 (d, J= 2.0 Hz, 1H), 7.00 (d, J= 5.2 Hz, 1H), 3.87 (d, J= 6.0 Hz, 2H), 3.16-3.12 (m, 1H), 2.91- 2.83 (m, 2H).
[0337] 7-chloro-8-((3-hydroxy-2-(thiophen-3-yl)propyl)thio)-6- (trifluoromethyl)quinazoline-2,4-diol (5)
[0338] To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-diol (2.12 g, 5.44 mmol) in 1,4-dioxane (70 mL), potassium carbonate (1.5 g, 10.88 mmol), 3- mercapto-2-(thiophen-3-yl)propan-1-ol (4) (1.42 g, 8.16 mmol), 4,5-Bis(diphenyl- phosphino)-9,9-dimethylxanthene (472 mg, 0.816 mmol) and Tris(dibenzylideneacetone) dipalladium (498 mg, 0.544 mmol) were added. The mixture was stirred at 60 °C under nitrogen atmosphere for 18 hours. After completion, the mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate = 4/1) to afford 7-chloro-8-((3-hydroxy-2-(thiophen-3- yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (5) (1.0 g, 42% yield) as pale yellow solid. MS (ESI) m/z 435.1 [M-H] + .
[0339] 11-chloro-8-hydroxy-3-(thiophen-3-yl)-10-(trifluoromethyl)-3 ,4-dihydro- [1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (6)
[0340] To a mixture of 7-chloro-8-((3-hydroxy-2-(thiophen-3-yl)propyl)thio)-6- (trifluoromethyl)quinazoline-2,4-diol (5) (1.0 g, 2.29 mmol) and triphenylphosphine (1.2 g, 4.58 mmol) in tetrahydrofuran (40 mL) was added diethyl azodicarboxylate (797 mg, 4.58 mmol) at 0 °C. The mixture was stirred at 0 °C for 45 min. After completion, the mixture was poured into ice-water (50 mL) and extracted with ethyl acetate (50 mL x 3). Concentrated and the residue was purified by C18 with 30-95% acetonitrile in water to afford 11 -chloro-8-hydroxy-3-(thiophen-3-yl)- 10-(trifluoromethyl)-3,4-dihydro- [1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (6) (610 mg, 64% yield) as a yellow solid. MS (ESI) m/z 417.1 [M-H] + .
[0341] (2S,6R)-tert-butyl 4-(11-chloro-6-oxo-3-(thiophen-3-yl)-10-(trifluoromethyl)- 2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl) -2,6-dimethylpiperazine-1- carboxylate (7)
[0342] To a mixture of 1 l-chloro-8-hydroxy-3-(thiophen-3-yl)-10-(trifluoromethyl)-3, 4- dihydro-[1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (6) (610 mg, 1.46 mmol) and potassium carbonate (2.01 g, 14.6 mmol) in acetonitrile (50 mL) was added 2,4,6- Tris(prop-2-yl)benzenesulphonyl chloride (675 mg, 2.19 mmol). The mixture was stirred at 35 °C for 4 hours. After completion, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1- carboxylate (625 mg, 2.92 mmol) was added into the reaction solution. The reaction mixture was stirred at 35 °C for 1 hour. After completion, the mixture was poured into icewater (50 mL) and extracted with ethyl acetate (50 mL x 3). Concentrated and the residue was purified by C18 column with 20-95% acetonitrile in water to afford (2S,6R)-tert-butyl 4-(11-chloro-6-oxo-3-(thiophen-3-yl)-10-(trifluoromethyl)-2, 3,4,6-tetrahydro- [1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpipera zine-1-carboxylate (7) (630 mg, 70% yield) as a pale yellow solid. MS (ESI) m/z 615.2[M+H] + .
