NZ728127B2 - Antiproliferative compounds and methods of use thereof - Google Patents

Antiproliferative compounds and methods of use thereof Download PDF

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Publication number
NZ728127B2
NZ728127B2 NZ728127A NZ72812715A NZ728127B2 NZ 728127 B2 NZ728127 B2 NZ 728127B2 NZ 728127 A NZ728127 A NZ 728127A NZ 72812715 A NZ72812715 A NZ 72812715A NZ 728127 B2 NZ728127 B2 NZ 728127B2
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alkyl
halo
optionally substituted
compound
independently
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NZ728127A
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NZ728127A (en
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Brian E Cathers
Matthew Daniel Correa
Joshua Hansen
Ehab M Khalil
Girona Antonia Lopez
Kyle Macbeth
Hon Wah Man
George W Muller
Michael Pourdehnad
Raj Raheja
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Celgene Corporation
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Priority to NZ765933A priority Critical patent/NZ765933B2/en
Priority claimed from PCT/US2015/039926 external-priority patent/WO2016007848A1/en
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Publication of NZ728127B2 publication Critical patent/NZ728127B2/en

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A—HUMAN NECESSITIES
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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Abstract

Compounds of formula (I) for treating, preventing or managing cancer are disclosed. Also disclosed are methods of treating, preventing or managing cancer, such as leukemia, comprising administering the compounds. In certain embodiments, the method of treatment comprise administering a compound provided herein in combination with a second agent. Pharmaceutical compositions and single unit dosage forms comprising the compounds are also disclosed. In Formula (I) R1 is optionally substituted cycloalkyi, aryl, heteroaryl or heterocyclyl; and R2 and R3 are each halo. ded herein in combination with a second agent. Pharmaceutical compositions and single unit dosage forms comprising the compounds are also disclosed. In Formula (I) R1 is optionally substituted cycloalkyi, aryl, heteroaryl or heterocyclyl; and R2 and R3 are each halo.

Description

(12) Granted patent specificaon (19) NZ (11) 728127 (13) B2 (47) aon date: 2021.12.24 (54) ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF (51) Internaonal Patent Classificaon(s): C07D 401/14 C07D 401/04 A61K 31/454 A61P 35/00 (22) Filing date: (73) Owner(s): 2015.07.10 CELGENE CORPORATION (23) Complete specificaon filing date: (74) Contact: 7.10 HENRY HUGHES IP LIMITED (30) Internaonal Priority Data: (72) Inventor(s): US 62/023,775 2014.07.11 MULLER, George W.
MAN, Hon-wah (86) Internaonal aon No.: LOPEZ-GIRONA, Antonia H, Kyle HANSEN, Joshua (87) Internaonal Publicaon number: CORREA, Matthew, Daniel WO/2016/007848 RAHEJA, Raj KHALIL, Ehab, M.
CATHERS, Brian E.
POURDEHNAD, Michael (57) Abstract: Compounds of a (I) for g, prevenng or managing cancer are disclosed. Also disclosed are methods of treang, prevenng or managing cancer, such as leukemia, comprising administering the compounds. In certain embodiments, the method of treatment comprise stering a compound provided herein in combinaon with a second agent. Pharmaceucal composions and single unit dosage forms comprising the compounds are also disclosed. In Formula (I) R1 is oponally substuted cycloalkyi, aryl, heteroaryl or heterocyclyl; and R2 and R3 are each halo. 728127 B2 PCT/U82015/039926 ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF 1. CROSS REFERENCE TO D APPLICATIONS This application claims the benefit of the priority of US. Provisional Application No. 62/023,775, filed July 1 l, 2014, the disclosure of which is incorporated herein by reference in its entirety. 2. FIELD Provided herein are compounds for treating, preventing or ng cancer. Also ed are pharmaceutical compositions comprising the compounds and methods of use of the compounds and compositions. In certain embodiments, the s encompass treating, ting or managing cancer, ing solid tumors and blood borne tumors using the compounds provided herein. 3. BACKGROUND Pathobiology Of Cancer Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of nt tissues by these abnormal cells, or lymphatic or blood-bome spread of malignant cells to regional lymph nodes and to distant sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under n conditions progress to sia. The stic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host’s immune surveillance. Roitt, I., Brostoff, J and Kale, D., Innnunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).
There is an enormous variety of cancers which are described in detail in the medical literature. Examples include cancer of the lung, colon, rectum, prostate, breast, brain, and intestine. The incidence of cancer ues to climb as the general tion ages, as new cancers develop, and as susceptible populations (e.g., people infected with AIDS or excessively exposed to sunlight) grow. A tremendous demand therefore exists for new methods and compositions that can be used to treat patients with cancer.
Many types of cancers are associated with new blood vessel formation, a process known as angiogenesis. Several of the mechanisms involved in tumor-induced angiogenesis have been elucidated. The most direct of these mechanisms is the secretion by the tumor cells of cytokines with angiogenic properties. Examples of these cytokines include acidic and basic f1broblastic growth factor (a,b-FGF), angiogenin, vascular endothelial growth factor (VEGF), and TNF-u. Alternatively, tumor cells can release angiogenic peptides through the tion of proteases and the subsequent breakdown of the extracellular matrix where some cytokines are stored (e.g., b-FGF). Angiogenesis can also be induced indirectly through the tment of inflammatory cells (particularly macrophages) and their subsequent release of angiogenic cytokines (e.g., TNF-u, .
Lymphoma refers to cancers that originate in the lymphatic system. ma is characterized by malignant neoplasms of lymphocytes—B lymphocytes and T lymphocytes (l'.e., s and T-cells). Lymphoma generally starts in lymph nodes or collections of lymphatic tissue in organs including, but not limited to, the stomach or intestines. Lymphoma may involve the marrow and the blood in some cases. Lymphoma may spread from one site to other parts of the body.
The treatment of various forms of lymphomas are described, for example, in US. patent no. 363, the ty of which is incorporated herein by reference.
Such lymphomas include, but are not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous B-cell lymphoma, activated B-cell ma, diffilse large B-cell lymphoma ), mantle cell lymphoma (MCL), follicular center lymphoma, transformed lymphoma, lymphocytic lymphoma of intermediate entiation, intermediate lymphocytic lymphoma (ILL), diffilse poorly differentiated lymphocytic lymphoma (PDL), centrocytic ma, diffuse small-cleaved cell lymphoma (DSCCL), peripheral T-cell lymphomas (PTCL), cutaneous T-Cell lymphoma and mantle zone lymphoma and low grade follicular lymphoma.
Non-Hodgkin's lymphoma (NHL) is the fifth most common cancer for both men and women in the United , with an estimated 63,190 new cases and 18,660 deaths in 2007. Jemal A, et al., CA CancerJ Clin 2007; 57(1):43-66. The probability of developing NHL increases with age and the incidence ofNHL in the elderly has been steadily increasing in the past decade, causing concern with the aging trend of the US population. Id. Clarke C A, et al., Cancer 2002; 94(7):2015-2023.
Diffuse large B-cell lymphoma (DLBCL) accounts for approximately ird of non-Hodgkin’s lymphomas. While some DLBCL patients are cured with traditional chemotherapy, the der die from the disease. Anticancer drugs cause rapid and persistent depletion of lymphocytes, possibly by direct apoptosis ion in mature T and B cells. See K. Stahnke. et al., Blood 2001, 98:3066-3073. Absolute lymphocyte count (ALC) has been shown to be a prognostic factor in follicular non-Hodgkin's lymphoma and recent results have suggested that ALC at sis is an important prognostic factor in diffuse large B-cell lymphoma. See D. Kim et al., Journal ofClinical gy, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 8082.
Leukemia refers to ant neoplasms of the blood-forming tissues.
Various forms of leukemias are described, for example, in US. patent no. 7,393,862 and US. provisional patent application no. 60/380,842, filed May 17, 2002, the entireties of which are incorporated herein by reference. Although s reportedly cause several forms of leukemia in animals, causes of leukemia in humans are to a large extent unknown. The Merck Manual, 944-952 (17th ed. 1999). Transformation to malignancy typically occurs in a single cell h two or more steps with subsequent proliferation and clonal expansion. In some leukemias, specific chromosomal translocations have been fied with consistent leukemic cell morphology and special clinical features (e.g., translocations of 9 and 22 in chronic myelocytic leukemia, and of 15 and 17 in acute promyelocytic leukemia). Acute leukemias are inantly undifferentiated cell populations and chronic ias more mature cell forms.
Acute leukemias are divided into lymphoblastic (ALL) and non- lymphoblastic (ANLL) types. The Merck Manual, 946-949 (17th ed. 1999). They may be further ided by their morphologic and cytochemical appearance according to the French-American-British (FAB) fication or according to their type and degree of differentiation. The use of specific B- and T-cell and myeloid-antigen monoclonal antibodies are most l for classification. ALL is predominantly a childhood disease which is established by laboratory findings and bone marrow examination. ANLL, also known as acute myelogenous leukemia or acute myeloblastic ia (AML), occurs at all ages and is the more common acute leukemia among adults; it is the form usually associated with irradiation as a causative agent.
Chronic leukemias are described as being lymphocytic (CLL) or myelocytic (CML). The Merck Manual, 949-952 (17th ed. 1999). CLL is characterized by the appearance of mature lymphocytes in blood, bone marrow, and lymphoid organs. The hallmark of CLL is sustained, absolute lymphocytosis (> 5,000/uL) and an increase of cytes in the bone marrow. Most CLL patients also have clonal ion of lymphocytes with B-cell characteristics. CLL is a disease of middle or old age. In CML, the characteristic feature is the predominance of granulocytic cells of all stages of differentiation in blood, bone marrow, liver, spleen, and other organs. In the matic patient at diagnosis, the total white blood cell (WBC) count is usually about 200,000/uL, but may reach 1,000,000/uL. CML is vely easy to diagnose because of the presence of the Philadelphia chromosome.
In addition to the acute and chronic categorization, neoplasms are also rized based upon the cells giving rise to such disorder into precursor or peripheral.
See e. g., US. patent publication no. 2008/0051379, the disclosure of which is incorporated herein by reference in its entirety. Precursor sms include ALLs and lymphoblastic lymphomas and occur in lymphocytes before they have differentiated into either a T- or B-cell. Peripheral neoplasms are those that occur in lymphocytes that have differentiated into either T- or B-cells. Such peripheral neoplasms include, but are not limited to, B-cell CLL, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma, follicular lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone lymphoma, c marginal zone lymphoma, hairy cell leukemia, plasmacytoma, diffuse large B-cell lymphoma and Burkitt lymphoma. In over 95 percent of CLL cases, the clonal expansion is of a B cell lineage. See Cancer: Principles & Practice of Oncology (3rd Edition) (1989) (pp. 847). In less than 5 percent of CLL cases, the tumor cells have a T-cell phenotype. Notwithstanding these fications, however, the pathological ment of normal poiesis is the rk of all leukemias.
Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow.
Normally, plasma cells produce antibodies and play a key role in immune function.
However, uncontrolled growth of these cells leads to bone pain and fractures, anemia, infections, and other complications. Multiple myeloma is the second most common logical ancy, although the exact causes of multiple myeloma remain unknown. Multiple myeloma causes high levels of proteins in the blood, urine, and organs, including but not limited to M-protein and other immunoglobulins (antibodies), n, and betamicroglobulin. M-protein, short for monoclonal protein, also known as otein, is a particularly abnormal protein produced by the myeloma plasma cells and can be found in the blood or urine of almost all patients with multiple myeloma.
Skeletal symptoms, ing bone pain, are among the most clinically significant symptoms of multiple myeloma. Malignant plasma cells release osteoclast 2015/039926 stimulating factors (including IL-1, IL-6 and TNF) which cause calcium to be leached from bones causing lytic lesions; hypercalcemia is another symptom. The osteoclast stimulating s, also ed to as cytokines, may prevent sis, or death of myeloma cells. Fifty t of patients have radiologically detectable myeloma-related skeletal lesions at diagnosis. Other common clinical symptoms for multiple myeloma include polyneuropathy, anemia, hyperviscosity, infections, and renal insufficiency.
Solid tumors are abnormal masses of tissue that may, but usually do not contain cysts or liquid areas. Solid tumors may be benign (not ), or malignant (cancer). Different types of solid tumors are named for the type of cells that form them.
Examples of types solid tumors include, but are not limited to malignant melanoma, adrenal carcinoma, breast carcinoma, renal cell cancer, carcinoma of the pancreas, all-cell lung carcinoma (NSCLC) and carcinoma ofunknown primary. Drugs commonly administered to ts with various types or stages of solid tumors include, but are not limited to, celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination f.
While patients who achieve a te remission after initial therapy have a good chance for cure, less than 10% of those who do not respond or relapse achieve a cure or a response lasting longer than 3 years. See Cemy T, et al., Ann Oncol 2002; 13 Suppl 4:21 l-2l6.
Rituximab is known to deplete normal host B cells. See M. Aklilu et al., Annals of Oncology 15:1109-1 1 14, 2004. The long-term immunologic effects of B cell depletion with rituximab and the characteristics of the reconstituting B cell pool in lymphoma patients are not well defined, despite the read usage of this y. See er H. Anolik et al., Clinical Immunology, vol. 122, issue 2, February 2007, pages 1 3 9- 145 .
The ch for patients with relapsed or refractory disease relies heaVily on experimental treatments followed by stem cell transplantation, which may not be appropriate for patients with a poor performance status or advanced age. Therefore, a tremendous demand exists for new methods that can be used to treat patients with NHL.
The link between cancer an altered cellular metabolism has been well established. See Cairns, R.A., et al. Nature Rev., 2011, 11:85-95. Understanding tumor cell metabolism and the associated genetic changes thereofmay lead to the identification of improved methods of cancer treatment. Id. For example, tumor cell survival and 2015/039926 proliferation via increased e metabolism has been linked to the PIK3 pathway, whereby mutations in tumor suppressor genes such as PTEN activate tumor cell metabolism. Id. AKTl (a.k.a., PKB) stimulates glucose metabolism associtated with tumor cell growth by various interactions with PFKFB3, ENTPDS, mTOR and TSC2 (a.k.a., tuberin). Id.
Transcription factors HIFl and HIF2 are largely responsible for cellular response to low oxygen conditions often associated with tumors. Id. Once activated, HIFl promotes tumor cell capacity to carry out glycolysis. Id. Thus, inhibition of HIFl may slow or reverse tumor cell lism. Activation of HIFl has been linked to PI3K, tumor suppressor proteins such as VHL, succinate dehydrogenase (SDH) and fiamarate ase. Id. The oncogenic transcription factor MYC has also been linked to tumor cell lism, cally glycolysis. Id. MYC also promotes cell eration by ine metabolic ys. Id.
AMP-activated protein kinase (AMPK) fianctions as a metabolic check point which tumor cells must overcome in order to proliferate. Id. Several mutations have been ifed which suppress AMPK signaling in tumor cells. See Shackelford, D.B. & Shaw, R.J., Nature Rev. Cancer, 2009, 9: 563-575. STKll has been identified as a tumor suppressor gene related to the role ofAMPK. See Cairns, R.A., et al. Nature Rev., 2011, l 1:85-95.
The transcription factor p53, a tumor suppressor, also has an important role in the tion of cellular metabolism. Id. The loss of p53 in tumor cells may be a significant contributor to changes in tumor cell metabolism to the glycolytic pathway. Id.
The OCTl transcription factor, another potential target for chemotherapeutics, may cooperate with p53 in regulating tumor cell metabolism. Id.
Pyruvate kinate M2 (PKM2) promotes changes in cellular metabolism which confer metabolic advantages to cancer cells by supporting cell proliferation. Id.
For example, lung cancer cells which express PKM2 over PKMl have been found to have such an advantage. Id. In the clinic, PKM2 has been identified as being overexpressed in a number of cancer types. Id. Thus PKM2 may be a useful biomarker for the early detection of tumors.
Mutations in isocitrate dehydrogenases IDHl and IDH2 have been linked to tumorigenesis, specifically, in glioblastoma and acute myeloid leukemia. See Mardis, E.R. et al., N. Engl. J. Med, 2009, 361: 1058-1066; Parsons, D.W. et al., Science, 2008, 321: 1807-1812.
The incidence of cancer continues to climb as the general population ages, as new s p, and as susceptible populations (e.g., people infected with AIDS, the y or excessively exposed to sunlight) grow. A tremendous demand therefore exists for new s, treatments and compositions that can be used to treat patients with cancer including but not limited to those with lymphoma, NHL, multiple myeloma, AML, leukemias, and solid tumors.
Accordingly, compounds that can control and/or inhibit unwanted angiogenesis or t the production of certain cytokines, including TNF-(x, may be useful in the treatment and prevention of various forms of cancer. s Of Treating Cancer Current cancer therapy may e surgery, chemotherapy, hormonal therapy and/or radiation treatment to eradicate neoplastic cells in a patient (see, for example, Stockdale, 1998, Medicine, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV). Recently, cancer therapy could also involve biological therapy or immunotherapy. All of these approaches may pose significant drawbacks for the patient.
Surgery, for example, may be contraindicated due to the health of a patient or may be unacceptable to the patient. Additionally, surgery may not completely remove neoplastic . ion therapy is only effective when the neoplastic tissue ts a higher sensitivity to radiation than normal tissue. Radiation therapy can also often elicit serious side effects. Hormonal therapy is rarely given as a single agent. Although hormonal therapy can be effective, it is often used to prevent or delay recurrence of cancer after other treatments have d the majority of cancer cells. Certain biological and other ies are limited in number and may produce side effects such as rashes or swellings, flu-like symptoms, ing fever, chills and fatigue, digestive tract problems or allergic reactions.
With respect to chemotherapy, there are a variety of chemotherapeutic agents available for treatment of cancer. A number of cancer chemotherapeutics act by inhibiting DNA synthesis, either directly or indirectly by inhibiting the biosynthesis of deoxyribonucleotide triphosphate precursors, to prevent DNA ation and concomitant cell division. Gilman et al., Goodman and Gilman ’s.‘ The Pharmacological Basis of eutics, Tenth Ed. (McGraw Hill, New York).
Despite availability of a variety of chemotherapeutic agents, chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant and often dangerous side effects including severe nausea, bone marrow depression, and immunosuppression. Additionally, even with administration of combinations of chemotherapeutic agents, many tumor cells are ant or develop resistance to the chemotherapeutic agents. In fact, those cells resistant to the particular chemotherapeutic agents used in the treatment protocol often prove to be ant to other drugs, even if those agents act by different ism from those of the drugs used in the specific treatment. This enon is referred to as multidrug resistance. Because of the drug resistance, many cancers prove refractory to standard chemotherapeutic treatment protocols.
There exists a significant need for safe and effective compounds and methods for treating, preventing and managing , including for cancers that are refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and hormonal therapy, while reducing or avoiding the toxicities and/or side effects associated with the conventional therapies. 4. SUMMARY Provided herein are nds, pharmaceutical compositions ning the compounds and methods of use thereof in treating cancer, including solid tumors and blood borne tumors. In one ment, the compounds for use in the compositions and methods provided herein are of a I: O O NUCElNO§kR1 NH or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: R1 is H, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; R2 and R3 are each halo; and where the substituents on R1, when present, are one to three groups Q, where each Q is ndently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, lkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, -R4OR5, -R4OR5-R4OR5, -R4N(R6)(R7), -R4SR5, — R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), —C(J)R9 or R4S(O)tR8; each R4 is ndently ne, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or cyclylalkyl groups in R5 are each independently optionally substituted with 1-3 groups Q1, where each Q1 is independently alkyl, kyl or halo; R6 and R7 are selected as s: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are tuted form a or ered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl; R8 is alkyl, haloalkyl, or hydroxyalkyl; R9 is alkyl or aryl; J is O or S; and t is l or 2. ed herein are compounds, pharmaceutical compositions containing the compounds and s of use thereof in treating cancer, including solid tumors and blood borne .
In one embodiment, the compounds for use in the compositions and methods provided herein are of Formula I or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: R1 is H, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; R2 and R3 are each halo; and where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, cycloalkylalkyl, -R4OR5, 6)(R7), -R4SR5, -R4OR4N(R6)(R7) or -R4OR4C(J)N(R6)(R7); each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently en, alkyl, haloalkyl or hydroxyalkyl; and R6 and R7 are each independently hydrogen or alkyl.
In one embodiment, the compounds for use in the compositions and methods provided herein are of Formula I or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: R1 is optionally substituted cycloalkyl, aryl, heteroaryl or heterocyclyl; R2 and R3 are each halo; and where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, ally substituted cycloalkylalkyl, optionally substituted aryl, -R4OR5, -R4N(R6)(R7), -R4SR5, -R4OR4N(R6)(R7) or -R4OR4C(J)N(R6)(R7); each R4 is independently alkylene, lene or a direct bond; each R5 is independently en, alkyl, haloalkyl or hydroxyalkyl; and R6 and R7 are each independently hydrogen or alkyl or R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
In one embodiment, the nd provided herein is a compound of formula I. In one embodiment, the compound ed herein is a pharmaceutically acceptable salt of the compound of formula I. In one embodiment, the compound provided herein is a e of the nd of formula I. In one embodiment, the nd provided herein is a hydrate of compound of a I. In one embodiment, the compound provided herein is a clathrate of the compound of formula I.
Also provided are pharmaceutical compositions formulated for administration by an appropriate route and means containing effective concentrations of one or more of the nds provided herein, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and optionally comprising at least one pharmaceutical carrier.
In one embodiment, the ceutical compositions deliver amounts effective for the ent of cancer, including solid tumors and blood borne tumors. In one embodiment, the pharmaceutical compositions deliver amounts effective for the prevention of cancer, including solid tumors and blood borne tumors. In one embodiment, the pharmaceutical compositions deliver amounts effective for the ration of cancer, including solid tumors and blood borne tumors.
Also provided herein are combination therapies using one or more compounds or compositions provided herein, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof in combination with a therapy e.g., another pharmaceutical agent with activity against cancer or its symptoms. Examples of therapies Within the scope of the s include, but are not limited to, surgery, herapy, radiation therapy, hormonal therapy, biological therapy, immunotherapy, and combinations thereof.
The compounds or compositions provided herein, or pharmaceutically acceptable derivatives f, may be stered simultaneously with, prior to, or after administration of one or more of the above ies. Pharmaceutical compositions containing a compound provided herein and one or more of the above agents are also provided.
In n embodiments, provided herein are methods of treating, preventing or ameliorating cancer, including solid tumors and blood borne tumors, or one or more symptoms or causes thereof. In certain embodiments, provided herein are s of preventing , including solid tumors and blood borne tumors, or one or more symptoms or causes thereof. In certain embodiments, ed herein are methods of ameliorating cancer, including solid tumors and blood borne tumors, or one or more symptoms or causes thereof In certain embodiments, the blood borne tumor is leukemia.
In certain embodiments, methods provided herein encompass methods of treating various forms of leukemias such as chronic lymphocytic ia, chronic myeloid leukemia, acute lymphocytic leukemia, acute myeloid leukemia and acute myeloblastic leukemia. In certain embodiments, s provided herein encompass methods of preventing various forms of leukemias such as chronic lymphocytic leukemia, c myeloid ia, acute lymphocytic leukemia, acute myeloid leukemia and acute myeloblastic leukemia. In certain embodiments, methods provided herein ass methods of managing various forms of leukemias such as chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, acute d leukemia and acute myeloblastic leukemia.
The methods provided herein include treatment of leukemias that are relapsed, refractory or resistant. The methods provided herein include prevention of leukemias that are relapsed, refractory or resistant. The methods provided herein include management of ias that are relapsed, tory or resistant. In one ment, methods provided herein encompass methods of treating acute myeloid leukemia. In one embodiment, methods provided herein encompass methods of preventing acute myeloid leukemia. In one embodiment, methods provided herein encompass methods of managing acute myeloid leukemia.
In practicing the methods, effective amounts of the compounds or compositions containing therapeutically effective concentrations of the compounds are administered to an individual exhibiting the ms of the disease or disorder to be treated.
The amounts are effective to ameliorate or ate one or more ms of the e or disorder.
Further provided is a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions.
Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological ts, which notice reflects al by the agency of manufacture, use of sale for human administration. The pack or kit can be labeled with information regarding mode of administration, sequence of drug administration (e.g., separately, sequentially or concurrently), or the like. [0042a] The present invention particularly provides for aspects and embodiments as set out in the clauses below: 1. A compound of a I: or an omer or a mixture of enantiomers thereof, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or rph thereof, n: R1 is optionally substituted monocyclic C3-10 cycloalkyl, optionally substituted monocyclic C6-18 aryl, optionally substituted monocyclic heteroaryl, or optionally substituted monocyclic cyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently C1-6 alkyl, halo, halo C1-6 alkyl, oxo, optionally substituted monocyclic C3-10 cycloalkyl, optionally substituted monocyclic C3-10cycloalkylC1-6 alkyl, optionally substituted monocyclic heterocyclyl, optionally substituted monocyclic heterocyclyl C1-6 alkyl, optionally substituted monocyclic C6-18 aryl, optionally substituted monocyclic heteroaryl, -R4OR5, - R4O-R4OR5, -R4N(R6)(R7), -R4SR5, - R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), -C(J)R9 or R4S(O)tR8; (followed by 12A) where the substituents on Q, when present are one to three groups Qa, where each Qa is independently C1-6 alkyl, halo, halo C1-6 alkyl, C1-6 alkoxy C1-6 alkyl, oxo, hydroxyl or C1-6 ; each R4 is independently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxy C1-6 alkyl, monocyclic C3-10 cycloalkyl, monocyclic C6-18 aryl, monocyclic heteroaryl, monocyclic heterocyclyl or monocyclic heterocyclyl C1-6 alkyl, where hydroxy C1-6 alkyl, C1-6 alkoxy C1-6 alkyl, C3-10 cycloalkyl, C6-18 aryl, heteroaryl, heterocyclyl or cyclyl C1-6 alkyl groups in R5 are each independently optionally substituted with 1-3 Q1 groups, where each Q1 is independently C1-6 alkyl, halo C1-6 alkyl or halo; where the heterocyclyl in R1, Q and R5 is a 3 to 15 ed heterocyclyl containing one to five heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur; and the aryl in R1, Q and R5 is a 5 to 15 membered aryl containing one to five heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur; R6 and R7 are selected as s: i) R6 and R7 are each independently en or C1-6 alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, C1-6 alkyl or halo C1-6 alkyl; R8 is C1-6 alkyl, halo C1-6 alkyl, or hydroxy C1-6 alkyl; R9 is C1-6 alkyl or C6-18 aryl; J is O or S; and t is 1 or 2. 2. The compound of clause 1, wherein R1 is optionally substituted clic C6-18 aryl. 3. The compound of clause 1 having Formula II: or an enantiomer or a mixture of enantiomers thereof, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: (followed by 12B) R1 is optionally substituted monocyclic C3-10 cycloalkyl, ally substituted monocyclic C6-18 aryl, optionally substituted monocyclic heteroaryl or optionally substituted monocyclic heterocyclyl; the heterocyclyl in R1 is a 3 to 15 ed heterocyclyl containing one to five heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur; and the heteroaryl in R1 is a 5 to 15 membered aryl containing one to five heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur where the substituents on R1, when present, are one to three groups Q, where each Q is independently C1-6 alkyl, halo, halo C1-6 alkyl, optionally substituted monocyclic C3-10 cycloalkyl, optionally substituted monocyclic C3-10 cycloalkyl C1-6 alkyl, ally substituted clic C6-18 aryl, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl or hydroxy C1-6 alkyl; R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or C1-6 alkyl; or ii) R6 and R7 er with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, C1-6 alkyl or halo C1-6 alkyl. 4. The compound of clause 1, wherein R1 is optionally substituted monocyclic C6-18 aryl; where the substituents on R1, when present, are one to three groups Q, where each Q is independently C1-6 alkyl, halo, halo C1-6 alkyl, optionally substituted monocyclic C3-10 cycloalkyl, optionally substituted monocyclic C3-10 cycloalkyl C1-6 alkyl, optionally substituted monocyclic C6-18 aryl, , -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently C1-8 ne, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl or hydroxy C1-6 alkyl; R6 and R7 are selected as s: (followed by 12C) i) R6 and R7 are each independently hydrogen or C1-6 alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are tuted form a 5 or 6-membered cyclyl or heteroaryl ring, optionally tuted with one or two halo, C1-6 alkyl or halo C1-6 alkyl.
. The compound of clause 1, wherein R1 is optionally substituted phenyl, optionally tuted cyclohexyl, optionally substituted piperidinyl, or optionally substituted pyridyl, where the substituents on R1, when present, are one to three groups Q, where each Q is independently halo, C1-6 alkyl, -R4OR5 or 6)(R7); each R4 is ndently a direct bond or C1-8 alkylene; each R5 is independently hydrogen, C1-6 alkyl, or halo C1-6 alkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or C1-6 alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl ring. 6. The compound of clause 1, wherein R1 is optionally substituted phenyl, where the substituents on R1, when present, are one to three groups Q, where each Q is independently fluoro, chloro, methyl, tert butyl, -R4OR5, -R4SR5 or R4OR4C(J)N(R6)(R7); each R4 is independently a direct bond or ene; each R5 is independently hydrogen, methyl, ethyl or oromethyl; and R6 and R7 are each independently hydrogen or methyl. 7. The compound of clause 1, wherein the compound has formula III or an enantiomer or a mixture of enantiomers thereof, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, n: each Q1 is independently C1-6 alkyl, halo, halo C1-6 alkyl, optionally substituted monocyclic C3-10 cycloalkyl, optionally substituted monocyclic C3-10 cycloalkylalkyl, optionally tuted monocyclic C6-18 aryl, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently C1-8 alkylene, C2-8 alkenylene or a direct bond; (followed by 12D) each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl or hydroxy C1-6 alkyl; R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or C1-6 alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or aryl ring, optionally substituted with one or two halo, C1-6 alkyl or halo C1-6 alkyl; and n is 0-3. 8. The compound of clause 1, wherein the compound has a IV or an enantiomer or a mixture of enantiomers thereof, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: Q2 is en, C1-6 alkyl, halo, haloalkyl, optionally substituted monocyclic C3-10 cycloalkyl, optionally tuted monocyclic C3-10 cycloalkyl C1-6 alkyl, optionally tuted monocyclic C6-18 aryl, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is ndently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl or hydroxy C1-6 alkyl; R6 and R7 are each independently hydrogen or C1-6 alkyl. 9. The compound of clause 1, wherein the compound has formula V or an enantiomer or a mixture of enantiomers f, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: (followed by 12E) Q3 and Q4 are each independently hydrogen, C1-6 alkyl, halo, halo C1-6 alkyl, optionally substituted monocyclic C3-10 cycloalkyl, optionally substituted clic C3-10 lkylalkyl, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl, hydroxy C1-6 alkyl,or C1-6 alkoxy C1-6 alkyl; and R6 and R7 are each independently hydrogen or C1-6 alkyl.
. The compound of clause 1, wherein the compound has formula VI or an enantiomer or a mixture of enantiomers thereof, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or rph thereof, n: Q4 and Q5 are each ndently hydrogen, C1-6 alkyl, halo, halo C1-6 alkyl, optionally substituted monocyclic C3-10 cycloalkyl, optionally substituted monocyclic C3-10 cycloalkyl C1-6 alkyl, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy C1-6 alkyl or y C1-6 alkyl; and R6 and R7 are selected as s: i) R6 and R7 are each independently hydrogen or C1-6 alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, ally substituted with one or two halo, C1-6 alkyl or halo C1-6 alkyl. 11. The compound of clause 10, wherein Q4 and Q5 are each independently hydrogen, halo, C1-6 alkyl, -R4N(R6)(R7), or -R4OR5; R4 is a direct bond or C1-8 alkylene; R5 is hydrogen, C1-6 alkyl or halo C1-6 alkyl; and R6 and R7 together with the nitrogen atom on which they are substituted form a 6-membered heterocyclyl. (followed by 12F) 12. The compound of clause 1, wherein the compound has formula VII or an enantiomer or a mixture of enantiomers thereof, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: Q5 is hydrogen, C1-6 alkyl, halo, halo C1-6 alkyl, ally substituted monocyclic C3- 4OR5, -R4SR5, - cycloalkyl, optionally substituted monocyclic C3-10cycloalkylC1-6alkyl, -R R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy C1-6 alkyl or hydroxy C1-6 alkyl; and R6 and R7 are selected as s: i) R6 and R7 are each independently hydrogen or C1-6 alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally tuted with one or two halo, C1-6 alkyl or halo C1-6 alkyl. 13. The compound of clause 11, wherein Q5 is en, halo, C1-6 alkyl, - R4N(R6)(R7) or -R4OR5; R4 is a direct bond or C1-8 alkylene; and R5 is hydrogen, C1-6 alkyl or halo C1-6 alkyl; and R6 and R7 er with the nitrogen atom on which they are substituted form a 6-membered heterocyclyl. 14. The compound of clause 1, wherein the compound has formula VIII VIII or an enantiomer or a mixture of omers thereof, a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph thereof, wherein: (followed by 12G) Q2 and Q5 are each independently en, C1-6 alkyl, halo, halo C1-6 alkyl, optionally substituted monocyclic C3-10 lkyl, optionally substituted monocyclic C3-10 cycloalkyl C1-6 alkyl, optionally substituted C6-18 aryl, -R4OR5, , -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is ndently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl or hydroxy C1-6 alkyl; R6 and R7 are each independently hydrogen or C1-6 alkyl, or R6 and R7 together with the nitrogen atom on which they are substituted form a 6-membered heterocyclyl.
. The compound clause 14, wherein Q2 and Q5 are each independently hydrogen, halo, C1-6 alkyl, optionally substituted C6-18 aryl, or ; R4 is a direct bond or C1-8 alkylene; and R5 is hydrogen, C1-6 alkyl or halo C1-6 alkyl. 16. The compound of clause 1, wherein the compound is selected from Table 1. 17. The nd of clause 1, wherein the compound is selected from N-((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoro(4- methoxyphenyl)acetamide; 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoroacetamide; 2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoroacetamide; N-((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoro(4- fluorophenyl)acetamide; and 2-(2-chlorophenyl)-N-((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoroacetamide; or an omer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. 18. The compound of clause 1, wherein the compound is N-((2-(2,6- iperidinyl)oxoisoindolinyl)methyl)-2,2-difluoro(4- methoxyphenyl)acetamide. 19. The compound of clause 1, wherein the compound is 2-(4-chlorophenyl)-N- ((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoroacetamide. (followed by 12H) . The compound of clause 1, wherein the compound is 2-(3-chlorophenyl)-N- ((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoroacetamide. 21. The compound of clause 1, n the compound is N-((2-(2,6- dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoro(4-fluorophenyl)acetamide. 22. The compound of clause 1, wherein the compound is 2-(2-chlorophenyl)-N- ((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoroacetamide. 23. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of clauses 1-22 and a pharmaceutically acceptable ent, 24. Use of the compound of any one of clauses 1-22 in the manufacture of a medicament for the treatment of cancer.
. The use of clause 24, wherein the cancer is leukemia. 26. The use of clause 25, wherein the ia is chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia or acute myeloid leukemia. 27. The use of clause 25, wherein the leukemia is an acute myeloid leukemia. 28. The use of clause 25, wherein the leukemia is relapsed, tory or resistant to conventional therapy. 29. The use of clause 24, wherein the treatment comprises administration of the compound of any one of clauses 1 to 22 in combination with another second active agent or a support care y.
. The use of clause 29, wherein the other second active agent is a therapeutic antibody that specifically binds to a cancer antigen, hematopoietic growth , cytokine, anti-cancer agent, otic, cox-2 inhibitor, immunomodulatory agent, immunosuppressive agent, corticosteroid or a pharmacologically active mutant or derivative thereof. 31. A compound of any one of clauses 1-22 for use as a medicament.
These and other aspects of the subject matter described herein will become evident upon reference to the following detailed description. Certain aspects may form the t of the divisional application, NZ 765933 but are included herein for teness. (followed by 12I) DETAILED DESCRIPTION OF THE INVENTION Provided herein are compounds of a I. Provided herein is an enantiomer of compounds of formula I. Provided herein is a mixture of enantiomers of compounds of a I. Provided herein is a pharmaceutically acceptable salt of a compound of formula I. ed herein is a pharmaceutically acceptable solvate of a compound of formula I. Provided herein is a pharmaceutically acceptable hydrate of a compound of formula I. Provided herein is a pharmaceutically acceptable co-crystal of a compound of formula I. ed herein is a pharmaceutically acceptable clathrate of a compound of formula I. Provided herein is a ceutically acceptable polymorph of a compound of formula I. Further provided are methods of treating cancer, including solid tumors blood borne tumors, and pharmaceutical itions and dosage forms useful for such methods. Further provided are methods of preventing cancer, ing solid tumors blood borne tumors, and pharmaceutical compositions and dosage forms useful for such methods. Further provided are s of ameliorating cancer, including solid tumors blood borne tumors, and pharmaceutical compositions and dosage forms useful for such methods.
The compounds, methods and compositions are described in detail in the sections below. (followed by 13) WO 07848 A. Definitions Unless defined otherwise, all cal and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term , those in this section prevail unless stated otherwise.
"Alkyl" refers to a ht or branched arbon chain group consisting solely of carbon and hydrogen atoms, containing no ration, having from one to ten, one to eight, one to six or one to four carbon atoms, and which is attached to the rest of the le by a single bond, e.g., methyl, ethyl, n-propyl, l-methylethyl (iso-propyl), n-butyl, n-pentyl, l,l-dimethylethyl (t—butyl), and the like.
"Alkylene" and "alkylene chain" refer to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having from one to eight carbon atoms, 6.g. , methylene, ne, propylene, n-butylene and the like. The alkylene chain may be attached to the rest of the molecule through any two carbons within the chain.
"Alkenylene" or "alkenylene chain" refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to eight carbon atoms, wherein the unsaturation is present only as double bonds and wherein the double bond can exist between any two carbon atoms in the chain, e.g., ethenylene, prop-l-enylene, enylene and the like. The alkenylene chain may be attached to the rest of the molecule through any two carbons within the chain.
"Alkoxy" refers to the group haVing the formula -OR wherein R is alkyl or haloalkyl. An "optionally substituted alkoxy" refers to the group having the formula -OR wherein R is an optionally tuted alkyl as defined herein.
"Amino" refers to a radical haVing the formula -NR’R’ ’ wherein R’ and R’ ’ are each independently en, alkyl or haloalkyl. An "optionally tuted amino" refers to a radical having the formula —NR’R’ ’ wherein ’ one or both of R’ and R’ are optionally substituted alkyl as defined herein.
"Aryl" refers to a group of carbocylic ring system, including monocyclic, bicyclic, tricyclic, tetracyclic C6-C18 ring systems, wherein at least one of the rings is aromatic. The aryl may be fully aromatic, examples of which are phenyl, naphthyl, anthracenyl, acenaphthylenyl, azulenyl, fluorenyl, indenyl and pyrenyl. The aryl may also contain an aromatic ring in combination with a non-aromatic ring, examples of which are acenaphene, indene, and e.
"Cycloalkyl" refers to a stable monovalent monocyclic or bicyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms which is saturated, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, norbomane, norbomene, adamantyl, bicyclo[2.2.2]octane and the like.
"Halo, "halogen" or "halide" refers to F, Cl, Br or I.
"Haloalkyl" refers to an alkyl group, in certain embodiments, C1_6all "Heterocycle" or "Heterocyclyl" refers to a stable 3- to 15-membered non- aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur. In one ment, the heterocyclic ring system radical may be a monocyclic, ic or tricyclic ring or tetracyclic ring system, which may include fiased or bridged ring systems; and the nitrogen or sulfur atoms in the heterocyclic ring system radical may be optionally oxidized; the nitrogen atom may be optionally quatemized; and the cyclyl l may be partially or fully saturated. The heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Exemplary heterocylic radicals include, morpholinyl, piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, oxetanyl, azetidinyl, quinuclidinyl, octahydroquinolizinyl, decahydroquinolizinyl, azabicyclo[3 .2. l]octanyl, yclo[2.2 anyl, olinyl, indolinyl and others.
"Heteroaryl" refers to a cyclyl group as defined above which is aromatic. The heteroaryl groups include, but are not limited to monocyclyl, bicyclyl and tricyclyl , and may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heteroaryl groups include, but are not limited to: furanyl, imidazolyl, oxazolyl, isoxazolyl, pyrimidinyl, pyridinyl, pyridazinyl, thiazolyl, thienyl, benzimidazolyl, o[4,5- dinyl, imidazo[ l ,2-a]pyridinyl, imidazo[ l ,2-b]pyridazinyl, imidazo[ l ,2-a]pyrazinyl and others.
"IC50" refers to an amount, tration or dosage of a particular test nd that achieves a 50% tion of a maximal response, such as cell growth or proliferation, measured via any of the in vitro or cell based assay described herein.
Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N—methylglucamine, procaine, N—benzylphenethylamine, l-para-chlorobenzylpyrrolidin-l'-ylmethyl- benzimidazole, diethylamine and other alkylamines, zine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not d to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, es, ascorbates, succinates, tes, valerates, filmarates and organic sulfonates.
As used herein and unless ise indicated, the term "hydrate" means a compound provided herein or a salt thereof, that further includes a stoichiometric or non- stoichiometeric amount of water bound by non-covalent intermolecular forces.
As used herein and unless otherwise indicated, the term "solvate" means a solvate formed from the association of one or more solvent molecules to a compound provided . The term "solvate" includes hydrates (e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like).
Unless stated otherwise specifically described in the cation, it is understood that the substitution can occur on any atom of the alkyl, l, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group.
Where the number of any given substituent is not specified (e.g., haloalkyl), there may be one or more substituents present. For example, "haloalkyl" may include one or more of the same or different halogens.
When the groups described herein, with the exception of alkyl group, are said to be "substituted," they may be tuted with any appropriate substituent or substituents. Illustrative examples of substituents are those found in the exemplary compounds and embodiments sed herein, as well as halogen o, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; her; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulf1nyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aryloxyamine, xyamine; N—oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; ocyanate; cyanate; thiocyanate; oxygen (=0); B(OH)2, O(alkyl)aminocarbonyl; lkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may be monocyclic or fused or non-fused clic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or nyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g, phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, olyl, lyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, inyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy. When the alkyl groups described herein are said to be "substituted," they may be substituted with any substituent or substituents as those found in the exemplary compounds and ments sed herein, as well as halogen o, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulf1nyl; sulfone; amide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aryloxyamine, aralkoxyamine; N—oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or O(alkyl)aminocarbonyl.
Unless specifically stated otherwise, where a compound may assume alternative tautomeric, regioisomeric and/or stereoisomeric forms, all alternative isomers are intended to be encompassed within the scope of the claimed subject matter. For example, where a nd is described as having one of two tautomeric forms, it is intended that the both tautomers be encompassed herein.
Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or reomeric es.
It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in viva. As such, one of skill in the art will recognize that administration of a compound in its (R) form is lent, for nds that undergo epimerization in vivo, to administration of the compound in its (S) form.
Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using tional techniques, such as chromatography on a chiral stationary phase.
In the description herein, if there is any discrepancy between a chemical name and chemical structure, the structure controls.
As used herein and unless otherwise indicated, the terms "treat, 3, CCtreating" and "treatment" refer to alleviating or reducing the severity of a symptom ated with the disease or condition being treated.
The term "prevention" includes the inhibition of a symptom of the particular disease or er. In some embodiments, patients with familial history of cancer, including solid tumors and blood borne tumors, are candidates for preventive regimens. Generally, the term "preventing" refers to administration of the drug prior to the onset of symptoms, particularly to patients at risk of cancer, including solid tumors and blood borne tumors.
As used herein and unless otherwise indicated, the term "managing" encompasses ting the recurrence of the particular disease or disorder in a patient who had suffered from it, lengthening the time a patient who had suffered from the disease or disorder remains in remission, reducing ity rates of the patients, and/or maintaining a reduction in ty or avoidance of a symptom associated with the disease or condition being managed.
As used herein, "subject" is an animal, typically a mammal, including a human, such as a human patient.
As used herein, the term "tumor," refers to all neoplastic cell growth and proliferation, r malignant or , and all pre-cancerous and cancerous cells and tissues. "Neoplastic," as used , refers to any form of dysregulated or unregulated cell growth, whether malignant or benign, resulting in abnormal tissue growth. Thus, "neoplastic cells" include malignant and benign cells haVing dysregulated or unregulated cell growth.
As used herein, "hematologic malignancy" refers to cancer of the body's blood-forming and immune system-the bone marrow and lymphatic tissue. Such cancers e leukemias, lymphomas (Non-Hodgkin's ma), Hodgkin's disease (also called Hodgkin's Lymphoma) and myeloma.
The term "leukemia" refers to malignant neoplasms of the blood-forming tissues. The leukemia es, but is not limited to, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and acute myeloblastic leukemia. The leukemia can be ed, refractory or ant to conventional therapy.
As used herein, "promyelocytic leukemia" or "acute promyelocytic ia" refers to a malignancy of the bone marrow in which there is a deficiency of mature blood cells in the myeloid line of cells and an excess of immature cells called promyelocytes. It is usually marked by an exchange of regions of chromosomes 15 and l 7.
As used herein, "acute lymphocytic leukemia (ALL)", also known as "acute lymphoblastic leukemia" refers to a malignant disease caused by the abnormal growth and development of early nongranular white blood cells, or lymphocytes.
As used herein, "T- cell leukemia" refers to a disease in which certain cells of the lymphoid system called T lymphocytes or T cells are malignant. T cells are white blood cells that normally can attack Virus-infected cells, foreign cells, and cancer cells and produce nces that regulate the immune response.
The term "relapsed" refers to a situation where patients who have had a remission of ia after therapy have a return of leukemia cells in the marrow and a decrease in normal blood cells.
The term "refractory or resistant" refers to a circumstance where patients, even after intensive treatment, have residual leukemia cells in their marrow.
As used herein, and unless ise specified, the terms "therapeutically ive amount" and "effective amount" of a compound refer to an amount sufficient to provide a therapeutic benefit in the treatment, prevention and/or management of a disease, to delay or minimize one or more symptoms associated with the e or disorder to be treated. The terms "therapeutically effective amount" and "effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.
The terms "co-administration" and "in combination wit " include the stration of two therapeutic agents (for example, a compound provided herein and another anti-cancer agent) either simultaneously, concurrently or sequentially with no specific time limits. In one embodiment, both agents are present in the cell or in the patient’s body at the same time or exert their biological or therapeutic effect at the same time. In one embodiment, the two eutic agents are in the same composition or unit dosage form. In another embodiment, the two therapeutic agents are in separate itions or unit dosage forms.
The term "the supportive care agent" refers to any substance that , prevents or manages an adverse effect from treatment with the compound of a I.
The term "biological therapy" refers to administration of biological therapeutics such as cord blood, stem cells, growth factors and the like.
The term "about," as used herein, unless ise indicated, refers to a value that is no more than 10% above or below the value being modified by the term. For e, the term "about 10 mg/m2" means a range of from 9 mg/m2 to 11 mg/m2.
"Anti-cancer agents" refers to anti-metabolites (e. g., S-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel, docetaxel), alkylating agents (e. g., cyclophosphamide, melphalan, carmustine, nitrosoureas such as bischloroethylnitrosurea and hydroxyurea), platinum agents (e. g. cisplatin, carboplatin, oxaliplatin, JM-2l6 or satraplatin, CI-973), anthracyclines (e.g., doxorubicin, daunorubicin), antitumor antibiotics (e.g., mitomycin, idarubicin, adriamycin, daunomycin), topoisomerase inhibitors (e. g., ide, thecins), anti-angiogenesis agents (e.g. Sutent® and Bevacizumab) or any other cytotoxic agents, (estramustine phosphate, prednimustine), hormones or hormone agonists, antagonists, partial agonists or partial antagonists, kinase inhibitors, and radiation treatment.
As used herein, the abbreviations for any tive , amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, Biochem. 1972, 11:942-944).
B. Compounds In certain embodiments, provided herein are compounds of Formula I: O O R1 NH 0 1, or an enantiomer or a e of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, ate, or polymorph thereof, wherein: R1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, , optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, ally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, ally substituted aryl, , -R4OR5-R4OR5, 6)(R7), -R4SR5, - R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), -C(J)R9 or R4S(O)tR8; J is O or S; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently en, alkyl, haloalkyl or hydroxyalkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
In certain embodiments, provided herein is a compound of Formula I, wherein: R1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is ndently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted lkyl, optionally substituted cycloalkylalkyl, optionally tuted heterocyclyl, ally substituted heterocyclylalkyl, optionally substituted aryl, ally substituted heteroaryl, -R4OR5, -R4OR5-R4OR5, -R4N(R6)(R7), -R4SR5, - R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), -C(J)R9 or R4S(O)tR8; J is O or S; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
In certain embodiments, provided herein is an enantiomer of a compound of Formula I, wherein: R1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, , optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally tuted heterocyclylalkyl, optionally substituted aryl, optionally tuted heteroaryl, -R4OR5, -R4OR5-R4OR5, -R4N(R6)(R7), -R4SR5, - R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), 9 or R4S(O)tR8; J is O or S; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl or yalkyl; and R6 and R7 are ed as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
In certain embodiments, provided herein is a mixture of enantiomers of a compound of a I, wherein: R1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, ally substituted aryl, optionally tuted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, , optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, ally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -R4OR5, -R4OR5-R4OR5, -R4N(R6)(R7), -R4SR5, - R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), -C(J)R9 or R4S(O)tR8; J is O or S; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
In certain embodiments, provided herein is a ceutically acceptable salt of a compound of Formula I, n: R1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted cycloalkyl, ally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally tuted heterocyclylalkyl, ally substituted aryl, optionally substituted heteroaryl, , -R4OR5-R4OR5, -R4N(R6)(R7), -R4SR5, - R4OR4N(R6)(R7), C(J)N(R6)(R7), -C(J)R9 or R4S(O)tR8; J is O or S; each R4 is independently ne, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each ndently hydrogen or alkyl; or ii) R6 and R7 together with the en atom on which they are substituted form a or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
In certain embodiments, provided herein is a solvate of a compound of Formula I, wherein: R1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally tuted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, kyl, alkyl, oxo, hydroxyl, alkoxy, ally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally tuted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -R4OR5, -R4OR5-R4OR5, -R4N(R6)(R7), -R4SR5, - R4OR4N(R6)(R7), C(J)N(R6)(R7), -C(J)R9 or R4S(O)tR8; Jis()orS; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
In certain embodiments, provided herein is a e of a compound of Formula I, wherein R1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally tuted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; where the substituents on R1, when t, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, ally tuted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -R4OR5, -R4OR5-R4OR5, -R4N(R6)(R7), -R4SR5, - R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), 9 or R4S(O)tR8; J is O or S; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
In certain embodiments, provided herein is a co-crystal of a compound of Formula I, wherein: R1 is H, ally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, , optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally tuted aryl, ally substituted aryl, -R4OR5, -R4OR5-R4OR5, 6)(R7), -R4SR5, - R4OR4N(R6)(R7), C(J)N(R6)(R7), -C(J)R9 or R4S(O)tR8; J is O or S; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, kyl or hydroxyalkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a or 6-membered heterocyclyl or heteroaryl ring, ally substituted with one or two halo, alkyl or haloalkyl.
In certain embodiments, provided herein is polymorph of a compound of Formula I, wherein: R1 is H, optionally substituted alkyl, optionally substituted lkyl, optionally tuted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally tuted cycloalkyl, optionally substituted lkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -R4OR5, -R4OR5-R4OR5, -R4N(R6)(R7), -R4SR5, - R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), 9 or R4S(O)tR8; J is O or S; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each ndently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
In certain embodiments, provided herein are nds of a I or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or polymorph thereof, wherein: R1 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, cycloalkylalkyl, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R6 and R7 are each independently hydrogen or alkyl.
In certain embodiments, provided herein are compounds of Formula I or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, e, hydrate, stal, ate, or polymorph thereof, n: R1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; where the tuents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, ally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -R4OR5 - , -R4OR5, R4N(R6)(R7), -R4SR5, — R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), com9 or R4S(O)tR8; each R4 is ndently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, aryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groups in R5 are each independently optionally substituted with l- 3 Q1 groups, where each Q1 is independently alkyl, haloalkyl or halo; R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl; R8 is alkyl, haloalkyl, or hydroxyalkyl; R9 is alkyl or aryl; rS;and t is l or 2.
In certain embodiments, ed herein are compounds of Formula I or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or rph thereof, wherein: R1 is optionally tuted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -R4OR5 - , -R4OR5, R4N(R6)(R7), -R4SR5, — (R6)(R7), -R4OR4C(J)N(R6)(R7), com9 or R4S(O)tR8; where the substituents on Q, when present are one to three groups Qa, where each Q21 is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl or alkoxy; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently en, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, aryl, heterocyclyl or heterocyclylalkyl groups in R5 are each independently optionally tuted with l- 3 Q1 groups, where each Q1 is independently alkyl, haloalkyl or halo; R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl; R8 is alkyl, haloalkyl, or hydroxyalkyl; R9 is alkyl or aryl; J is O or S; and t is l or 2.
] In certain embodiments, ed herein are nds of Formula I, wherein: R1 is optionally substituted cycloalkyl, ally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, yl, alkoxy, optionally tuted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted cyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -R4OR5 - , -R4OR5-R4OR5, R4N(R6)(R7), -R4SR5, — R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), com9 or R4S(O)tR8; where the substituents on Q, when present are one to three groups Qa, where each Q21 is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl or alkoxy; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or cyclylalkyl, where alkyl, kyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, aryl, heterocyclyl or heterocyclylalkyl groups in R5 are each independently optionally substituted with l- 3 Q1 groups, where each Q1 is independently alkyl, haloalkyl or halo; R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, ally substituted with one or two halo, alkyl or haloalkyl; R8 is alkyl, haloalkyl, or hydroxyalkyl; R9 is alkyl or aryl; Jis()orS;and t is l or 2.
In certain embodiments, provided herein is an enatiomer of a compound of a I, wherein: R1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cyclyl; R2 and R3 are each halo; where the tuents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, ally substituted heteroaryl, -R4OR5 - , -R4OR5-R4OR5, R4N(R6)(R7), -R4SR5, — R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), com9 or tR8; where the substituents on Q, when present are one to three groups Qa, where each Q21 is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, yl or alkoxy; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl WO 07848 2015/039926 or heterocyclylalkyl groups in R5 are each independently optionally substituted with l- 3 Q1 groups, where each Q1 is independently alkyl, haloalkyl or halo; R6 and R7 are ed as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl; R8 is alkyl, haloalkyl, or hydroxyalkyl; R9 is alkyl or aryl; J is O or S; and t is l or 2.
] In certain embodiments, provided herein is a mixture of enatiomers of a compound of Formula I, wherein: R1 is optionally substituted cycloalkyl, ally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, ally substituted aryl, optionally substituted heteroaryl, -R4OR5 - , -R4OR5-R4OR5, R4N(R6)(R7), -R4SR5, — R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), com9 or R4S(O)tR8; where the substituents on Q, when present are one to three groups Qa, where each Q21 is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, yl or alkoxy; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, lkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, lkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groups in R5 are each independently optionally substituted with l- 3 Q1 groups, where each Q1 is ndently alkyl, haloalkyl or halo; R6 and R7 are selected as s: i) R6 and R7 are each independently hydrogen or alkyl; or WO 07848 ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally tuted with one or two halo, alkyl or haloalkyl; R8 is alkyl, haloalkyl, or hydroxyalkyl; R9 is alkyl or aryl; J is O or S; and t is l or 2.
] In n embodiments, provided herein is a pharmaceutically acceptable salt of a compound of Formula I, wherein: R1 is ally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cyclyl; R2 and R3 are each halo; where the tuents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -R4OR5 - , -R4OR5-R4OR5, R4N(R6)(R7), -R4SR5, — R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), com9 or R4S(O)tR8; where the tuents on Q, when present are one to three groups Qa, where each Q21 is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl or alkoxy; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groups in R5 are each independently optionally tuted with l- 3 Q1 groups, where each Q1 is independently alkyl, haloalkyl or halo; R6 and R7 are selected as s: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl; R8 is alkyl, haloalkyl, or hydroxyalkyl; R9 is alkyl or aryl; J is O or S; and t is l or 2.
In certain embodiments, provided herein is a solvate of a compound of Formula I, wherein: R1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; where the tuents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, , optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally tuted heterocyclyl, optionally substituted cyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -R4OR5 - , -R4OR5-R4OR5, R4N(R6)(R7), -R4SR5, — R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), com9 or R4S(O)tR8; where the substituents on Q, when present are one to three groups Qa, where each Q21 is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl or alkoxy; each R4 is independently alkylene, lene or a direct bond; each R5 is ndently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, aryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groups in R5 are each independently ally substituted with l- 3 Q1 groups, where each Q1 is independently alkyl, haloalkyl or halo; R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl; R8 is alkyl, haloalkyl, or hydroxyalkyl; R9 is alkyl or aryl; J is O or S; and t is l or 2.
In certain ments, provided herein is a hydrate of a compound of Formula I, wherein: R1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, kyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, ally substituted heteroaryl, -R4OR5 - , -R4OR5-R4OR5, R4N(R6)(R7), -R4SR5, — R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), com9 or R4S(O)tR8; where the substituents on Q, when present are one to three groups Qa, where each Q21 is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl or alkoxy; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is ndently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groups in R5 are each independently optionally substituted with l- 3 Q1 groups, where each Q1 is independently alkyl, haloalkyl or halo; R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are tuted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally tuted with one or two halo, alkyl or haloalkyl; R8 is alkyl, haloalkyl, or hydroxyalkyl; R9 is alkyl or aryl; J is O or S; and t is l or 2.
In certain embodiments, provided herein is a ate of a compound of Formula I, wherein: 2015/039926 R1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; where the tuents on R1, when t, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, ally tuted heteroaryl, -R4OR5 - , -R4OR5-R4OR5, R4N(R6)(R7), -R4SR5, — R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), com9 or tR8; where the substituents on Q, when present are one to three groups Qa, where each Q21 is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl or alkoxy; each R4 is independently alkylene, lene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl, aryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groups in R5 are each independently optionally substituted with l- 3 Q1 groups, where each Q1 is independently alkyl, haloalkyl or halo; R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl; R8 is alkyl, haloalkyl, or hydroxyalkyl; R9 is alkyl or aryl; J is O or S; and t is l or 2.
In n embodiments, provided herein is a co-crystal of a compound of Formula I, wherein: R1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; 2015/039926 where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, yl, alkoxy, optionally substituted cycloalkyl, ally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -R4OR5 - , -R4OR5-R4OR5, R4N(R6)(R7), -R4SR5, — R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), com9 or R4S(O)tR8; where the substituents on Q, when present are one to three groups Qa, where each Q21 is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, yl or alkoxy; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, lkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groups in R5 are each independently optionally substituted with l- 3 Q1 groups, where each Q1 is independently alkyl, haloalkyl or halo; R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the en atom on which they are substituted form a 5 or 6-membered cyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl; R8 is alkyl, haloalkyl, or hydroxyalkyl; R9 is alkyl or aryl; rS;and t is l or 2.
In n embodiments, provided herein is a polymorph of a compound of Formula I, wherein: R1 is optionally tuted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, alkoxyalkyl, oxo, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally tuted heteroaryl, -R4OR5 - , -R4OR5-R4OR5, R4N(R6)(R7), -R4SR5, — R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), com9 or R4S(O)tR8; where the substituents on Q, when t are one to three groups Qa, where each Q21 is independently alkyl, halo, haloalkyl, alkyl, oxo, hydroxyl or alkoxy; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, aryl, heterocyclyl or heterocyclylalkyl groups in R5 are each independently optionally substituted with l- 3 Q1 groups, where each Q1 is independently alkyl, haloalkyl or halo; R6 and R7 are ed as follows: i) R6 and R7 are each ndently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are tuted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl; R8 is alkyl, haloalkyl, or hydroxyalkyl; R9 is alkyl or aryl; J is O or S; and t is l or 2.
In one embodiment, provided herein are compounds of Formula 11: O O FwnmNgboR1 NH 0 II, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, n: R1 is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, ally substituted aryl, -R4OR5, — 4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
In one embodiment, provided herein is a compound of Formula II, wherein the substituents are as described above.
In one embodiment, provided herein is an enantiomer of a compound of Formula II, wherein the substituents are as described above.
] In one embodiment, provided herein is a mixture of enantiomers of a compound of Formula II, wherein the substituents are as described above.
In one embodiment, provided herein is a pharmaceutically acceptable salt of a compound of a II, wherein the substituents are as described above.
] In one embodiment, ed herein is a solvate of a compound of Formula II, wherein the substituents are as described above.
In one ment, ed herein is a hydrate of a compound of Formula II, wherein the substituents are as described above.
In one embodiment, provided herein is a clathrate of a compound of Formula II, wherein the substituents are as described above.
In one embodiment, ed herein is a co-crystal of a compound of Formula II, n the substituents are as described above.
In one ment, provided herein is a polymorph of a compound of Formula II, wherein the tuents are as described above.
In one embodiment, the compounds have Formula I or Formula II, wherein R1 is optionally substituted aryl; where the substituents on R1, when present, are one to three groups Q, where each Q is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, -R4OR5, — 4SR5, -R4N(R6)(R7), (R6)(R7) or R4OR4C(J)N(R6)(R7); each R4 is ndently alkylene, alkenylene or a direct bond; each R5 is ndently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a or ered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
In one ment, the compounds have Formula I or Formula II, wherein R1 is ally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, where the tuents on R1, when present, are one to three groups Q, where each Q is independently halo, alkyl, optionally substituted cycloalkyl, optionally substituted aryl, -R40R5 or -R4N(R6)(R7); each R4 is independently a direct bond or alkylene; each R5 is independently en, halo, alkyl, alkoxy, haloalkoxy or haloalkyl; and R6 and R7 are ed as s: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl.
In one embodiment, the compounds have Formula I or Formula II, wherein R1 is optionally substituted phenyl, optionally substituted cyclohexyl, optionally substituted piperidinyl, or optionally substituted pyridyl, where the substituents on R1, when present, are one to three groups Q, where each Q is independently halo, alkyl, -R40R5 or -R4N(R6)(R7); each R4 is independently a direct bond or alkylene; each R5 is independently hydrogen, halo, alkyl, alkoxy, koxy or haloalkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl ring.
In one embodiment, the compounds have a I or Formula II, wherein R1 is optionally substituted phenyl, optionally tuted exyl, optionally substituted piperidinyl, or optionally substituted pyridyl, where the substituents on R1, when present, are one to three groups Q, where each Q is independently chloro, bromo, fluoro, methyl, isopropyl, tert butyl, trifluromethyl, y, ethoxy, isopropyloxy, methoxyethoxy, isopropyloxyethoxy, trifluoromethoxy, amino, dimethylamino or piperidinyl.
In one embodiment, the compounds have Formula I or Formula II, wherein R1 is optionally substituted aryl, where the substituents on R1, when present, are one to three groups Q, where each Q is independently halo, alkyl, -R4OR5, - 4SR5 or R4OR4C(O)N(R6)(R7); each R4 is independently a direct bond or ne; each R5 is independently hydrogen, halo, alkyl or haloalkyl; and R6 and R7 are each independently en or alkyl.
In one embodiment, the compounds have Formula I or Formula II, wherein R1 is optionally substituted aryl, where the substituents on R1, when t, are one to three groups Q, where each Q is independently fluoro, chloro, methyl, -R4OR5, - R4N(R6)(R7), -R4SR5 or (O)N(R6)(R7); each R4 is ndently a direct bond or methylene; each R5 is independently hydrogen, methyl, ethyl or trifluoromethyl; and R6 and R7 are each independently hydrogen or methyl.
In one embodiment, the compounds have a I or Formula II, wherein R1 is optionally substituted phenyl, where the tuents on R1, when present, are one to three groups Q, where each Q is ndently fluoro, chloro, methyl, tert butyl, -R4OR5, -R4N(R6)(R7), -R4SR5 or R4OR4C(O)N(R6)(R7); each R4 is independently a direct bond or methylene; each R5 is independently hydrogen, methyl, ethyl or trifluoromethyl; and R6 and R7 are each independently hydrogen or methyl.
In one embodiment, provided herein are compounds of Formula III: \(Qm I o O F N O F /J©El{"%H 0 III or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: each Q1 is independently alkyl, halo, haloalkyl, alkoxyalkyl, hydroxyl, alkoxy, optionally tuted lkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently ne, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, halo, alkoxy, haloalkyl or hydroxyalkyl; R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are tuted form a or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or haloalkyl; and n is 0-3.
In one embodiment, ed herein is a nd of Formula III, wherein the substituents are as described above.
In one embodiment, provided herein is an enantiomer of a compound of Formula III, wherein the substituents are as described above.
In one embodiment, provided herein is a mixture of enantiomers of a compound of Formula III, n the substituents are as bed above.
In one embodiment, ed herein is a pharmaceutically acceptable salt of a compound of Formula III, wherein the substituents are as described above.
In one embodiment, provided herein is a solvate of a compound of Formula III, wherein the substituents are as described above.
In one embodiment, provided herein is a hydrate of a compound of Formula III, wherein the substituents are as bed above.
In one embodiment, provided herein is a clathrate of a compound of Formula III, wherein the substituents are as bed above.
In one embodiment, provided herein is a co-crystal of a compound of Formula III, n the tuents are as described above.
In one embodiment, provided herein is a polymorph of a compound of Formula III, wherein the substituents are as described above.
In one embodiment, provided herein are compounds of Formula III or an enantiomer or a e of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: each Q1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally tuted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, - R4OR5, — 4SR5, -R4N(R6)(R7); each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently en, alkyl, haloalkyl or hydroxyalkyl; R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 er with the nitrogen atom on which they are substituted form a or ered heterocyclyl; and n is 0-3.
In one embodiment, the compounds herein are of Formula 111, where each Q1 is independently hydrogen, Br, Cl, F, methyl, isopropyl, t-butyl, isopropyl, cyclopropyl, -CF3, OH, -SCH3, -SCF3, -C(CH3)2F, -OCH3, -OCF3, -OCH2CH3, - OCH(CH3)2, -OCH2CF3, -O(CH2)20CH3, -O(CH2)20CH(CH3)2, -O(CH2)20(CH2)ZOCH3, -NHCH3, )2, -O(CH2)2-morpholinyl, piperidyl, morpholinyl, orpholinyl, -O(CH2)2-4,4-difluoro-l-piperidyl, or p-fluorophenyl.
In one embodiment, provided herein are compounds of a IV: 0 0 F mi}N O 0 IV or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: Q2 is hydrogen, alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, , — 4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R6 and R7 are each independently hydrogen or alkyl.
In one embodiment, provided herein is a compound of Formula IV, wherein the substituents are as bed above.
In one embodiment, provided herein is an enantiomer of a compound of Formula IV, wherein the substituents are as described above.
] In one embodiment, provided herein is a mixture of enantiomers of a compound of Formula IV, wherein the substituents are as described above.
] In one embodiment, provided herein is a pharmaceutically acceptable salt of a compound of Formula IV, wherein the substituents are as described above.
In one ment, provided herein is a solvate of a compound of Formula IV, wherein the substituents are as described above.
] In one embodiment, ed herein is a e of a compound of Formula IV, wherein the tuents are as described above.
In one embodiment, provided herein is a clathrate of a nd of Formula IV, wherein the substituents are as described above.
In one embodiment, ed herein is a co-crystal of a compound of Formula IV, wherein the substituents are as described above.
In one embodiment, provided herein is a polymorph of a compound of a IV, wherein the substituents are as described above.
In one embodiment, the compounds herein are of Formula IV, where Q2 is hydrogen, halo, alkyl, optionally substituted aryl, -R40R5 or -R4N(R6)(R7); R4 is independently a direct bond or alkylene; R5 is hydrogen, alkyl or haloalkyl; and R6 and R7 are each independently hydrogen or alkyl. In some embodiments, Q2 is hydrogen, Br, Cl, F, methyl, isopropyl, t-butyl, isopropyl, -OCH3, -SCH3, -C(CH3)2F, -OCH(CH3)2, -O(CH2)20CH3, or p-fluorophenyl.
In one ment, provided herein are compounds of Formula V: O O F N O O V or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph thereof, wherein: Q3 and Q4 are each independently hydrogen, alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, -R4OR5, - R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); Jis()orS; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is ndently en, alkyl, haloalkyl, hydroxyalkyl,or alkyl; R6 and R7 are each independently hydrogen or alkyl.
] In one embodiment, provided herein is a compound of Formula V, wherein the substituents are as described above.
In one embodiment, provided herein is an enantiomer of a compound of Formula V, wherein the substituents are as described above.
In one embodiment, provided herein is a mixture of enantiomers of a compound of Formula V, wherein the substituents are as described above.
In one ment, provided herein is a pharmaceutically acceptable salt of a compound of Formula V, wherein the substituents are as described above.
In one ment, provided herein is a solvate of a compound of Formula V, wherein the tuents are as described above.
In one embodiment, provided herein is a hydrate of a compound of Formula V, wherein the substituents are as described above.
In one embodiment, provided herein is a clathrate of a compound of Formula V, wherein the tuents are as described above.
In one embodiment, provided herein is a co-crystal of a compound of Formula V, wherein the tuents are as described above.
In one ment, provided herein is a polymorph of a compound of Formula V, wherein the substituents are as described above.
In one embodiment, the compounds herein are of Formula V, where Q4 and Q3 are each independently hydrogen, halo, alkyl, alkoxyalkyl, -R4OR5, or -R4N(R6)(R7); R4 is a direct bond or alkylene; and R5 is hydrogen, alkyl or haloalkyl; and R6 and R7 are each independently hydrogen or alkyl. In some such embodiments, Q4 and Q3 are each independently hydrogen, F, methyl, -CF3, OH, -OCF3, -OCH2CH3, OCH(CH3)2, -OCH2CF3, or -NHCH3.
In one embodiment, the compounds herein are of Formula V, where Q4 is hydrogen, Q3 is hydrogen, halo, alkyl, alkyl, -R4N(R6)(R7), or -R4OR5; R4 is a direct bond or alkylene; R5 is hydrogen, alkyl or kyl; and R6 and R7 are each independently hydrogen or alkyl.
In one embodiment, provided herein are nds of Formula VI: 0 O H N FF O 0 VI or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph f, wherein: Q4 and Q5 are each independently hydrogen, alkyl, halo, haloalkyl, yl, alkoxy, optionally substituted cycloalkyl, ally substituted cycloalkylalkyl, -R4OR5, — 4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently en, alkyl, haloalkyl, alkoxyalkyl or hydroxyalkyl; R6 and R7 are selected as follows: i) R6 and R7 are each independently en or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, alkyl or kyl.
In one embodiment, provided herein is a compound of Formula VI, wherein the substituents are as described above.
] In one embodiment, provided herein is an enantiomer of a compound of a VI, wherein the substituents are as described above.
In one embodiment, provided herein is a mixture of enantiomers of a compound of Formula VI, wherein the substituents are as described above.
In one embodiment, provided herein is a pharmaceutically acceptable salt of a nd of Formula VI, wherein the substituents are as described above.
In one embodiment, provided herein is a solvate of a compound of Formula VI, wherein the substituents are as described above.
In one ment, ed herein is a hydrate of a compound of Formula VI, wherein the substituents are as described above.
In one embodiment, provided herein is a clathrate of a compound of Formula VI, wherein the substituents are as described above.
In one embodiment, provided herein is a co-crystal of a compound of Formula VI, wherein the substituents are as described above.
In one embodiment, ed herein is a polymorph of a compound of Formula VI, wherein the substituents are as described above.
In one embodiment, the compounds herein are of Formula VI, where Q4 and Q5 are each ndently hydrogen, halo, alkyl, alkoxyalkyl, -R4N(R6)(R7), or -R4OR5; R4 is a direct bond or alkylene; R5 is hydrogen, alkyl or haloalkyl; and R6 and R7 together with the nitrogen atom on which they are tuted form a 6-membered heterocyclyl. In some such embodiments, Q4 and Q5 are each independently hydrogen, F, Cl, OH, methyl, -CF3, -NHCH3, -N(CH3)2, -OCF3, -OCH2CH3, -OCH2CF3, -OCH(CH3)2, -O(CH2)20CH3, -O(CH2)20CH(CH3)2, -O(CH2)20(CH2)20CH3, O(CH2)2-morpholinyl, piperidyl, morpholinyl, -CH2-morpholinyl, or -O(CH2)2-4,4-difluoro-l-piperidyl.
In one embodiment, provided herein are compounds of Formula VII: 0 0 '7: N O Npi 4i"; O VII or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically able salt, solvate, e, co-crystal, clathrate, or polymorph thereof, wherein: Q5 is hydrogen, alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally tuted cycloalkyl, optionally substituted cycloalkylalkyl, -R4OR5, — 4SR5, -R4N(R6)(R7), (R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl, alkoxyalkyl or hydroxyalkyl; R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are tuted form a or 6-membered heterocyclyl or aryl ring, optionally substituted with one or two halo, alkyl or haloalkyl. 2015/039926 In one embodiment, ed herein is a compound of Formula VII, wherein the substituents are as described above.
In one embodiment, provided herein is an enantiomer of a compound of Formula VII, wherein the substituents are as described above.
In one embodiment, ed herein is a mixture of omers of a compound of Formula VII, wherein the substituents are as described above.
In one embodiment, provided herein is a pharmaceutically acceptable salt of a compound of Formula VII, n the tuents are as described above.
In one embodiment, provided herein is a solvate of a compound of Formula VII, wherein the substituents are as described above.
In one embodiment, provided herein is a e of a compound of Formula VII, wherein the substituents are as described above.
In one embodiment, provided herein is a clathrate of a compound of Formula VII, wherein the tuents are as described above.
In one embodiment, ed herein is a co-crystal of a compound of Formula VII, wherein the tuents are as described above.
In one embodiment, provided herein is a polymorph of a compound of Formula VII, wherein the substituents are as bed above.
] In one embodiment, the compounds herein are of Formula VII, where Q5 is hydrogen, halo, alkyl, alkyl, -R4N(R6)(R7) or -R4OR5; R4 is a direct bond or alkylene; and R5 is hydrogen, alkyl or haloalkyl; and R6 and R7 together with the nitrogen atom on which they are substituted form a 6-membered heterocyclyl. In some such embodiments, Q5 is hydrogen, F, Cl, methyl, piperidyl, morpholinyl, -CH2-morpholinyl, -N(CH3)2, -O(CH2)20CH3, -O(CH2)20CH(CH3)2, -O(CH2)20(CH2)20CH3, or -O(CH2)2-4,4-difluoro- l -piperidyl.
In one embodiment, provided herein are compounds of Formula VIII: O 0 Hmi"):N F O 0 VIII or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: WO 07848 Q2 and Q5 are each independently hydrogen, alkyl, halo, haloalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, optionally tuted cycloalkylalkyl, optionally substituted aryl, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); Jis()orS; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, alkyl, haloalkyl or hydroxyalkyl; and R6 and R7 are each independently en or alkyl, or R6 and R7 together with the en atom on which they are substituted form a 6-membered heterocyclyl.
In one embodiment, provided herein is a compound of Formula VIII, wherein the substituents are as described above.
In one embodiment, provided herein is an enantiomer of a compound of Formula VIII, wherein the substituents are as described above.
In one embodiment, provided herein is a e of enantiomers of a compound of Formula VIII, wherein the substituents are as described above.
In one embodiment, provided herein is a pharmaceutically acceptable salt of a compound of Formula VIII, wherein the substituents are as described above.
In one embodiment, provided herein is a solvate of a compound of Formula VIII, wherein the substituents are as bed above.
In one embodiment, provided herein is a hydrate of a compound of Formula VIII, n the substituents are as described above.
In one embodiment, provided herein is a clathrate of a compound of Formula VIII, wherein the substituents are as bed above.
In one embodiment, provided herein is a co-crystal of a compound of Formula VIII, wherein the substituents are as described above.
In one embodiment, provided herein is a polymorph of a compound of Formula VIII, wherein the tuents are as described above.
In one embodiment, the compounds herein are of Formula VIII, where Q2 and Q5 are each independently hydrogen, halo, alkyl, alkoxyalkyl, optionally substituted aryl, or ; R4 is a direct bond or ne; and R5 is hydrogen, alkyl or kyl. In some such embodiments, Q2 and Q5 are each independently en, F, Br, Cl, methyl, isopropyl, t-butyl, -C(CH3)2F, p-fluorophenyl, cyclopropyl, -N(CH3)2, -OCH3, -OCH(CH3)2, O(CH2)20CH3, -O(CH2)ZOCH(CH3)2, -O(CH2)20CH3, -O(CH2)20(CH2)20CH3, -OCF3, -O(CH2)2-4,4-difluoro-l-piperidyl, -SCF3, morpholinyl, dyl, or CHz-morpholinyl.
] In one ment, provided herein are compounds of Formula IX: (QUn (I1 00 F N o 0 IX or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or polymorph thereof, wherein: each Q1 is independently alkyl, halo, haloalkyl, alkoxyalkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl; optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, -R4OR5, -R4OR5-R4OR5, -R4N(R6)(R7), , - R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), -C(J)R9 or R4S(O)tR8; J is O or S; each R4 is independently alkylene, alkenylene or a direct bond; each R5 is independently hydrogen, oxo, alkyl, kyl, hydroxyalkyl, alkyl, lkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groups in R5 are each independently optionally substituted with 1-3 Q1 groups ed from alkyl, haloalkyl or halo; R6 and R7 are each independently hydrogen or alkyl; R8 is alkyl, haloalkyl, or hydroxyalkyl; R9 is alkyl or aryl; J is O or S; tis l or 2; and n is 0-3.
In one embodiment, provided herein is a compound of Formula IX, wherein the substituents are as described above.
In one embodiment, provided herein is an enantiomer of a compound of Formula IX, wherein the substituents are as described above.
In one embodiment, provided herein is a mixture of enantiomers of a compound of Formula IX, wherein the substituents are as described above.
WO 07848 In one embodiment, provided herein is a pharmaceutically acceptable salt of a compound of Formula IX, wherein the substituents are as described above.
In one embodiment, provided herein is a solvate of a compound of Formula IX, wherein the substituents are as described above.
In one embodiment, provided herein is a hydrate of a compound of Formula IX, wherein the tuents are as described above.
] In one ment, provided herein is a clathrate of a compound of Formula IX, wherein the substituents are as bed above.
In one embodiment, provided herein is a co-crystal of a compound of Formula IX, wherein the substituents are as described above.
In one embodiment, provided herein is a polymorph of a compound of Formula IX, wherein the substituents are as described above.