[0343] (2S,6R)-tert-butyl 4-(11-(4-fluorophenyl)-6-oxo-3-(thiophen-3-yl)-10- (trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-i j]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate (8)
[0344] To a solution of (2S,6R)-tert-butyl 4-(11-chloro-6-oxo-3-(thiophen-3-yl)-10- (trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-i j]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate (7) (180 mg, 0.29 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL), tripotassium phosphate (120 mg, 0.87 mmol), (4-fluorophenyl)boronic acid (162 mg, 1.16 mmol), and chloro(2-dicyclohexylphosphino-2', 6'- diisopropoxy- 1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (23 mg, 0.03 mmol) were added. The mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. After completion, the mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol = 50/1) to afford (2S,6R)-tert-butyl 4-(11-(4-fluorophenyl)-6-oxo-3-(thiophen-3-yl)-10-(trifluoro methyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[2,3,4-ij]quinazol in-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8) (210 mg, crude) as a yellow solid. MS (ESI) m/z 675.1 [M+H] + .
[0345] 8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3 -(thiophen-3- yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-i j]quinazolin-6(2H)-one (9) [0346] To a mixture of (2S,6R)-tert-butyl 4-(11-(4-fluorophenyl)-6-oxo-3-(thiophen-3- yl)-10-(trifluoromethyl)-2,3,4,6-tetrahydro-[1,4]thiazepino[ 2,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate (8) (210 mg, crude) in di chloromethane (2 mL) was added trifluoroacetic acid (2 mL) at 0 °C. The reaction solution was stirred at room temperature for 1 hour. After completion, the mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 15/1) to afford 8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3 -(thiophen-3-yl)- 10- (trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]quina zolin-6(2H)-one (9) (160 mg, crude) as a pale yellow solid. MS (ESI) m/z 575.1[M+H] + . [0347] 8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluo rophenyl)-3- (thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiaze pino[2,3,4-ij]quinazolin- 6(2H)-one (10)
[0348] To a mixture of 8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3 - (thiophen-3-yl)- 10-(trifluoromethyl)-3,4-dihydro-[1,4]thiazepino[2,3,4-ij]qu inazolin- 6(2H)-one (9) (160 mg, 0.28 mmol) and triethyl amine (57 mg, 0.56 mmol) in dichloromethane (4 ml) was added acrylic anhydride (53 mg, 0.42 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. After completion, the mixture was poured into icewater (10 mL) and extracted with dichloromethane (10 mL x 3). Concentrated and the residue was purified by preparative High Performance Liquid Chromatography (20 % to 95 % acetonitrile in water) to afford 8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)- 1 l-(4-fluorophenyl)-3-(thiophen-3-yl)-10-(trifluoromethyl)-3, 4-dihydro- [1,4]thiazepino[2,3,4-ij]quinazolin-6(2H)-one (10) (70 mg, 40% yield) as a white solid. MS (ESI) m/z 629.2 [M+H] + .
[0349] The above racemate (70 mg) was dissolved in ethanol (5 mL) and separated by chiral supercritical fluid chromatography (separation condition: Column: IF 5 pm 20 x 250 mm; Mobile Phase: MeOH/DCM = 90/10 at 25 mL/min; Temp: 30 °C; Wavelength: 254 nm) to afford the title compounds Pl (20 mg, yield: 29 %, 100% ee) and P2 (22 mg, yield: 31%, 99.6% ee); Chiral HPLC Analytical: on IF was using 5 pm 4.6 x 250 mm column, Mobile Phase: MeOH/DCM = 90/10 at 1 mL/min; temperature: 30 °C; Wavelength: 254 nm).