In one embodiment, the compounds herein are of Formula IX, where each Q1 is independently hydrogen, halo, alkyl, haloalkyl, alkoxyalkyl or haloalkoxyalkyl. In some embodiments, each Q1 is independently fluoro, , bromo, methyl, isopropyl, t-butyl, -CF3, -O-CH2CH3, -O-CH(CH3)2, or cyclopropyl.
In one ment, the compound provided herein is selected from the group consisting of : F F F F NH NH 0 0 O O 9 9 F F NH NH 0 o 0 o 0 o O, O, WO 07848 F F F F N NH CI 0 o \—< 2700N O {1%O ) ) 9 9 NH W NH 0 o O o In one embodiment, the compound ed herein is a compound of Table 1.
Also provided herein are ically ed analogs of the compounds provided . Isotopic enrichment (for example, deuteration) of pharmaceuticals to improve cokinetics ("PK"), pharmacodynamics ("PD"), and toxicity profiles, has been demonstrated previously with some classes of drugs. See, for example, Lijinsky et. al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst, 69: 1127 (1982); Mangold et. al., Mutation Res. 308: 33 (1994); Gordon et. al., Drug Metab.
Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43: 487 (1994); Gately et. al., J. Nucl.
Med, 27: 388 (1986); Wade D, Chem. Biol. Interact. 117: 191 .
Without being limited by any particular theory, iotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the ife of the parent drug, (3) decrease the number of doses needed to achieve a d effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and/or (6) decrease the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.
Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction. This enon is known as the Kinetic Isotope Effect ("KIE"). For e, if a C—H bond is broken during a rate-determining step in a chemical reaction (i.e. the step with the highest transition state energy), substitution of a ium for that hydrogen will cause a decrease in the reaction rate and the process will slow down. This phenomenon is known as the Deuterium c e Effect ("DKIE"). (See, eg, Foster et al., Adv. Drug Res., vol. 14, pp. l-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999)).
] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C-H bond is broken, and the same reaction where deuterium is substituted for hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, g that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen. Without being limited by a particular theory, high DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy. Because deuterium has more mass than hydrogen, it statistically has a much lower probability of undergoing this phenomenon.
Tritium ("T") is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators and radiopharmaceuticals. Tritium is a hydrogen atom that has 2 neutrons in the nucleus and has an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly found as T20. Tritium decays slowly (half-life = 12.3 years) and emits a low energy beta particle that cannot ate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope, yet it must be ingested in large amounts to pose a significant health risk. As compared with deuterium, a lesser amount of m must be consumed before it reaches a ous level. Substitution of m ("T") for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects.
Similarly, substitution of isotopes for other elements, including, but not limited to, 13C or 14C for carbon, 33S, 34S, or 36S for sulfur, 15N for en, and 17O or 18O for oxygen, will provide a similar kinetic isotope s.
The animal body ses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system.
Examples of such enzymes include the cytochrome P450 enzymes ("CYPs"), ses, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar ediates or metabolites for renal excretion.
Some of the most common metabolic reactions of pharmaceutical nds involve the oxidation of a carbon-hydrogen (C-H) bond to either a carbon-oxygen (C-O) or carbon-carbon (C-C) pi-bond. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles relative to the parent compounds. For many drugs, such oxidations are rapid. As a result, these drugs often require the administration of multiple or high daily doses.
Isotopic enrichment at certain positions of a compound provided herein may produce a detectable KIE that affects the pharmacokinetic, pharmacologic, and/or toxicological profiles of a compound ed herein in ison with a similar nd having a natural ic composition. In one embodiment, the deuterium enrichment is performed on the site of C-H bond cleavage during metabolism.
C. Methods Of Treatment And Prevention In one embodiment, provided herein is a method of treating and preventing cancer, which comprises administering to a patient a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph thereof.
] In another embodiment, provided herein is method of managing cancer, which comprises administering to a patient a compound ed herein, e.g., the compound of a I, or an enantiomer or a e of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
Also provided herein are methods of treating patients who have been previously treated for cancer but are non-responsive to standard therapies, as well as those who have not previously been treated. The invention also encompasses methods of treating patients regardless of t’s age, although some diseases or disorders are more common in certain age groups. The invention fithher encompasses s of treating patients who have undergone surgery in an attempt to treat the e or condition at issue, as well as those who have not. Because patients with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on his/her prognosis. The skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based rd therapy that can be ively used to treat an individual patient with cancer.
As used herein, the term "cancer" includes, but is not limited to, solid tumors and blood borne tumors. The term "cancer" refers to disease of skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone, blood, brain, breast, cervix, chest, colon, etrium, esophagus, eye, head, , liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, and uterus. c cancers include, but are not limited to, advanced ancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain ase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant giolma, anaplastic ytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D WO 07848 colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi’s sarcoma, karotype acute myeloblastic leukemia, Hodgkin’s lymphoma, non- Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous itis, hans cell histiocytosis, leiomyosarcoma, ysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, Waldenstrom’s macroglobulinemia, smoldering myeloma, indolent a, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone- insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary d carcinoma, and leiomyoma In certain embodiments, the cancer is a solid tumor. In certain embodiments, the solid tumor is metastatic. In certain ments, the solid tumor is drug-resistant. In certain embodiments, the solid tumor is hepatocellular carcinoma, prostate cancer, n cancer, or astoma.
In certain ments, the cancer is a blood borne tumor. In certain embodiments, the blood borne tumor is metastatic. In certain embodiments, the blood borne tumor is drug resistant. In certain embodiments, the cancer is leukemia.
In one embodiment, methods provided herein encompass treating, preventing or managing s types of ias such as chronic lymphocytic leukemia (CLL), c ytic leukemia (CML), acute lymphoblastic ia (ALL), acute myeloid ia (AML), and acute myeloblastic leukemia (AML) by administering a therapeutically effective amount of a compound of formula I or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, e, co- l, clathrate, or polymorph thereof In some embodiments, the methods provided herein encompass treating, preventing or managing acute leukemia in a subject. In some embodiments, the acute leukemia is acute myeloid leukemia (AML), which includes, but is not limited to, undifferentiated AML (M0), myeloblastic leukemia (Ml), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]), onocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), and megakaryoblastic leukemia (M7). In one embodiment, the acute myeloid leukemia is erentiated AML (M0). In one embodiment, the acute myeloid leukemia is myeloblastic leukemia (Ml). In one embodiment, the acute myeloid ia is myeloblastic ia (M2). In one embodiment, the acute myeloid leukemia is promyelocytic leukemia (M3 or M3 variant [M3V]). In one embodiment, the acute myeloid leukemia is myelomonocytic leukemia (M4 or M4 t with eosinophilia [M4E]). In one embodiment, the acute myeloid ia is monocytic leukemia (M5). In one embodiment, the acute myeloid leukemia is erythroleukemia (M6). In one embodiment, the acute myeloid leukemia is megakaryoblastic leukemia (M7). Thus, the methods of treating, preventing or managing acute myeloid leukemia in a subject se the step of administering to the subject an amount of a compound ed herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, e, hydrate, co-crystal, clathrate, or polymorph thereof effective to treat, prevent or manage acute myeloid leukemia alone or in combination. In some embodiments, the methods comprise the step of administering to the subject a nd ed herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof in combination with a second active agent in amounts effective to treat, prevent or manage acute myeloid leukemia.
In some embodiments, the methods provided herein encompass treating, preventing or managing acute lymphocytic leukemia (ALL) in a subject. In some embodiments, acute lymphocytic leukemia includes leukemia that originates in the blast cells of the bone marrow (B-cells), thymus (T-cells), and lymph nodes. The acute lymphocytic leukemia can be rized according to the French-American-British (FAB) Morphological Classification Scheme as Ll - Mature-appearing lymphoblasts (T-cells or cells), L2 - Immature and pleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells), and L3 - Lymphoblasts (B-cells; Burkitt's cells). In one embodiment, the acute cytic leukemia originates in the blast cells of the bone marrow (B-cells). In one embodiment, the acute lymphocytic leukemia originates in the thymus (T-cells). In one embodiment, the acute cytic leukemia originates in the lymph nodes. In one embodiment, the acute lymphocytic leukemia is Ll type characterized by mature-appearing lymphoblasts (T-cells or pre-B-cells). In one embodiment, the acute lymphocytic leukemia is L2 type characterized by immature and rphic (variously ) lymphoblasts (T-cells or pre-B-cells). In one ment, the acute lymphocytic leukemia is L3 type characterized by lymphoblasts (B-cells; t's cells). In certain embodiments, the acute lymphocytic leukemia is T-cell leukemia. In one embodiment, the T-cell leukemia is eral T-cell leukemia. In another embodiment, the T-cell leukemia is T-cell lymphoblastic leukemia. In another ment, the T-cell leukemia is cutaneous T-cell leukemia. In another embodiment, the T-cell leukemia is adult T-cell leukemia.Thus, the methods of treating, preventing or managing acute lymphocytic ia in a t comprise the step of administering to the subject an amount of a compound provided herein or an omer or a e of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or polymorph thereof ive to treat, prevent or manage acute lymphocytic ia alone or in ation with a second active agent. In some ments, the methods comprise the step of administering to the subject a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or rph thereof in combination with a second active agent in amounts effective to treat, prevent or manage acute lymphocytic leukemia.
In some embodiments, the methods provided herein encompass treating, preventing or managing chronic myelogenous leukemia (CML) in a t. The methods comprise the step of administering to the subject an amount of a nd provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof effective to treat, prevent or manage chronic myelogenous leukemia. In some embodiments, the methods comprise the step of administering to the subject a compound provided herein or an enantiomer or a e of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof in combination with a second active agent in amounts effective to treat, t or manage chronic myelogenous leukemia.
In some embodiments, the methods provided herein encompass treating, preventing or managing chronic lymphocytic leukemia (CLL) in a subject. The methods comprise the step of administering to the subject an amount of a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof effective to treat, prevent or manage chronic lymphocytic leukemia. In some embodiments, the methods comprise the step of administering to the subject a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or rph thereof in combination with a second active agent in amounts effective to treat, prevent or manage chronic lymphocytic In certain embodiments, provided herein are methods of treating, preventing, and/or managing disease in patients with ed renal function. In certain embodiments, ed herein are method of treating, preventing, and/or managing cancer in patients with impaired renal function. In certain embodiments, ed herein are methods of providing appropriate dose adjustments for patients with impaired renal function due to, but not limited to, disease, aging, or other patient factors.
] In certain ments, provided herein are methods of treating, preventing, and/or managing lymphoma, including non-Hodgkin’s lymphoma. In some embodiments, provided herein are methods for the treatment or management of non- Hodgkin's ma (NHL), including but not limited to, diffuse large B-cell lymphoma (DLBCL), using prognostic factors.
] In certain embodiments, provided herein are methods of ng, preventing, and/or managing multiple myeloma, including relapsed/refractory multiple myeloma in patients with impaired renal function or a symptom thereof, comprising administering a therapeutically effective amount of the nd of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, sdwm;MdmmfimmmmmmnmmmmnmmmmmcmmmmsmflafmapmmmhmMQ ed/refractory multiple myeloma with impaired renal fianction.
In certain embodiments, a therapeutically or prophylactically effective amount of the compound is from about 0.005 to about 1,000 mg per day, from about 001toaboutSOOrngperday,fioniaboutODltoabout2501ngperday,fioniabout 001toaboutlOOrngperday,fion1about01toaboutlOOrngperday,fion1about05to aboutlOOrngperday,fion1aboutltoaboutlOOrngperday,fioniaboutODltoabout 501ngperday,fion1about01toaboutSOrngperday,fion1about05toaboutSOrngper day,fioniaboutltoaboutSOrngperday,fion1about002toabout251ngperday,fion1 about005toaboutlOrngperday,fion1about005toaboutSrngperday,fioniaboutOJ to about 5 mg per day, or from about 0.5 to about 5 mg per day.
In certain ments, the therapeutically or prophylactically effective anunnuisaboutOJ,about02,about05,aboutl,about2,about3,about4,about5,about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day. In some such embodiments, the therapeutically or lactically effective amount is about 2, about 3, about 4, about 5, about 6 or about 7 mg per day.
In one embodiment, the recommended daily dose range of the compound of Formula I, or an enantiomer or a e of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, for the conditions described herein lie within the range of from about 0.5 mg to about 50 mg per day, preferably given as a single -day dose, or in divided doses throughout a day. In some embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In other embodiments, the dosage ranges from about 0.5 to about 5 mg per day. c doses per dayindude0.L(l2,05,l,2,3,4,5,6,7,8,9,10,ll,l2,l3,l4,l5,l6,l7,l8,l9,20, 21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,4l,42,43,44, 45, 46, 47, 48, 49 or 50 mg per day.
In a specific embodiment, the recommended starting dosage may be 0.5, l, 2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In another embodiment, the recommended starting dosage may be 0.5, l, 2, 3, 4, or 5 mg per day. The dose may be escalated to 15, , 25, 30, 35, 40, 45 and 50 mg/day. In a specific embodiment, the compound can be administered in an amount of about 25 mg/day to patients with leukemia, including AML.
In a particular embodiment, the nd can be stered in an amount of about mg/day to patients with leukemia, including AML. In a ular embodiment, the compound can be administered in an amount of about 5 mg/day to patients with leukemia, including AML. In a particular embodiment, the compound can be administered in an amount of about 4 mg/day to ts with leukemia, including AML. In a particular embodiment, the compound can be administered in an amount of about 3 mg/day to patients with leukemia, including AML.
In certain embodiments, the therapeutically or prophylactically effective amount is from about 0.001 to about 100 mg/kg/day, from about 0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, from about 0.01 to about day, from about 0.01 to about 9 mg/kg/day, 0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, from about 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day, from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3 mg/kg/day, from about 0.01 to about 2 mg/kg/day, from about 0.01 to about 2015/039926 1 mg/kg/day, or from about 0.01 to about 0.05 mg/kg/day.
] The administered dose can also be expressed in units other than mg/kg/day.
For example, doses for eral administration can be expressed as mg/mz/day. One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/mz/day to given either the height or weight of a subject or both (see, www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1 day for a 65 kg human is approximately equal to 38 mg/mZ/day.
In certain embodiments, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 0.001 to about 500 uM, about 0.002 to about 200 uM, about 0.005 to about 100 uM, about 0.01 to about 50 uM, from about 1 to about 50 uM, about 0.02 to about 25 uM, from about 0.05 to about 20 uM, from about 0.1 to about 20 uM, from about 0.5 to about uM, or from about 1 to about 20 uM.
In other embodiments, the amount of the compound administered is sufficient to provide a plasma concentration of the nd at steady state, ranging from about 5 to about 100 nM, about 5 to about 50 nM, about 10 to about 100 nM, about 10 to about 50 nM or from about 50 to about 100 nM.
As used herein, the term "plasma concentration at steady state" is the concentration reached after a period of administration of a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or polymorph thereof. Once steady state is reached, there are minor peaks and troughs on the time dependent curve of the plasma concentration of the compound.
In certain embodiments, the amount of the compound administered is sufficient to e a maximum plasma tration (peak concentration) of the compound, ranging from about 0.001 to about 500 uM, about 0.002 to about 200 uM, about 0.005 to about 100 uM, about 0.01 to about 50 uM, from about 1 to about 50 uM, about 0.02 to about 25 uM, from about 0.05 to about 20 uM, from about 0.1 to about uM, from about 0.5 to about 20 uM,or from about 1 to about 20 uM.
In certain embodiments, the amount of the compound administered is sufficient to provide a minimum plasma concentration h concentration) of the compound, ranging from about 0.001 to about 500 uM, about 0.002 to about 200 uM, about 0.005 to about 100 uM, about 0.01 to about 50 uM, from about 1 to about 50 uM, about 0.01 to about 25 uM, from about 0.01 to about 20 uM, from about 0.02 to about uM, from about 0.02 to about 20 uM, or from about 0.01 to about 20 uM.
In certain embodiments, the amount of the compound administered is sufficient to provide an area under the curve (AUC) of the compound, ranging from about 100 to about 100,000 ng*hr/mL, from about 1,000 to about 50,000 ng*hr/mL, from about ,000 to about 25,000 mL, or from about 5,000 to about 10,000 ng*hr/mL.
In certain embodiments, the patient to be treated with one of the methods ed herein has not been treated with anticancer therapy prior to the administration of the compound of Formula I, or an omer or a mixture of enantiomers thereof, or a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. In n embodiments, the patient to be treated with one of the methods provided herein has been treated with anticancer therapy prior to the administration of the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or rph thereof. In certain embodiments, the patient to be treated with one of the methods provided herein has developed drug resistance to the anticancer therapy.
The methods provided herein encompass treating a t regardless of patient’s age, although some diseases or disorders are more common in certain age .
Depending on the disease to be treated and the subject’s condition, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, e, e, co-crystal, clathrate, or polymorph thereof, may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infilsion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. The compound of Formula I, or an omer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or rph thereof, may be formulated, alone or together, in le dosage unit with pharmaceutically able excipients, carriers, adjuvants and vehicles, appropriate for each route of administration.
In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, c1athrate, or polymorph thereof, is administered orally. In another embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, e, hydrate, co-crystal, clathrate, or polymorph thereof, is administered erally. In yet another embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered intravenously.
The compound of a I, or an enantiomer or a e of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, can be delivered as a single dose such as, e.g., a single bolus injection, or oral s or pills; or over time, such as, e.g., continuous infusion over time or divided bolus doses over time. The compound can be administered repeatedly if necessary, for example, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. For example, stable e for solid tumors generally means that the perpendicular diameter of measurable lesions has not increased by 25% or more from the last measurement. se Evaluation Criteria in Solid Tumors (RECIST) Guidelines, l 0fthe National Cancer Institute 92(3): 205-216 (2000). Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities.
The compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or polymorph thereof, can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID). In addition, the administration can be continuous (z'.e., daily for consecutive days or every day), intermittent, e.g., in cycles (z'.e., including days, weeks, or months of rest without drug). As used herein, the term " is intended to mean that a therapeutic compound, such as the compound of a I, is administered once or more than once each day, for example, for a period of time. The term "continuous" is intended to mean that a therapeutic nd, such as the compound of Formula I, is administered daily for an uninterrupted period of at least 10 days to 52 weeks. The term mittent" or "intermittently" as used herein is intended to mean ng and starting at either regular or irregular intervals. For example, intermittent administration of the compound of Formula I is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days. The term "cycling" as used herein is intended to mean that a therapeutic compound, such as the compound of Formula I, is administered daily or continuously but with a rest period. In some such embodiments, administration is once a day for two to six days, then a rest period with no administration for five to seven days.
In some embodiments, the frequency of administration is in the range of about a daily dose to about a monthly dose. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, e, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once a day. In another embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph thereof, is administered twice a day. In yet another embodiment, the compound of Formula I, or an enantiomer or a mixture of omers thereof; or a pharmaceutically able salt, solvate, e, co-crystal, clathrate, or polymorph thereof, is administered three times a day. In still another embodiment, the nd of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph thereof, is administered four times a day.
In certain ments, the nd of Formula I, or an enantiomer or a e of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co- crystal, clathrate, or polymorph thereof, is administered once per day from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks. In certain embodiments, the compound of Formula I, or a ceutically acceptable salt or solvate thereof, is administered once per day for one week, two weeks, three weeks, or four weeks. In one embodiment, the compound of Formula I, or an omer or a mixture of enantiomers thereof; or a ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph f, is administered once per day for 4 days. In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, e, co-crystal, ate, or polymorph thereof, is administered once per day for 5 days. In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or rph thereof, is administered once per day for 6 days. In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co- crystal, clathrate, or polymorph thereof, is stered once per day for one week. In another embodiment, the compound of Formula I, or an enantiomer or a e of enantiomers thereof; or a ceutically acceptable salt, solvate, hydrate, stal, clathrate, or rph thereof, is administered once per day for two weeks. In yet another embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered once per day for three weeks. In still another embodiment, the compound of a I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or rph f, is administered once per day for four weeks.
C-l. Combination Therapy With A Second Active Agent The compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of cancer bed herein.
In one embodiment, provided herein is a method of treating, preventing, or managing , comprising administering to a patient a compound of Formula I, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof; in combination with one or more second active agents, and optionally in combination with radiation therapy, blood transfusions, or surgery. Examples of second active agents are disclosed herein (see, e.g., section 5.4).
As used herein, the term "in combination" includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term "in ation" does not restrict the order in which therapies (e.g. prophylactic and/or therapeutic agents) are administered to a patient with a disease or er. A first therapy (6.g. a prophylactic or therapeutic agent such as a compound provided herein, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph thereof) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 s, 45 s, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g, a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein.
] Administration of the compound of Formula I and one or more second active agents to a patient can occur aneously or sequentially by the same or different routes of administration. The ility of a particular route of stration employed for a particular active agent will depend on the active agent itself (6.g. whether it can be administered orally without decomposing prior to entering the blood stream) and the cancer being treated.
The route of administration of the compound of Formula I is independent of the route of administration of a second therapy. In one ment, the compound of Formula I is administered orally. In another embodiment, the compound of Formula I is administered intravenously. Thus, in accordance with these embodiments, the compound of Formula I is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by er or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, the nd of a I and a second y are administered by the same mode of administration, orally or by IV. In another ment, the compound of Formula I is administered by one mode of administration, e.g., by IV, whereas the second agent (an anticancer agent) is administered by another mode of administration, e.g., orally.
In one embodiment, the second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent used, the type of disease being d or managed, the ty and stage of e, and the amount of the compound of Formula I provided herein and any optional additional active agents concurrently administered to the patient.
One or more second active ingredients or agents can be used together with the compound of formula I in the methods and compositions provided herein. Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., tic inorganic, metallic, or organic les).
Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies, particularly, therapeutic antibodies to cancer antigens. Typical large molecule active agents are biological molecules, such as naturally occurring or synthetic or recombinant proteins. Proteins that are particularly useful in the methods and compositions provided herein e proteins that stimulate the survival and/or proliferation of hematopoietic precursor cells and immunologically active poietic cells in vitro or in viva. Other useful proteins ate the division and differentiation of committed erythroid progenitors in cells in vitro or in viva. Particular proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II ("rIL2") and canarypox IL-2), IL-lO, IL-12, and IL-18; interferons, such as eron alfa-2a, interferon alfa-2b, interferon alfa-nl , interferon alfa-n3, eron beta-I a, and interferon gamma-I b; GM-CF and GM-CSF; and EPO.
In certain embodiments, GM-CSF, G-CSF, SCF or EPO is stered subcutaneously during about five days in a four or six week cycle in an amount ranging from about 1 to about 750 mg/mZ/day, from about 25 to about 500 mg/mZ/day, from about 50 to about 250 day, or from about 50 to about 200 mg/mZ/day. In certain embodiments, GM-CSF may be administered in an amount of from about 60 to about 500 mcg/m2 intravenously over 2 hours or from about 5 to about 12 mcg/mz/day subcutaneously. In certain embodiments, G-CSF may be administered subcutaneously in an amount of about 1 mcg/kg/day initially and can be adjusted depending on rise of total granulocyte counts. The nance dose of G-CSF may be administered in an amount of about 300 (in smaller patients) or 480 mcg subcutaneously. In certain embodiments, EPO may be administered subcutaneously in an amount of 10,000 Unit 3 times per week.
Particular proteins that can be used in the methods and compositions include, but are not limited to: filgrastim, which is sold in the United States under the trade name en® (Amgen, nd Oaks, CA); sargramostim, which is sold in the United States under the trade name Leukine® ex, Seattle, WA); and recombinant EPO, which is sold in the United States under the trade name ® (Amgen, Thousand Oaks, CA).
Recombinant and mutated forms of GM-CSF can be prepared as described in US. patent nos. 5,391,485; 5,393,870; and 5,229,496; all ofwhich are incorporated herein by reference. Recombinant and mutated forms of G-CSF can be prepared as described in US. patent nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755; the entireties of which are incorporated herein by reference.
Also provided for use in combination with a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof are native, naturally occurring, and recombinant proteins. Further encompassed are s and derivatives (e.g., modified forms) of naturally occurring proteins that exhibit, in viva, at least some of the pharmacological ty of the proteins upon which they are based. Examples of mutants include, but are not limited to, proteins that have one or more amino acid residues that differ from the corresponding es in the naturally occurring forms of the proteins.
Also encompassed by the term "mutants" are proteins that lack carbohydrate es ly present in their naturally occurring forms (e.g., nonglycosylated forms).
Examples of tives include, but are not limited to, pegylated derivatives and fusion ns, such as proteins formed by fiasing IgG1 or IgG3 to the protein or active portion of the protein of interest. See, e. g., Penichet, ML. and Morrison, S.L., J. Immunol.
Methods 248:91-101 (2001).
Antibodies that can be used in combination with a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, e, hydrate, co-crystal, clathrate, or polymorph thereof include monoclonal and onal antibodies. Examples of antibodies include, but are not limited to, trastuzumab (Herceptin®), rituximab (Rituxan®), bevacizumab (AvastinTM), pertuzumab (OmnitargTM), momab (Bexxar®), edrecolomab (Panorex®), and G250.
The compounds provided herein or an enantiomer or a mixture of enantiomers f, or a pharmaceutically acceptable salt, e, hydrate, co-crystal, clathrate, or polymorph f can also be combined with, or used in combination with, anti-TNF-(x antibodies, and/or GFR antibodies, such as, for example, Erbitux® or mumab.
Large molecule active agents may be administered in the form of anti- cancer vaccines. For example, vaccines that secrete, or cause the secretion of, cytokines such as IL-2, G-CSF, and GM-CSF can be used in the methods and pharmaceutical compositions provided. See, e. g., Emens, L.A., et al., Curr. Opinion M01. Ther. 3(1):77- 84 .
Second active agents that are small molecules can also be used to alleviate adverse effects associated with the administration of a compound ed herein or an enantiomer or a mixture of enantiomers f, or a pharmaceutically acceptable salt, solvate, hydrate, stal, clathrate, or polymorph thereof However, like some large molecules, many are believed to be capable of providing a istic effect when administered with (e.g., before, after or simultaneously) a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof Examples of small molecule second active agents include, but are not limited to, anti-cancer agents, antibiotics, immunosuppressive agents, and steroids.
In certain embodiments, the second agent is an HSP inhibitor, a proteasome inhibitor, a FLT3 inhibitior or a TOR kinase inhibitor.
Examples of anti-cancer agents to be used within the methods or compositions described herein include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine; ozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; tamide; bisantrene hydrochloride; bisnaf1de dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; ngol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; cladribine; abine; crisnatol mesylate; cyclophosphamide; Ara-C; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hloride; droloxifene; droloxifene citrate; dromostanolone propionate; ycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; icin hydrochloride; zole; esorubicin hydrochloride; WO 07848 2015/039926 estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; lide e; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; omacetaxine; atin; an; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porf1mer sodium; porf1romycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; saf1ngol; saf1ngol hloride; semustine; simtrazene; sorafenib; sparfosate ; sparsomycin; spirogermanium hloride; ustine; spiroplatin; streptonigrin; ozocin; sulofenur; talisomycin; lan sodium; taxotere; r; teloxantrone hydrochloride; temoporf1n; teniposide; teroxirone; testolactone; thiamiprine; anine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; lone acetate; ibine phosphate; trimetrexate; trimetrexate onate; triptorelin; zole hydrochloride; uracil d; uredepa; vapreotide; verteporfin; Vinblastine sulfate; Vincristine sulfate; Vindesine; Vindesine sulfate; Vinepidine sulfate; Vinglycinate sulfate; Vinleurosine sulfate; lbine tartrate; Vinrosidine sulfate; Vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.
Other anti-cancer drugs to be included Within the methods or compositions include, but are not limited to: 20-epi-l,25 dihydroxyVitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; lvene; adecypenol; esin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin l; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; l; batimastat; BCIVABL antagonists; benzochlorins; lstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; rene; ridinylspermine; bisnaf1de; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; tabine; carboxamide-amino-triazole; yamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; in B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; bine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; nin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A tives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; Ara-C ate; cytolytic factor; cytostatin; imab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; sfamide; dexrazoxane; apamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-S-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; mycin SA; ebselen; tine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; ecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib (e.g., Gleevec®); imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; eron agonists; interferons; interleukins; iobenguane; xorubicin; ipomeanol, 4-; iroplact; adine; isobengazole; isohomohalicondrin B; itasetron; j asplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia ting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix oproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; opramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; azone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; ntrone; mofarotene; molgramostim; Erbitux, human chorionic gonadotrophin; monophosphoryl lipid acterium cell wall sk; mopidamol; mustard ncer agent; mycaperoxide B; mycobacterial cell wall t; myriaporone; N—acetyldinaline; N—substituted benzamides; lin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense®); 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; latin; oxaunomycin; paclitaxel; paclitaxel ues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; triol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; acetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum- triamine complex; r sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune tor; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin yethylene conjugate; raf nists; raltitrexed; ramosetron; ras famesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; ; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin g protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin l; squalamine; stipiamide; stromelysin tors; sulfinosine; ctive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; tallimustine; fen methiodide; tauromustine; tene; tecogalan sodium; tegafur; tellurapyrylium; telomerase tors; temoporf1n; teniposide; hlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin c; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene ride; tin; toremifene; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; etron; eride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase or antagonists; vapreotide; variolin B; sol; veramine; verdins; orfin; vinorelbine; vinxaltine; n; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. c second active agents particularly useful in the methods or compositions include, but are not limited to, rituximab, oblimersen (Genasense®), remicade, xel, celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-l l, interferon alpha, pegylated interferon alpha (e.g., PEG INTRON—A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, Ara-C, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt®), sulindac, and etoposide.
In n embodiments of the methods provided herein, use of a second active agent in combination with a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co- crystal, clathrate, or polymorph thereofmay be modified or delayed during or shortly following administration of a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, e, hydrate, co-crystal, clathrate, or polymorph thereof as deemed appropriate by the practitioner of skill in the art. In certain embodiments, subjects being administered a compound ed herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph thereof alone or in combination with other ies may receive tive care including antiemetics, myeloid growth factors, and transfusions of ets, when appropriate. In some embodiments, subjects being administered a compound ed herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereofmay be administered a growth factor as a second active agent according to the nt of the tioner of skill in the art. In some embodiments, ed is administration of a compound provided herein or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof in combination with erythropoietin or darbepoetin (Aranesp).
In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an omer or a mixture of enantiomers thereof, or a ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph f, is administered with gemcitabine and cisplatinum to patients with locally advanced or metastatic transitional cell bladder cancer.
In certain embodiments, a compound ed , e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph thereof, is administered in ation with a second active ingredient as follows: temozolomide to pediatric patients with relapsed or progressive brain tumors or recurrent neuroblastoma; celecoxib, etoposide and hosphamide for relapsed or progressive CNS cancer; temodar to patients with recurrent or progressive meningioma, malignant meningioma, hemangiopericytoma, multiple brain metastases, relapased brain tumors, or newly diagnosed glioblastoma multiforms; irinotecan to ts with recurrent glioblastoma; carboplatin to pediatric patients with brain stem glioma; procarbazine to pediatric patients with progressive malignant gliomas; cyclophosphamide to patients with poor prognosis malignant brain tumors, newly diagnosed or recurrent glioblastoma multiforms; Gliadel® for high grade recurrent ant gliomas; lomide and tamoxifen for anaplastic astrocytoma; or topotecan for gliomas, glioblastoma, anaplastic astrocytoma or anaplastic endroglioma.
In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, ate, or polymorph thereof, is administered with methotrexate, cyclophosphamide, taxane, abraxane, lapatinib, herceptin, aromatase inhibitors, selective estrogen modulators, estrogen receptor antagonists, and/or PLX3397 (Plexxikon) to patients with metastatic breast cancer.
In certain embodiments, a compound provided herein, e.g., the compound of a I, or an enantiomer or a mixture of enantiomers thereof, or a ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with temozolomide to patients with ndocrine tumors.
In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers f, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, ate, or polymorph thereof, is administered with gemcitabine to patients with recurrent or metastatic head or neck cancer.
] In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an omer or a mixture of enantiomers f, or a ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with gemcitabine to patients with pancreatic cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with colon cancer in combination with ARISA®, avastatin, taxol, and/or taxotere.
In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically able salt, e, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with capecitabine and/or PLX4032 (Plexxikon) to patients with refractory colorectal cancer or patients who fail first line therapy or have poor performance in colon or rectal adenocarcinoma.
In n embodiments, a compound provided herein, e.g., the nd of Formula I, or an enantiomer or a mixture of enantiomers f, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with fluorouracil, leucovorin, and irinotecan to patients with Dukes C & D colorectal cancer or to patients who have been previously treated for metastatic colorectal cancer.
In certain ments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with refractory ctal cancer in combination with capecitabine, xeloda, and/or CPT-l I.
In n embodiments, a nd provided herein, e.g., the compound of Formula I, or an omer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, e, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with capecitabine and ecan to patients with tory colorectal cancer or to patients with ctable or metastatic colorectal oma.
In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered alone or in combination with interferon alpha or capecitabine to patients with unresectable or metastatic hepatocellular carcinoma; or with cisplatin and thiotepa to patients with primary or atic liver cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph f, is administered in combination with pegylated interferon alpha to patients with ’s sarcoma.
In certain embodiments, a compound provided herein, e.g., the compound of a I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph thereof, is administered in combination with fludarabine, carboplatin, and/or topotecan to ts with refractory or relapsed or isk acute myeloid leukemia.
In certain embodiments, a compound provided , e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with liposomal daunorubicin, topotecan and/or cytarabine to patients with unfavorable karotype acute myeloblastic ia.
In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is stered in combination with gemcitabine, abraxane, erlotinib, geftinib, and/or ecan to patients with non-small cell lung .
In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with carboplatin and irinotecan to patients with non-small cell lung cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered with doxetaxol to patients with non-small cell lung cancer who have been usly treated with carbo/VP 16 and radiotherapy.
In n embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a e of enantiomers thereof, or a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with carboplatin and/or taxotere, or in combination with latin, pacilitaxel and/or thoracic radiotherapy to patients with non-small cell lung cancer.
In certain embodiments, a nd provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with taxotere to patients with stage IIIB or IV all cell lung cancer.
In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an omer or a mixture of omers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with oblimersen ense®) to patients with small cell lung cancer.
In certain embodiments, a compound provided herein, e.g., the nd of Formula I, or an enantiomer or a e of enantiomers f, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or rph thereof, is administered in combination with ABT-737 (Abbott Laboratories) and/or obatoclax (GX15-070) to patients with lymphoma and other blood cancers.
In certain ments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or rph thereof, is stered alone or in combination with a second active ingredient such as vinblastine or fludarabine to patients with various types of lymphoma, including, but not limited to, Hodgkin’s ma, non-Hodgkin’s lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or relapsed or refractory low grade ular lymphoma.
In certain embodiments, a compound ed herein, e.g., the compound of Formula I, or an enantiomer or a e of enantiomers thereof, or a pharmaceutically acceptable salt, e, hydrate, co-crystal, clathrate, or polymorph thereof, is stered in combination with taxotere, IL-2, IFN, GM-CSF, PLX4032 (Plexxikon) and/or dacarbazine to patients with various types or stages of melanoma.
In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered alone or in combination with vinorelbine to patients with malignant mesothelioma, or stage IIIB non-small cell lung cancer with pleural implants or malignant l effiasion mesothelioma me.
In certain embodiments, a compound provided herein, e.g., the nd of Formula I, or an omer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to ts with s types or stages of multiple myeloma in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan, cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate, celecoxib, arsenic de, PEG INTRON—A, vincristine, or a combination thereof.
In certain embodiments, a compound ed herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, e, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with relapsed or refractory multiple myeloma in combination with doxorubicin (Doxil®), vincristine and/or dexamethasone (Decadron®).
In certain embodiments, a compound provided herein, e.g., the compound of a I, or an enantiomer or a mixture of enantiomers thereof, or a ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of ovarian cancer such as peritoneal carcinoma, papillary serous carcinoma, refractory ovarian cancer or recurrent ovarian cancer, in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, axel, dexamethasone, or a combination thereof.
In certain embodiments, a compound provided herein, e.g, the nd of Formula I, or an omer or a mixture of enantiomers thereof, or a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with various types or stages of te cancer, in combination with xeloda, 5 FU/LV, gemcitabine, ecan plus gemcitabine, cyclophosphamide, vincristine, dexamethasone, GM-CSF, xib, taxotere, ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine, Emcyt, denderon or a combination thereof In certain embodiments, a compound provided , e.g, the compound of Formula I, or an omer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or rph thereof, is administered to patients with various types or stages of renal cell cancer, in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, ex®, or a combination thereof In certain embodiments, a compound provided herein, e.g, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, e, hydrate, co-crystal, ate, or polymorph thereof, is administered to patients with various types or stages of logic, uterus or soft tissue sarcoma cancer in combination with IFN, a COX-2 inhibitor such as Celebrex®, and/or sulindac.
In certain embodiments, a compound provided herein, e.g, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is stered to patients with various types or stages of solid tumors in combination with celebrex, ide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
In certain embodiments, a compound provided herein, e.g, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, ate, or polymorph thereof, is 2015/039926 administered to patients with scleroderma or cutaneous vasculitis in combination with celebrex, etoposide, hosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination f.
Also encompassed herein is a method of increasing the dosage of an anti- cancer drug or agent that can be safely and effectively administered to a patient, which comprises administering to the t (6.g. , a human) or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Patients that can benefit by this method are those likely to suffer from an adverse effect associated with ancer drugs for treating a specific cancer of the skin, subcutaneous tissue, lymph nodes, brain, lung, liver, bone, intestine, colon, heart, pancreas, adrenal, kidney, prostate, breast, colorectal, or combinations thereof. The stration of a compound provided herein, e.g., the compound of a I, or an enantiomer or a mixture of omers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, alleviates or reduces adverse effects which are of such ty that it would otherwise limit the amount of anti-cancer drug.
In one embodiment, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered orally and daily in an amount ranging from about 0.1 to about 150 mg, from about 1 to about 50 mg, or from about 2 to about 25 mg, prior to, during, or after the occurrence of the adverse effect associated with the administration of an anti-cancer drug to a t. In n embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of omers thereof, or a ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered in combination with specific agents such as heparin, aspirin, coumadin, or G-CSF to avoid adverse effects that are associated with anti-cancer drugs such as but not limited to neutropenia or ocytopenia.
In one embodiment, a compound provided herein, e.g., the compound of Formula I, or an omer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered to patients with diseases and disorders associated with or terized by, undesired angiogenesis in combination with additional active ingredients, including, but not limited to, anti-cancer drugs, anti-inflammatories, antihistamines, antibiotics, and steroids.
In another embodiment, encompassed herein is a method of ng, preventing and/or managing cancer, which comprises administering the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in ction with (e.g. before, , or after) conventional therapy including, but not d to, surgery, immunotherapy, biological y, radiation therapy, or other non-drug based therapy presently used to treat, t or manage cancer. The combined use of the compound provided herein and conventional therapy may provide a unique treatment regimen that is unexpectedly effective in certain patients. Without being limited by theory, it is believed that the compound of Formula I may provide additive or synergistic effects when given concurrently with conventional therapy.
As discussed elsewhere herein, encompassed herein is a method of reducing, ng and/or preventing adverse or undesired effects associated with conventional therapy ing, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. A compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and other active ient can be administered to a t prior to, during, or after the ence of the adverse effect associated with tional therapy.
In one embodiment, the compound of Formula I can be administered in an amount g from about 0.1 to about 150 mg, from about I to about 25 mg, or from about 2 to about 10 mg orally and daily alone, or in combination with a second active agent disclosed herein (see, e.g., section 5.4), prior to, during, or after the use of conventional therapy.
In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, and xol are administered to patients with non-small cell lung cancer who were previously d with carbo/VP 16 and radiotherapy.
C-2. Use With Transplantation Therapy The compound of Formula I, or an enantiomer or a e of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or rph thereof, provided herein can be used to reduce the risk of Graft Versus Host Disease (GVHD). Therefore, encompassed herein is a method of treating, preventing and/or managing cancer, which comprises administering the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph f, in conjunction with transplantation therapy.
As those of ordinary skill in the art are aware, the treatment of cancer is often based on the stages and mechanism of the disease. For example, as able leukemic transformation develops in certain stages of cancer, transplantation of peripheral blood stem cells, poietic stem cell preparation or bone marrow may be necessary.
The combined use of the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, ate, or polymorph thereof, provided herein and transplantation therapy es a unique and unexpected ism. In ular, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, exhibits immunomodulatory activity that may provide additive or synergistic effects when given concurrently with transplantation therapy in patients with .
The compound of Formula I, or an enantiomer or a mixture of omers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, can work in combination with transplantation therapy reducing cations associated with the invasive procedure of transplantation and risk of GVHD. Encompassed herein is a method of ng, preventing and/or managing cancer which comprises administering to a t (e.g., a human) the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, before, , or after the transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation, or bone marrow. Some examples of stem cells suitable for use in the methods provided herein are sed in US. patent no. 7,498,171, the disclosure of which is incorporated herein by reference in its entirety.
In one embodiment, the compound of Formula I, or an omer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co- WO 07848 crystal, clathrate, or polymorph thereof, is administered to patients with multiple myeloma before, during, or after the transplantation of autologous peripheral blood progenitor cell.
In one embodiment, the compound of Formula I, or an enantiomer or a mixture of enantiomers f, or a pharmaceutically acceptable salt, solvate, hydrate, co- crystal, clathrate, or polymorph thereof, is administered to patients with NHL (e.g., DLBCL) before, during, or after the transplantation of gous peripheral blood progenitor cell.
C-3. Cycling Therapy In certain embodiments, the prophylactic or therapeutic agents provided herein are cyclically administered to a patient. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid, or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment. uently, in certain embodiments, the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, provided herein is administered daily in a single or divided doses in a four to six week cycle with a rest period of about a week or two weeks. The cycling method fiarther allows the frequency, , and length of dosing cycles to be increased. Thus, assed herein in certain embodiments is the administration of a nd ed , e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, for more cycles than are typical when it is administered alone. In certain embodiments, a compound provided herein, e.g., the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a ceutically acceptable salt, solvate, hydrate, co- l, clathrate, or polymorph thereof, is administered for a greater number of cycles that would lly cause dose-limiting toxicity in a patient to whom a second active ingredient is not also being administered.
In one embodiment, the nd of Formula I, or an enantiomer or a mixture of omers thereof, or a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, is administered daily and continuously for three or four weeks at a dose of from about 0.1 to about 150 mg/d followed by a break of one or two weeks.
] In another embodiment, the compound of Formula I, or an enantiomer or a mixture of omers thereof, or a ceutically acceptable salt, solvate, hydrate, co- crystal, clathrate, or polymorph thereof, and a second active ingredient are administered orally, with administration of the compound of Formula I occurring 30 to 60 minutes prior to a second active ingredient, during a cycle of four to six weeks. In certain embodiments, the combination of the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph thereof, and a second active ingredient is administered by intravenous infiJsion over about 90 minutes every cycle. In certain embodiments, one cycle comprises the administration from about 0.1 to about 150 mg/day of the compound of Formula I, or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph f, and from about 50 to about 200 mg/mz/day of a second active ingredient daily for three to four weeks and then one or two weeks of rest. In certain embodiments, the number of cycles during which the combinatorial treatment is administered to a patient is ranging from about one to about 24 cycles, from about two to about 16 cycles, or from about four to about three cycles.
D. Patient Population ] In certain embodiments of the s provided herein, the t is an , preferably a mammal, more preferably a non-human primate. In particular embodiments, the subject is a human. The subject can be a male or female t.
Particularly useful subjects for the s provided herein include human cancer patients, for example, those who have been diagnosed with leukemia, including acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and chronic myelogenous leukemia. In certain embodiments, the subject has not been diagnosed with acute promyelocytic ia.
] In some embodiments, the subject has a higher than normal blast population. In some embodiments, the subject has a blast population of at least 10%. In some embodiments, the subject has a blast population of between 10 and 15%. In some embodiments, the subject has a blast population of at least 15%. In some embodiments, the subject has a blast population of between 15 and 20%. In some embodiments, the t has a blast population of at least 20%. In some embodiments, the subject has a blast population of about lO-lS%, about 15-20%, or about 20-25%. In other embodiments, the t has a blast population of less than 10%. In the context of the methods bed herein, useful subjects having a blast population of less than 10% includes those subjects that, for any reason ing to the judgment of the skilled practitioner in the art, are in need of treatment with a compound provided , alone or in combination with a second active agent.
In some embodiments, the subject is treated based on the Eastern Cooperative Oncology Group (ECOG) performance status score of the subject for leukemia. ECOG performance status can be scored on a scale of 0 to 5, with 0 denoting asymptomatic; l denoting symptomatic but completely ambulant; 2 denoting symptomatic and <50% in bed during the day; 3 denoting symptomatic and >50% in bed, but not bed bound; 4 denoting bed bound; and 5 ng death. In some embodiments, the t has an ECOG performance status score of 0 or 1. In some embodiments, the subject has an ECOG performance status score of 0. In some ments, the subject has an ECOG mance status score of 1. In other embodiments, the subject has an ECOG mance status score of 2.
In certain embodiments, the methods provided herein encompass the treatment of subjects who have not been previously treated for leukemia. In some embodiments, the subject has not undergone neic bone marrow transplantation. In some embodiments, the subject has not one a stem cell transplantation. In some embodiments, the subject has not received hydroxyurea treatment. In some embodiments, the subject has not been treated with any investigational products for leukemia. In some embodiments, the subject has not been treated with systemic glucocorticoids.
In other embodiments, the methods encompass treating subjects who have been previously treated or are currently being treated for leukemia. For example, the t may have been previously treated or are currently being treated with a standard treatment regimen for leukemia. The subject may have been treated with any standard leukemia treatment regimen known to the practitioner of skill in the art. In certain embodiments, the subject has been previously treated with at least one induction/reinduction or consolidation AML regimen. In some embodiments, the t has undergone autologous bone marrow transplantation or stem cell transplantation as part of a consolidation regimen. In some embodiments, the bone marrow or stem cell transplantation occurred at least 3 months prior to treatment ing to the methods provided herein. In some embodiments, the subject has undergone hydroxyurea treatment.
In some embodiments, the hydroxyurea treatment occurred no later than 24 hours prior to treatment according to the methods ed herein. In some ments, the subject has undergone prior induction or consolidation therapy with cytarabine (Ara-C). In some embodiments, the subject has undergone treatment with systemic glucocorticosteroids. In some embodiments, the glucocorticosteroid treatment occurred no later 24 hours prior to treatment according to the methods bed herein. In other embodiments, the methods encompass treating subjects who have been previously treated for , but are non- responsive to standard ies.
Also encompassed are methods of treating subjects having relapsed or refractory leukemia. In some embodiments, the subject has been diagnosed with a relapsed or refractory AML subtype, as defined by the World Health Organization (WHO). Relapsed or tory disease may be de novo AML or ary AML, e.g., therapy-related AML (t-AML).
In some embodiments, the methods provided herein are used to treat drug resistant leukemias, such as chronic myelogenous leukemia (CML). Thus, treatment with a nd provided herein could provide an alternative for patients who do not respond to other methods of treatment. In some embodiments, such other methods of treatment encompass ent with Gleevec® nib mesylate). In some ments, provided herein are methods of treatment of Philadelphia chromosome positive chronic myelogenous leukemia (Ph+CML). In some embodiments, provided herein are methods of treatment of Gleevec® (imatinib mesylate) ant Philadelphia chromosome positive chronic myelogenous leukemia (Ph+CML).
Also encompassed are methods of treating a subject regardless of the subject’s age, although some diseases or disorders are more common in certain age groups. In some embodiments, the subject is at least 18 years old. In some embodiments, the subject is more than 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years old. In other embodiments, the subject is less than 65 years old. In some embodiments, the subject is less than 18 years old. In some embodiments, the subject is less than 18, 15, 12, 10, 9, 8 or 7 years old.
In some ments, the methods may find use in ts at least 50 years of age, although younger subjects could benefit from the method as well. In other embodiments, the subjects are at least 55, at least 60, at least 65, and at least 70 years of WO 07848 age. In another embodiment, the subjects have adverse cytogenetics. "Adverse cytogenetics" is defined as any loid karyotype, or greater than or equal to 3 chromosomal abnormalities. In another embodiment, the subjects are at least 60 years of age and have adverse cytogenetics. In another embodiment, the subjects are 60-65 years of age and have adverse cytogenetics. In another embodiment, the subjects are 65-70 years of age and have adverse cytogenetics.
In certain ments, the subject treated has no history of myocardial tion within three months of treatment according to the methods provided herein. In some embodiments, the t has no history of cerebrovascular accident or transient ischemic attack within three months of treatment according to the methods provided herein. In some embodiments, the subject has no suffered no oembelic event, ing deep vein thrombosis or pulmonary embolus, within 28 days of treatment according to the methods provided herein. In other embodiments, the subject has not experienced or is not experiencing uncontrolled disseminated intravascular coagulation.
Because ts with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on his/her prognosis. The skilled clinician will be able to y determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based standard therapy that can be effectively used to treat an individual subject with cancer.
It will be appreciated that every suitable combination of the compounds provided herein with one or more of the aforementioned compounds and optionally one or more r pharmacologically active substances is contemplated herein.
E. Formulation of pharmaceutical itions The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of compounds provided herein and a pharmaceutically able carrier, diluent or excipient.
The compounds can be formulated into suitable pharmaceutical preparations such as solutions, sions, tablets, dispersible s, pills, es, powders, sustained release ations or elixirs, for oral administration or in sterile solutions or sions for ophthalmic or parenteral administration, as well as transdermal patch preparation and dry powder inhalers. Typically the compounds described above are formulated into pharmaceutical compositions using techniques and ures well known in the art (see, e.g, Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).
In the compositions, effective concentrations of one or more compounds or pharmaceutically acceptable salts is (are) mixed with a suitable pharmaceutical carrier or vehicle. In n embodiments, the concentrations of the compounds in the compositions are ive for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms and/or progression of cancer, including solid tumors and blood borne tumors.
Typically, the compositions are ated for single dosage administration. To ate a composition, the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved or ameliorated. Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.
Liposomal suspensions, including -targeted mes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as known in the art. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg atidyl choline and brain atidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is sed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.
The active compound is included in the pharmaceutically able carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. The eutically effective concentration may be determined empirically by g the compounds in in vitro and in viva systems described herein and then extrapolated therefrom for dosages for humans. 2015/039926 The concentration of active compound in the pharmaceutical composition will depend on absorption, tissue distribution, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to ameliorate one or more of the symptoms of cancer, including solid tumors and blood borne tumors.
In certain ments, a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/mL to about 50-100 ug/mL. In one ment, the pharmaceutical compositions provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day.
Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1000 mg and in certain embodiments, from about 10 to about 500 mg of the essential active ingredient or a combination of ial ingredients per dosage unit form.
The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known g protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further tood that for any particular subject, specific dosage regimens should be ed over time according to the individual need and the professional judgment of the person administering or ising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
Thus, effective concentrations or amounts of one or more of the compounds described herein or ceutically able salts thereof are mixed with a suitable pharmaceutical carrier or vehicle for systemic, topical or local administration to form pharmaceutical compositions. Compounds are included in an amount effective for rating one or more symptoms of, or for treating, retarding progression, or preventing. The concentration of active compound in the composition will depend on absorption, tissue bution, inactivation, excretion rates of the active compound, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art.
The itions are intended to be administered by a suitable route, including but not limited to orally, parenterally, rectally, topically and locally. For oral administration, capsules and tablets can be formulated. The compositions are in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.
Solutions or sions used for parenteral, ermal, subcutaneous, or topical application can include any of the following ents: a sterile diluent, such as water for ion, saline solution, fixed oil, polyethylene , glycerine, propylene glycol, dimethyl acetamide or other synthetic solvent; crobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulf1te; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium de or se. Parenteral preparations can be enclosed in ampules, pens, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.
In instances in which the compounds exhibit insufficient lity, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as , or dissolution in aqueous sodium bicarbonate.
Upon mixing or addition of the compound(s), the ing mixture may be a solution, sion, emulsion or the like. The form of the resulting mixture s upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.
The pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable salts thereof. The pharmaceutically eutically active compounds and salts thereof are formulated and administered in unit dosage forms or multiple dosage forms.
Unit dose forms as used herein refer to physically discrete units le for human and animal subjects and packaged individually as is known in the art. Each unit dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the d therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dose forms include ampules and syringes and individually packaged tablets or capsules. Unit dose forms may be administered in fractions or multiples thereof A multiple dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in segregated unit dose form. Examples of multiple dose forms include vials, bottles of s or capsules or bottles of pints or gallons. Hence, le dose form is a multiple of unit doses which are not segregated in packaging.
Sustained-release preparations can also be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hobic polymers ning the compound provided herein, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release matrices include iontophoresis patches, polyesters, hydrogels (for example, poly(2-hydroxyethyl- methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-) ybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid- glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated compound remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37 0C, resulting in a loss of biological activity and possible changes in their structure. Rational strategies can be devised for stabilization depending on the mechanism of action involved.
For example, if the ation mechanism is discovered to be intermolecular S--S bond formation through thio-disulf1de interchange, ization may be achieved by modifying dryl residues, lizing from acidic ons, controlling moisture content, using appropriate additives, and developing specific r matrix compositions.
Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from non toxic carrier may be prepared. For oral administration, a pharmaceutically acceptable non toxic composition is formed by the incorporation of any of the normally employed ents, such as, for example ceutical grades of mannitol, lactose, , magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and . Methods for preparation of these itions are known to those skilled in the art. The contemplated compositions may n about 0.001% 100% active ingredient, in certain embodiments, about 0.1 85% or about 75-95%.
The active compounds or pharmaceutically acceptable salts may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.
The compositions may include other active compounds to obtain desired combinations of properties. The compounds provided herein, or pharmaceutically acceptable salts thereof as described herein, may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to above, such as diseases related to oxidative stress. It is to be understood that such combination therapy constitutes a fiarther aspect of the compositions and methods of treatment provided herein.
Lactose-free compositions provided herein can contain ents that are well known in the art and are listed, for e, in the US. Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-free compositions contain an active ingredient, a binder/filler, and a lubricant in pharmaceutically ible and pharmaceutically able amounts. Exemplary lactose-free dosage forms contain an active ingredient, microcrystalline ose, latinized starch and magnesium stearate.
Further encompassed are anhydrous ceutical compositions and dosage forms containing a compound provided . For example, the addition of water (e.g., 5%) is widely accepted in the ceutical arts as a means of simulating long- term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel , NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate the osition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly 2015/039926 encountered during manufacture, handling, packaging, storage, shipment and use of formulations. ous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a y or secondary amine are anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
An anhydrous pharmaceutical composition should be ed and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be ed in suitable formulary kits. es of suitable packaging include, but are not d to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs and strip packs.
E-l. Oral Dosage Forms Oral pharmaceutical dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk s. Types of oral tablets include compressed, le lozenges and tablets which may be c coated, sugar coated or film coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.
In certain embodiments, the ations are solid dosage forms, such as capsules or tablets. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a ; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.
Examples of binders include microcrystalline ose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, , salt, ol and dicalcium phosphate. ts include, but are not limited to, colloidal silicon dioxide.
Disintegrating agents include crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors.
Flavoring agents include natural flavors ted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate. Wetting agents e propylene glycol earate, an monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether.
Emetic coatings e fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate ates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose e phthalate.
If oral administration is desired, the compound could be provided in a ition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.
When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, gs of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active nds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound or pharmaceutically acceptable salt thereof as bed herein. Higher concentrations, up to about 98% by weight of the active ingredient may be ed.
Pharmaceutically acceptable carriers included in s are binders, lubricants, diluents, disintegrating , coloring agents, flavoring agents, and wetting agents. Enteric coated tablets, because of the enteric coating, resist the action of h acid and dissolve or disintegrate in the neutral or alkaline intestines. Sugar coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances are applied. Film coated tablets are compressed tablets which have been coated with a polymer or other suitable coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the ceutically acceptable substances usly mentioned. Coloring agents may also be used in the above dosage forms. Flavoring and sweetening agents are used in compressed tablets, sugar coated, multiple compressed and chewable tablets. Flavoring and sweetening agents are ally useful in the formation of chewable tablets and lozenges.
Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil in-water or water in oil.
Elixirs are clear, sweetened, hydroalcoholic ations. Pharmaceutically able carriers used in elixirs include solvents. Syrups are concentrated s solutions of a sugar, for example, sucrose, and may contain a vative. An emulsion is a two phase system in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non aqueous s, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. ceutically acceptable substances used in non effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents. Pharmaceutically acceptable nces used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.
Solvents include glycerin, sorbitol, ethyl alcohol and syrup. es of vatives include glycerin, methyl and propylparaben, c add, sodium benzoate and alcohol. Examples ofnon aqueous liquids utilized in emulsions include mineral oil and seed oil. Examples of fying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as yethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia.
Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol earate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic adds include citric and tartaric acid. Sources of carbon dioxide e sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof.
Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation.
For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is encapsulated in a gelatin capsule.
Such solutions, and the preparation and encapsulation thereof, are disclosed in US. Patent Nos 4,328,245; 4,409,239; and 545. For a liquid dosage form, the solution, e.g., for example, in a hylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e. g., water, to be easily measured for administration.
] Alternatively, liquid or semi solid oral formulations may be prepared by dissolving or sing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e. g., ene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
Other useful formulations include, but are not limited to, those ning a nd provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, l,2-dimethoxymethane, e, me, tetraglyme, polyethylene glycoldimethyl ether, polyethylene glycoldimethyl ether, polyethylene dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, oric acid, thiodipropionic acid and its esters, and dithiocarbamates.
Other ations include, but are not limited to, aqueous alcoholic solutions including a pharmaceutically acceptable acetal. Alcohols used in these formulations are any ceutically acceptable water-miscible solvents having one or more hydroxyl groups, ing, but not limited to, propylene glycol and ethanol.
Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal.
In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional cally digestible coating, such as phenylsalicylate, waxes and ose acetate phthalate.
E-2. Injectables, solutions and emulsions Parenteral administration, generally characterized by ion, either subcutaneously, intramuscularly or intravenously is also contemplated . Inj ectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
Suitable excipients are, for example, water, , dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts ofnon toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
Implantation of a slow release or ned release system, such that a constant level of dosage is maintained is also contemplated herein. Briefly, a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, tylmethacrylate, plasticized or ticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-Vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is nded by an outer polymeric membrane, e. g., hylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl te copolymers, ethylene/vinylacetate mers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, Vinylchloride copolymers with Vinyl acetate, Vinylidene chloride, ethylene and propylene, r polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol mer, ne/Vinyl acetate/Vinyl alcohol terpolymer, and ethylene/Vinyloxyethanol copolymer, that is insoluble in body fluids. The compound es through the outer polymeric membrane in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.
Parenteral administration of the itions includes intravenous, subcutaneous and intramuscular administrations. ations for parenteral stration include sterile ons ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, e suspensions ready for ion, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.
If administered intravenously, suitable carriers e physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing , such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
] Pharmaceutically acceptable carriers used in parenteral preparations e aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, idants, local anesthetics, suspending and dispersing agents, emulsifying , sequestering or chelating agents and other pharmaceutically acceptable substances.
Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, ic se Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include fixed oils of ble origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to eral preparations packaged in multiple dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate.
Local anesthetics include procaine hloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water le vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
The concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the d cological effect. The exact dose depends on the age, weight and condition of the patient or animal as is known in the art.
The unit dose parenteral preparations are packaged in an ampule, a Vial or a e with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art.
Illustratively, enous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or sion ning an active material injected as necessary to produce the desired pharmacological effect.
] Injectables are designed for local and systemic administration. Typically a therapeutically effective dosage is ated to contain a concentration of at least about 0.1% w/w up to about 90% w/w or more, such as more than 1% w/w of the active nd to the treated tissue(s). The active ingredient may be administered at once, or may be diVided into a number of smaller doses to be administered at intervals of time. It is tood that the precise dosage and duration of treatment is a fianction of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the dual treated. It is to be fiarther understood that for any particular subject, specific dosage regimens should be adjusted over time ing to the dual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the d formulations.
The compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined.
E-3. Lyophilized powders Of interest herein are also lyophilized powders, which can be tituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted and formulated as solids or gels.
The sterile, lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically able salt thereof, in a le solvent. The solvent may n an excipient which improves the ity or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other le agent. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, in one embodiment, about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. Generally, the resulting solution will be ioned into vials for lyophilization. Each vial will n a single dosage (including but not limited to 10-1000 mg or 100-500 mg) or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4 °C to room temperature.
Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, about 1-50 mg, about 5-35 mg, or about 9-30 mg of lyophilized , is added per mL of sterile water or other le carrier. The precise amount depends upon the selected compound. Such amount can be empirically ined.
E-4. Topical administration Topical mixtures are prepared as described for the local and systemic administration. The resulting mixture may be a solution, suspension, on or the like and are formulated as creams, gels, ointments, emulsions, ons, elixirs, lotions, sions, tinctures, pastes, foams, aerosols, irrigations, sprays, itories, bandages, dermal patches or any other ations le for topical administration.
The compounds or pharmaceutically acceptable salts thereofmay be formulated as aerosols for topical application, such as by inhalation (see, e. g., US. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a d useful for ent of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microf1ne powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will have diameters of less than 50 microns or less than 10 microns.
The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracistemal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation ies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable ents can also be administered.
These ons, particularly those intended for ophthalmic use, may be formulated as 0.01% - 10% isotonic ons, pH about 5-7, with appropriate salts.
E-S. Compositions for other routes of administration Other routes of administration, such as topical application, transdermal patches, and rectal administration are also contemplated herein.
For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for ion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ients. %mmmwmdwmwmwwamm%MMRdmmddeMMM%meMmMH vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene ) and appropriate mixtures ofmono di and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. An exemplary weight of a rectal suppository is about 2 to 3 grams.
Tablets and capsules for rectal administration are manufactured using the same pharmaceutically able substance and by the same methods as for ations for oral administration.
E-6. Sustained Release Compositions Active ingredients provided herein can be stered by controlled release means or by delivery s that are well known to those of ordinary skill in the mtEmmkflmhfifiMmmmfimMMQmmmMmmmeSPmmNm; 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, ,591,767, 548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, ,891,474, 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 970, 6,267,981, 461,6,419,961, 6,589,548, 6,613,358, 6,699,500 and 6,740,634, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, ble membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.
All controlled-release pharmaceutical ts have a common goal of improving drug therapy over that ed by their non-controlled rparts. In one embodiment, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug nce being employed to cure or control the condition in a minimum amount of time. In certain embodiments, advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release ations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly es the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of eutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being lized and excreted from the body.
Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological ions or compounds.
In certain embodiments, the agent may be administered using intravenous infusion, an table osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used (see, Sefton, CRC Crit. Ref.
Biomed. Eng. 14:201 (1987); ld et al., Surgery 88:507 (1980); Saudek et al., N.
Engl. J. Med. 321 :5 74 (1989). In another embodiment, ric materials can be used.
In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical ations of Controlled Release, vol. 2, pp. 1 15-138 (1984).
] In some embodiments, a controlled e device is introduced into a subject in proximity of the site of inappropriate immune activation or a tumor. Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990). The active ingredient can be sed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, cized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked lly hydrolyzed polyvinyl acetate, that is surrounded by an outer ric membrane, e. g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate mers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, nylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and ene, ionomer polyethylene thalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol ymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject.
E-7. Targeted ations The compounds ed , or pharmaceutically acceptable salts thereof, may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated. Many such targeting s are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non-limiting examples of targeting methods, see, e. g., US.
Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, ,840,674, 542 and 5,709,874.
In one embodiment, mal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in US.
Patent No. 4,522,811. Briefly, mes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline g divalent cations (PBS) is added and the flask shaken until the lipid film is sed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by fugation, and then resuspended in PBS.
E-8. Articles of Manufacture ] The compounds or ceutically acceptable salts can be packaged as articles of manufacture containing packaging material, a compound or pharmaceutically acceptable salt thereof provided herein, which is used for treatment, prevention or amelioration of one or more symptoms or progression of cancer, including solid tumors and blood borne tumors, and a label that indicates that the compound or pharmaceutically acceptable salt thereof is used for treatment, prevention or amelioration of one or more symptoms or progression of cancer, including solid tumors and blood borne .
The articles of manufacture provided herein contain packaging materials.
Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. See, e.g., US. Patent Nos. 5,323,907, 558 and 252.
Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, es, pens, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide array of formulations of the compounds and compositions provided herein are contemplated.
F. Evaluation Of The ty Of The Compounds Standard physiological, pharmacological and biochemical procedures are available for testing the compounds to identify those that s the desired anti- proliferative activity.
Such assays e, for example, biochemical assays such as binding assays, radioactivity incorporation assays, as well as a variety of cell based assays.
G. Preparation of compounds The compounds provided herein can be prepared by methods known to one of skill in the art and ing procedures similar to those bed in the Examples section herein and routine modifications thereof An exemplary reaction scheme for the preparation of compounds is illustrated below.
HZN-C): Acid ROH BdOR Bromination o’R —H(:Br/©dN@0 Br Base CINONHPd, Zn (CN)2 It is understood that the foregoing detailed ption and accompanying examples are merely illustrative, and are not to be taken as tions upon the scope of the subject matter. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such s and modifications, including Without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use provided herein, may be made Without departing from the spirit and scope thereof. US. patents and ations referenced herein are incorporated by reference. 6. EXAMPLES ] Certain embodiments of the invention are rated by the following non- limiting example.
Example 1 Synthesis of N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluor0(4-meth0xyphenyl)acetamide 0 2 :N o film0 -lO3- 2015/039926 Methyl 4-br0m0methylbenz0ate: omethylbenzoic acid (100 g, 465.02 mmol), concentrated sulfiaric acid (52 mL) in methanol (1L) were combined and heated to 65 0C for 18 h. The reaction was concentrated and the residue diluted with ethyl acetate (500 mL), washed with saturated sodium bicarbonate solution (150 mL), water (200 mL), brine (250 mL) and dried over sodium sulfate. The organic phase was concentrated under reduced pressure and further dried under high vacuum to give methyl 4-bromomethylbenzoate (102 g, 445.27 mmol, 95% yield) as a red liquid. 1H NMR (400 MHz, Chloroform-dl) 5 7.78 (d, J=8.3 Hz, 1H), 7.45 — 7.30 (m, 2H), 3.88 (s, 3H), 2.57 (s, 3H).
Methylbr0m0(br0m0methyl) benzoate: Methyl 4-bromo methylbenzoate (102 g, 445.27 mmol), NBS (79.2 g, 445.27 mmol), Azo-isobutyronitrile (2.58 g, 16 mmol) in acetonitrile (600 mL) were combined and d at 85 0C for 18 h.
The mixture was concentrated, and to the residue was added dichloromethane (150 mL).
The resultant solid was removed by filtration. The filtrate was concentrated and purified by flash column chromatography (0-4% EtOAc in Hexanes). Fractions containing product was concentrated under reduced re and further dried under high vacuum to give Methylbromo(bromomethyl) benzoate (100 g, 324.70 mmol, 72.9 % yield) as an off- white solid. 1H NMR (300 MHz, Dimethylsulfoxide-dg) 5 7.88 (d, J=2.2 Hz, 1H), 7.82 (dd, J=8.4, 2.1 Hz, 1H), 7.72 — 7.64 (m, 1H), 5.00 (s, 2H), 3.88 (s, 3H). 3-(5-Br0m0oxoisoindolin-Z-yl)piperidine—2,6-dione: Methylbromo- 2-(bromomethyl) benzoate (100 g, 324.70 mmol), 3-Aminopiperidine-2,6- dione.hydrochloride (53.2 g, 324.70 mmol), triethylamine (113.29 mL, 811.75 mmol), and dry dimethylformamide (400 mL) were ed and d at room temperature under inert here for 18 h. The reaction was cooled to 5 °C and d with water (400 mL), acetic acid (115 mL), diethylether (300 mL) with continued stirring at room temperature for 2h. The ant solid was filtered, washed with ether (100 mL) and further dried under high vacuum to give 3-(5-Bromooxoisoindolinyl)piperidine-2,6- dione (46 g, 142.35 mmol, 43.8 % yield) as a light blue solid. MS (ESI) m/z 325.0 [M+1]+. 2-(2,6-di0x0piperidinyl)—1-oxoisoindoline-S-carbonitrile: 3-(5-Bromooxoisoindolinyl)piperidine-2,6-dione (46 g, 142.35 mmol), 1,1 ’-Bis(diphenylphosphino)ferrocene (788 mg, 1.423 mmol), zinc cyanide (25 g, 213.52 mmol), zinc acetate (7.83 g, 42.7 mmol) and dry dimethylformamide (360 mL) were combined and degassed before addition of tris(dibenzylideneacetone)dipalladium(0) —104— (0.364 g, 0.398 mmol). The mixtures was evacuated and ed with argon 3 times, then stirred at 120 CC for 20 h. The mixture was cooled to room temperature, filtered and purified by silica column chromatography (0-5% ol in dichloromethane). Fractions containing product were combined and solvent removed under reduced pressure and then further dried under high vacuum to give 2-(2,6-dioxopiperidinyl)oxoisoindoline carbonitrile (22 g, 81.78 mmol, 57.2 % yield) as a brown solid. MS (ESI) m/z 268.0 [M-H+]. 3-(5-(amin0methyl)—1-0x0is0ind01inyl)piperidine—Z,6-di0ne: -Dioxopiperidinyl)oxoisoindolinecarbonitrile (10 g, 37.13 mmol), methanesulfonic acid (2.6 mL, 40.85 mmol), 10% dry Palladium on carbon (4 g) and dimethylacetamide (320 mL) were combined and shaken in a hydrogenation vessel and kept under 50 Psi at 40 0C for 20 h. The hydrogen atmosphere was evacuated and the mixture was filtered through a celite pad, washed with water (100 mL), and concentrated.
To the resulting residue was added 1% methanol-dichloromethane which upon filtration and drying under high vacuum gave 3-(5-(aminomethyl)oxoisoindolinyl)piperidine- 2,6-dione (5.6 g, 15.17 mmol, 40 % yield) as an off-white solid. MS (ESI) m/z 272.0 [M-l].
N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluor0(4-meth0xyphenyl)acetamide. To 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione methanesulfonate (.200 g, 0.541 mmol) in DMF (3 mL) was added HATU (0.226 g, 0.596 mmol), fiuoro(4-methoxyphenyl)acetic acid (0.109 g, 0.541 mmol) followed by N—ethyl-N—isopropylpropanamine (0.262 mL, 1.624 mmol).
Let stir at 25 CC for 16 h. Added 30 mL of water and d. Rinsed with EtOAc, dried under vacumm to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)- fiuoro(4-methoxyphenyl)acetamide (0.080 g, 0.175 mmol, 32.3 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 ppm 10.98 (s, 1 H) 9.57 (t, J=6.15 Hz, 1 H) 7.69 (d, J=7.88 Hz, 1 H) 7.48 - 7.57 (m, 2 H) 7.34 - 7.45 (m, 2 H) 7.07 (m, J=8.83 Hz, 2 H) 5.11 (dd, J=13.24, 5.36 Hz, 1 H) 4.38 - 4.50 (m, 3 H) 4.23 - 4.36 (m, 1 H) 3.81 (s, 3 H) 2.85 - 2.98 (m, 1 H) 2.56 - 2.68 (m, 1 H) 2.39 (dd, J=12.93, 4.73 Hz, 1 H) 1.95 - 2.07 (m, 1 H). MS (ESI) m/Z 458.2 [M+1]+.
Example 2 Synthesis of 2-(3-chlorophenyl)-N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)—2,2-difluoroacetamide g > SFF CI 0 Nb—Qfo o 2-(3-chlorophenyl)—N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)—2,2-diflu0r0acetamide. To 3-(5-(arninornethyl)—1-oxoisoindolin yl)piperidine-2,6-dione rnethanesulfonate (.200 g, 0.541 rnrnol) in DMF (3 rnL) was added HATU (0.226 g, 0.596 ), 2-(3-chlorophenyl)-2,2-difluoroacetic acid (0.112 g, 0.541 rnrnol) followed by N—ethyl-N—isopropylpropanarnine (0.262 rnL, 1.624 rnrnol).
Let stir at 25 CC for 16 h. Added 30 rnL of water and filtered. Rinsed with EtOAc, dried under vacurnrn to afford 2-(3-chlorophenyl)-N—((2-(2,6-dioxopiperidinyl)-1 - indolinyl)rnethyl)-2,2-difluoroacetarnide (.090 g, 0.195 rnrnol, 36.0 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 ppm 10.98 (s, 1 H) 9.70 (t, J=5.99 Hz, 1 H) 7.53 - 7.71 (rm, 5 H) 7.32 - 7.45 (rm, 2 H) 5.11 (dd, J=13.40, 5.20 Hz, 1 H) 4.39 - 4.51 (rm, 3 H) 4.25 - 4.38 (rm, 1 H) 2.85 - 2.99 (rm, 1 H) 2.55 - 2.68 (rm, 1 H) 2.40 (dd, J=13.08, 4.57 Hz, 1 H) 1.95 - 2.05 (rm, 1 H). MS (ESI) m/z 462.2 [M+1]+.
Example 3 Synthesis of N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- o-Z-(4-flu0r0phenyl)acetamide o MCI—Q?) o N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluor0(4-flu0r0phenyl)acetamide. To 3-(5-(arninornethyl)—1-oxoisoindolin yl)piperidine-2,6-dione rnethanesulfonate (.200 g, 0.541 rnrnol) in DMF (3 rnL) was added HATU (0.226 g, 0.596 rnrnol), 2,2-difluoro(4-fluorophenyl)acetic acid (0.103 g, 0.541 rnrnol) followed by N—ethyl-N—isopropylpropanarnine (0.262 rnL, 1.624 rnrnol).
Let stir at 25 CC for 16 h. Added 30 rnL of water and d. Rinsed with EtOAc, dried under vacurnrn to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolin-5 -yl)rnethyl)- 2,2-difluoro(4-fluorophenyl)acetarnide (0.100 g, 0.225 rnrnol, 41.5 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 ppm 10.98 (br. s., 1 H) 9.66 (t, J=5.99 Hz, 1 H) 7.58 - 7.73 (rm, 3 H) 7.29 - 7.47 (rm, 4 H) 5.11 (dd, J=13.40, 5.20 Hz, 1 H) 4.38 - 4.53 (rm, 3 H) 4.24 - 4.36 (rm, 1 H) 2.81 - 3.00 (rm, 1 H) 2.56 - 2.67 (rm, 1 H) 2.40 (qd, J=13.19, 4.57 Hz, 1 H) 1.91 - 2.07 (rm, 1 H).
Example 4 Synthesis of (2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)-2,2- diflu0r0(p-tolyl)acetamide _< >_§F o hie—Q?) o N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)-2,2- diflu0r0(p-tolyl)acetamide. To 3-(5-(arninornethyl)oxoisoindolinyl)piperidine- 2,6-dione methanesulfonate (.200 g, 0.541 rnrnol) in DMF (3 mL) was added HATU (0.226 g, 0.596 rnrnol), 2,2-difluoro(p-tolyl)acetic acid (0.101 g, 0.541 mmol) followed by N—ethyl-N—isopropylpropanarnine (0.262 rnL, 1.624 rnrnol). Let stir at 25 CC for 16 h. Added 30 mL of water and filtered. Rinsed with EtOAc, dried under vacurnrn to afford N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)rnethyl)-2,2-difluoro (p-tolyl)acetarnide (.110 g, 0.249 rnrnol, 46.0 % yield) as a White solid. 1H NMR (500 MHz, DMSO-d6) 8 ppm 10.98 (s, 1 H) 9.59 (t, J=6.15 Hz, 1 H) 7.68 (d, J=7.88 Hz, 1 H) 7.48 (d, J=8.20 Hz, 2 H) 7.26 - 7.43 (rm, 4 H) 5.11 (dd, 4, 5.04 Hz, 1 H) 4.37 - 4.50 (rm, 3 H) 4.22 - 4.34 (rm, 1 H) 2.84 - 2.99 (rm, 1 H) 2.56 - 2.67 (rm, 1 H) 2.31 - 2.45 (rm, 4 H) 1.93 - 2.07 (rm, 1 H). MS (ESI) m/z 442.2 [M+1]+.
Example 5 Synthesis of 2-(3,4-dichlorophenyl)-N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)-2,2-difluoroacetamide 2-(3,4-dichlorophenyl)-N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin- -yl)methyl)-2,2-difluoroacetamide. To 3-(5-(arninornethyl)—1-oxoisoindolin yl)piperidine-2,6-dione rnethanesulfonate (.200 g, 0.541 rnrnol) in DMF (3 rnL) was added HATU (0.226 g, 0.596 rnrnol), 2-(3,4-dichlorophenyl)—2,2-difluoroacetic acid (0.130 g, 0.541 rnrnol) followed by N—ethyl-N—isopropylpropanarnine (0.262 rnL, 1.624 ).
Let stir at 25 CC for 16 h. Added 30 rnL of water and filtered. Rinsed with EtOAc, dried under vacurnrn to afford 2-(3,4-dichlorophenyl)—N—((2-(2,6-dioxopiperidinyl) oxoisoindolinyl)rnethyl)-2,2-difluoroacetarnide (.110 g, 0.222 rnrnol, 40.9 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 ppm 10.98 (s, 1 H) 9.71 (t, J=5.99 Hz, 1 H) 7.79 - 7.88 (rm, 2 H) 7.69 (d, J=7.88 Hz, 1 H) 7.59 (dd, , 2.21 Hz, 1 H) 7.43 (s, 1 H) 7.38 (d, J=7.88 Hz, 1 H) 5.11 (dd, J=13.08, 5.20 Hz, 1 H) 4.39 - 4.51 (rm, 3 H) 4.26 - 4.37 (rm, 1 H) 2.86 - 2.98 (rm, 1 H) 2.61 (d, 2 Hz, 1 H) 2.39 (dd, J=13.40, 4.89 Hz, 1 H) 1.95 — 2.06 (rm, 1 H). MS (ESI) m/Z 498.0 [M+1]+.
Synthesis of 2-(2-chlorophenyl)-N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)—2,2-difluoroacetamide Qfi;F NH O ‘—< 270 O N{1% 2-(2-chlorophenyl)—N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)—2,2-diflu0r0acetamide. To 3 -(5-(arninornethyl)oxoisoindolin yl)piperidine-2,6-dione rnethanesulfonate (0.200 g, 0.541 rnrnol) in DMF (3 rnL) was added HATU (0.226 g, 0.596 rnrnol), 2-(2-chlorophenyl)-2,2-difluoroacetic acid (0.112 g, 0.541 rnrnol) followed by l-N—isopropylpropanarnine (0.262 rnL, 1.624 rnrnol).