[0350] (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3- (thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiaze pino[2,3,4-ij]quinazolin- 6(2H)-one (Pl)
[0351] 1 HNMR (400 MHz, CDCl 3 ) δ 8.10 (s, 1H), 7.31-7.29 (m, 1H), 7.24 (s, 1H), 7.20-7.15 (m, 4H), 7.10 (d, J= 4.8 Hz, 1H), 6.63 (dd, J = 16.4 Hz, 10.8 Hz, 1H), 6.42 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.78 (dd, J= 10.4 Hz, 1.6 Hz, 1H), 4.87-4.60 (m, 4H), 4.17 (t, J = 12.0 Hz, 2H), 3.89-3.85 (m, 1H), 3.62 (d, J= 10.4 Hz, 1H), 3.41-3.32 (m, 2H), 3.07 (d, J = 14.8 Hz, 1H), 1.60 (d, J= 7.2 Hz, 3H), 1.51 (d, J= 6.8 Hz, 3H); Chiral HPLC fraction 1: e.e. = 100%, Rt = 7.610 min.
[0352] (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3- (thiophen-3-yl)-10-(trifluoromethyl)-3,4-dihydro-[1,4]thiaze pino[2,3,4-ij]quinazolin- 6(2H)-one (P2) [0353] !H NMR (400 MHz, CDCl 3 ) δ 8.10 (s, 1H), 7.31-7.29 (m, 1H), 7.24 (s, 1H), 7.20-7.15 (m, 4H), 7.10 (d, J= 4.0 Hz, 1H), 6.63 (dd, J = 16.0 Hz, 10.0 Hz, 1H), 6.42 (dd, .7= 16.4 Hz, 1.6 Hz, 1H), 5.78 (dd, J= 10.4 Hz, 1.6 Hz, 1H), 4.85-4.60 (m, 4H), 4.18 (t, J = 11.6 Hz, 2H), 3.88-3.84 (m, 1H), 3.62 (d, J= 8.8 Hz, 1H), 3.41-3.32 (m, 2H), 3.07 (d, J = 16.4 Hz, 1H), 1.60 (d, J= 7.2 Hz, 3H), 1.51 (d, J= 6.8 Hz, 3H); Chiral HPLC fraction 1: e.e. = 99.6%, Rt = 9.489 min.
[0354] Example 124: (R')-8-((3S.5R')-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-( 4- fluorophenyl)-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dih ydro-2H,6H- [1,4]thiazepino[2,3,4-ii]quinazolin-6-one (Pl)
[0355] Example 125: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl-11-(4- fluorophenyl)-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dih ydro-2H,6H- [1,4]thiazepino[2,3,4-ii]quinazolin-6-one (P2)
[0356] 3-(thiophen-2-yl)oxetan-3-ol (2)
[0357] To a solution of 2-bromothiophene (10 g, 61.35 mmol) in tetrahydrofuran (205 mL) was added isopropyl magnesium chloride lithium chloride solution (49.6 mL, 64.42 mmol, 1.3M tetrahydrofuran) at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 1 hour. Then oxetan-3-one (5.3 g, 73.62 mmol) was added slowly. The mixture was slowly warmed up to room temperature and stirred for 2 hours. Saturated ammonium chloride aqueous solution (200 mL) was added slowly and extracted with ethyl acetate (300 mL x 3). After concentration, the residue was purified by silica gel column (with petroleum ether/ethyl acetate = 3/1) to afford 3-(thiophen-2-yl)oxetan-3-ol (2) (6.9 g, 72% yield) as a pale yellow oil. NMR (400 MHz, CDCl 3 ) δ 7.31-7.30 (m, 1H), 7.19- 7.18 (m, 1H), 7.05-7.04 (m, 1H), 4.93-2.89 (m, 4H).
[0358] 3-(thiophen-2-yl)oxetane (3)
[0359] To a mixture of 3-(thiophen-2-yl)oxetan-3-ol (2) (6.9 g, 44.17 mmol) and trifluoroacetic acid (15.4 mL, 200.85 mmol) in dichloromethane (75 mL) was added triethylsilane (32.1 mL, 200.85 mmol) at 0 °C. The mixture was stirred at 30 °C for 3 hours. After completion, the mixture was poured into ice -water (150 mL) and extracted with dichloromethane (150 mL x 3). After concentration, the residue was purified by silica gel column (with petroleum ether/ethyl acetate = 10/1) to afford 3-(thiophen-2-yl)oxetane (3) (5.8 g, 94% yield) as a colorless oil. ! H NMR (400 MHz, CDCl 3 ) δ 7.23-7.21 (m, 1H), 7.00-6.96 (m, 2H), 5.06-5.02 (m, 2H), 4.82-2.79 (m, 2H), 4.56-4.48 (m, 1H).