Let stir at 25 CC for 16 h. Added 30 rnL of water and filtered. Rinsed with EtOAc, dried under vacurnrn to afford 2-(2-chlorophenyl)-N-((2-(2,6-dioxopiperidinyl)-1 - oxoisoindolinyl)rnethyl)-2,2-difluoroacetarnide (.090 g, 0.195 rnrnol, 36.0 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 ppm 10.98 (s, 1 H) 9.68 (t, J=6.31 Hz, 1 H) 7.68 - 7.79 (rm, 2 H) 7.56 - 7.63 (rm, 2 H) 7.49 - 7.56 (rm, 2 H) 7.46 (d, J=7.88 Hz, 1 H) .12 (dd, J=13.24, 5.36 Hz, 1 H) 4.40 - 4.56 (rm, 3 H) 4.27 - 4.38 (rm, 1 H) 2.92 (ddd, J=17.50, 13.71, 5.36 Hz, 1 H) 2.61 (d, 1 Hz, 1 H) 2.32 - 2.46 (rm, 1 H) 1.94 - 2.10 (rm, 1 H). MS (ESI) m/Z 462.0 [M+1]+.
Example 7 Synthesis of 2-(4-chlorophenyl)-N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)-2,2-difluoroacetamide 0 NW00 2-(4-chlorophenyl)—N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)-2,2-diflu0r0acetamide. To 3 rninornethyl)oxoisoindolin yl)piperidine-2,6-dione methanesulfonate (.200 g, 0.541 rnrnol) in DMF (3 mL) was added HATU (0.226 g, 0.596 rnrnol), 2-(4-chlorophenyl)-2,2-difluoroacetic acid (0.112 g, 0.541 rnrnol) followed by N—ethyl-N—isopropylpropanarnine (0.262 rnL, 1.624 rnrnol).
Let stir at 25 CC for 16 h. Added 30 rnL of water and filtered. Rinsed With EtOAc, dried under vacurnrn to afford 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidinyl)-1 - oxoisoindoliny1)rnethy1)-2,2-difluoroacetarnide (.080 g, 0.173 , 32.0 % yield) as a White solid. 1H NMR (500 MHz, DMSO-d6) 8 ppm 10.98 (s, 1 H) 9.68 (t, J=6.15 Hz, 1 H) 7.69 (d, J=7.88 Hz, 1 H) 7.58 - 7.66 (rm, 4 H) 7.33 - 7.44 (rm, 2 H) 5.11 (dd, J=13.24, .04 Hz, 1 H) 4.39 - 4.50 (rm, 3 H) 4.24 - 4.35 (rm, 1 H) 2.85 - 2.98 (rm, 1 H) 2.61 (dd, J=15.29, 2.05 Hz, 1 H) 2.39 (dd, J=12.93, 4.73 Hz, 1 H) 1.95 - 2.07 (rm, 1 H). MS (ESI) m/Z 462.0 [M+1]+.
Example 8 Synthesis of N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)-2,2- difluoro-Z-(2-(trifluoromethyl)phenyl)acetamide O Z:N O 1&1" (2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)-2,2- difluor0(2-(triflu0r0methyl)phenyl)acetamide. To 3-(5-(aminornethyl)— 1 - oxoisoindolinyl)piperidine-2,6-dione rnethanesulfonate (.200 g, 0.541 rnrnol) in DMF (3 rnL) was added HATU (0.226 g, 0.596 ), 2,2-difluoro(2- (trifluorornethyl)phenyl)acetic acid (0.130 g, 0.541 rnrnol) ed by N—ethyl-N— isopropylpropanarnine (0.262 rnL, 1.624 rnrnol). Let stir at 25 CC for 16 h. Added rnL of water and filtered. Rinsed with EtOAc, dried under vacurnrn to afford N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 ethyl)-2,2-difluoro(2- (trifluorornethyl)phenyl)acetarnide (.080 g, 0.161 rnrnol, 29.8 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 ppm 10.98 (s, 1 H) 9.70 (t, J=6.15 Hz, 1 H) 7.66 - 7.81 (rm, 3 H) 7.47 - 7.59 (rm, 3 H) 7.44 (d, J=8.51 Hz, 1 H) 5.12 (dd, J=13.40, 5.20 Hz, 1 H) 4.40 - 4.54 (rm, 3 H) 4.27 - 4.38 (rm, 1 H) 2.85 - 3.00 (rm, 1 H) 2.57 - 2.67 (rm, 1 H) 2.35 - 2.45 (rn, 1H) 1.94 - 2.07 (rm, 1 H).
Synthesis of 2-(4-(tert—butyl)phenyl)-N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin- -yl)methyl)—2,2-diflu0roacetamide : : F g—NHF O O Z :N 0 f1"0 2-(4-(tert—butyl)phenyl)-N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To 3-(5-(arninornethyl) oxoisoindolinyl)piperidine-2,6-dione rnethanesulfonate (0.200 g, 0.541 ) in DMF (3 rnL) was added HATU (0.226 g, 0.596 rnrnol), 2-(4-(tert-butyl)phenyl)-2,2- difluoroacetic acid (0.124 g, 0.541 rnrnol) followed by N-ethyl-N-isopropylpropan amine (0.262 rnL, 1.624 rnrnol). Let stir at 25 CC for 16 h. Added 30 rnL of water and filtered. Rinsed with EtOAc, dried under vacurnrn to afford 2-(4-(tert-butyl)phenyl)—N— ((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)rnethyl)-2,2-difluoroacetarnide (0.095 g, 0.196 rnrnol, 36.3 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 ppm 10.98 (s, 1 H) 9.61 (t, J=5.99 Hz, 1 H) 7.68 (d, J=7.88 Hz, 1 H) 7.49 - 7.60 (rm, 4 H) 7.33 - 7.44 (rm, 2 H) 5.11 (dd, J=13.24, 5.04 Hz, 1 H) 4.37 - 4.50 (rm, 3 H) 4.24 - 4.35 (rm, 1 H) 2.86 - 2.98 (rm, 1 H) 2.57 - 2.67 (rm, 1 H) 2.38 (dd, J=13.40, 4.57 Hz, 1 H) 1.92 - 2.06 (rm, 1 H) 1.22 - 1.36 (rm, 9 H). MS (ESI) m/z 484.0 [M+1]+.
Example 10 Synthesis of N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- 0phenylacetamide A. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluor0phenylacetamide. 3 -(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6- dione, c acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—dimethylformamide (1.0 mL), 2,2-difluorophenylacetic acid (0.023 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was taken up in dimethylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). Fractions containing desired product were combined and volatile organics were removed under reduced pressure to give (2,6- dioxopiperidin-3 -yl)— 1 -oxoisoindolin-5 -yl)methyl)-2,2-difluorophenylacetamide (0.039 g, 0.091 mmol, 67.4 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 11.00 (s, 1H), 9.67 (t, J: 6.25 Hz, 1H), 7.67 (d, J: 7.81 Hz, 1H), 7.50 - 7.62 (m, 5H), 7.34 - 7.42 (m, 2H), 5.11 (dd, J: 5.08, 13.28 Hz, 1H), 4.38 - 4.47 (m, 3H), 4.24 - 4.31 (m, 1H), 2.86 - 2.97 (m, 1H), 2.55 - 2.64 (m, 1H), 2.32 - 2.45 (m, 1H), 1.99 (dtd, J= 2.34, .25, 12.55 Hz, 1H). MS (ESI) m/z 428.2 [M+1]+.
Example 11 sis of 2-(3-chlor0flu0rophenyl)—N-((2-(2,6-di0x0piperidinyl) oxoisoindolin-S-yl)methyl)—2,2-diflu0roacetamide .. of H N O ] A. 2-(3-chlor0flu0r0phenyl)—N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)—2,2-difluoroacetamide. 3 -(5-(aminomethyl)oxoisoindolin- 2-yl)piperidine-2,6-dione, c acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2-(3-chlorofluorophenyl)-2,2-difluoroacetic acid (0.030 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and (dimethylamino)methylene]-1H-1 ,2,3 olo [4,5-b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was taken up in dimethylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). Fractions containing desired product were combined and volatile organics were removed under reduced pressure to give 2-(3-chloro- 4-fluorophenyl)-N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- oacetamide as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 11.01 (s, 1H), 9.72 (t, J: 6.05 Hz, 1H), 7.81 (dd, J: 1.76, 7.23 Hz, 1H), 7.69 (d, J: 7.81 Hz, 1H), 7.58 - 7.65 (m, 2H), 7.43 (s, 1H), 7.35 - 7.39 (m, 1H), 5.11 (dd, J: 5.08, 13.28 Hz, 1H), 4.40 - 4.48 (m, 3H), 4.26 - 4.34 (m, 1H), 2.92 (ddd, J: 5.47, 13.77, 17.48 Hz, 1H), 2.56 - 2.64 (m, 1H), 2.31 - 2.45 (m, 1H), 1.95 - 2.04 (m, 1H). MS (ESI) m/z 480.0 [M+1]+.
Example 12 Synthesis of 2-(2,6-diflu0rophenyl)-N-((2-(2,6-di0x0piperidinyl)-l-oxoisoindolin-S- yl)methyl)—2,2-difluoroacetamide A. 2-(2,6-diflu0rophenyl)-N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. 3 -(5-(aminomethyl)oxoisoindolin- 2-yl)piperidine-2,6-dione, Mesylic acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2-(2,6-difluorophenyl)-2,2-difluoroacetic acid (0.028 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was taken up in dimethylsulfoxide and purified using reverse-phase semi atory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). Fractions containing desired product were combined and volatile organics were d under reduced pressure to give 2-(2,6- difluorophenyl)-N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoroacetamide (0.039 g, 0.084 mmol, 62.2 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.98 (s, 1H), 9.73 (t, J: 5.99 Hz, 1H), 7.65 - 7.73 (m, 2H), 7.49 (s, 1H), 7.43 (d, J: 7.88 Hz, 1H), 7.27 (dd, J: 8.67, 9.62 Hz, 2H), 5.11 (dd, J: 5.20, 13.40 Hz, 1H), 4.50 (d, J: 5.99 Hz, 2H), 4.46 (d, J: 17.34 Hz, 1H), 4.29 - 4.35 (m, 1H), 2.91 (ddd, J: 5.36, 13.71, 17.50 Hz, 1H), 2.57 - 2.63 (m, 1H), 2.40 (qd, J: 4.57, 13.19 Hz, 1H), 2.01 (dtd, J: 2.36, 5.26, 12.65 Hz, 1H). MS (ESI) m/z 464.2 [M+1]+.
Example 13 Synthesis of 2-(5-chlor0meth0xyphenyl)-N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-diflu0roacetamide A. 2-(5-chlor0methoxyphenyl)-N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. 3 -(5-(aminomethyl)oxoisoindolin- 2-yl)piperidine-2,6-dione, Mesylic acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2-(5-chloromethoxyphenyl)—2,2-difluoroacetic acid (0.032 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The on mixture was stirred at room temperature for 18 h. The reaction mixture was taken up in dimethylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). ons containing desired product were ed and volatile organics were d under reduced pressure to give 2-(5-chloro- 2-methoxyphenyl)—N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoroacetamide (0.044 g, 0.089 mmol, 66.1 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.97 (s, 1H), 9.41 (t, J: 5.99 Hz, 1H), 7.73 (d, J: 7.88 Hz, 1H), 7.59 (dd, J: 2.84, 8.83 Hz, 1H), 7.53 (d, J: 2.52 Hz, 1H), 7.48 (s, 1H), 7.43 (d, J = 7.57 Hz, 1H), 7.17 (d, J: 8.83 Hz, 1H), 5.11 (dd, J: 5.20,13.40 Hz, 1H), 4.43 - 4.49 (m, 3H), 4.29 - 4.35 (m, 1H), 3.68 (s, 3H), 2.91 (ddd, J: 5.36, 13.71, 17.50 Hz, 1H), 2.57 - 2.63 (m, 1H), 2.40 (qd, J= 4.26, 13.08 Hz, 1H), 2.00 (dtd, J= 2.52, 5.32, 12.69 Hz, 1H).
MS (ESI) m/Z 492.2 [M+1]+.
WO 07848 Example 14 Synthesis of N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- diflu0r0(5-flu0r0methoxyphenyl)acetamide ] A. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- diflu0r0(5-flu0r0methoxyphenyl)acetamide. 3-(5 -(aminomethyl)oxoisoindolin- 2-yl)piperidine-2,6-dione, Mesylic acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2,2-difluoro(5-fluoromethoxyphenyl)acetic acid (0.030 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was taken up in dimethylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). Fractions ning desired product were combined and volatile organics were removed under reduced pressure to give N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)-2,2-difluoro(5-fluoro methoxyphenyl)acetamide (0.043 g, 0.090 mmol, 66.8 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.97 (s, 1H), 9.40 (t, J: 5.99 Hz, 1H), 7.73 (d, J: 7.57 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J: 7.88 Hz, 1H), 7.36 - 7.41 (m, 2H), 7.13 - 7.18 (m, 1H), 5.11 (dd, J: 5.20, 13.40 Hz, 1H), 4.43 - 4.50 (m, 3H), 4.29 - 4.35 (m, 1H), 3.65 (s, 3H), 2.92 (ddd, J: 5.52, 13.64, 17.42 Hz, 1H), 2.57 - 2.63 (m, 1H), 2.40 (qd, J: 4.10, 13.24 Hz, 1H), 2.01 (dtd, J: 2.21, 5.34, 12.65 Hz, 1H). MS (ESI) m/z 476.0[M+1]+.
Example 15 Synthesis of N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- diflu0r0(o-tolyl)acetamide —114— A. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- diflu0r0(o-tolyl)acetamide. 3 -(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6- dione, Mesylic acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2,2-difluoro(o-tolyl)acetic acid (0.025 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction e was stirred at room temperature for 18 h. The reaction mixture was taken up in dimethylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). Fractions containing desired product were combined and volatile organics were removed under reduced pressure to give N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)-2,2-difluoro yl)acetamide (0.038 g, 0.086 mmol, 63.6 % yield) as a white solid. 1H NMR (500 MHz, 6) 8 10.97 (s, 1H), 9.59 (t, J: 5.99 Hz, 1H), 7.69 (d, J: 8.20 Hz, 1H), 7.50 - 7.53 (m, 1H), 7.39 - 7.46 (m, 3H), 7.28 - 7.34 (m, 2H), 5.10 (dd, J: 5.36, 13.24 Hz, 1H), 4.41 - 4.49 (m, 3H), 4.27 - 4.33 (m, 1H), 2.87 - 2.95 (m, 1H), 2.57 - 2.63 (m, 1H), 2.39 (qd, J: 4.41, 13.24 Hz, 1H), 2.33 (s, 3H), 2.00 (dtd, J: 2.21, 5.32, 12.69 Hz, 1H). MS (ESI) m/z 442.2 [M+1]+.
Example 16 Synthesis of 2-(dimethylamin0)0x0ethoxy)phenyl)—N-((2-(2,6-di0x0piperidin- 3-yl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0roacetamide /m"0N O A. 2-(4-(2-(dimethylamino)oxoethoxy)phenyl)-N-((2-(2,6- dioxopiperidin-3 -yl)oxoisoindolin—5-yl)methyl)-2,2-difluoroacetamide. 3 -(5 - (aminomethyl)oxoisoindolinyl)piperidine-2,6-dione, c acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2-(4-(2-(dimethylamino)oxoethoxy)phenyl)-2,2-difluoroacetic acid (0.037 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid orophosphate (0.057 g, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction e was taken up in ylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). Fractions containing desired product were combined and volatile organics were removed under reduced pressure to give 2-(4-(2-(dimethylamino)oxoethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3 -yl)-1 - oxoisoindolinyl)methyl)-2,2-difluoroacetamide (0.021 g, 0.040 mmol, 29.4 % yield) as a white solid. 1H NMR (500 MHz, 6) 8 10.97 (s, 1H), 9.56 (t, J: 6.15 Hz, 1H), 7.67 (dd, J: 0.63, 7.57 Hz, 1H), 7.46 - 7.50 (m, 2H), 7.35 - 7.38 (m, 2H), 7.00 - 7.04 (m, 2H), 5.10 (dd, J: 5.20, 13.40 Hz, 1H), 4.89 (s, 2H), 4.39 - 4.46 (m, 3H), 4.26 - 4.31 (m, 1H), 2.99 (s, 3H), 2.87 - 2.95 (m, 1H), 2.84 (s, 3H), 2.57 - 2.62 (m, 1H), 2.33 - 2.43 (m, 1H), 2.00 (dtd, J= 2.36, 5.18, 12.49 Hz, 1H). MS (ESI) m/z 529.2 .
Example 17 Synthesis of 2-(2,5-dimeth0xyphenyl)-N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin- -yl)methyl)—2,2-diflu0roacetamide A. -dimeth0xyphenyl)-N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. 3 -(5-(aminomethyl)oxoisoindolin- 2-yl)piperidine-2,6-dione, Mesylic acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2-(2,5-dimethoxyphenyl)-2,2-difluoroacetic acid (0.031 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was taken up in dimethylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). Fractions containing desired product were combined and volatile organics were removed under reduced pressure to give 2-(2,5 -dimethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3 -oxoisoindolin-5 -yl)methyl)- 2,2-difluoroacetamide (0.043 g, 0.088 mmol, 65.2 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.97 (s, 1H), 9.33 (t, J: 5.99 Hz, 1H), 7.72 (d, J: 7.88 Hz, 1H), 7.49 (s, 1H), 7.42 - 7.46 (m, 1H), 7.04 - 7.10 (m, 3H), 5.11 (dd, J: 5.20, 13.40 Hz, 1H), 4.43 - 4.49 (m, 3H), 4.29 - 4.35 (m, 1H), 3.75 (s, 3H), 3.61 (s, 3H), 2.91 (ddd, J = 5.52, 13.56, 17.50 Hz, 1H), 2.57 - 2.64 (m, 1H), 2.40 (qd, J= 4.73, 13.24 Hz, 1H), 2.00 (dtd, J: 2.36, 5.30, 12.57 Hz, 1H). MS (ESI) m/z 488.2 [M+1]+.
Example 18 Synthesis of N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluoro-Z-(2-flu0r0phenyl)acetamide A. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluoro-Z-(2-flu0r0phenyl)acetamide. 3-(5-(aminomethyl)oxoisoindolin eridine-2,6-dione, Mesylic acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2,2-difluoro(2-fluorophenyl)acetic acid (0.026 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was taken up in dimethylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % itrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). Fractions containing desired product were combined and volatile organics were removed under reduced pressure to give N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)-2,2-difluoro(2- fluorophenyl)acetamide (0.030 g, 0.067 mmol, 49.8 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.97 (s, 1H), 9.69 (t, J: 6.15 Hz, 1H), 7.70 (d, J: 8.20 Hz, 1H), 7.61 - 7.67 (m, 2H), 7.47 (s, 1H), 7.40 - 7.44 (m, 1H), 7.34 - 7.40 (m, 2H), 5.11 (dd, J = 5.20, 13.40 Hz, 1H), 4.50 (d, J: 6.31 Hz, 2H), 4.45 (d, J: 17.34 Hz, 1H), 4.29 - 4.34 (m, 1H), 2.91 (ddd, J: 5.52, 13.64, 17.42 Hz, 1H), 2.57 - 2.63 (m, 1H), 2.40 (qd, J= 4.73, 13.24 Hz, 1H), 2.01 (dtd, J: 2.36, 5.26, 12.65 Hz, 1H). MS (ESI) m/z 446.2 [M+1]+.
Example 19 Synthesis of N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolinyl)methyl)—2-(2- eth0xyphenyl)—2,2-difluoroacetamide L O A. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2-(2- eth0xyphenyl)—2,2-difluoroacetamide. 3 -(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione, Mesylic acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2-(2-ethoxyphenyl)—2,2-difluoroacetic acid (0.029 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo ]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was taken up in dimethylsulfoxide and purified using reverse-phase semi atory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). ons containing desired product were combined and volatile organics were removed under reduced pressure to give N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)(2-ethoxyphenyl)-2,2- difluoroacetamide (0.045 g, 0.095 mmol, 70.5 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.97 (s, 1H), 9.31 (t, J: 6.15 Hz, 1H), 7.70 (d, J: 7.88 Hz, 1H), 7.55 (dd, J: 1.58, 7.57 Hz, 1H), 7.47 - 7.52 (m, 2H), 7.45 (d, J: 8.51 Hz, 1H), 7.11 (d, J: 8.20 Hz, 1H), 7.05 (td, J= 0.79, 7.49 Hz, 1H), 5.11 (dd, J: 5.20, 13.40 Hz, 1H), 4.42 - 4.48 (m, 3H), 4.28 - 4.34 (m, 1H), 3.99 (q, .1: 6.94 Hz, 2H), 2.87 - 2.96 (m, 1H), 2.57 - 2.63 (m, 1H), 2.40 (qd, J= 4.41, 13.24 Hz, 1H), 2.00 (dtd, J= 2.21, 5.08, 12.53 Hz, 1H), 1.13 (t, .1: 6.94 Hz, 3H). MS (ESI) m/z 472.2 [M+1]+. e 20 Synthesis of N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluoro-Z-(2-(trifluoromethoxy)phenyl)acetamide FXO F A. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluor0(2-(triflu0r0methoxy)phenyl)acetamide. 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione, Mesylic acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2,2-difluoro(2- (trifluoromethoxy)phenyl)acetic acid (0.035 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was taken up in ylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). Fractions containing desired product were ed and volatile organics were removed under d pressure to give N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)- 2,2-difluoro(2-(trifluoromethoxy)phenyl)acetamide (0.047 g, 0.092 mmol, 67.9 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.97 (s, 1H), 9.69 (t, J: 5.83 Hz, 1H), 7.77 (dd, J: 1.58, 7.88 Hz, 1H), 7.68 - 7.74 (m, 2H), 7.48 - 7.56 (m, 3H), 7.43 (d, J: 7.88 Hz, 1H), 5.11 (dd, J: 5.04, 13.24 Hz, 1H), 4.49 (d, .1: 6.31 Hz, 2H), 4.44 (d, .1: 17.34 Hz, 1H), 4.28 - 4.33 (m, 1H), 2.91 (ddd, J: 5.36, 13.79, 17.42 Hz, 1H), 2.57 - 2.63 (m, 1H), 2.40 (qd, J: 4.26, 13.19 Hz, 1H), 2.00 (dtd, J: 2.36, 5.26, 12.65 Hz, 1H).
MS (ESI) m/Z 512.2 [M+1]+.
Example 21 Synthesis of 2-(3-br0m0(triflu0r0meth0xy)phenyl)-N-((2-(2,6-di0x0piperidinyl)— soindolin-S-yl)methyl)—2,2-diflu0r0acetamide ] A. 2-(3-br0m0(trifluorometh0xy)phenyl)-N-((2-(2,6-di0x0piperidin- 3-yl)—1-oxoisoindolinyl)methyl)—2,2-difluoroacetamide. 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione, Mesylic acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2-(3-bromo (trifluoromethoxy)phenyl)-2,2-difluoroacetic acid (0.045 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and 1-[Bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol).
The reaction mixture was stirred at room ature for 18 h. The reaction e was taken up in dimethylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min).
Fractions containing d product were combined and le organics were removed under reduced pressure to give 2-(3-bromo(trifluoromethoxy)phenyl)—N—((2-(2,6- dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoroacetamide (0.048 g, 0.081 mmol, 60.1 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.99 (s, 1H), 9.75 (t, J: 6.15 Hz, 1H), 8.01 (d, J: 1.89 Hz, 1H), 7.73 - 7.78 (m, 2H), 7.69 (d, J = 7.57 Hz, 1H), 7.45 (s, 1H), 7.38 (d, J: 7.88 Hz, 1H), 5.11 (dd, J: 5.04, 13.24 Hz, 1H), 4.41 - 4.49 (m, 3H), 4.28 - 4.34 (m, 1H), 2.92 (ddd, J: 5.36, 13.71, 17.50 Hz, 1H), 2.58 - 2.64 (m, 1H), 2.39 (qd, J: 4.41, 13.24 Hz, 1H), 2.01 (dtd, J: 2.21, 5.20, 12.61 Hz, 1H). MS (ESI) m/Z 592.0 [M+2]+.
Example 22 Synthesis of N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluoropropanamide A. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluoropropanamide. aminomethyl)oxoisoindolinyl)piperidine-2,6-dione, Mesylic acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2,2-difluoropropanoic acid (0.015 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was taken up in dimethylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). Fractions containing d product were combined and volatile organics were removed under reduced pressure to give N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)- 2,2-difluoropropanamide (0.016 g, 0.044 mmol, 32.4 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.98 (s, 1H), 9.36 (t, J: 5.99 Hz, 1H), 7.71 (d, J: 7.88 Hz, 1H), 7.49 (s, 1H), 7.42 (d, J: 7.88 Hz, 1H), 5.12 (dd, J: 5.20, 13.40 Hz, 1H), 4.43 - 4.49 2015/039926 (m, 3H), 4.30 - 4.35 (m, 1H), 2.92 (ddd, J: 5.52, 13.64, 17.42 Hz, 1H), 2.58 - 2.64 (m, 1H), 2.40 (qd, J: 4.57,13.19 Hz, 1H), 2.01 (dtd, J= 2.21, 5.16, 12.69 Hz, 1H), 1.74 - 1.84 (m, 3H). MS (ESI) m/Z 366.2 [M+1]+.
Example 23 Synthesis of N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2,3,3- tetrafluoropropanamide A. (2,6-di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2,3,3- tetrafluoropropanamide. 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione, Mesylic acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2,2,3,3-tetrafluoropropanoic acid (0.020 g, 0.135 mmol), ropylethylamine (0.071 mL, 0.406 mmol), and 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The on mixture was stirred at room temperature for 18 h. The reaction mixture was taken up in dimethylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). Fractions containing desired product were combined and volatile organics were removed under reduced pressure to give N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)- 2,2,3,3-tetrafluoropropanamide (0.013 g, 0.032 mmol, 23.93 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.97 (s, 1H), 9.92 (t, J: 5.99 Hz, 1H), 7.71 (d, J = 7.88 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J: 7.88 Hz, 1H), 6.64 - 6.89 (m, 1H), 5.11 (dd, J = 5.04, 13.24 Hz, 1H), 4.50 (d, J: 6.31 Hz, 2H), 4.46 (d, J: 17.34 Hz, 1H), 4.29 - 4.34 (m, 1H), 2.87 - 2.95 (m, 1H), 2.57 - 2.63 (m, 1H), 2.39 (qd, J= 4.73, 13.24 Hz, 1H), 2.00 (dtd, J: 2.21, 5.24, 12.53 Hz, 1H). MS (ESI) m/z 402.0 [M+1]+.
Example 24 Synthesis of N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)-2,2- difluorobutanamide MWFF WO 07848 A. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- obutanamide. 3-(5-(aminomethyl)- l -oxoisoindolinyl)piperidine-2,6-dione, Mesylic acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2,2-difluorobutanoic acid (0.017 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction e was taken up in dimethylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). Fractions containing desired product were combined and volatile organics were d under reduced pressure to give (2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)- 2,2-difluorobutanamide (0.027 g, 0.071 mmol, 52.6 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.97 (s, 1H), 9.37 (t, J: 5.99 Hz, 1H), 7.70 (d, J: 7.88 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J: 7.88 Hz, 1H), 5.10 (dd, J: 5.20, 13.40 Hz, 1H), 4.42 - 4.48 (m, 3H), 4.28 - 4.34 (m, 1H), 2.91 (ddd, J: 5.36, 13.64, 17.58 Hz, 1H), 2.57 - 2.63 (m, 1H), 2.39 (qd, J= 4.57, 13.29 Hz, 1H), 1.97 - 2.14 (m, 3H), 0.92 (t, .1: 7.41 Hz, 3H). MS (ESI) m/Z 380.2 [M+1]+.
Example 25 Synthesis of N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- diflu0r0hydr0xymethylbutanamide ] A. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- diflu0r0hydroxymethylbutanamide. 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione, Mesylic acid (0.050 g, 0.135 mmol) was placed in a vial with N,N—Dimethylformamide (1.0 mL), 2,2-difluorohydroxymethylbutanoic acid (0.021 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and l- [Bis(dimethylamino)methylene] - l H- l ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate (0.057 g, 0.149 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was taken up in dimethylsulfoxide and d using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). Fractions containing desired product were -l22- WO 07848 combined and volatile organics were removed under reduced pressure to give N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)-2,2-difiuorohydroxy-3 - methylbutanamide (0.049 g, 0.120 mmol, 88 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.97 (s, 1H), 9.07 (t, J: 5.99 Hz, 1H), 7.68 (d, J: 8.20 Hz, 1H), 7.50 (s, 1H), 7.43 (d, J: 7.25 Hz, 1H), 5.46 (br. s., 1H), 5.10 (dd, J: 5.04, 13.24 Hz, 1H), 4.41 - 4.46 (m, 3H), 4.27 - 4.33 (m, 1H), 2.86 - 2.96 (m, 1H), 2.57 - 2.63 (m, 1H), 2.39 (qd, J: 4.57, 13.19 Hz, 1H), 2.00 (dtd, J: 2.36, 5.26, 12.65 Hz, 1H), 1.24 (s, 6H).
MS (ESI) m/Z 410.2 [M+1]+.
Example 26 2-(3-ch10r0methylphenyl)-N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)—2,2-difluoroacetamide o O F F H N 0 CI N\/©i B. Ethyl 2-(3-chlor0methylphenyl)0x0acetate. To a stirred solution of 1-(3-chloromethylphenyl) ethanone (500 mg, 2.97 mmol) in pyridine (5 mL) was added selenium dioxide (660 mg, 5.95 mmol) and stirred for 12h at 100 oC. The on mixture was diluted with dichloromethane (20 mL) and filtered through Celite pad. To the e was added ethyl chloroformate (2 mL) at 0 CC and d at room temperature for 2h. The reaction mixture was acidified with 1N aqueous hydrochloric acid (up to pH-4) and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with water (2 X 5 mL), brine (5 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(3-chloromethylphenyl)oxoacetate (300 mg, 1.32 mmol, 45%) as a brown liquid. 1H NMR (300 MHZ, DMSO-d6) 5 7.99 (dd, J = 5.5, 1.7 Hz, 1H), 7.86 (dd, J: 7.9, 1.8 Hz, 1H), 7.59 (dd, J: 11.6, 7.9 Hz, 1H), 4.42 (q, J: 7.1 Hz, 2H), 2.44 (s, 3H), 1.33 (t, J: 7.1 Hz, 3H).
C. Ethyl 2-(3-chlor0methylphenyl)—2,2-difluoroacetate. To ethyl hloromethylphenyl)oxoacetate (300 mg, 1.32 mmol) was added diethyl amino sulfur trifluoride (2 mL) and d for 12h at room temperature. The reaction mixture was neutralized with aqueous ted sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with water (2 X 5 mL), brine (10 mL), dried over sodium sulphate and was concentrated to afford ethyl 2-(3-chloromethylphenyl)-2,2-difluoroacetate (200 mg, 0.804 mmol, 61 %) as a brown liquid. 1H NMR (400 MHz, DMSO-d6) 8 7.63 — 7.52 (m, 2H), 7.47 (dd, J: 7.9, 1.9 Hz, 1H), 4.32 (q, .1: 7.1 Hz, 2H), 2.39 (s, 3H), 1.23 (t, J = 7.1 Hz, 4H).
D. 2-(3-chloromethylphenyl)-2,2-diflu0r0acetic acid. To a cold (0 CC) stirred solution of ethyl 2-(3 -chloromethylphenyl)-2,2-difluoroacetate (200 mg, 0.806 mmol) in methanol/ ydrofuran /water (10 mL, 1:1:1) was added lithium hydroxide monohydrate (169 mg, 4.03 mmol) and stirred at room temperature for 2h.
The on mixture was concentrated and the residue was neutralized with 10% aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2 X 15 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2-(3-chloromethylphenyl) -2,2-difluoroacetic acid (150 mg, 0.68 mmol, 84% yield) as a brown semi solid. 1H NMR (300 MHz, DMSO-d6) 8 7.61 — 7.50 (m, 2H), 7.45 (dd, J: 8.0, 1.8 Hz, 1H), 2.39 (s, 3H).
] E. 2-(3-Chlor0methylphenyl)—N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolinyl)methyl)—2,2-diflu0roacetamide. To a cold (0 oC) stirred solution of 3-(5-(amino methyl)oxoisoindolinyl)piperidine-2,6-dione methane sulfonate (200 mg, 0.619 mmol) in N,N—dimethylformamide (20 mL) was added 2-(3-chloro methylphenyl) -2,2-difluoroacetic acid (150 mg, 0.68 mmol) followed by isopropylethylamine (240 mg, 1.85 mmol), 1-[Bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (352 mg, 0.92 mmol) and stirred at room temperature for 12h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl e (2 X 10 mL) and the combined organic —124— WO 07848 layers were washed with brine (20 mL), dried over sodium sulphate and concentrated under vacuum. The product was purified by Reveleris C-18 reversed phase column using 70% acetonitrile in aqueous formic acid (0.1%) to give 2-(3-chloro methylphenyl)-N-((2-(2,6-dioxopiperidinyl)oxoisoindolin-5 -yl)methyl)-2,2- difiuoroacetamide (40 mg, 0.08 mmol, 14% yield) as an off white solid. MS (ESI) m/z 476.18 [M+1]+. 1H NMR (300 MHz, 6) 8 10.98 (s, 1H), 9.66 (t, J: 6.0 Hz, 1H), 7.68 (d, J: 7.9 Hz, 1H), 7.61 — 7.50 (m, 2H), 7.49 — 7.33 (m, 3H), 5.10 (dd, J = 13.3, 5.0 Hz, 1H), 4.51 — 4.12 (m, 4H), 2.98-2.83 (m, 1H), 2.65-2.55 (m, 1H), 2.46 — 2.27 (m, 4H), 2.06-1.93 (m, 1H).
Example 27 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(4- (trifluoromethylthi0)phenyl)acetamide F>l\s O A. 1-(4-(Trifluoromethylthi0)phenyl)ethan0ne. In a stirred and evacuated round bottom flask were taken potassium phosphate (19.38 g, 91.44 mmol), molecular sieves (5 g, 4A), r-8 (2.92 g, 91.44 mmol), silver carbonate (16.80 g, 60.96 mmol), (4-acetylphenyl)boronic acid (5 g, 30.48 mmol),copper (1) thiocyanate (370 mg, 3.04 mmol) and 1,10-phenanthroline (1.09 g, 6.09). Trimethyl (trifluoromethyl)silane (21.67 g, 152.43 mmol) in dry N,N—dimethylformamide (50 mL) was added to the round bottom flask and stirred for 12h at room temperature.
The reaction e was filtered through Celite pad, cold water (20 mL) was added and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography (100-200 silica) using 10% ethyl acetate in pet.ether to afford 1-(4-(trifluoromethylthio)phenyl)ethanone (2.8 g, 13.20 mmol, 45%) as a light yellow . 1H NMR (400 MHz, CDClg) 8 8.03 — 7.89 (m, 2H), 7.75 (d, J: 7.9 Hz, 2H), 2.80 — 2.42 (m, 3H).
B. Ethyl 2-0x0(4-(triflu0r0methylthi0)phenyl)acetate. To a stirred solution of 1-(4-(trifluoromethylthio)phenyl)ethanone (2.5 g, 11.79 mmol) in pyridine (50 mL) was added selenium dioxide (2.61 g, 23.58 mmol) and stirred for 4h at 100 CC. The reaction e was diluted with dichloromethane (50 mL) and filtered through Celite pad. To the filtrate was added dichloromethane (30 mL) followed by ethyl chloroformate (5 mL) at 0 CC and stirred for 2h.The pH of the reaction mixture was adjusted to pH-4 with 1N s hydrochloric acid and ted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography (100-200 silica) using 10% ethyl acetate in pet.ether to afford ethyl 2-oxo(4-(trifiuoromethylthio)phenyl)acetate (2.0 g, 7.19 mmol, 62%) as a liquid. 1H NMR (400 MHz, CDClg) 5 8.12 — 8.04 (m, 2H), 7.84 — 7.72 (m, 2H), 4.61 — 4.33 (m, 2H), 1.49 — 1.34 (m, 3H).
C. Ethyl fluoro-Z-(4-(triflu0r0methylthi0)phenyl)acetate. To ethyl 2-oxo(4-(trifiuoromethylthio)phenyl)acetate (2.0 g, 7.19 mmol) was added diethyl amino sulfur trifiuoride (1.4 mL, 10.79 mmol) and stirred for 12h at room temperature.
The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layer was washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difiuoro(4-(trifiuoromethylthio)phenyl)acetate (2.0 g, 6.66 mmol, 95 %) as a liquid. 1H NMR (400 MHz, CDClg) 8 7.75 (d, J = 8.2 Hz, 2H), 4.32 (q, J: 7.1 Hz, 2H), 1.32 (t, J: 7.1Hz,3H).
D. flu0r0(4-(trifluor0methylthi0)phenyl)acetic acid. To a stirred cold (0 oC) solution of ethyl 2,2-difluoro(4- (trifiuoromethylthio)phenyl)acetate (1.5 g, 5.0 mmol) in aqueous methanol (10 mL, 80%) was added sodium hydroxide (0.4 g, 10.0 mmol) and stirred at room ature for 6h. The reaction mixture was trated and the residue was neutralized with % aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2 X 20 mL).
The combined organic layers were washed with brine (20 mL), dried over sodium te and concentrated to afford 2,2-difiuoro(4- (trifiuoromethylthio)phenyl)acetic acid (1 g, 3.67 mmol, 73% yield) as an brown solid.
MS (ESI) m/Z 271.22 [M-1]+.
E. N-((2-(2,6-Di0x0piperidinyl)—1-0xois0ind01inyl)methyl)-2,2— difluor0(4-(triflu0r0methylthi0) phenyl)acetamide. To a cold (0 oC) stirred on of 3-(5-(amino methyl)oxoisoindolinyl)piperidine-2,6-dione methane sulfonate (500 mg, 1.61 mmol) in N,N-dimethylformamide (20 mL) was added 2,2-difluoro(4-(trifluoromethylthio)phenyl)acetic acid (520 mg, 1.94 mmol), N,N—diisopropylethylamine (0.86 mL, 4.8 mmol) ed by 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (920 mg, 2.4 mmol) and stirred at room temperature for 12h.
The reaction mixture was diluted with water (100 mL) and the solid precipitated was filtered, dried under vacuum and purified by Reveleris C-18 reversed phase column using 70% acetonitrile in aqueous formic acid (0.1%) to give N—((2-(2,6- dioxopiperidin-3 -yl)—1-oxoisoindolin-5 -yl)methyl)-2,2-difluoro(4- (trifiuoromethylthio) phenyl)acetamide (60 mg, 0.11 mmol, 7% yield)as an off white solid. MS (ESI) m/z 528.07 [M+1]+. 1H NMR (400 MHz, DMSO-d6) 5 10.98 (s, 1H), 9.76 (t, J: 6.1 Hz, 1H), 7.91 (d, J: 8.1 Hz, 2H), 7.81 — 7.61 (m, 3H), 7.53 — 7.21 (m, 2H), 5.10 (dd, J: 13.4, 5.1 Hz, 1H), 4.57 — 4.10 (m, 4H), 2.85-2.93 (m, 1H), 2.72 — 2.56 (m, 1H), 2.42 — 2.26 (m, 1H), 2.10 — 1.94 (m, 1H). e 28 2-(3-Chlor0methoxyphenyl)—N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)-2,2-difluoroacetamide A. Ethyl 2-(3-chlor0meth0xyphenyl)0x0acetate. To a stirred solution of 1-(3-chloromethoxyphenyl)ethanone (2 g, 10.83 mmol) in pyridine (15 mL) was added selenium dioxide (3 g, 27.08 mmol) at room temperature. The on mixture was d at 100 CC for 16h. The on mixture was filtered through a Celite pad and washed with dichloromethane (30 mL). Ethyl chloroformate (6 mL) was added to the filtrate at 0 CC and stirred at room temperature for 4h. The reaction mixture was quenched with ice water and extracted with dichloromethane (3 X 25 mL). The combined c layers were washed with 1N hydrochloride solution (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated to afford ethyl 2-(3-chloromethoxyphenyl)oxoacetate (1.45 g, .98 mmol, 55% yield) as a colourless liquid. MS (ESI) m/z 242.1 [M]+‘ B. Ethyl 2-(3-chlor0methoxyphenyl)—2,2-diflu0r0acetate. Ethyl 2-(3- chloromethoxyphenyl)oxoacetate (1.45 g, 5.99 mmol) was added in portion into laminosulfur trifiuoride (2.35 mL) at 0 CC and stirred at room temperature for 16h. The reaction e was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate, filtered and trated.