[0360] 3-bromo-2-(thiophen-2-yl)propan-1-ol (4)
[0361] To a solution of 3-(thiophen-2-yl)oxetane (3) (5.8 g, 41.37 mmol) in dichloromethane (140 mL) was added slowly boron tribromide (41.4 mL, 41.4 mmol, 1.0 M in dichloromethane) at -78°C under nitrogen atmosphere. The mixture was stirred at - 78°C for 2 hours. After completion, the mixture was poured into ice-water (150 mL) and extracted with dichloromethane (150 mL x 3). After concentration, the residue was purified by silica gel column (with petroleum ether/ethyl acetate = 2/1) to afford 3-bromo- 2-(thiophen-2-yl)propan-1-ol (4) (5.3 g, 58% yield). ' l l NMR (400 MHz, CDCl 3 ) δ 7.25- 7.23 (m, 1H), 7.01-6.99 (m, 1H), 6.97-6.96 (m, 1H), 3.97-3.96 (m, 2H), 3.74-3.64 (m, 2H), 3.51-3.48 (m, 1H).
[0362] 3-mercapto-2-(thiophen-2-yl)propan-1-ol (5)
[0363] To a solution of 3-bromo-2-(thiophen-2-yl)propan-1-ol (4) (5.3 g, 23.97 mmol) in N,N- dimethylformamide (48 mL), sodium bisulfide (5.76 g, 71.91 mmol, 70%) was added at 0 °C. The mixture was stirred at 30 °C under nitrogen atmosphere for 4 hours. After completion, the mixture was poured into ice-water (200 mL) and extracted with ethyl acetate (200 mL x 3). After concentration, the residue was purified by silica gel column (with petroleum ether/ethyl acetate = 2/1) to afford 3-mercapto-2-(thiophen-2- yl)propan-1-ol (5) (2.5 g, 60% yield) as pale yellow oil. ' l l NMR (400 MHz, CDCl 3 ) δ 7.23-7.22 (m, 1H), 7.00-6.98 (m, 1H), 6.93-6.92 (m, 1H), 3.89-3.87 (m, 2H), 3.32-3.26 (m, 1H), 2.95-2.82 (m, 2H), 1.44-1.40 (m, 1H).
[0364] 7-chloro-8-((3-hydroxy-2-(thiophen-3-yl)propyl)thio)-6- (trifluoromethyl)quinazoline-2,4-diol (6)
[0365] To a solution of 7-chloro-8-iodo-6-(trifluoromethyl)quinazoline-2,4-diol (2.24 g, 5.74 mmol) in 1,4-dioxane (60 mL), potassium carbonate (2.38 g, 17.22 mmol), 3- mercapto-2-(thiophen-2-yl)propan-1-ol (5) (2.5 g, 14.34 mmol), 4,5-Bis(diphenyl- phosphino)-9,9-dimethylxanthene (498 mg, 0.86 mmol) and Tris(dibenzylideneacetone) dipalladium (522 mg, 0.57 mmol) were added. The mixture was stirred at 60 °C under nitrogen atmosphere for 18 hours. After completion, the mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane/methanol = 30/1) to afford 7-chloro-8-((3-hydroxy-2-(thiophen-3- yl)propyl)thio)-6-(trifluoromethyl)quinazoline-2,4-diol (6) (2.2 g, crude) as pale yellow solid. MS (ESI) m/z 435.0 [M-H]-.