Obtained crude was d by flash column chromatography (100-200 silica gel, % ethyl acetate in pet ether) to afford ethyl 2-(3-chloromethoxyphenyl)-2,2- difiuoroacetate (1 g, 3.78 mmol, 63% yield) as a colourless liquid. MS (ESI) m/z 264.1 [M]+‘ ] C. 2-(3-Chlor0methoxyphenyl)-2,2-diflu0roacetic acid. To a d solution of ethyl 2-(3-chloromethoxyphenyl)-2,2-difluoroacetate (1 g, 3.78 mmol) in tetrahydrofuran: ethanol: water (15 mL, 1:1:1) was added lithium hydroxide monohydrate (480 mg, 11.36 mmol) and stirred at room temperature for 16h. The reaction mixture was concentrated under reduced pressure and the resultant residue was dissolved in water (20 mL) and washed with ethyl acetate (2 X 15 mL). Aqueous layer was acidified with 1N hydrochloride solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layer was washed with brine (15 mL), dried over sodium sulphate, filtered and concentrated to afford 2-(3-chloromethoxyphenyl)- 2,2-difluoroacetic acid (550 mg, 2.32 mmol, 61% yield) as semi-solid compound. 1H NMR (300 MHz, 6) 8 7.57 — 7.52 (m, 2H), 7.29 (d, J: 8.7 Hz, 1H), 3.92 (s, 3H).
D. 2-(3-Chlor0meth0xyphenyl)—N-((2-(2,6-di0x0piperidinyl)—1- indolin-S-yl)methyl)-2,2-difluoroacetamide. To a stirred solution of 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) in dry N,N—dimethylformamide (6 mL) was added hloro methoxyphenyl)-2,2-difiuoroacetic acid (252 mg, 1.07 mmol) ed by 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (442 mg, 1.16 mmol) and diisoproylethylamine (375 mg, 2.91 mmol) at 0°C and stirred at room temperature for 16h. The reaction mixture was concentrated under reduced pressure and obtained residue was dissolved in water (15 mL) and extracted with ethyl acetate (3 X 15 mL). The combined organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated.
The resultant residue was purified by Reveleris C-18 reversed phase Grace column chromatography (45-55% acetonitrile in aqueous 0.1% formic acid) to afford 2-(3-Chloromethoxyphenyl)-N-((2-(2,6-dioxopiperidinyl)oxoisoindolin 2015/039926 yl)methyl)-2,2-difluoro acetamide (58 mg, 11.7 mmol, 12% yield) as an off-white solid. MS (ESI) m/z 492.47 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.98 (s, 1H), 9.62 (t, 1H), 7.68 (d, J: 7.8 Hz, 1H), 7.60 (d, J: 2.3 Hz, 1H), 7.53 (d, J: 8.7 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J: 8.0 Hz, 1H), 7.29 (d, J: 8.7 Hz, 1H), 5.10 (dd, J: 13.2, .1 Hz, 1H), 4.45 (d, J: 5.4 Hz, 2H), 4.42 (d, J: 17.9 Hz, 1H), 4.28 (d, J: 17.9 Hz, 1H), 3.91 (s, 3H), 2.96 — 2.86 (m, 1H), 2.64 — 2.55 (m, 1H), 2.47 — 2.25 (m, 1H), 2.08 — 1.94 (m, 1H).
Example 29 N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2—diflu0r0(m- tolyl)acetamide 0 O F F HNVOf/{fN O A. Ethyl 2-0x0m-tolylacetate. To a stirred solution of l-m-tolylethanone (3.0 g, 22.37 mmol) in pyridine (50 mL) was added selenium dioxide (4.96 g, 44.74 mmol) and stirred for 16 h at 100 CC. The reaction mixture was diluted with dichloromethane (50 mL) and filtered through Celite pad. To the filtrate was added ethyl formate (6 mL) at 0 CC and stirred for 2h.The reaction mixture was neutralized with 1N aqueous hydrochloric acid (up to pH-4) and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with water (2 X 100 mL), brine (100 mL) and dried over sodium sulphate and trated. The ant residue was purified by column chromatography (100-200 silica) using 10% ethyl acetate in pet.ether to afford ethyl 2-oxom-tolylacetate (2.0 g, 10.41 mmol, 46.6 %) as a liquid. GC-MS (ESI) m/Z 192.2.
] B. Ethyl flu0ro-Z-m-tolylacetate. To a stirred solution of ethyl 2-oxom-tolylacetate (2.0 g, 10.41 mmol) was reacted with diethyl amino sulfur trifiuoride (3.41 mL, 26.02 mmol) and stirred for 12h at room temperature. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined c layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difiuorom-tolylacetate (1.2 g, 5.60 mmol, 52.4 %) as a liquid. GC-MS (ESI) m/z 214.1.
C. 2,2-Diflu0ro-Z-m-tolylacetic acid. To a cold (0 oC) stirred solution of ethyl 2,2-difluorom-tolylacetate (1.2 g, 7.47 mmol) in tetrahydrofuran-methanol- water t mixture (45 mL, 1:1:1), was added lithium hydroxide (1.85 g, 44.84 mmol) and stirred at room temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous hydrochloric acid (10 mL) and ted with ethyl acetate (2 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2, 2-difluorom-tolylacetic acid (900 mg, 4.83 mmol, 86.5% yield) as a brown solid. MS (ESI) m/z 185.21 .
D. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- difluor0(m-tolyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluorom- tolylacetic acid(216.6 mg, 0.970 mmol) in pyridine (10 mL) was added phosphorus trichloride (0.3 mL, 2.912 mmol) and stirred at 0 C’C-5 °C for 1h. (300 mg, 2.40 mmol) was added to the reaction mixture at 0 CC and continued stirring at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The ed organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The crude product was purified by Reveleris C-18 reversed phase Grace column chromatography using 45% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolin- -yl) methyl)-2,2-difluoro(m-tolyl)acetamide(63 mg, 0.147 mmol, 14.7% yield) as an off white solid. MS (ESI) m/Z 442.25 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 .98 (s, 1H), 9.61 (t, J: 6.1 Hz, 1H), 7.68 (d, J: 7.8 Hz, 1H), 7.48 — 7.32 (m, 6H), .10 (dd, J: 13.3, 5.0 Hz, 1H), 4.49 — 4.22 (m, 4H), 2.98 — 2.82 (m, 1H), 2.64 — 2.53 (m, 1H), 2.45 - 2.24 (m, 4H), 2.05 — 1.93 (m, 1H).
Example 30 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(4— poxyphenyl)acetamide O O A0 0 A. 1-(4-Isopr0p0xyphenyl)ethan0ne. To a stirred solution of ydroxyphenyl)ethanone (2.5 g, 18.38 mmol) in N,N—dimethylformamide was added ium carbonate (6.34 g, 45.95 mmol) followed by isopropyl iodide (4.59 g, 27.57 mmol) at 0 0C and then heated at 100 0C for 16h. The reaction mixture was quenched with ice water and extracted with ethyl acetate (3 X 25 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulphate, filtered, concentrated. Obtained crude compound was purified by flash column chromatography (100-200 silica gel, 20% ethyl acetate/pet ether) to afford 1-(4-isopropoxyphenyl)ethanone (2 g, 11.23 mmol, 61% yield) as a liquid. MS (ESI) m/Z 179.13 [M+H]+' B. Ethyl 2-(4-is0prop0xyphenyl)—2-0x0acetate. To a stirred solution of 1-(4-isopropoxyphenyl)ethanone (3 g, 16.85 mmol) in pyridine (15 mL) was added selenium dioxide (4.67 g, 42.1 mmol) at room temperature and stirred at 100 0C for 16h. The on mixture was filtered through a Celite pad and washed with dichloromethane (30 mL). Filtrate was cooled to 0 0C, treated with ethyl chloroformate (6 mL) and stirred at room temperature for 4h. The reaction mixture was quenched with ice water and extracted with dichloromethane (3 X 30 mL). The combined organic layers were washed with 1N hydrochloride solution (30 mL), brine (30 mL), dried over sodium sulphate, filtered and concentrated to afford ethyl 2-(4- poxyphenyl)oxoacetate (3 g, 12.76 mmol, 75% yield) as a colourless liquid.
MS (ESI) m/Z 236.2 [Mr C. Ethyl 2,2-difluoro-Z-(4-is0pr0p0xyphenyl)acetate. To ethyl 2-(4-isopropoxyphenyl)oxoacetate (3 g, 12.76 mmol) was added diethylaminosulfilr ride (4.9 mL) at 0 0C and stirred at room ature for 16h. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 X 30 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulphate, filtered and concentrated. ed crude was purified by flash column chromatography (100-200 silica gel, 10% ethyl acetate/pet ether) to afford ethyl fiuoro(4-isopropoxyphenyl)acetate (2 g, 7.75 mmol, 61% yield) as a less liquid. MS (ESI) m/z 258.2 [M+H]+‘ D. 2,2-Diflu0r0(4-is0pr0p0xyphenyl)acetic acid. To a d solution of ethyl 2,2-difiuoro(4-isopropoxyphenyl)acetate (2 g, 7.75 mmol) in tetrahydrofuran: ethanol: water (20 mL, 1:1:1) was added lithium hydroxide monohydrate (1.6 g, 38.75 mmol) and stirred at room temperature for 16h. The reaction mixture was concentrated under reduced re and the resultant residue was dissolved in water (20 mL) and washed with ethyl acetate (2 X 20 mL). Aqueous layer was acidified with 1N hloride solution and extracted with ethyl acetate (3 X 20 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulphate, filtered and concentrated to afford 2,2-difiuoro(4- isopropoxyphenyl)acetic acid (1.2 g, 5.21 mmol, 67% yield) as semi-solid compound. 1H NMR (300 MHz, DMSO-d6) 8 7.47 (d, J: 8.7 Hz, 2H), 7.03 (d, J: 9 Hz, 2H), 4.71 — 4.63 (m, 1H), 1.28 (d, J: 6 Hz, 6H).
E. N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluor0(4-isopr0p0xyphenyl)acetamide. To an ice cold solution of 2,2-difluoro- 2-(4-isopropoxyphenyl)acetic acid (267 mg, 1.16 mmol) in pyridine (6 mL) was added oryl de (0.27 mL, 2.91 mmol) dropwise and stirred at 0-5°C for 1h. Then, 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) was added into the on mixture and stirred at room temperature for min. The reaction mixture was neutralized with aqueous saturated sodium onate (up to pH-8) and extracted with ethyl acetate (3 X 15 mL). The combined organic layer was washed with water (15 mL), brine (15 mL), dried over sodium sulphate, d and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography (45-55% acetonitrile in aqueous formic acid 0.1%) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolin-5 -yl)methyl)-2,2- difiuoro(4-isopropoxyphenyl) acetamide (27 mg, 0.05 mmol, 6% yield) as an off-white solid. MS (ESI) m/z 486.09 [M+1]+. 1H NMR (400 MHz, DMSO-d6) 8 10.98 (s, 1H), 9.56 (t, J: 6.3 Hz, 1H), 7.67 (d, J: 7.7 Hz, 1H), 7.48 (d, J: 8.4 Hz, 2H), 7.43 — 7.33 (m, 2H), 7.03 (d, J: 8.4 Hz, 2H), 5.10 (dd, J: 13.3, 5.2 Hz, 1H), 4.74 - 4.62 (m, 1H), 4.49 — 4.27 (m, 4H), 3.02 — 2.83 (m, 1H), 2.69 — 2.58 (m, 1H), 2.39 — 2.28 (m, 1H), 2.05 — 1.95 (m, 1H), 1.27 (d, J: 6.0 Hz, 6H).
Example 31 2-(3,4-Diflu0r0phenyl)—N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)—2,2-diflu0roacetamide A. Ethyl -difluorophenyl)0x0acetate. To a stirred solution of 1-(3,4-difiuorophenyl)ethanone (1 g, 6.4 mmol) in pyridine (15 mL) was added selenium dioxide (1.7 g, 16.01 mmol) at room temperature. The reaction mixture was stirred at 100 CC for 16h. The reaction mixture was filtered through Celite pad and washed with dichloromethane (30 mL). ethyl chloroformate (4 mL) was added to the filtrate at 0 CC and stirred at room temperature for 4h. The reaction mixture was quenched with ice water and extracted with dichloromethane (3 X 25 mL). The combined organic layers were washed with 1N hydrochloride solution (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated to afford ethyl 2-(3,4- difiuorophenyl)—2-oxoacetate (750 mg, 3.50 mmol, 55% yield) as a colourless liquid.
MS (ESI) m/Z 214.1 [M]+.
] B. Ethyl 2-(3,4-difluorophenyl)—2,2-diflu0r0acetate. Ethyl 2-(3,4- difiuorophenyl)—2-oxoacetate (750 mg, 3.5 mmol) was added to diethylamino sulfur trifiuoride (1.37 mL) under nitrogen atmosphere at 0 CC and stirred at room temperature for 16h. The reaction mixture was quenched with aqueous sodium bicarbonate solution and ted with ethyl acetate (3 X 20 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. Obtained crude was purified by flash column tography (100- 200 silica gel, 10% ethyl e in pet ether) to afford ethyl 2-(3,4-difiuorophenyl)- 2,2-difiuoroacetate (520 mg, 2.20 mmol, 63% yield) as a colourless liquid. MS (ESI) m/Z 236.1 [M]+‘ C. 2-(3,4-Diflu0r0phenyl)—2,2-difluoroacetic acid. To a stirred solution of ethyl 2-(3,4-difiuorophenyl)-2,2-difiuoroacetate (500 mg, 2.11 mmol) in tetrahydrofuran: ethanol: water (15 mL, 1:1:1) was added lithium hydroxide monohydrate (267 mg, 6.35 mmol) and stirred at room temperature for 16h. The les were removed under reduced pressure and obtained crude was ved in water (15 mL) and washed with ethyl acetate (2 X 10 mL). Aqueous layer was ed with 1N hydrochloride solution and extracted with ethyl acetate (3 X 15 mL).
The combined organic layer was washed with brine (10 mL) dried over sodium e, filtered and concentrated to afford -difiuorophenyl)-2,2-difiuoroacetic acid (300 mg, 1.44 mmol, 68% yield) as semi-solid compound. MS (ESI) m/z 208.1 [M]+.
D. 2-(3,4-Diflu0r0phenyl)-N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a stirred solution of 3-(5- (aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) in dry N,N—dimethylformamide (6 mL) was added 2-(3,4-difiuorophenyl)- 2,2-difiuoroacetic acid (222 mg, 1.07 mmol) ed by 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafiuorophosphate (442 mg, 1.16 mmol) and diisoproylethylamine (0.5 mL, 2.91 mmol) at 0 CC and stirred at room temperature for 16h. The reaction mixture was concentrated under reduced re and the obtained crude was dissolved in water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated.
The crude compound was purified by Reveleris C-18 reversed phase Grace column chromatography (45-55% acetonitrile in 0.1% s formic acid to afford 2-(3 ,4-difiuorophenyl)-N-((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)- 2,2-difiuoro acetamide (75 mg, 0.16 mmol, 17% yield) as an off-white solid. MS (ESI) m/z 463.99 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.98 (s, 1H), 9.69 (t, J = 5.9 Hz, 1H), 7.72 — 7.62 (m, 2H), 7.61 (d, J: 8.4 Hz, 1H), 7.51 — 7.44 (m, 1H), 7.43 (s, 1H), 7.37 (d, J: 7.8 Hz, 1H), 5.10 (dd, J: 13.3, 5.0 Hz, 1H), 4.46 (d, J = 5.4 Hz, 2H), 4.43 (d, J: 17.4 Hz, 1H), 4.29 (d, J: 17.1 Hz, 1H), 2.98 — 2.87 (m, 1H), 2.65 — 2.56 (m, 1H), 2.45 — 2.29 (m, 1H), 2.08 — 1.90 (m, 1H).
Example 32 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(3- fluorophenyl)acetamide A. Ethyl 2-(3-fluorophenyl)0x0acetate. To a stirred solution of 1-(3-fiuorophenyl)ethanone (2 g, 14.48 mmol) in pyridine (15 mL) was added selenium dioxide (4.01 g, 36.19 mmol) at room temperature. The reaction mixture was d at 100 CC for 16h. The reaction mixture was d through Celite pad and washed with dichloromethane (30 mL). Ethyl chloroformate (6 mL) was added to the filtrate at 0 CC and stirred at room temperature for 4h. The reaction mixture was ed with ice water and ted with dichloromethane (3 X 25 mL). The combined organic layers were washed with 1N hydrochloride on (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated to afford ethyl 2-(3- fiuorophenyl)—2-oxoacetate (1.5 g, 7.65 mmol, 53% yield) as a colourless liquid. MS (ESI) m/Z 196.1 [Mr —134— B. Ethyl 2,2-diflu0r0(3-flu0r0phenyl)acetate. Ethyl 2-(3- henyl)—2-oxoacetate (1.5 g, 7.65 mmol) was added to diethylaminosulfur trifiuoride (3 mL) at 0 CC and stirred at room temperature for 16h. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. Obtained crude was d by flash column chromatography (100-200 silica gel, 10% ethyl acetate in pet ether) to afford ethyl 2,2-difiuoro(3-fiuorophenyl)acetate (850 mg, 3.89 mmol, 90% yield) as a colourless liquid. MS (ESI) m/z 218.1 [M]+.
C. 2,2-Diflu0r0(3-flu0r0phenyl)acetic acid. To a d on of ethyl 2,2-difluoro(3-fluorophenyl)acetate (850 mg, 3.89 mmol) in tetrahydrofuran: ethanol: water (15 mL, 1:1:1) was added lithium hydroxide monohydrate (491 mg, 11.69 mmol) and stirred at room temperature for 16h. The reaction mixture was concentrated under reduced pressure and obtained crude was dissolved in water (15 mL) and washed with ethyl acetate (2 X 10 mL). The aqueous layer was acidified with 1N hydrochloride solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with brine (10 mL) dried over sodium sulfate, d and concentrated to afford 2,2-difiuoro(3-fiuorophenyl)acetic acid (500 mg, 2.63 mmol, 67% yield) as semi-solid compound. MS (ESI) m/z 190.1 [M]+.
D. N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- diflu0r0(3-flu0r0phenyl)acetamide. To a stirred solution of aminomethyl)— 1-oxoisoindolinyl)piperidine-2,6-dione hydrochloride (203 mg, 1.07 mmol) in dry N,N—dimethylformamide. (6 mL) was added 2,2-difiuoro(3-fiuorophenyl)acetic acid (300 mg, 0.97 mmol) followed by 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (442 mg, 1.16 mmol) and N,N—diisopropylethylamine (375 mg, 2.91 mmol) at 0 CC and stirred at room temperature for 16h. The reaction mixture was concentrated under reduced pressure and obtained crude was ved in water (10 mL) and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate, filtered and concentrated. Obtained crude compound was purified by Reveleris C-18 reversed phase column chromatography (45-55% itrile in 0.1% aqueous formic acid to afford N-((2-(2,6-dioxopiperidin-3 -yl) oxoisoindolinyl)methyl)-2,2-difluoro(3-fluorophenyl)acetamide (45 mg, 0.1 mmol, 10% yield) as an off-white solid. MS (ESI) m/z 446.04 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.98 (s, 1H), 9.68 (t, J: 5.9 Hz, 1H), 7.67 (d, J: 8.1 Hz, 1H), 7.60 (dd, J: 13.5, 7.8 Hz, 1H), 7.47 — 7.41 (m, 4H), 7.36 (d, J: 8.1 Hz, 1H), .10 (dd, J: 13.3, 5.0 Hz, 1H), 4.46 (d, J: 5.7 Hz, 2H), 4.42 (d, J: 15.0 Hz,1H), 4.28 (d, J: 17.4 Hz, 1H), 2.96 — 2.86 (m, 1H), 2.65 — 2.54 (m, 1H), 2.46 — 2.28 (m, 1H), 2.05 — 1.92 (m, 1H).
Example 33 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(3- (triflu0r0methyl)pyridinyl)acetamide A. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- diflu0r0(3-(trifluor0methyl)pyridin-Z-yl)acetamide. 3-(5-(Aminomethyl) oxoisoindolinyl)piperidine-2,6-dione, mesylic acid (0.050 g, 0.135 mmol) was placed in a vial with N,N-dimethylformamide (1.0 mL), 2,2-difluoro(3- (trifluoromethyl)pyridinyl)acetic acid (0.033 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), and 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol). The on mixture was d at RT for 18 h. The reaction e was taken up in dimethylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). Fractions containing d product were combined and volatile organics were removed under reduced pressure to give N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)-2,2-difluoro(3 - (trifluoromethyl)pyridinyl)acetamide (0.033 g, 0.066 mmol, 49.1 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.98 (s, 1H), 9.59 (t, J: 6.15 Hz, 1H), 8.99 (d, J: 4.73 Hz, 1H), 8.47 (dd, J: 1.26, 8.20 Hz, 1H), 7.88 (dd, J: 4.73, 8.20 Hz, 1H), 7.74 (d, J: 7.57 Hz, 1H), 7.60 (s, 1H), 7.51 (dd, J: 0.63, 7.88 Hz, 1H), 5.12 (dd, J: 5.20, 13.40 Hz, 1H), 4.55 (d, J: 6.31 Hz, 2H), 4.49 (d, J: 17.34 Hz, 1H), 4.32 - 4.37 (m, 1H), 2.88 - 2.97 (m, 1H), 2.58 - 2.64 (m, 1H), 2.36 - 2.46 (m, 1H), 2.02 (dtd, J: 2.21, 5.16, 12.69 Hz, 1H). MS (ESI) m/z 497.4 [M+1]+.
Example 34 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(4- isopropylphenyl)acetamide O O F F HNmfi):N O A. Ethyl 2-(4-is0pr0pylphenyl)—2-oxoacetate. To a stirred solution of 1-(4-isopropylphenyl)ethanone (2.0 g, 12.33 mmol) in pyridine (25 mL) was added selenium dioxide (3.42 g, 30.82 mmol) and d for 16h at 100 oC. The reaction mixture was d with dichloromethane (50 mL) and filtered through Celite pad. To the filtrate was added ethyl chloroformate (6 mL) at 0 CC and stirred for 2h.The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 X 100 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium te and concentrated to afford ethyl 2-(4-isopropylphenyl)oxoacetate (2.0 g, 9.09 mmol, 74% yield). MS (ESI) m/Z 221.29 [M+1]+.
B. Ethyl flu0r0(4-is0pr0pylphenyl)acetate. To ethyl 2-(4- isopropylphenyl)oxoacetate (1.0 g, 4.27 mmol) was added l amino sulfur trifluoride (3 mL) at 0 CC and stirred at room temperature for 16h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 25 mL), brine (25 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(4-isopropylphenyl)acetate (1.0 g, 4.13 mmol, 91% yield). GCMS (m/z) 242.2 [Mi C. 2,2-Diflu0r0(4-is0pr0pylphenyl)acetic acid. To a d on of ethyl 2,2-difluoro(4-isopropylphenyl)acetate (1.0 g, 4.13 mmol) in tetrahydrofilran:methanol:water (30 mL, 1:1:1) was added lithium hydroxide (868 mg, .66 mmol) and stirred at room temperature for 4h. The reaction mixture was concentrated and the residue was lized with saturated potassium bisulphate (20 mL) and extracted with ethyl acetate (2 X 25 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(4-isopropylphenyl)acetic acid (700 mg, 3.27 mmol, 79% yield) as an brown . MS (ESI) m/Z 213.33 [M-1]+.
D. N-((2-(2,6-di0x0piperidinyl)0x0is0ind0]inyl)methyl)-2,2- difluor0(4-is0pr0pylphenyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(4-isopropylphenyl)acetic acid (200 mg, 0.93 mmol) in pyridine (20 mL) was added phosphoryl chloride (429 mg, 2.80 mmol) dropwise and stirred at 0-5 CC for 1h. To this reaction mixture was then added aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (290 mg, 0.93 mmol) and d at room temperature for 30 min. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl e (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 50-55% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl) oxoisoindolinyl)methyl)-2,2-difluoro(4-isopropylphenyl)acetamide (85 mg, 0.18 mmol, 19% yield) as a pale yellow solid. MS (ESI) m/z 470.21 [M+1]+. 1H NMR (300MHz, DMSO-d6) 5 10.99 (s, 1H), 9.60 (t, J=6.1 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.45 - 7.30 (m, 4H), 5.10 (dd, J=5.1, 13.2 Hz, 1H), 4.48 - 4.22 (m, 4H), 3.02 - 2.84 (m, 2H), 2.74 — 2.54 (m, 1H), 2.46 - 2.30 (m, 1H), 2.05 - 1.93 (m, 1H), 1.3-1.12 (m, 6H).
Example 35 2-(2,4-Dichlor0phenyl)—N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin yl)methyl)—2,2-diflu0roacetamide A. Ethyl -dichlor0phenyl)0x0acetate. To a stirred solution of 1-(2,4-dichlorophenyl)ethanone (3.0 g, 15.87 mmol) in ne (20 mL) was added selenium dioxide (3.5 g, 31.74 mmol) and stirred at 100 0C for 16h. The reaction mixture was diluted with dichloromethane (30 mL) and filtered through Celite pad. To the filtrate was added ethyl chloroformate (6 mL) at 0 CC and stirred at room temperature for 3h. The reaction mixture was neutralized with 1N aqueous hydrochloric acid (up to pH-4) and ted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(2,4-dichlorophenyl) oxoacetate (3.0 g, 12.19 mmol, 76% yield). 1HNMR complies. 1H NMR (400MHz, DMSO-d6) 8 7.88 — 7.82 (m, 2H), 7.65 (d, J=8.4 Hz, 1H), 4.37 (q, J=7.0 Hz, 2H), 1.30 (t, J=7.0 Hz, 3H), B. Ethyl 2-(2,4-dichlor0phenyl)-2,2-diflu0roacetate. A solution of ethyl 2-(2,4-dichlorophenyl)oxoacetate (1.0 g, 4.58 mmol) and diethyl amino sulfur ride (3.7 g, 22.89 mmol) was stirred at room temperature for 16h. The reaction mixture was neutralized with aqueous ted sodium onate (up to pH-8) and extracted with ethyl e (3 X 50 mL). The combined organic layers were washed with water (2 X 30 mL), brine (30 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(2,4-dichlorophenyl)-2,2-difluoroacetate (1.0 g, 3.73 mmol, 92 % yield). GCMS (m/Z) 268 [Mi C. 2-(2,4-Dichlor0phenyl)-2,2-diflu0roacetic acid. To a stirred solution of ethyl 2-(2,4-dichlorophenyl)-2,2-difluoroacetate (1.0 g, 3.73 mmol) in tetrahydrofilran:methanol:water mixture (30 mL, 1:1:1) was added lithium hydroxide monohydrate (940.2 mg, 22.38 mmol) and stirred at room temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2-(2,4-dichlorophenyl)-2,2-difluoroacetic acid (800 mg, 3.33 mmol, 89% yield. MS (ESI) m/Z 241 [M+2]+.
D. -Dichlor0phenyl)—N-((2-(2,6—di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a cold (0 oC) d solution of 2-(2,4-dichlorophenyl)-2,2-difluoroacetic acid (279.6 mg, 1.165 mmol) in pyridine (10 mL) was added phosphoryl chloride (0.3 mL, 2.91 mmol) and stirred at 0-5 0C for 30min. To this reaction mixture was then added 3-(5-(aminomethyl)oxoisoindolin- 2-yl)piperidine-2,6-dione hloride (300 mg, 0.97 mmol) and stirred at room temperature for 1h. The on mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and ted with ethyl acetate (2 X 25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase Grace column chromatography using 50-55% acetonitrile in aqueous formic acid (0.1%) to afford -Dichlorophenyl)-N-((2-(2,6- dioxopiperidinyl)oxoisoindolin—5-yl)methyl)-2,2-difluoroacetamide (60 mg, 0.12 mmol, 12 % yield) as an offwhite solid. MS (ESI) m/Z 496.03 [M+1]+. 1H NMR (300MHz, DMSO-d6) 8 10.99 (m, 1H), 9.70 (t, J=6.3 Hz, 1H), 7.84 — 7.65 (m, 3H), 7.66 — 7.57 (d, J=8.4 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J=8.0 Hz, 1H),, 5.11 (dd, J=5.1, 13.2 Hz, 1H), 4.49 (br d, J=5.5 Hz, 2H), 4.43 (s, 1H), 4.34 (s, 1H), 4.28 (s, 1H), 2.99 — 2.84 (m, 1H), 2.60 — 2.57 (m, 1H), 2.44 — 2.31 (m, 1H), 2.05 — 1.94 (m, 1H).
Example 36 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(2- methoxyphenyl)acetamide A. Ethyl 2-(2-methoxyphenyl)—2-0x0acetate. To a stirred solution of 1-(2-methoxyphenyl)ethanone (2.0 g, 13.32 mmol) in pyridine (25 mL) was added selenium e (3.7 g, 33.29 mmol) and stirred for 16h at 100 oC. The reaction mixture was diluted with dichloromethane (50 mL) and ed through Celite pad. To the filtrate was added ethyl chloroformate (6 mL) at 0 CC and stirred for 2h.The reaction e was diluted with water (30 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(2- methoxyphenyl)oxoacetate (2.0 g, 9.62 mmol, 72% yield). GCMS (m/Z) 208.2 [M]+.
] B. Ethyl 2,2-diflu0r0(2-methoxyphenyl)acetate. To ethyl 2-(2- methoxyphenyl)oxoacetate (1.0 g, 4.81 mmol) was added l amino sulfur trifluoride (3 mL) at 0 CC and stirred at room temperature for 16h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 25 mL), brine (25 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(2-methoxyphenyl)acetate (1.0 g, 4.35 mmol, 90% yield). GCMS (m/Z) 230.2 [M].
C. 2,2-Diflu0r0(2-methoxyphenyl)acetic acid. To a stirred solution of ethyl fluoro(2-methoxyphenyl)acetate (1.0 g, 4.35mmol) in tetrahydrofiaran:methanol:water mixture (30 mL, 1:1:1) was added lithium hydroxide —140— monohydrate (913 mg, 21.74 mmol) and d at room temperature for 4h. The reaction mixture was concentrated and the residue was neutralized with ted potassium bisulphate (20 mL) and extracted with ethyl acetate (2 X 25 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulphate and concentrated to afford fluoro(2-methoxyphenyl)acetic acid (700 mg, 3.46 mmol, 79% yield). MS (ESI) m/Z 201.29 [M-1]+.
D. N-((2-(2,6-di0x0piperidinyl)0x0is0ind01inyl)methyl)-2,2- difluor0(2-meth0xyphenyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(2-methoxyphenyl)acetic acid (200 mg, 0.99 mmol) in pyridine (20 mL) was added phosphoryl chloride (454 mg, 0.99 mmol) dropwise and stirred at 0-5 0C for 1h and then added 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (306 mg, 0.99 mmol) and stirred at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodium onate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 50-55% acetonitrile in aqueous formic acid (0.1%) to give N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoro(2- methoxyphenyl)acetamide (80 mg, 0.17 mmol, 17% yield) as an off white solid. MS (ESI) m/z 458.15 [M+1]+.1H NMR (300MHz, 6) 5 10.99 (s, 1H), 9.37 (t, J=5.9 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.59 - 7.41 (m, 4H), 7.17 - 7.03 (m, 2H), 5.11 (dd, J=5.0, 13.0 Hz, 1H), 4.53 - 4.26 (m, 4H), 3.66 (s, 3H), 3.01 - 2.85 (m, 1H), 2.74 — 2.54 (m, 1H), 2.45 - 2.29 (m, 1H), 2.09 - 1.90 (m, 1H) Example 37 2-(4-Cyclopropylphenyl)-N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)—2,2-diflu0roacetamide O O F F HN\/©j{fN O A. 1-(4-Cyclopr0pylphenyl)ethan0ne. To a d and degassed solution of romophenyl)ethanone (1 g, 5.02 mmol) in water: 1,4-dioxane (1 :10, 50 mL) was added cyclopropylboronic acid (519 mg, 6.02 mmol) followed by potassium —141— WO 07848 phosphate (3.2g, 15.07 mmol), [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane x (205 mg, 0.25 mmol). The reaction mixture was degassed for 10min and heated at 100 CC for 8h. The reaction mixture was cooled to room temperature and filtered through the Celite pad. To the filtrate was added cold water (50 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was d by column chromatography (100-200 silica) using 20% ethyl acetate in pet ether to afford 1-(4-cyclopropylphenyl)ethanone (700 mg, 4.37 mmol, 87% yield). GCMS (m/Z) 160.2 [M]+.
] B. Ethyl 2-(4-cyclopropylphenyl)0x0acetate. To a stirred on of 1-(4-cyclopropylphenyl)ethanone (700 mg, 4.37 mmol) in pyridine (10 mL) was added selenium dioxide (1.2 g, 10.93 mmol) and d at 100 CC for 16h. The reaction mixture was diluted with dichloromethane (20 mL) and filtered h Celite pad. To the filtrate was added ethyl chloroformate (2 mL) at 0 CC and stirred at room temperature for 3h. The reaction mixture was neutralized with 1N aqueous hloric acid (up to pH-4) and extracted with ethyl acetate (2 X 60 mL). The combined organic layers were washed with water (2 X 30 mL), brine (30 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(4-cyclopropylphenyl) oxoacetate (890 mg, 4.08 mmol, 93% yield). GCMS (m/z) 218.2 [M]+ C. Ethyl 2-(4-cyclopr0pylphenyl)—2,2-difluoroacetate. A solution of ethyl 2-(4-cyclopropylphenyl)oxoacetate (890 mg, 4.08 mmol) and diethyl amino sulfur trifluoride (3.7 g, 22.89 mmol) was stirred at room temperature for 16h. The reaction mixture was neutralized with s saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 30 mL), brine (30 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(4-cyclopropylphenyl)-2,2-difiuoroacetate (920 mg, 3.83 mmol, 94 % yield). GCMS (m/z) 240.2 [M]+ D. 2-(4-Cyclopr0pylphenyl)-2,2-difluoroacetic acid. To a stirred solution of ethyl 2-(4-cyclopropylphenyl)-2,2-difiuoroacetate (920 mg, 3.83 mmol) in ydrofuran -methanol-water (30 mL, 1:1:1) was added lithium hydroxide monohydrate (483 mg, 11.49 mmol) and stirred at room temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous —142— hydrochloric acid (10 mL) and extracted with ethyl acetate (2 X 50 mL). The ed organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford yclopropylphenyl)-2,2-difluoroacetic acid (750 mg, 3.53 mmol, 92% yield). GCMS (m/Z) 212.1 [Mi E. 2-(4-Cyclopr0pylphenyl)-N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a cold (0 oC) stirred solution of 2-(4-cyclopropylphenyl)-2,2-difluoroacetic acid (200 mg, 0.943 mmol) in pyridine (10 mL) was added phosphoryl chloride (0.4 mL, 2.830 mmol) and d at 0-5 0C for 30min. To this reaction mixture was then added 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (359 mg, 1.16 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (2 X 25 mL). The combined c layers were washed with water (25 mL), brine (25 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 ed phase column chromatography using 40-45% acetonitrile in aqueous formic acid (0.1%) to afford 2-(4-cyclopropylphenyl)-N- ((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)-2,2-difluoroacetamide (90 mg, 0.192 mmol, 20.0 % yield)as an offwhite solid. MS (ESI) m/z 468.13 [M+1]+. 1H NMR (300MHz, DMSO-d6) 5 10.99 (s, 1H), 9.58 (t, J=5.9 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.39 - 7.31 (m, 2H), 7.21 (d, J=8.1 Hz, 2H), .10 (dd, J=5.1, 13.2 Hz, 1H), 4.49 - 4.21 (m, 4H), 3.00 - 2.81 (m, 1H), 2.67 - 2.56 (m, 1H), 2.45 - 2.29 (m, 1H), 2.07 - 1.92 (m, 2H), 1.04 - 0.97 (m, 2H), 0.55 — 0.77 (m, 2H).
Example 38 2-(4-Chlor0flu0r0phenyl)—N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- hyl)—2,2-diflu0roacetamide CI F0 A. Ethyl 2-(4-chlor0flu0r0phenyl)—2-0xoacetate. To a stirred solution of 1-(4-chlorofluorophenyl)ethanone (2.0 g, 11.588 mmol) in pyridine (30 mL) was added selenium dioxide (2.57 g, 23.176 mmol) and stirred for 16h at 100 oC. The reaction mixture was diluted with dichloromethane (30 mL) and ed through Celite —143— 2015/039926 pad. To the filtrate was added ethyl chloroformate (4 mL) at 0 CC and stirred for 2h. To the reaction mixture was added water (30 mL) and ted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 20 mL), brine (20 mL), dried over sodium sulphate and trated. The resultant residue was purified by column chromatography (100-200 silica) using 5-10% ethyl acetate in petroleum ether to afford ethyl 2-(4-chlorofluorophenyl)oxoacetate (1.71 g, 7.434 mmol, 64% yield) as a colourless liquid. MS (ESI) m/z.230.1.
B. Ethyl 2-(4-chloro-Z-fluorophenyl)-2,2-diflu0r0acetate. Ethyl 2-(4- chlorofluorophenyl)oxoacetate (1.71 g, 7.434 mmol) was reacted with diethylaminosulfur ride (2.45 mL, 18.585 mmol) and stirred for 12h at room temperature. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The ed organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated to afford ethyl hlorofluorophenyl)-2,2- difluoroacetate (1.0 g, 4.087 mmol, 55% yield) as a colorless liquid. MS (ESI) m/Z.252. 1.
C. 2-(4-Chloro-Z-fluorophenyl)-2,2-diflu0r0acetic acid. To a cold (0 CC) stirred solution of ethyl 2-(4-chloromethylphenyl)-2,2-difluoroacetate (1.0 g, 4.087 mmol) in tetrahydrofuran:ethanol:water mixture (30 mL, 1:1:1) was added lithium ide monohydrate (0.85 g, 20.436 mmol) and stirred at room temperature for 6h. The reaction mixture was trated and the residue was neutralized with % aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2 X 20 mL).
The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to 2-(4-chlorofluorophenyl)-2,2-difluoroacetic acid (550 mg, 2.455 mmol, 62% yield) as an brown solid. MS (ESI) 4.0.