[0366] 11-chloro-8-hydroxy-3-(thiophen-2-yl)-10-(trifluoromethyl)-3 ,4-dihydro- 2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (7)
[0367] To a mixture of 7-chloro-8-((3-hydroxy-2-(thiophen-3-yl)propyl)thio)-6- (trifluoromethyl)quinazoline-2,4-diol (6) (2.2 g, 5.04 mmol) and triphenylphosphine (2.64 g, 10.08 mmol) in tetrahydrofuran (100 mL) was added diethyl azodicarboxylate (1.76 g, 10.08 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. After completion, the mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was concentrated and the residue was purified by C18 with 30-95 % acetonitrile in water to afford 11 -chloro- 8-hydroxy-3-(thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro -2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-6-one (7) (665 mg, 28% yield for two steps) as a yellow solid. MS (ESI): m/z 419.2 [M+H] + .
[0368] tert-butyl (2S,6R)-4-(11-chloro-6-oxo-3-(thiophen-2-yl)-10-(trifluorome thyl)- 3,4-dihydro-2H,6H- [1,4 ] thiazepino [2,3,4-ij ] quinazolin-8-yl)-2,6-dimethylpiperazine- 1-carboxylate (8)
[0369] To a mixture of 11-chloro-8-hydroxy-3-(thiophen-2-yl)-10-(trifluoromethyl)-3 ,4- dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (7) (665 mg, 1.59 mmol) and potassium carbonate (1.10 g, 7.95 mmol) in acetonitrile (60 mL) was added 4- methylbenzenesulfonic anhydride (1.30 g, 3.98 mmol). The mixture was stirred at 35 °C for 8 hours. After completion, (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (1.02 g, 4.77 mmol) was added into the reaction solution. The reaction mixture was stirred at 35 °C overnight. After completion, the mixture was poured into ice-water (200 mL) and extracted with ethyl acetate (100 mL x 3). Concentrated and the residue was purified by C18 column with 20-95% acetonitrile in water to afford tert-butyl (2S,6R)-4-(11-chloro-6- oxo-3-(thiophen-2-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 - ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (8) (720 mg, 74% yield) as a pale yellow solid. MS (ESI) m/z 615.2 [M+H] + .
[0370] tert-butyl (2S,6R)-4-(11-(4-fluorophenyl)-6-oxo-3-(thiophen-2-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate (9) [0371] To a mixture of (2S,6R)-4-(11-chloro-6-oxo-3-(thiophen-2-yl)-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate (8) (150 mg, 0.24 mmol) in 1,4-dioxane and water was added [2'-(Amino)[ 1 , 1 ’-biphenyl] -2-yl] [[2', 6'-bis( 1 -methylethoxy) [ 1 , 1 '-biphenyl]-2- yl]dicyclohexylphosphine]chloropalladium (38 mg, 0.048 mmol), potassium phosphate trihydrate (320 mg, 1.2 mmol) and (4-fluorophenyl)boronic acid (101 mg, 0.72 mmol) at 25 °C. The mixture was stirred at 80 °C for 2 hours. After completion, the mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 50/1) to afford tert-butyl (2S,6R)-4-(11-(4-fluorophenyl)-6- oxo-3-(thiophen-2-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 - ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate (9) (220 mg, crude) as a yellow solid. (ESI) m/z 675.2 [M+H] + .
[0372] 8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3 -(thiophen-2- yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2 ,3,4-ij]quinazolin-6-one (10)
[0373] To a mixture of tert-butyl (2S,6R)-4-(11-(4-fluorophenyl)-6-oxo-3-(thiophen-2- yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2 ,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate (9) (220 mg, crude) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) at 25 °C. The mixture was stirred at 25 °C for 1 hour. After completion, the mixture was concentrated and adjusted PH to 8 with ammonia in methanol at 0 °C. The mixture was concentrated and purified by silica gel column chromatography (dichloromethane/ methanol = 20/1) to afford 8-((3S,5R)-3,5- dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3-(thiophen-2-yl )- 10-(trifluoromethyl)-3,4- dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (10) (130 mg, crude) as yellow solid. MS (ESI) m/z 575.2 [M+H] + .