D. 2—(4-Chloro-Z-flu0r0phenyl)—N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a cold (0 oC) stirred solution of 2-(4-chlorofluorophenyl)-2,2-difluoroacetic acid (217 mg, 0.968 mmol) in pyridine was added phosphorus oxychloride (0.27 mL, 2.906 mmol) dropwise and stirred at 0-5 0C for 1h. To this reaction mixture was added 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.968 mmol) and stirred at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodium onate (up to pH-8) and extracted with ethyl acetate —144— (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 ed phase column chromatography using 40-55% acetonitrile in aqueous formic acid (0.1%) to give 2-(4-chlorofiuorophenyl)-N-((2- (2,6-dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)-2,2-difiuoroacetamide (59 mg, 0.123 mmol, 12% yield) as an offwhite solid. MS (ESI) m/Z 480.07 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.99 (s, 1H), 9.74 (s, 1H), 7.69 (dd, J: 11.1, 7.8 Hz, 3H), 7.55 — 7.29 (m, 3H), .09 (dd, J: 5.1 Hz, 1H), 4.52 — 4.27 (m, 4H), 3.00 — 2.84 (m, 1H), 2.66-2.55 (m, 1H), 2.41-2.30 (m, 1H), 2.04-1.94 (m, 1H).
Example 39 2-(4-Chlor0flu0r0phenyl)—N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- hyl)—2,2-difluoroacetamide A. Ethyl 2-(4-chlor0flu0r0phenyl)—2-0x0acetate. To a stirred solution of 1-(4-chlorofiuorophenyl)ethanone (2.0 g, 11.62 mmol) in pyridine (20 mL) was added selenium dioxide (2.5 g, 23.25 mmol) and stirred at 100 0C for 16h. The reaction mixture was diluted with dichloromethane (30 mL) and filtered through Celite pad. To the filtrate was added ethyl chloroformate (6 mL) at 0 CC and stirred at room temperature for 3h. The reaction mixture was neutralized with 1N aqueous hydrochloric acid (up to pH-4) and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and trated to afford ethyl 2-(4-chlorofiuorophenyl) oxoacetate (2.0 g, 8.69 mmol, 75% yield). GCMS (m/z) 230 [M]+.
] B. Ethyl 2-(4-chlor0fluorophenyl)-2,2-diflu0r0acetate. A solution of ethyl 2-(4-chlorofiuorophenyl)oxoacetate (1.0 g, 4.34 mmol) and diethyl amino sulfur trifiuoride (3.7 g, 22.89 mmol) was stirred at room temperature for 16h. The reaction mixture was neutralized with aqueous ted sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined c layers were washed with water (2 X 30 mL), brine (30 mL), dried over sodium sulphate and —145— concentrated to afford ethyl 2-(4-chlorofluorophenyl)-2,2-difluoroacetate (900 mg, 3.57 mmol, 82 % yield). GCMS (m/z) 2521 [Mi C. 2-(4-Chlor0flu0rophenyl)-2,2-difluoroacetic acid. To a stirred solution of ethyl 2-(4-chlorofluorophenyl)-2,2-difluoroacetate (800 mg, 3.17 mmol) in tetrahydrofuran:methanol:water mixture (20 mL, 1:1:1) was added lithium ide monohydrate (798 mg, 19.04 mmol) and stirred at room temperature for 2h.
The reaction mixture was concentrated and the residue was neutralized with 10% aqueous hydrochloric acid (10 mL) and extracted with ethyl e (2 X 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2-(4-chlorofluorophenyl)-2,2-difluoroacetic acid (600 mg, 2.67 mmol, 84% yield. MS (ESI) m/Z 223.1 [M-1]+.
D. 2-(4-Chlor0flu0r0phenyl)-N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a cold (0 oC) stirred solution of 2-(4-chlorofluorophenyl)-2,2-difluoroacetic acid (261 mg, 1.165 mmol) in pyridine (10 mL) was added phosphoryl chloride (0.3 mL, 2.91 mmol) and stirred at 0-5 °C for 30min. To this reaction mixture was then added aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) and stirred at room ature for 1h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (2 X 25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over sodium te and concentrated. The resultant residue was purified by ris C-18 reversed phase Grace column chromatography using 50-55% acetonitrile in aqueous formic acid (0.1%) to afford 2-(4-Chloro fluorophenyl)-N-((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)-2,2- difluoroacetamide (50 mg, 0.10 mmol, 11 % yield) as an off white solid. MS (ESI) m/z 480.05 [M+1]+.1H NMR (300MHz, DMSO-d6) 5 10.99 (s, 1H), 9.70 (br s, 1H), 7.81 (br t, J=7.9 Hz, 1H), 7.71 — 7.60 (m, 2H), 7.49 — 7.32 (m, 3H), 5.10 (br dd, J=5.1, 13.2 Hz, 1H), 4.49 — 4.38 (m, 3H), 4.34 — 4.25 (m, 1H), 2.99 — 2.83 (m, 1H), 2.63 — 2.56 (br s, 1H), 2.44 — 2.26 (m, 1H), 2.06 —1.94 (m, 1H).
Example 40 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(3- fluor0methylphenyl)acetamide 0 O F F H N F Mm4&0 A. 1-(3-Flu0ro-Z-methylphenyl)ethan0ne. To a stirred solution of 3-fluoromethylbenzonitrile (3 g, 22.22 mmol) in benzene (20 mL) was added methyl magnesium iodide (9.0 mL, 26.64 mmol, 3M in diethyl ether) at 0 CC and stirred at 80 CC for 8h. Then the reaction mixture was cooled to room temperature, added 6N hydrochloric acid (25 mL) and stirred at heated 80 0C for 8h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 X 100 mL). The combined c layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and concentrated to afford l-(3-fluoro methylphenyl)ethanone (920 mg, 6.05 mmol, 27% . GCMS (m/z) 152.2 [M]+ ] B. Ethyl 2—(3-flu0r0-2—methylphenyl)0xoacetate. To a d solution of l-(3-fluoromethylphenyl)ethanone (900 mg, 5.91 mmol) in pyridine (25 mL) was added selenium dioxide (1 .7 g, 14.79 mmol) and stirred for 12h at 100 CC. The reaction mixture was diluted with dichloromethane (20 mL) and filtered through Celite pad. To the filtrate was added ethyl formate (3 mL) at 0 CC and stirred at room temperature for 2h.The reaction mixture was neutralized with lN aqueous hydrochloric acid (up to pH-4) and extracted with ethyl acetate (3 X 50 mL).
The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(3-fluoro methylphenyl)oxoacetate (1.2 g, 5.71 mmol, 96%). GCMS (m/Z) 210.2 [M]+ C. Ethyl 2,2-diflu0r0(3-flu0r0methylphenyl)acetate. A solution of ethyl 2-(3-fluoromethylphenyl)oxoacetate (l .2 g, 5.71 mmol) and l amino sulfur trifluoride (4.3 g, 26.67 mmol) were stirred at room temperature for 16h. The reaction mixture was neutralized with s saturated sodium bicarbonate (up to pH-8) and extracted with ethyl e (3 X 50 mL). The combined organic layer was washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(3-fluoromethylphenyl)acetate (1.0 g, 4.31 mmol, 76 %) as a brown liquid. GCMS (m/z) 232.2 [M]+ D. 2,2-Difluoro-2—(3-fluoromethylphenyl)acetic acid. To a cold (0 CC) stirred solution of ethyl 2,2-difluoro(3-fluoromethylphenyl)acetate (1.0 g, 4.31 mmol) in in methanol: tetrahydrofuran:water (l : l :l, 30 mL) was added lithium —147— ide monohydrate (543 mg, 12.93 mmol) and stirred at room temperature for 2h.
The reaction mixture was concentrated and the residue was neutralized with 10% aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(3-fluoromethylphenyl)acetic acid (800 mg, 3.92 mmol, 91% yield). GCMS (m/z) 204.1 [M]+ E. N-((2-(2,6-di0x0piperidinyl)0x0is0ind01inyl)methyl)-2,2- 0(3-fluoro—Z-methylphenyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(3-fluoromethylphenyl)acetic acid (200 mg, 0.98 mmol) in pyridine (10 mL) was added oryl de (0.3 mL, 2.94 mmol) dropwise and d at 0-5 °C for 30min. To this reaction mixture was then added aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (303 mg, 0.98 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (2 X 25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over sodium sulphate and concentrated. The resultant residue was d by Reveleris C-18 reversed phase column chromatography using 40-45% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl) oxoisoindolinyl)methyl)-2,2-difluoro(3-fluoromethylphenyl)acetamide (80 mg, 0.17 mmol, 18.0 % yield)as an offwhite solid. MS (ESI) m/z 460.10 [M+1]+. 1H NMR (300MHz, DMSO-d6) 5 10.98 (s, 1H), 9.68 (t, J=5.9 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.49 — 7.31 (m, 5H), 5.10 (dd, J=4.8, 13.2 Hz, 1H), 4.52 - 4.22 (m, 4H), 3.00 - 2.82 (m, 1H), 2.67 - 2.54 (m, 1H), 2.46 - 2.30 (m, 1H), 2.21 (br s, 3H), 2.09 - 1.92 (m, 1H).
Example 41 2-(3-Chlor0methylphenyl)—N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin yl)methyl)—2,2-difluoroacetamide A. 1-(3-Chlor0methylphenyl)ethan0ne. To a stirred solution of 3-chloromethylbenzonitrile (2.0 g, 13.245 mmol) in benzene (30 mL) was added WO 07848 methyl magnesium iodide ( 3M ) in diethyl ether solution (5.3 mL, 15.89 mmol) at 0 OC and stirred for 16h at 75 oC. The reaction mixture was treated with 6N aqueous hydrochloric acid solution (20 mL) at 0 CC and stirred for 4h at 75 CC. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 20 mL), brine (20 mL), dried over sodium sulphate and concentrated. The obtained residue was purified by column chromatography (100-200 silica) using 5-8% ethyl acetate in petroleum ether to afford 1-(4-chloromethylphenyl)ethanone (1.4 g, 8.333 mmol, 63% yield) as a colorless . GCMS (ESI) m/z.168.1.
B. Ethyl 2-(3-chlor0methylphenyl)0x0acetate. To a stirred solution of 1-(4-chloromethylphenyl)ethanone (1.4 g, 8.333 mmol) in pyridine (30 mL) at 0 0C, was added selenium dioxide (1.85 g, 16.666 mmol) and stirred for 16h at 100 CC. The reaction mixture was diluted with dichloromethane (30 mL) and filtered through Celite pad. To the filtrate was added ethyl chloroformate (3 mL) at 0 CC and stirred for 2h.The reaction mixture quenched with water and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 20 mL), brine (20 mL), dried over sodium te and concentrated. The resultant residue was purified by column chromatography (100-200 silica) using -10% ethyl e in pet. ether to give ethyl 2-(3-chloromethylphenyl) oxoacetate (1.1 g, 4.867 mmol, 58.5% yield) as a colorless liquid. GCMS (ESI) m/Z.226. 1.
] C. Ethyl 2-(3-chlor0methylphenyl)—2,2-diflu0roacetate. To ethyl 2- (3-chloromethylphenyl)oxoacetate (1.1 g, 4.867 mmol ) was added l amino sulfur trifiuoride (1.6 mL, 12.168 mmol) and stirred for 12h at room ature. The reaction mixture was lized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(3-chloromethylphenyl)-2,2-difiuoroacetate (710 mg, 2.862 mmol, 58% yield) as a colourless . GCMS (ESI) m/z.248.1.
D. 2-(3-Chlor0methylphenyl)-2,2-diflu0roacetic acid. To a cold (0 CC) d solution of ethyl 2-(3-chloromethylphenyl)-2,2-difiuoroacetate (710 mg, 2.862 mmol) in tetrahydrofuran:ethanol:water mixture (30 mL, 1:1:1) was added lithium hydroxide (0.6 g, 14.314 mmol) and stirred at room temperature for 6h. —149— WO 07848 2015/039926 The reaction mixture was concentrated and the residue was lized with 10% aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2 X 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2-(3-chloromethylphenyl)-2,2-difluoroacetic acid (382 g, 1.736 mmol, 60% yield) as an solid. MS (ESI) m/z 219.17 [M-1]'.
E. 2-(3-Chloro-Z-methylphenyl)-N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a cold (0 oC) stirred solution of 2-(3-chloromethylphenyl)-2,2-difluoroacetic acid (213 mg, 0.968 mmol) in pyridine was added phosphorus oxychloride (0.27 mL, 2.906 mmol) dropwise and stirred at 0-5°C for 1h and then added 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione hydrochloride (300 mg, 0.968 mmol) and stirred at room ature for 30min. The reaction mixture was neutralized with aqueous saturated sodium onate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The ed organic layer was washed with water (2 X 10 mL), brine (10 mL) and dried over sodium sulphate and concentrated. The resultant residue was purified by ris C-18 reversed phase column chromatography using 40-55% acetonitrile in aqueous formic acid (0.1%) to afford 2-(3-chloromethylphenyl)-N-((2-(2,6- dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoroacetamide (62 mg, 0.130 mmol, 13% yield)as white solid. MS (ESI) m/Z 476.07 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.98 (s, 1H), 9.68 (s, 1H), 7.68 (dd, J: 15.3, 7.9 Hz, 2H), 7.55 (d, J: 7.3 Hz, 1H), 7.46 (s, 1H), 7.44 — 7.34 (m, 2H), 5.11 (dd, J: 13.3, 5.0 Hz, 1H), 4.52 — 4.27 (m, 4H), 3.00 — 2.84 (m, 1H), 2.66-2.55 (m, 1H), 2.43-2.30 (m, 4H), 2.04-1.94 (m, 1H).
Example 42 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(4- fluor0(triflu0r0methyl)phenyl)acetamide A. Ethyl 2,2-difluoro—Z-(4-flu0r0(triflu0r0methyl)phenyl)acetate. To a stirred solution of 4-fluoroiodo(trifluoromethyl)benzene (500 mg, 1.72 mmol) in dimethylsulfoxide (5.2 mL) was added copper (329 mg, 5.17 mmol) and ethyl 2- bromo-2,2-difluoroacetate (418 mg, 2.07 mmol) at room temperature and stirred at 55 CC for 16h. The reaction mixture was neutralized with aqueous saturated ammonium chloride solution and extracted with ethyl acetate (3 X 25 mL). The combined organic layers were washed with water (2 X 25 mL), brine (25 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(4-fluoro (trifluoromethyl)phenyl)acetate (300 mg, 1.05 mmol, 61 %). 1H NMR (400 MHz, CDC13)5 7.87 — 7.83 (m, 1H), 7.51 — 7.48 (m, 1H), 7.39 — 7.34 (m, 1H), 4.35 — 4.30 (m, 2H), 1.30 (t, J: 5.1 Hz, 3H).
B. 2,2-Diflu0r0(4-flu0r0(triflu0r0methyl)phenyl)acetic acid. To a stirred solution of ethyl 2,2-difluoro(4-fluoro(trifluoromethyl)phenyl)acetate (300 mg, 1.05 mmol) in tetrahydrofuran:methanol:water mixture (15 mL, 1:1 :1) was added lithium hydroxide (132 mg, 3.15 mmol) and d at room temperature for 4h.
The reaction mixture was trated and the residue was neutralized with saturated potasiium hate (20 mL) and ted with ethyl acetate (2 X 25 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulphate and concentrated to afford fluoro(4-fluoro(trifluoromethyl)phenyl)acetic acid (220 mg, 0.85 mmol, 81% yield). MS (ESI) m/z 257.1[M-1]+.
C. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- 0(4-fluor0(trifluor0methyl)phenyl)acetamide. To a cold (0 oC) stirred on of 2,2-difluoro(4-fluoro(trifluoromethyl)phenyl)acetic acid (200 mg, 0.78 mmol) in pyridine (20 mL) was added phosphoryl chloride (356 mg, 2.32 mmol) dropwise and stirred at 0-5 0C for 1h and then added 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (302 mg, 0.78 mmol) and stirred at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodium onate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 55-60% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl) oxoisoindolinyl)methyl)-2,2-difluoro(4-fluoro (trifluoromethyl)phenyl)acetamide (75 mg, 0.17mmol, 21% as a white solid. MS (ESI) m/z 514.07 [M+1]+.1H NMR (300MHz, DMSO-d6) 5 = 10.98 (s, 1H), 9.73 — 9.62 (m, 1H), 7.96 - 7.82 (m, 2H), 7.78 - 7.67 (m, 2H), 7.49 - 7.37 (m, 2H), 5.11 (dd, J=4.8, 13.2 Hz, 1H), 4.53 - 4.26 (m, 4H), 3.00 - 2.82 (m, 1H), 2.77 - 2.54 (m, 1H), 2.44 - 2.23 (m, 1H), 2.08 - 1.93 (m, 1H) Example 43 2-(4-Chlor0methylphenyl)—N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin yl)methyl)-2,2-diflu0roacetamide A. 1-(4-Chlor0 methylphenyl)ethan0ne. To a stirred solution of 4-chloromethylbenzonitrile (2.0 g, 13.193 mmol) in benzene (30 mL) was added methyl magnesium iodide ( 3M ) in l ether solution (5.27 mL, 15.83 mmol) at 0 OC and stirred for 16h at 75 oC. The reaction mixture was cooled to 0 oC and quenched with 6N hydrochloric acid on (20 mL) and continued to stir at 75 0C for 4h. The reaction mixture was quenched with water and ted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 20 mL), brine (20 mL), dried over sodium sulphate and concentrated. The obtained residue was purified by column chromatography (100-200 silica) using 5-10% ethyl e in eum ether to afford 1-(4-chloromethylphenyl)ethanone (1.5 g, 8.928 mmol, 67% yield) as a colorless liquid. GCMS (ESI) m/z.168.1.
B. Ethyl 2-(4-chlor0methylphenyl)0x0acetate. To a stirred solution of 1-(4-chloromethylphenyl)ethanone (1.5 g, 8.928 mmol) in pyridine (30 mL) was added selenium dioxide (2 g, 17.857 mmol) and stirred for 16h at 100 OC. The reaction mixture was cooled to room temperature, diluted with dichloromethane (30 mL) and filtered through Celite pad. To the filtrate was added ethyl chloroformate (3 mL) at 0 CC and d for 2h.The reaction mixture was quenched with water and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 20 mL), brine (20 mL), dried over sodium sulphate and concentrated.
The ed residue was d by column chromatography (100-200 silica) using -10% ethyl acetate in pet. ether to afford ethyl 2-(4-chloromethylphenyl) oxoacetate (1.1 g, 4.867 mmol, 54% yield) as a colorless liquid. MS (ESI) m/z.226.2.
C. Ethyl 2-(4-chlor0methylphenyl)—2,2-difluoroacetate. To ethyl 2- (4-chloromethylphenyl)oxoacetate (1.1 g, 4.867 mmol) was added diethylaminosulfur trifiuoride (1.6 mL, 12.168 mmol) and stirred for 12h at room temperature. The reaction mixture was neutralized with aqueous ted sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and trated to afford ethyl 2-(4-chloromethylphenyl)-2,2- oacetate (692 mg, 2.790 mmol, 57% yield) as a colorless liquid. GCMS (ESI) m/Z.248. 1.
D. 2-(4-Chlor0methylphenyl)-2,2-diflu0roacetic acid. To a cold (0 CC) stirred on of ethyl 2-(4-chloromethylphenyl)-2,2-difluoroacetate (692 mg, 2.790 mmol) in tetrahydrofuran:ethanol:water mixture (30 mL, 1:1:1) was added m hydroxide (585 mg, 13.951 mmol) and stirred at room temperature for 6h. The on mixture was concentrated and the residue was neutralized with 10% aqueous hydrochloric acid (10 mL) and extracted with ethyl e (2 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2-(4-chloromethylphenyl)-2,2-difluoroacetic acid (446 g, 2.027 mmol, 72% yield) as an brown liquid. MS (ESI) m/z 219.29 [M-1]'.
E. 2-(4-Chloro-Z-methylphenyl)—N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a cold (0 oC) stirred solution of 2-(4-chloromethylphenyl)-2,2-difluoroacetic acid (213 mg, 0.968 mmol) in pyridine was added phosphorus oxychloride (0.27 mL, 2.906 mmol) dropwise and stirred at 0-5°C for 1h and then added 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione hydrochloride (300 mg, 0.968 mmol) and stirred at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated. The obtained residue was purified by Reveleris C-18 reversed phase column chromatography using 40-60% itrile in aqueous formic acid (0.1%) to afford 2-(4-chloromethylphenyl)-N-((2-(2,6- dioxopiperidinyl)oxoisoindolin—5-yl)methyl)-2,2-difluoroacetamide (90 mg, 0.189 mmol, 19.5% yield) as an offwhite solid. MS (ESI) m/z 476.09 . 1H NMR (300 MHz, DMSO-d6) 8 10.99 (s, 1H), 9.65 (t, J: 5.9 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.54 (d, J: 8.3 Hz, 1H), 7.50 — 7.31 (m, 4H), 5.11 (dd, J: 13.2, .1 Hz, 1H), 4.52 — 4.25 (m, 4H), 3.00 — 2.85 (m, 1H), 2.65-2.55 (m, 1H), 2.45-2.31 (m, 4H), 2.08 — 1.94 (m, 1H).
Example 44 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2—diflu0r0(4— fluor0methylphenyl)acetamide A. 1-(4-Flu0r0methylphenyl)ethanone. To a stirred solution of 4-fluoromethylbenzonitrile (2.0 g, 14.803 mmol) in benzene (30 mL) was added methyl magnesium iodide (3M ) in diethyl ether solution (5.92 mL, 17.764 mol) at 0 OC and stirred for 16h at 75 OC. The reaction mixture was cooled to 0 oC and ed with 6N hloric acid solution (20 mL) and continued to stir at 75 0C for 4h. The reaction mixture was quenched with water and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 20 mL), brine (20 mL), dried over sodium sulphate and trated. The residue obtained was purified by column chromatography (100-200 silica) using 5-10% ethyl e in petroleum ether to afford 1-(4-fiuoromethylphenyl)ethanone (1.6 g, 10.526 mmol, 71% yield) as a colourless liquid. GCMS (ESI) m/z.152.2.
B. Ethyl 2-(4-flu0r0methylphenyl)0x0acetate.To a stirred solution of 1-(4-fiuoromethylphenyl)ethanone (1.6 g, 10.526 mmol) in pyridine (30 mL) was added selenium dioxide (2.3 g, 21.052 mmol) and stirred for 16h at 100 oC. The reaction mixture was cooled to room temperature, diluted with romethane (30 mL) and d through Celite pad. To the e was added ethyl chloroformate (3.2 mL) at 0 CC and stirred for 2h.The reaction mixture was quenched with water and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 20 mL), brine (20 mL), dried over sodium sulphate and concentrated.
Obtained residue was purified by column chromatography (100-200 silica) using -10% ethyl e in petether to afford ethyl 2-(4-fiuoromethylphenyl) oxoacetate (1.37 g, 6.523 mmol, 62% yield) as a colourless liquid. GCMS (ESI) m/z.2 1 0. 1 .
C. Ethyl 2,2-diflu0r0(4-flu0r0methylphenyl)acetate. To ethyl 2-(4- chloromethylphenyl)oxoacetate (1.37 g, 6.523 mmol) was added diethylaminosulfur trifiuoride (2.1 mL, 16.307 mmol) and d for 12h at room temperature. The reaction mixture was neutralized with aqueous saturated sodium —154— bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 20 mL), brine (20 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(4-fluoro methylphenyl)acetate (860 mg, 3.706 mmol, 57% yield) as a colourless liquid. GCMS (ESI) m/z.232.2.
D. 2,2-Diflu0r0(4-flu0r0methylphenyl)acetic acid. To a cold (0 oC) stirred solution of ethyl 2-(4-chloromethylphenyl)-2,2-difluoroacetate (860 mg, 3.706 mmol) in tetrahydrofuran:ethanol:water mixture (30 mL, 1:1:1) was added lithium hydroxide monohydrate (933 mg, 22.241 mmol) and stirred at room temperature for 6h. The on e was concentrated and the residue was neutralized with 10% aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(4-fluoro methylphenyl)acetic acid (684 g, 2.948 mmol, 72% yield) as an brown liquid. LCMS (ESI) m/z 203.37 [M-1]'Ve.
E. (2,6-Di0x0piperidinyl)—1-0xois0ind01inyl)methyl)-2,2— diflu0r0(4-fluoro—Z-methylphenyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(4-fluoromethylphenyl)acetic acid (197 mg, 0.968 mmol) in pyridine was added phosphorus oxychloride (0.27 mL, 2.906 mmol) dropwise and d at 0-5°C for 1h. To this reaction mixture was then added 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.968 mmol) and d at room temperature for 30min. The reaction e was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated. The residue obtained was purified by Reveleris C-18 reversed phase column chromatography using 50-60% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-Dioxopiperidinyl) oxoisoindolinyl)methyl)-2,2-difluoro(4-fluoromethylphenyl)acetamide (79 mg, 0.172 mmol, 18% yield) as an off white solid. MS (ESI) m/z 460.10 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.99 (s, 1H), 9.63 (t, J: 6.0 Hz, 1H), 7.70 (d, J: 7.8 Hz, 1H), 7.56 (dd, J: 8.7, 5.8 Hz, 1H), 7.46 (s, 1H), 7.40 (d, J: 7.6 Hz, 1H), 7.25 — 7.11 (m, 2H), 5.11 (dd, J: 13.3, 5.0 Hz, 1H), 4.50 — 4.27 (m, 4H), 2.98-2.86 (m, 1H), 2.68 — 2.55 (m, 1H), .28 (m, 4H), 2.08-1.94 (m, 1H).
Example 45 2-(4-Chlor0(triflu0r0methyl)phenyl)—N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-diflu0roacetamide A. Ethyl 2-(4-chlor0(triflu0r0methyl)phenyl)-2,2-diflu0r0acetate. To a stirred solution of 4-chloroiodo(trifluoromethyl)benzene (1.0 g, 3.26 mmol) in dimethylsulfoxide (15 mL) was added copper (539 mg, 8.48 mmol) and ethyl 2- bromo-2,2-difluoroacetate (994 mg, 4.89 mmol) at room temperature and stirred at 55 CC for 16h. The reaction e was lized with aqueous saturated ammonium chloride solution and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(4-chloro (trifluoromethyl)phenyl)—2,2-difluoroacetate (900 mg, 2.98 mmol, 91%). GCMS (m/Z) 302.0 [Mi B. 2-(4-Chloro-Z-(trifluor0methyl)phenyl)-2,2-diflu0r0acetic acid. To a stirred solution of ethyl 2-(4-chloro(trifluoromethyl)phenyl)-2,2-difluoroacetate (900 mg, 2.98 mmol) in tetrahydrofuran:methanol:water (15 mL, 1:1:1) was added lithium hydroxide (375 mg, 8.94 mmol) and stirred at room temperature for 4h. The reaction mixture was trated and the residue was neutralized with saturated potassium hydrogen sulphate (20 mL) and extracted with ethyl acetate (2 X 100 mL).
The combined organic layers were washed with brine (100 mL), dried over sodium te and concentrated to afford 2-(4-chloro(trifluoromethyl)phenyl)—2,2- difluoroacetic acid (700 mg, 2.55 mmol, 86% yield). GCMS (m/z) 274.1 [M]+.
C. 2-(4-Chlor0(triflu0r0methyl)phenyl)—N-((2-(2,6-di0x0piperidin oxoisoindolinyl)methyl)—2,2-diflu0r0acetamide. To a cold (0 oC) d solution of hloro(trifluoromethyl)phenyl)-2,2-difluoroacetic acid (200 mg, 0.72 mmol) in pyridine (10 mL) was added phosphoryl de (336 mg, 2.18 mmol) dropwise and stirred at 0-5 0C for 1h. and then added 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (226 mg, 0.72 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 80-90% acetonitrile in aqueous formic acid (0.1%) to afford 2-(4-chloro (trifiuoromethyl)phenyl)-N-((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin—5 - yl)methyl)-2,2-difiuoroacetamide (80 mg, 0.11 mmol, 21% yield)as an ite solid.
LCMS (ESI) m/z 530.05 [M+1]+. 1H NMR (300MHz, 6) 5 10.98 (s, 1H), 9.70 (br t, J=5.9 Hz, 1H), 8.03 (s, 1H), 7.97 (br d, J=8.4 Hz, 1H), 7.85 (d, J=9 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.47 (s, 1H), 7.41 (br d, J=7.7 Hz, 1H), 5.11 (br dd, J=4.8, 13.2 Hz, 1H), 4.53 - 4.25 (m, 4H), 3.01 - 2.82 (m, 1H), 2.67 — 2.54 (m, 1H), 2.48 — 2.30 (m, 1H), 2.08 — 1.94 (m, 1H) Example 46 ohexyl-N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolinyl)methyl)—2,2- difluoroacetamide o 0 F F HNmN‘GO A. Ethyl 2-cyclohexyl-2,2-diflu0r0acetate. Ethylcyclohexyl oxoacetate (1 g, 5.43 mmol) was added into diethylamino sulfur trifiuoride (2.5 mL) at 0 CC and stirred at room temperature for 16h. The reaction mixture was quenched with aqueous sodium bicarbonate on and extracted with ethyl acetate (3 X 20 mL).
The combined c layers were washed with brine (20 mL), dried over sodium sulphate, filtered and t was evaporated. Obtained crude was purified by column chromatography (100-200 silica gel, 10% ethyl e in pet ether) to afford ethyl 2- cyclohexyl-2,2-difiuoroacetate (900 mg, 4.36 mmol, 80% yield) as a colourless liquid. 1H NMR (300 MHz, CDClg) 4.32 (q, J = 6.9 Hz, 2H), 2.06 — 2.04 (m, 1H), 1.80 — 1.60 (m, 6H), 1.37 — 1.30 (m, 4H), 1.26 — 1.19 (m, 3H).
B. ohexyl-Z,2-diflu0r0acetic acid. To a stirred solution of ethyl 2-cyclohexyl-2,2-difluoroacetate (900 mg, 4.36 mmol) in mixture of tetrahydrofuran: ethanol: water (15 mL, 1:1:1), was added lithium hydroxide monohydrate (550 mg, 13.10 mmol) and stirred at room temperature for 16h. The volatiles were evaporated under reduced pressure and the resultant residue was dissolved in water (15 mL) and washed with ethyl acetate (2 X 15 mL). Aqueous layer was acidified with 1N 2015/039926 hydrochloride aqueous solution and extracted with ethyl e (3 X 20 mL). The combined c layers were washed with brine (20 mL), dried over sodium sulphate, filtered and t was evaporated to afford 2-cyclohexyl-2,2-difiuoroacetic acid (550 mg, 3.08 mmol, 70% yield) as semi-solid compound. MS (ESI) m/z 178 [M]+.
C. 2-Cyclohexyl—N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)—2,2-diflu0r0acetamide. To an ice cold solution of 2-cyclohexyl-2,2- difiuoroacetic acid (207 mg, 1.16 mmol) in pyridine (6 mL) was added phosphorus oxychloride (0.27 mL, 2.9 mmol) dropwise and stirred at 0-5°C for 1h. Then, the reaction mixture was treated with 3-(5-(aminomethyl)oxoisoindolinyl)piperidine- 2,6-dione hloride (300 mg, 0.97 mmol) and stirred at room temperature for 2h.
The reaction mixture was basified with aqueous saturated sodium bicarbonate solution and extracted with ethyl e (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulphate, filtered and solvent was evaporated. The resultant residue was purified by Reveleris C-18 reversed phase column tography (50-55% acetonitrile in 0.1% aqueous formic acid) to afford 2-cyclohexyl-N-((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)-2,2- di fiuoro acetamide (53 mg, 0.122 mmol, 12% yield) as white solid. MS (ESI) m/z 434.07 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 10.99 (s, 1H), 9.35 (t, J = 6.0Hz,lH), 7.70 (d, J: 7.8 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J: 7.8 Hz, 1H ), 5.11 (dd,.] = 13.2, 5.4Hz, 1H), 4.45 (d,.]= 16.8 Hz, 1H), 4.44 (d,.]= 6.6 Hz, 2H), 4.31 (d, J = 17.7 Hz, 1H), 2.93 — 2.85 (m, 1H), 2.63 — 2.56 (m, 1H), 2.45 — 2.36 (m, 1H), 2.10 — 1.97 (m, 2H), 1.74 — 1.64 (m, 5H), 1.23 — 1.08 (m, 5H).
Example 47 2-(4-Chlor0(triflu0r0meth0xy)phenyl)—N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-diflu0roacetamide O O mNm{f0NHFF H N CI 0 F/i\F A. 4-Chlor0i0d0(triflu0r0meth0xy)benzene. To a solution of 4-chloro(trifluoromethoxy)aniline (2 g, 10.025 mmol) in 66% aqueous sulfuric acid (10 mL) was added a solution of sodium nitrite (760 mg, 11.027 mmol) in water (2 mL) at 0 CC and stirred at 0 CC for 20min. Then a solution of urea (90 mg, 1.5 mmol) in water (1 mL) was added at 0 CC and stirred at same temperature for 10min.
Then a on of potassium iodide (3.49 g, 21.052 mmol) in water (5 mL) was added at 0 CC and stirred at 50 CC for 2h.To the reaction mixture was added ethyl acetate (300 mL) and washed with water (2 X 100 mL), brine (100 mL) and dried over sodium sulphate, and trated. The resultant residue was purified by silica gel (100-200) chromatography using pentane as eluent to afford the 4-chloroiodo (trifluoromethoxy)benzene (2.1 g, 6.52 mmol, 69 % yield) as a colorless syrup. 1H NMR (400 MHz, CDClg) 5 (ppm) 7.79 (d, J=8.8 Hz, 1H), 7.32 — 7.26 (m, 1H), 7.05 (mLJi24,83}h,lH) B. Ethyl 2-(4-chlor0(triflu0rometh0xy)phenyl)-2,2-diflu0r0acetate.
To a stirred solution of 4-fluoroiodo(trifluoromethyl)benzene (2.1 g, 6.525 mmol) in dimethyl sulfoxide (10 mL) was added copper powder (1.03 g, 16.31 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.25 mL, 9.78 mmol) at room temperature and stirred at 60 CC for 16h. The reaction mixture was lized with aqueous saturated ammonium chloride solution and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (25 mL), dried over sodium te and trated. The resultant residue was purified by silica gel 00) chromatography using 5% diethyl ether in pentane as eluent to afford ethyl 2-(4-chloro(trifluoromethoxy)phenyl)-2,2-difluoroacetate (1.8 g, 5.66 mmol, 87 %). 1H NMR (300 MHz, CDClg) 8 (ppm) 7.70 (d, J=8.4 Hz, 1H), 7.44 - 7.32 (m, 2H), 4.34 (q, J=7.3 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).
C. 2-(4-Chloro-Z-(trifluor0meth0xy)phenyl)-2,2-diflu0roacetic acid. To a stirred solution of 2-(4-chloro(trifluoromethoxy)phenyl)-2,2-difluoroacetate (1.8 g, 6.14 mmol) in tetrahydrofuran:methanol:water mixture (15 mL, 1:1:1) was added lithium hydroxide monohydrate (774 mg, 18.42 mmol) and d at room ature for 2h. The reaction mixture was concentrated and the residue was neutralized with saturated potasiium bisulphate (20 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulphate and concentrated to afford 2-(4-chloro (trifluoromethoxy)phenyl)-2,2-difluoroacetic acid (1.2 g, 4.137 mmol, 73% yield). MS (ESI) m/Z 289.14[M-1]+.
D. 2-(4-Chlor0(triflu0r0meth0xy)phenyl)-N-((2-(2,6-di0x0piperidin- 3-yl)—1-0x0is0indolin-S-yl)methyl)-2,2-difluoroacetamide. To a cold (0 oC ) stirred solution of 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) and hloro(trifluoromethoxy)phenyl)-2,2- oacetic acid (280 mg, 0.97 mmol) in N,N—dimethylformamide (10 mL) was added N,N—diisopropylethylamine (375 mg, 2.91 mmol) followed by 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid orophosphate (480 mg, 1.26 mmol) and continued stirring at room temperature for 16h. The on mixture was diluted with water (100 mL) and the solid obtained was filtered, washed with diethyl ether (20 mL), dried and purified using silica gel chromatography (3% methanol in chloroform) to afford 2-(4-chloro (trifluoromethoxy)phenyl)-N—((2-(2,6-dioxopiperidinyl)oxoisoindolin-5 - yl)methyl)-2,2-difluoroacetamide (70 mg, 0.128 mmol, 13% yield) as a white solid.
MS (ESI) m/z 545.97 (M+l)+. 1H NMR (300 MHz, DMSO-d6) 5 (ppm) 10.95 (br s, 1H), 9.72 (br t, J=5.7 Hz, 1H), 7.79 (d, J=9.2 Hz, 1H), 7.71 — 7.61 (m, 3H), 7.46 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 5.10 (br dd, J=5.1, 13.2 Hz, 1H), 4.50 — 4.25 (m, 4H), 2.99 — 2.80 (m, 1H), 2.68 — 2.53 (m, 1H), 2.47 — 2.30 (m, 2H), 2.04 — 1.92 (m, 1H).
Example 48 N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0indolinyl)methyl)-2,2—diflu0r0(3-(2- methoxyeth0xy)phenyl)acetamide O O A. 1-I0do(2-methoxyethoxy)benzene. To a stirred solution of 3-iodophenol (2 g, 9.09 mmol) in N,N—dimethylformamide (20 mL) was added potassium carbonate (3.13 g, 22.72 mmol) followed by 1-bromomethoxyethane (1.51 g, 10.90 mmol) at RT and stirred at 70 CC for 16h. The reaction mixture was quenched with ice water (30 mL) and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated. Obtained crude was purified by column chromatography (100-200 silica gel) using 15% ethyl e in pet ether was used as eluent to afford 1-iodo(2-methoxyethoxy)benzene (1.3 g, 4.69 mmol, 52% yield) as colorless liquid. MS (ESI) m/Z 279.04 [M+l]+.
B. Ethyl 2,2-diflu0r0(3-(2-meth0xyeth0xy)phenyl)acetate. To a stirred solution of 1-iodo(2-methoxyethoxy)benzene (1 g, 3.6 mmol) in dimethylsulfoxide (15 mL) was added ethyl 2-bromo-2,2-difluoroacetate (0.69 mL, .41 mmol) and copper (0.59 g, 9.36 mmol) at 0 oC and stirred at 60 0C for 5h. The reaction mixture was quenched with ice water and filtered through celite pad; e was extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated to afford ethyl 2,2-difiuoro(3-(2-methoxyethoxy)phenyl)acetate (0.60 g, 2.19 mmol, 61 %) as a brown liquid. MS (ESI) m/z 274.1 [M]+.
C. 2,2-Diflu0r0(3-(2-meth0xyeth0xy)phenyl)acetic acid. To a cold (0 CC) stirred solution of ethyl 2,2-difluoro(3-(2-methoxyethoxy)phenyl)acetate (800 mg, 2.93 mmol) in methanol: tetrahydrofuran:water mixture (15 mL, 1:1:1) was added lithium hydroxide monohydrate (370 mg, 8.79 mmol) and stirred at room temperature for 5h. The reaction mixture was concentrated and ed crude was diluted with water (10 mL) and washed with ethyl e (2 X 10 mL). Aqueous layer was ed with 2N aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (3 X 15 mL). The ed organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered; filtrate was concentrated to afford 2,2-difluoro (3-(2-methoxyethoxy)phenyl)acetic acid (600 mg, 3.47 mmol, 83% yield) as a brown semi solid. 1H NMR (300 MHz, DMSO-d6) 8 7.37 — 7.33 (m, 1H), 7.22 — 7.15 (m, 2H), 7.05 — 7.03 (m, 1H), 4.84 (brs, 1H), 4.14 (s, 3H), 3.86 — 3.77 (m, 4H).