[0374] 8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4-fluo rophenyl)-3- (thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4] thiazepino[2,3,4- ij]quinazolin-6-one (11)
[0375] To a mixture of 8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3 - (thiophen-2-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 - ij]quinazolin-6-one (10) (130 mg, 0.23 mmol) in dichloromethane (6 mL) was added triethylamine (46 mg, 0.46 mmol) and acrylic anhydride (44 mg, 0.35 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour. After completion, the mixture was added methanol at 25 °C and concentrated. The mixture was purified by preparative high performance liquid chromatography (20% to 95% acetonitrile in water) to afford 8-((3S,5R)-4-acryloyl- 3,5 -dimethylpiperazin-1-yl)-11-(4-fluorophenyl)-3 -(thiophen-2-yl)- 10-(trifluoromethyl)- 3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-6-one (11) (50 mg, 33% yield for three steps) as a pale yellow powder. MS (ESI) m/z 629.0 [M+H] + .
[0376] The above racemate (50 mg) was dissolved in ethanol (5 mL) and separated by chiral supercritical fluid chromatography (separation condition: Column: IC 5 pm 20 x 250 mm; Mobile Phase: MeOH/DCM = 90/10 at 20 mL/min; Temp: 30 °C; Wavelength: 254 nm) to afford the title compounds CA-5578-F1 (18 mg, yield: 36%, 100% ee) and CA-5578-F2 (16 mg, yield: 32%, 99.8% ee); Chiral HPLC Analytical: on IC was using 5 pm 4.6 x 250 mm column, Mobile Phase: MeOH/DCM = 90/10 at 1 mL/min; temperature: 30 °C; Wavelength: 254 nm).
[0377] (R)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3- (thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4] thiazepino[2,3,4- ij]quinazolin-6-one (Pl)
[0378] 'HNMR (400 MHz, CDCl 3 ) δ 8.09 (s, 1H), 7.28-7.27 (m, 1H), 7.21-7.15 (m, 4H), 7.00-6.99 (m, 1H), 6.97-6.95 (m, 1H), 6.63 (dd, J= 16.4 Hz, 10.4 Hz, 1H), 6.41 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.78 (dd, J= 10.4 Hz, 2.0 Hz, 1H), 4.87-4.84 (m, 1H), 4.76-4.53 (m, 3H), 4.21-4.15 (m, 2H), 4.11-4.03 (m, 1H), 3.71-3.61 (m, 1H), 3.41-3.32 (m, 2H), 3.13-3.02 (m, 1H), 1.60 (d, J= 7.2 Hz, 3H), 1.52 (d, J= 6.8 Hz, 3H); Chiral HPLC fraction 1: e.e. = 100%, Rt = 10.566 min.
[0379] (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3- (thiophen-2-yl)-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4] thiazepino[2,3,4- ij]quinazolin-6-one (P2)
[0380] ‘HNMR (400 MHz, CDCl 3 ) δ 8.09 (s, 1H), 7.31-7.29 (m, 1H), 7.20-7.17 (m, 4H), 7.00-6.99 (m, 1H), 6.97-6.95 (m, 1H), 6.63 (dd, J= 16.8 Hz, 10.4 Hz, 1H), 6.41 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 5.78 (dd, J= 10.4 Hz, 1.6 Hz, 1H), 4.94-4.83 (m, 1H), 4.78-4.54 (m, 3H), 4.21-4.15 (m, 2H), 4.11-4.02 (m, 1H), 3.72-3.60 (m, 1H), 3.41-3.33 (m, 2H), 3.10-3.03 (m, 1H), 1.60-1.57 (m, 3H), 1.52 (d, J= 6.8 Hz, 3H); Chiral HPLC fraction 2: e.e. = 99.8%, Rt = 12.223 min.
[0381 ] Example 126: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)- 3,4-dihvdro-2H,6H- [1,4]thiazepino[2,3,4-ii]quinazolin-6-one
[0382] Step 1: tert-butyl (2S,6R)-4-((R)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate and tert-butyl (2S,6R)-4-((S)-11-chloro-3-(5- fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3,4-dihydro-2 H,6H-[1,4]thiazepino[2,3,4- ij]quinazolin-8-yl)-2,6-dimethylpiperazine-1-carboxylate
[0383] The title compounds were prepared analogously to Example 104, where pyridin- 3-ylboronic acid was replaced with (5-fluoropyridin-3-yl)boronic acid in step 1. The title compounds were isolated as a 1:1 mixture of diastereomers. tert-Butyl (2S,6R)-4-((R)-11- chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluoromethyl)-3 ,4-dihydro-2H,6H- [1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpipera zine-1-carboxylate and tertbutyl (2S,6R)-4-((S)-11-chloro-3-(5-fluoropyridin-3-yl)-6-oxo-10-( trifluoromethyl)-3,4- dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1- carboxylate were obtained as single diastereomers by purification of the mixture by SFC (column= Daicel Chiralpak IC 250mmx30mm, lOum; phase A: ethanol, phase B: CO2; gradient: 65% A in B for 7.45 minutes runtime) and characterized by SFC (Column: Chiralpak IC-3, 50x4.6 mm, I.D.= 3 um, stabilized at 35 °C with a back pressure of 100 bar. Mobile phase: 60% ethanol containing 0.05% diethylamine in CO2, flow rate- 3 mL/min. Detector: Photodiode-array). Int-a: SFC Rt= 1.58 min; MS (ESI) m/z: 628.2 [M+H]+. Int-b: SFC Rt= 2.87 min; MS (ESI) m/z: 628.2 [M+H]+. [0384] Step 2: tert-butyl (2S,6R)-4-((S)-11-(4-fluorophenyl)-3-(5-fluoropyridin-3-yl)- 6- oxo-10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2 ,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate
[0385] The title compound was prepared analogously to Example 100, step 9, where tert-butyl (2S,6R)-4-((S)-11-chloro-6-oxo-3-(pyridin-4-yl)-10-(trifluor omethyl)-3,4- dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6- dimethylpiperazine-1- carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-chloro-3-(5-fluoropyridin-3- yl)-6-oxo- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-8- yl)-2,6-dimethylpiperazine-1-carboxylate. The title compound was isolated in 36% yield as a yellow solid. MS (ESI) m/z: 688.2 [M+H]+.
[0386] Step 3: (S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluoropheny l)-3-(5- fluoropyridin-3-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -
[0387] The title compound was prepared analogously to Example 100, step 10, where tert-butyl (2S,6R)-4-((3 S)-11-(5-chloro-2,4-difluorophenyl)-6-oxo-3-(pyridin-4-yl)- 10- (trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4-ij ]quinazolin-8-yl)-2,6- dimethylpiperazine-1-carboxylate was replaced with tert-butyl (2S,6R)-4-((S)-11-(4- fluorophenyl)-3-(5-fluoropyridin-3-yl)-6-oxo-10-(trifluorome thyl)-3,4-dihydro-2H,6H- [1.4]thiazepino[2,3,4-ij]quinazolin-8-yl)-2,6-dimethylpipera zine-1-carboxylate. The title compound was isolated in 99% yield as a yellow solid. MS (ESI) m/z: 588.2 [M+H]+.
[0388] Step 4: (S)-8-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-11-(4- fluorophenyl)-3-(5-fluoropyridin-3-yl)-10-(trifluoromethyl)- 3,4-dihydro-2H,6H-
[1.4]thiazepino[2,3,4-ij]quinazolin-6-one
[0389] The title compound was prepared analogously to Example 100, step 11 , where (3S)-11-(5-chloro-2,4-difluorophenyl)-8-((3S,5R)-3,5-dimethy lpiperazin-1-yl)-3-(pyridin- 4-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 -ij]quinazolin-6-one was replaced with (S)-8-((3S,5R)-3,5-dimethylpiperazin-1-yl)-11-(4-fluoropheny l)-3-(5- fluoropyridin-3-yl)- 10-(trifluoromethyl)-3,4-dihydro-2H,6H-[1,4]thiazepino[2,3,4 - ij]quinazolin-6-one. The title compound was isolated in 84% yield as a yellow solid. MS (ESI) m/z: 642.2 [M+l]+.
[0390] 1H-NMR (400 MHz, CDC13)= 8.47 (s, 1H), 8.42 (s, 1H), 8.13 (S, 1H), 7.46 (m, 1H), 7.25-7.19 (m, 4 H), 6.61 (dd, J= 16 Hz, J= 6 Hz, 1H), 6.44 (d, J= 16 Hz, 1H), 5.80 (d, J= 6 Hz, 1H), 4.80 (m, 4H), 4.21 (m, 2H), 3.75 (m, 2H), 3.40 (m, 2H), 3.06 (m, 1H), 1.57 (m, 6H).
[0391] It will be appreciated by those skilled in the art that the compounds above possess chiral centers as well potential axial asymmetry, i.e., atropisomers. Each of the compounds may be provided as a mixture of diastereomers or in any diasteromerically pure form.
[0392] Additional embodiments are provided herein as follows:
[0393] Inhibition of KRAS G12C-mediates phospho-ERKl/2 inhibition by Compounds of Formula I
[0394] This Example illustrates that various compounds of the present disclosure inhibit KRAS G12C thereby mediating the downstream inhibition of phospho-ERKl/2.
[0395] KRAS G12C mutant cell lines, NCI H358 (ATCC, CRL-5807), and Ras Initiative (RI) KRAS G12C were cultured according to published protocols and maintained at 37 °C in 5% CO2. The phospho-ERK HTRF assay was executed following provider’s protocol (CisBio #64AERPEH). NCI-H358 or RI KRAS G12C cells were plated at a density of 50,000 cells per well in a 96-well plate (Coming #3903) in respective medias (for NCI-H358, RPMI + 10% FBS + 1% Pen/Strep, and for RI KRAS G12C, DMEM + 10% FBS + 1% Pen/Strep + 4ug/ml Blasticidin) and maintained at 37 °C in 5% CO2. Cells were allowed to adhere overnight and treated the following day with a Tecan D300e Digital Dispenser (Tecan Group Ltd., Switzerland) using an 11 -point dose response starting at 2,500 nM of exemplified compounds followed by sequential 1 :3 dilutions for either 4 hours or 16 hours. Following compound treatment, the cells were washed once with ice-cold PBS. Cells were lysed by adding 50 pl of lysis buffer (lx) supplemented with lx Pierce Halt Protease and Phosphatase inhibitor and incubated for 30 minutes at 4 °C with shaking. After lysis, 16 pL of cell lysate from the 96-well cell-culture plate was transferred to a 384-well plate (Perkin Elmer #6007290). The premixed antibody solution was prepared by mixing (vol/vol) advanced phospho-ERKl/2 d2 antibody and advanced phospho-ERKl/2 Eu Cryptate antibody. The premixed antibody solution (4 pL) was added to the detection plate containing cell lysate. The detection plate was incubated overnight at 4 °C, the HTRF signal was read the next day by using either a Spectramax M5 or Spectramax i3 microplate reader (Molecular Devices, San Jose, CA, USA), and data was processed according to manufacturer’s protocol.
[0396] Compounds prepared according to the preceding procedures and characterized for inhibition of p-ERK according to the protocol provided herein are summarized in Table 3:
Table 3
0.5-2.0 nM = ++++; 2.0 nM-20 nM = +++; 20 nM-250 nM = ++; >250 nM = +
[0397] Although the foregoing embodiments have been described in some detail by way of illustration and Example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.