D. N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluoro-Z-(3-(2-meth0xyeth0xy)phenyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(3-(2-methoxyethoxy)phenyl)acetic acid (285 mg, 1.16 mmol) in pyridine (3 mL) was added phosphoryl chloride (0.27 mL, 2.91 mmol) se and stirred at 0-5 0C for 1h and then added 3-(5-(aminomethyl)oxoisoindolin eridine-2,6-dione hydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 30 min. The reaction mixture was basified with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 15 mL). The combined c layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate and filtered, concentrated. The resultant residue was purified by Reveleris C-18 ed phase column chromatography using 50-55% acetonitrile in aqueous formic acid (0.1%) afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolin yl)methyl)-2,2-difluoro(3-(2-methoxyethoxy)phenyl)acetamide (48 mg, 0.09 mmol, 9% yield) as an off-white solid. MS (ESI) m/Z 501.96 [M+1]+. 1H NMR (300 MHz, g) 5 10.98 (s, 1H), 9.54 (t, J: 5.8 Hz, 1H), 7.67 (d, J: 8.1 Hz, 1H), 7.47 — 7.35 (m, 3H), 7.16 — 7.11 (m, 3H), 5.12 (dd, J: 13.2, 5.1 Hz, 1H), 4.45 — 4.27 (m, 4H), 4.11 (t, J: 4.2 Hz, 2H), 3.65 (t, J: 4.5 Hz, 2H), 3.30 (s, 3H), 2.91 — 2.80 (m, 1H), 2.63 — 2.57 (m, 1H), 2.44 — 2.36 (m, 1H), 2.08 — 2.05 (m, 1H).
Example 49 N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0indolinyl)methyl)-2,2—diflu0r0(3-(2- hydroxyethoxy)phenyl)acetamide Mom6*Q} A. (2--Br0m0eth0xy)(tertbutyl)dimethylsilane. To a stirred solution of 2-bromoethanol (10 g, 80 mmol)in dichloromethane (100 mL) was added tert- butylchlorodimethylsilane (14.5 g, 96.77 mmol) and imidazole (10 g,161.2 mmol) at 0 CC and stirred at room temperature for 12h. The reaction mixture was quenched with aqueous sodium bicarbonate solution (40 mL) and ted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (40 mL), brine (40 mL), dried over sodium sulfate and concentrated to afford (2-bromoethoxy)(tertbutyl )dimethylsilane (8 g, 33.61 mmol, 42% yield) as colorless liquid.
B. Tert—butyl(2-(3-i0dophenoxy)eth0xy)dimethylsilane. To a stirred solution of (2-bromoethoxy)(tert—butyl)dimethylsilane (5.19 g, 21.8 mmol) in N,N—dimethylformamide (20 mL) was added potassium carbonate (6.27 g, 45.45 mmol), tetrabutyl ammonium iodide (1.34 g, 3.63 mmol) followed by 3-iodophenol (4 g, 18.18 mmol) at RT and d at 70 CC for 16h. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (40 mL), brine (40 mL), dried over sodium sulfate, d and concentrated. Obtained crude was purified by column tography 00 silica gel, 15% ethyl acetate in pet ether) to afford tert—butyl(2-(3-iodophenoxy)ethoxy)dimethylsilane (3.5 g, 9.25 mmol, 43% yield) as colorless liquid. 1H NMR (300 MHz, CDClg) 8 7.28 — 7.26 (m, 2H), 6.98 (t, J = 8.4 Hz, 1H), 6.89 — 6.86 (m, 1H), 4.02 — 3.94 (m, 4H), 0.90 (s, 9H), 0.07 (s, 6H).
C. Methyl 2,2-diflu0r0(3-(2-hydr0xyeth0xy)phenyl)acetate. To a stirred solution of tert-butyl(2-(3 -iodophenoxy)ethoxy)dimethylsilane (1 g, 2.64 mmol) in dimethylsulfoxide (20 mL) was added ethyl o-2,2- difluoroacetate (0.8 g, 3.97 mmol) and copper (0.43 g, 6.87 mmol) at 0 oC and stirred at 60 CC for 5h. The on mixture was quenched with ice water and filtered through a Celite pad. The filtrate was extracted with ethyl acetate (3 X 20 mL) and the combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated to afford methyl 2,2-difluoro(3-(2- hydroxyethoxy)phenyl)acetate (0.2 g, 0.77 mmol, 29 %) as a brown liquid. MS (ESI) m/Z 260.2 [M]+.
D. flu0r0(3-(2-hydr0xyeth0xy)phenyl)acetic acid. To an ice cold solution of methyl 2,2-difluoro(3-(2-hydroxyethoxy)phenyl)acetate (200 mg, 0.77 mmol) in methanol: tetrahydrofi1ran:water mixture (15 mL, 1:1:1) was added lithium hydroxide drate (97 mg, 2.31 mmol) and stirred at room temperature for 5h. The volatiles were removed under reduced pressure and resultant residue was diluted with water (6 mL) and washed with ethyl acetate (2 X 5 mL). Aqueous layer was acidified with 2N aqueous hydrochloric acid (5 mL) and extracted with ethyl acetate (3 X 5 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, concentrated to afford 2,2-difluoro(3-(2- hydroxyethoxy)phenyl)acetic acid (150 mg, 0.65 mmol, 84% yield) as a brown semi solid. 1H NMR (300 MHz, CDC13)8 7.49 — 7.43 (m, 1H), 7.19 — 7.05 (m, 3H), 4.05 — 3.99 (m, 2H), 3.85 (brs, 1H), 3.73 — 3.70 (m, 2H).
E. N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0ind0linyl)methyl)-2,2- difluoro-Z-(3-(2-hydr0xyeth0xy)phenyl)acetamide. To an ice cold solution of aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) and 2,2-difiuoro(3-(2-hydroxyethoxy)phenyl)acetic acid (225 mg, 0.97 mmol) in N,N—dimethylformamide (10 mL) was added N,N—diisopropylethylamine (0.52 mL, 2.91 mmol) ed by 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (479 mg, 1.26 mmol) and stirred at room temperature for 4h.
The reaction mixture was diluted with ice water (15 mL) and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, concentrated and ed crude was purified by Reveleris C-18 reversed phase column (50% itrile in 0.1% s formic acid) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoro(3-(2-hydroxy ethoxy)phenyl)acetamide (61 mg, 0.16 mmol, 16% yield) as an off-white solid. MS (ESI) m/Z 488.08 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 .99 (s, 1H), 9.56 (s, 1H), 7.67 (d, J: 7.8 Hz, 1H), 7.47 — 7.35 (m, 3H), 7.15 — 7.12 (m, 3H), 5.10 (dd, J: 12.6, 4.5 Hz, 1H), 4.88 (t, J: 5.7 Hz, 1H), 4.45 — 4.27 (m, 4H), 4.11 (t, J: 4.8 Hz, 2H), 3.71 (q, J: 4.8 Hz, 2H), 2.91 — 2.87 (m, 1H), 2.62 — 2.56 (m, 1H), 2.41 — 2.35 (m, 1H), 2.02 — 1.97 (m, 1H).
Example 50 N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2-diflu0r0(4-(2- methoxyeth0xy)phenyl)acetamide O O ESKDQNHF F H /O\/\O 0 A. 1-I0do(2-methoxyethoxy)benzene. To a stirred solution of 4-iodophenol (2 g, 9.09mmol) in N,N—dimethylformamide (25 mL) was added 1-bromomethoxyethane (1.5 g, 10.90mmol) tetrabutyl ammonium iodide (670 mg,1.818 mmol) and ium carbonate(3.13 g, 22.72 mmol)at rt and stirred at 70 °C for 16 h. The reaction mixture was quenched with ice cold water (40 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated to afford 1-iodo(2-methoxyethoxy)benzene (600 mg, 2.15 mmol, 24% yield) as ess liquid. MS (ESI) m/z 277.9 [M+1]+.
B. Ethyl 2,2-Diflu0r0(4-(2-meth0xyeth0xy)phenyl)acetate. To a stirred solution of 1-iodo(2-methoxyethoxy)benzene (500 mg,1.798 mmol) in dimethylsulfoxide (5 mL) was reacted with ethyl 2-bromo-2,2-difluoroacetate (0.34mL, 2.69 mmol), copper (297 mg, 4.67 mmol) and stirred for 12h at 50 oC. The reaction mixture was neutralized with s saturated ammonium chloride solution and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodiumsulphate concentrated to afford ethyl 2,2-difluoro(4-(2-methoxyethoxy)phenyl)acetate (120 mg, 0.437 mmol, 24 %) as a brown liquid. GCMS (m/z) 274 [M]+ C. 2,2-Diflu0r0(4-(2-methoxyethoxy)phenyl)acetic acid. To a cold (0 CC) stirred on of ethyl ethyl 2,2-difluoro(4-(2- methoxyethoxy)phenyl)acetate (1 g, 3.64 mmol) in in ethanol/ ydrofuran/water mixture (15 mL, 1:1:1) was added lithium hydroxide drate (460 mg, .94 mmol) and stirred at room temperature for 12h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic layer was washed with brine (10 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(4-(2-methoxyethoxy)phenyl)acetic acid (600 mg, 2.43mmol, 66% yield) as a brown semi solid. Without fiirther purification crude compound used for next step.
D. N-((2-(2,6-di0x0piperidinyl)0x0isoindolinyl)methyl)-2,2- difluoro-Z-(4-(2-hydr0xyeth0xy)phenyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(4-(2-methoxyethoxy)phenyl)acetic acid (573 mg, 2.33 mmol) in pyridine was added phosphorus oxychloride (0.54mL, 5.82 mmol) dropwise and stirred at 0-5°C for 1h and then added 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione hydrochloride (600 mg, 1.94 mmol) and stirred at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodium onate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layer was washed with water (2 X 20 mL), brine (20 mL) and dried over sodium sulphate and concentrated. The resultant residue was purified by ris C-18 ed phase column chromatography using 40-55% acetonitrile in aqueous formic acid (0.1%) to afford (2,6-dioxopiperidinyl)oxoisoindolin- -yl)methyl)-2,2-difluoro(4-(2-methoxyethoxy)phenyl)acetamide (40 mg, 0.079 mmol, 4% yield) as a white solid. MS (ESI) m/Z 502.08 [M+1]+. 1H NMR (300MHz 8 10.98 (s, 1H), 9.57 (br t, J=6.1 Hz, 1H), 7.68 (d, J=7.7 Hz, , DMSO-d6): 1H), 7.50 (d, J=8.8 Hz, 2H), 7.42-7.32 (m, 2H), 7.07 (d, J=8.8 Hz, 2H), 5.10 (dd, J=13.2, 5.1 Hz, 1H), 4.44 -4.25 (m, 4H), 4.20-4.10 (m, 2H), 3.78-3.60 (m, 2H), 3.25 (s, 3H), 3.00-2.83 (m, 1H), 2.66-2.56 (m, 1H), 2.45-2.32 (m, 1H), 2.05-1.94 (m, 1H).
Example 51 N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0indolinyl)methyl)-2,2—diflu0r0(3-(2- hydroxyethyl)phenyl)acetamide H N O HO N A. 2-(3-Iod0phenyl)ethanol: To a stirred solution of 2-(3- iodophenyl)acetic acid (1 g, 3.81 mmol) in tetrahydrofuran (20 mL) was added borane dimethyl sulfide complex (1 mL, 11.45 mmol) at 0 CC and stirred at room temperature for 16h. The reaction mixture was quenched with 4N hydrochloride acid (15 mL) and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated to afford odophenyl)ethanol (0.9 g, 3.63 mmol, 95% yield) as ess liquid. 1H NMR (300 MHz, DMSO-d6) 8 7.61 (s, 1H), 7.55 (d, J: 7.8 Hz, 1H), 7.25 (d, J: 7.8 Hz, 1H), 7.08 (dd, J: 7.8, 7.5 Hz, 1H), 3.59 (t, J: 6.6 Hz, 2H), 2.67 (t, J: 6.0 Hz, 2H).
B. 3-Iod0phenethyl acetate. To a stirred on of 2-(3- iodophenyl)ethanol (900 mg, 3.62 mmol) in pyridine (15 mL) was added acetic anhydride (1.11 g, 10.88 mmol) at 0 CC and stirred at 80 CC for 2h. The reaction mixture was quenched with 1N aqueous hydrochloride (10 mL) at room temperature mmaMMmmeGXIMM)HmmewMmebwmwme washed with water (15 mL), brine (15 mL), dried over sodium sulfate and trated to afford 3-iodophenethyl acetate (700 mg, 2.41 mmol, 66% yield) as colorless liquid. 1H NMR (400 MHz, DMSO-d6) 8 7.66 (s, 1H), 7.59 (d, J: 5.7 Hz, 1H), 7.28 (d, J==651h,HD,711@MV]=80Ph,78Ph,HD,4200"]=68Ifi;2HL2850, J = 6.8 Hz, 2H), 1.97 (s, 3H).
C. Ethyl 2-(3-(2-acetoxyethyl)phenyl)-2,2-diflu0r0acetate. To a stirred solution of 3-iodophenethyl acetate (1 g, 3.46 mmol) in dimethyl sulfoxide (20 mL) wwawmmmfl2bmmqllmmmmmmMefl05g519mmdfldbwwby cqmmqmwdm1057g899nmmDanomnmnmmammandgnmdMSO°Cfin16h The reaction mixture was neutralized with s ted ammonium chloride solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate and concentrated to afford ethyl 2-(3-(2-acetoxyethyl)phenyl)-2,2-difluoroacetate (550 mg, 1.92 mmol, 55%) as a brown liquid. 1H NMR (400 MHZ, DMSO-d6) 5 7.49 — 7.46 (m, 2H), 7.41 — 7.34 (m, 2H), 4.31 — 4.27 (m, 4H), 2.98 (t, J: 7.2 Hz, 2H), 2.03 (s, 3H), 1.31 (t, J: 6.8 Hz, 3H).
D. 2,2-Diflu0r0(3-(2-hydr0xyethyl)phenyl)acetic acid. To an ice cold solution of ethyl 2-(3-(2-acetoxyethyl)phenyl)-2,2-difiuoroacetate (0.8 g, 2.77 mmol) in ethanol/tetrahydrofuran/water mixture (15 mL, 1:1:1) was added lithium hydroxide monohydrate (349 mg, 8.3 mmol) and stirred at room ature for 16h. The les were removed and the residue was diluted with water (10 mL), washed with wwmwmeQX1MM)AmmmflwmmfifiwwMflNmmmmMMmMmmmm (10 mL) and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium e, d and concentrated to afford fiuoro(3-(2-hydroxy ethyl)phenyl)acetic acid (450 mg, 2.08 mmol, 75% yield) as a brown semi solid. 1H NMR (300 MHz, DMSO-d6) 8 7.56 — 7.39 (m, MDJ62¢J=66HLHDJ78@J=66HLHDJ91@JH) E. N-((2-(2,6-Di0x0piperidinyl)—1-0xois0ind01inyl)methyl)-2,2— difluoro-Z-(3-(2-hydr0xyethyl)phenyl)acetamide. To an ice cold solution of 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) and 2,2-difiuoro(3-(2-hydroxyethyl)phenyl)acetic acid (209 mg, 0.97 mmol) in N,N—dimethylformamide (10 mL) was added N,N—diisopropylethylamine (0.52 mL, 2.91 mmol) followed by 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafiuorophosphate (479 mg, 1.26 mmol) and stirred at room temperature for 16h.
The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulphate, filtered and concentrated. The obtained crude product was purified by Reveleris C-18 reversed phase column (50% itrile in 0.1% s formic acid to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)- 2,2-difiuoro(3-(2-hydroxyethyl)phenyl)acetamide (50 mg, 0.10 mmol, 11% yield) as an off-white solid. MS (ESI) m/z 472.11 [M+1]+. 1H NMR (300 MHZ, DMSO-d6) 5 1098@,HD,9610HJ=63}h,HD,767@LJ=81}h,HD,743—741@m5HL 7.36 (d, J: 8.1 Hz, 1H), 6.67 (t, J: 5.1 Hz, 1H), 5.10 (dd, J: 13.8, 5.1 Hz, 1H), 4.45 (dfll=60lkg2HL4430"]=153Ph,HD,428@LJ=177P&,HD,361@LJ= 511k;2HL296—2830n,HD,275GVJ=69Ikg2HL267—2540n,HD,246— 2300n;HD,204—192(nn1H) 2015/039926 Example 52 2-(3-(Dimethylamin0)phenyl)-N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)-2,2-diflu0roacetamide / NH A. 3-Iod0-N,N-dimethylaniline. To a stirred solution of 3-iodoaniline (300 mg, 1.36 mmol) in ethanol (10 mL) was added formaldehyde (82 mg, 2.73 mmol), molecular sieves (1 g) and acetic acid (2 mL) at 0 OC, stirred at room temperature for 8h. The reaction mixture was cooled at 0 CC and treated with sodium cyano borohydride (200 g, 2.73 mmol) and stirred at room temperature for 16h. The reaction mixture was filtered through a Celite pad and the filtrate was d with water (10 mL) and basified with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 X 10 mL). Combined organic layers were washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude compound. Obtained crude was purified by silica gel column chromatography (30% ethyl acetate in pet ether) to afford -N,N— dimethylaniline (210 mg, 0.85 mmol, 74% yield) as a liquid. 1H NMR (300 MHZ, CDC13)5 7.03 — 6.89 (m, 3H), 6.67 — 6.64 (m, 1H), 2.92 (s, 6H).
] B. Ethyl 2-(3-(dimethylamino)phenyl)-2,2-diflu0r0acetate. To a stirred solution of 3-iodo-N,N—dimethylaniline (250 mg, 1.01 mmol) in dimethylsulfoxide (10 mL) was added ethyl 2-bromo-2,2-difiuoroacetate (0.19 mL, 1.52 mmol) followed by copper powder (167 mg, 2.63 mmol) at RT and stirred at 55 0C for 5h. The on mixture was diluted with water and filtered through a Celite pad. The filtrate was basified with s saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, d, trated to afford ethyl 2-(3- (dimethylamino)phenyl)-2,2-difluoroacetate (80 mg, 6.99 mmol, 33%) as a brown liquid. MS (ESI) m/Z 243.2 [M]+ C. 2-(3-(Dimethylamin0)phenyl)-2,2-diflu0r0acetic acid. To an ice cold solution of ethyl 2-(3 -(dimethylamino)phenyl)-2,2-difiuoroacetate (500 mg, 2.06 mmol) in in methanol/ tetrahydrofuran /water mixture (15 mL, 1:1:1) was added lithium hydroxide monohydrate (260 mg, 6.17 mmol) and stirred at room temperature for 4h. The reaction mixture was concentrated and the ant residue was diluted with water (10 mL) and washed with ethyl acetate (2 X 10 mL). Aqueous layer acidified with s potassium bi sulfate (10 mL) and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford 2-(3-(dimethylamino)pheny1)- 2,2-difluoroacetic acid (400 mg, 1.86 mmol, 91% yield) as a brown semi solid 1H NMR (300 MHz, DMSO-d6) 5 7.64 — 7.55 (m, 3H), 7.38 — 7.32 (m, 1H), 2.56 (s, D. 2-(3-(Dimethylamin0)phenyl)-N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To an ice cold solution of aminomethyl)oxoisoindoliny1)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) and 2-(3-(dimethylamino)phenyl)-2,2-difluoroacetic acid (208 mg, 0.97 mmol) in N,N—dimethylformamide (10 mL) was added N,N—diisopropylethylamine (0.52 mL, 2.91 mmol) ed by 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (479 mg, 1.26 mmol) and stirred at room temperature for 16h.
The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was purified by Reveleris C-18 reversed phase column (50% acetonitrile in 0.1% aqueous formic acid) to afford 2-(3-(dimethylamino)phenyl)-N-((2-(2,6-dioxopiperidinyl) indolinyl)methyl)-2,2-difluoroacetamide (63 mg, 0.13 mmol, 13% yield) as an off-white solid. MS (ESI) m/Z 470.8 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 1098G,HD,9210"]=58}h,HD,772@LJ=78fh,HD,762@LJ=75PH, HD,757—7480n¢flD,732@wv]=84,69fh,1H)511(&LJ=132,48P&, 1H), 4.48 (d, J: 6.6 Hz, 2H), 4.46 (d, J: 16.5 Hz, 1H), 4.32 (d, J: 17.4 Hz, 1H), 298—2860n,HD,273—257(nn1H)251—233(nn1H)234(s6HL207— 198(nn11D.
Exanqfle53 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(3- (piperidin-l-yl)phenyl)acetamide A. 1-(3-10d0phenyl)piperidine. To a stirred on of aniline (5 g, 22.83 mmol) in toluene (50 mL) was added N,N—diisopropylethylamine (20 mL, 114.1 mmol) followed by 1,5-dibromopentane (4.06 mL, 29.68 mmol) at 0 °C and d at 100 0C for 16h. The reaction mixture was basified aqueous ted sodium bicarbonate solution and extracted with ethyl acetate (3 X 40 mL). The combined organic layers were washed with water (40 mL), brine (40 mL), dried over sodium sulfate, filtered; filtrate and concentrated. The obtained crude was purified by flash column chromatography (25% ethyl e in pet ether) to afford 1-(3- iodophenyl)piperidine (2.8 g, 9.75 mmol, 43% yield) as a colorless liquid. MS (ESI) m/Z 287.90 [M+1]+.
B. Ethyl 2,2-diflu0r0(3-(piperidinyl)phenyl)acetate. To a d solution of 1-(3-iodophenyl)piperidine (500 mg, 1.74 mmol) in dimethyl sulfoxide (5 mL) was added ethyl 2-bromo-2,2-difluoroacetate (690 mg, 2.61 mmol) followed by copper powder (290 mg, 4.53 mmol) at room temperature and stirred at 55 0C for 16h. The reaction mixture was diluted with water and d through a Celite pad.
The filtrate was extracted with ethyl e (3 X 10 mL) and the combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated. The resultant crude product was purified by flash column chromatography (25% ethyl acetate in pet ether) to afford ethyl 2,2-difluoro(3- (piperidinyl)phenyl)acetate (200 mg, 0.71 mmol, 41% yield) as a colorless .
MS (ESI) m/Z 283.2 [M]+.
C. 2,2-Diflu0r0(3-(piperidinyl)phenyl)acetic acid. To a stirred solution of ethyl 2,2-difluoro(3-(piperidinyl)phenyl)acetate (250 mg, 0.88 mmol) in mixture of tetrahydrofuran: methanol: water (5 mL, 1:1 :1) was added lithium hydroxide monohydrate (110 mg, 2.65 mmol) and stirred at room temperature for 16h.
The reaction mixture was concentrated under reduced pressure and the obtained residue was dissolved in water (10 mL) and washed with ethyl acetate (2 X 10 mL).
Aqueous layer was acidified with aqueous ium bi sulfate and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford 2,2-difiuoro (3-(piperidinyl)phenyl)acetic acid (200 mg, 0.78 mmol, 88% yield) as semi-solid compound. 1H NMR (300 MHz, CDClg) 8 8.27 (d, J: 9.3 Hz, 1H), 7.89 (s, 1H), 7.70 (d, J: 7.5 Hz, 1H), 7.49 (dd, J: 7.8 Hz, 7.6 Hz, 1H), 4.28 (brs, 1H), 3.49 — 3.39 (m, 4H), 2.12 — 2.08 (m, 4H), 1.69 — 1.65 (m, 2H).
D. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- difluoro-Z-(3-(piperidinyl)phenyl)acetamide. To an ice cold solution of 2,2-difluoro(3-(piperidinyl)phenyl)acetic acid (206 mg, 0.81 mmol) in pyridine (6 mL) was added phosphorus oride (371 mg, 2.43 mmol) drop wise and d at 0-5°C for 1h. Then, 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (250 mg, 0.81 mmol) was added into the on mixture and stirred at room temperature for 2h. The reaction mixture was ed with aqueous saturated sodium bicarbonate and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography (50-55% acetonitrile in 0.1% s formic acid to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)- 2,2-difluoro(3-(piperidinyl)phenyl)acetamide (62 mg, 0.12 mmol, 15% yield) as white solid. MS (ESI) m/z 510.81 [M+1]+. 1H NMR (300 MHz, 6) 8 10.99 (s, 1H), 9.57 (t, J: 5.7 Hz, 1H), 7.66 (d, J: 7.5 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J: .1 Hz, 1H), 7.30 (d, J: 8.1 Hz, 1H), 7.08 (d, J: 8.7 Hz, 1H), 7.00 (s, 1H), 6.92 (d, J = 7.5 Hz, 1H), 5.10 (dd, J: 13.2, 4.8 Hz, 1H), 4.45 (d, J: 6.0 Hz, 2H), 4.41 (d, J: 17.7 Hz, 1H), 4.27 (d, J: 17.4 Hz, 1H), 3.31 — 3.11 (m, 4H), 2.98 — 2.86 (m, 1H), 2.63 — 2.57 (m, 1H), 2.40 — 2.27 (m, 2H), 2.01 — 1.97 (m, 1H), 1.57 — 1.54 (m, 5H).
Example 54 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(3- morpholinophenyl)acetamide A. 2,2'-Oxybis(ethane-2,l-diyl) dimethanesulfonate. To a stirred solution of 2,2'-oxydiethanol (2.0 g, 18.86 mmol) in dichloromethane (20 mL) was added methane sulfonylchloride (2.1 g, 47.16 mmol), triethylamine (13 mL, 94.33 mmol) at 0 CC and stirred at room temperature for 2h. The reaction mixture was quenched with water (100 mL) and extracted with dichloromethane (2 X 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and concentrated to afford 2,2'-oxybis(ethane-2,1-diyl) dimethanesulfonate (4.0 g, .26 mmol, 81% yield). GC MS (m/z) 263.1.
B. 4-(3-Iod0phenyl)m0rpholine. To a stirred on of 3-iodo aniline (1.0 g, 4.56 mmol) in toluene (20 mL) was added 2,2'-Oxybis(ethane-2,1-diyl) dimethanesulfonate (2.1 g, 9.13 mmol), ropylethylamine(4 mL, 22.82 mmol) and stirred under reflux for 16h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and concentrated to give 4-(3-iodophenyl)morpholine (1.2 g, 4.15 mmol, 91% yield). LCMS (ESI) m/Z 290.16[M+1]+.
C. Ethyl flu0r0(3-m0rpholinophenyl)acetate. To a stirred solution of odophenyl)morpholine (1.2 g, 4.15 mmol) in dimethylsulfoxide (50 mL) was added ethyl 2-bromo-2,2-difluoroacetate (0.6 mL, 4.98 mmol), copper (686 mg, 10.79 mmol) and stirred for 6h at 55 OC. The reaction e was neutralized with aqueous saturated ammonium chloride solution and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and trated to afford ethyl 2,2-difluoro(3-morpholinophenyl)acetate (700 mg, 2.45 mmol, 59% yield).
GC MS (m/z) 285.2.
D. fluoro(3-morpholinophenyl)acetic acid. To a cold (0 CC) stirred solution of ethyl 2,2-difluoro(3-morpholinophenyl)acetate (700 mg, 2.45 mmol) in tetrahydrofuran -methanol-water (20 mL, 1:1:1) was added lithium ide monohydrate (309 mg, 7.36 mmol) and stirred at room temperature for 2h.
The reaction mixture was concentrated and the residue was lized with 10% aqueous potassium bisulphate (5 mL) and extracted with ethyl acetate (2 X 50 mL).
The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(3-morpholinophenyl)acetic acid (550 mg, 2.14 mmol, 87 % yield). LCMS (ESI) m/Z 258.12[M+1]+.
E. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluoro-Z-(3-m0rpholin0phenyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(3-morpholinophenyl)acetic acid (300 mg, 1.16 mmol) in pyridine (5 mL) was added phosphoryl chloride (0.4 mL, 3.50 mmol) and stirred at 0-5 0C for 1h. To this reaction mixture was added 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione hydrochloride (361 mg, 1.16 mmol) and stirred at room temperature for 1h. The reaction mixture was lized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (2 X 25 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium te and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 40-45% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolin yl)methyl)-2,2-difluoro(3-morpholinophenyl) acetamide (80 mg, 0.15 mmol, 13% yield) as an off white solid. LCMS (ESI) m/Z 512.95 [M+1]+. 1H NMR (400MHz, DMSO-d6) 5 = 10.98 (s, 1H), 9.58 (br t, J=6.1 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.52 — 7.31 (m, 2H), 7.11 (br d, J=8.3 Hz, 1H), 7.07 —6.95 (m, 1H), 5.10 (dd, J=4.9, 13.2 Hz, 1H), 4.51 — 4.26 (m, 4H), 3.77 — 3.66 (m, 4H), 3.14 — 3.03 (m, 4H), 2.98 — 2.84 (m, 1H), 2.66 — 2.55 (m, 1H), 2.45 — 2.30 (m, 1H), 2.06 — 1.94 (m, 1H) Example 55 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2—diflu0r0(4— Z-isopropoxyphenyl)acetamide O O F 10 A. 1-(4-Flu0r0isoprop0xycyclohexyl)ethanone. To a stirred solution of 1-(4-fluorohydroxyphenyl)ethanone (3 g, 19.48 mmol) in N,N—dimethylformamide (15 mL) was added 2-bromopropane (5.94 g, 48.76 mmol) potassium ate (8.06 g 58.44 mmol) and stirred for 16h at 90 CC. The on mixture was diluted with ethyl acetate (30 mL) and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL) and dried over sodium te and was concentrated to afford 1-(4-fluoro isopropoxyphenyl)ethanone (2.5g, 12.75 mmol, 65% yield) as a brown liquid. MS (ESI) m/Z 197.33 [M]+ B. Ethyl 2-(4-fluoro-Z-isopropoxyphenyl)0x0acetate. To a stirred solution of 1-(4-fluoroisopropoxyphenyl)ethanone (2.0 g, 10.20 mmol) in ne (15 mL) was added selenium dioxide (2.83 g, 25.51 mmol) and stirred for 16h at 100 CC. The reaction mixture was d with dichloromethane (30 mL) and filtered through Ce1ite pad. The filtrate was treated with ethyl chloroformate (6 mL) at 0 CC and stirred at room ature for 3h. The reaction mixture was neutralized with 1N aqueous hydrochloric acid (up to pH-4) and extracted with ethyl e (2 X 100 mL).
The combined organic layers were washed with water (2 X 50 mL), brine (50 mL) and dried over sodium sulphate and concentrated. The crude was d with column chromatography using 100-200 mesh silica gel eluting 10% ethylacetate in hexanes to afford ethyl 2-(4-fiuoroisopropoxyphenyl)oxoacetate (800 g, 3.14 mmol, 32% yield) as a brown liquid. MS (ESI) m/Z 255.33 [M]+ C. Ethyl 2,2-diflu0r0(4-flu0r0is0pr0p0xyphenyl)acetate. To a stirred solution of ethyl uoroisopropoxyphenyl)oxoacetate (450 mg, 1.77 mmol) was added diethyl amino sulfur trifiuoride (714 mg, 4.42 mmol) and stirred at room temperature for 16h. The reaction mixture was basified with aqueous saturated sodium bicarbonate to pH-8 and extracted with ethyl acetate (3 X 50 mL).
The combined organic layers were washed with water (2 X 30 mL), brine (30 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difiuoro(4-fluoro- ropoxyphenyl)acetate (200mg, 0.724 mmol, 40% yield) as a brown liquid. GC- MS (ESI) m/Z 276 [M]+ D. 2,2-Diflu0r0(4-flu0r0is0pr0p0xyphenyl)acetic acid. To a stirred solution of ethyl 2,2-difiuoro(4-fiuoroisopropoxyphenyl)acetate (350 mg, 1.26 mmol) in tetrahydrofuran /Methanol/Water mixture (30 mL, 1:1:1) was added lithium hydroxide monohydrate (160 mg, 3.80 mmol) and stirred at room temperature for 4h. The reaction mixture was trated; the residue obtained was neutralized with 10% aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford fiuoro(4-fiuoro isopropoxyphenyl)acetic acid (200 mg, 0.806 mmol, 63% yield) as a brown semi solid.
GC-MS (ESI) m/z 224.0 [M]+; 1H NMR (300 MHz, CDClg) 5 ppm 7.62 (dd, J: 8.4, 2.1 Hz, 1H), 7.19 (brs, 1H), 6.72 (ddd,.]= 10.8, 8.4, 2.1 Hz, 1H), 6.65 (brd, J: .5 Hz, 1H), 4.58 (sep, .1: 5.7 Hz, 1H), 1.33 (d, J: 6.3 Hz, 6H). —174— E. N-((2-(2,6-Di0x0piperidinyl)—1-0xois0ind01inyl)methyl)-2,2— difluoro-Z-(4-flu0r0is0pr0p0xyphenyl)acetamide. To an ice cold solution of 2,2-difluoro(4-fluoroisopropoxyphenyl)acetic acid (289 mg, 1.165 mmol) in pyridine (10 mL) was added POC13 (446 mg 2.91 mmol) and stirring at 0-5 CC for 1h.
The reaction mixture was then treated with 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione hydrochloride (300 mg, 0.970 mmol) and stirred at 0-30 0C for 1h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated. The crude t was purified by Reveleris C-18 reversed phase column (45-55% itrile in 0.1% aqueous formic acid) to afford (2,6- dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)-2,2-difluoro(4-fluoro isopropoxyphenyl)acetamide (35 mg, 0.069 mmol, 7 % as an off white solid. MS (ESI) m/z 503.95 [M+1]+.1H NMR (300 MHz, DMSO-d6) 5 ppm 10.98 (s, 1 H), 9.32 (t, J: 5.7 Hz, 1H), 7.70 (d, J: 7.70 Hz, 1 H), 7.60 — 7.50 (m, 2H), 7.46 (br d, J: 7.7 Hz, 1 H), 7.08 (br d, J: 11.0 Hz, 1 H), 6.85 (dd, J: 8.7, 6.3 Hz, 1 H), 5.11 (dd, J=13.6, 4.77 Hz, 1 H), 4.68 (sep, J: 6.3 Hz, 1 H), 4.53 - 4.23 (m, 3 H), 3.00 — 2.81 (m, 1 H), 2.68 — 2.49 (m, 1H), 2.44 — 2.30 (m, 1 H), 2.07 — 1.93 (m, 1 H), 1.11 (dd, J: 4.5 Hz, 0.2 Hz, 6H).
Example 56 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(2- (2,2,2-triflu0r0eth0xy)phenyl)acetamide o o F F HNV©:l The reaction mixture was basified with s saturated sodium onate solution and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was purified by silica gel column tography (20% ethyl acetate in pet ether) to afford ethyl 2,2-difluoro(2-(2,2,2- trifluoroethoxy)phenyl)acetate (410 mg, 1.37 mmol, 24%) as a colorless liquid. MS (ESI) m/Z 298.1 [Mr- C. flu0r0(2-(2,2,2-triflu0r0eth0xy)phenyl)acetic acid. To a stirred on of ethyl 2,2-difluoro(2-(2,2,2-trifluoroethoxy)phenyl)acetate (400 mg, 1.34 mmol) in tetrahydrofuran: methanol: water (15 mL, 1:1:1) was added lithium hydroxide drate (169 mg, 4.02 mmol) and d at room temperature for 4h. The volatiles were removed under d pressure and obtained crude was dissolved in water (15 mL) and washed with ethyl acetate (2 X 10 mL). Aqueous layer was acidified with 1N hydrochloride aqueous solution and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and solvent was concentrated to afford 2,2-difluoro(2- (2,2,2-trifluoroethoxy)phenyl)acetic acid (270 mg, 1 mmol, 59% yield) as semi-solid compound. 1H NMR (400 MHz, CDClg) 8 7.72 (d, J: 6.3 Hz, 1H), 7.51 (t, J: 8.4 Hz, 1H), 7.19 (t, J: 7.8 Hz, 1H), 6.93 (d, J: 8.4 Hz, 1H), 6.68 (brs, 1H), 4.38 (q, J = 8.1 Hz, 1H).
D. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- diflu0r0(2-(2,2,2-triflu0r0eth0xy)phenyl)acetamide. To an ice cold solution of 2,2’-difluoro(2-(2,2,2-trifluoroethoxy)phenyl)acetic acid (262 mg, 1.16 mmol) in pyridine (6 mL) was added phosphorus oxychloride (0.27 mL, 2.9 mmol) drop wise and stirred at 0-5 CC for 1h and then added 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) and d at room temperature for 2h. The reaction mixture was basified with aqueous saturated sodium onate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column tography (50-55% acetonitrile in 0.1% aqueous formic acid) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoro(2-(2,2,2-tri fluoroethoxy)phenyl)acetamide (60 mg, 0.11 mmol, 11% yield) as white solid. MS (ESI) m/z 525.89 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.98 (s, 1H), 9.42 (t, J: 5.4 Hz, 1H), 7.70 (d, J: 7.5 Hz, 1H), 7.63 - 7.52 (m, 2H), 7.49 (s, 1H), 7.43 (d, J: 8.1 Hz, 1H), 7.26 (d, J: 8.1 Hz, 1H),7.18 (dd, J: 7.7, 7.6 Hz, 1H), .11 (dd, J: 13.2, 4.8 Hz, 1H), 4.75 (q, J: 8.7 Hz, 2H), 4.46 (d, J: 17.1 Hz, 1H), 4.45 (d, J: 6.0 Hz, 2H), 4.31 (d, J: 17.4 Hz, 1H), 2.92 — 2.86 (m, 1H), 2.63 — 2.57 (m, 1H), 2.42 — 2.37 (m, 1H), 2.02 — 1.98 (m, 1H).
Example 57 N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0indolinyl)methyl)(2-eth0xy fluor0phenyl)—2,2-difluoroacetamide A. th0xyflu0r0phenyl)ethan0ne. To a stirred solution of 1-(4-fluorohydroxyphenyl)ethanone (3 g, 19.48 mmol) in N,N-dimethylformamide (15 mL) was added bromoethane (5.30 g, 48.76 mmol) potassium carbonate (8.06 g 58.44 mmol) and stirred for 16h at 100 CC. The reaction mixture was diluted with ethylacetate (30 mL) and extracted with ethyl acetate (2 X 100 mL). The combined c layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford 1-(2-ethoxyfluorophenyl)ethanone (2.6 g, 14.28 mmol, 74% yield) as a brown liquid. MS (ESI) m/Z 183.17 [M]+ B. Ethyl 2-(2-eth0xyflu0r0phenyl)—2-0xoacetate. To a stirred solution of 1-(2-ethoxyfluorophenyl)ethanone (1.0 g, 5.49 mmol) in pyridine (15 mL) was added selenium dioxide (1.52 g, 13.73 mmol) and stirred for 16h at 100 OC. The reaction mixture was diluted with dichloromethane (30 mL) and filtered through Celite pad. To the te was added ethyl chloroformate (3 mL) at 0 CC and d at room temperature for 3h.The reaction mixture was neutralized with 1N aqueous hydrochloric acid (up to pH-4) and extracted with ethyl acetate (2 X 100 mL). The ed organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The crude was d with column chromatography using 100-200 mesh silica gel eluting10% ethylacetate-pet ether to afford ethyl 2-(2-ethoxyfluorophenyl)oxoacetate (880 g, 3.66 mmol, 67% yield) as a brown liquid. MS (ESI) m/Z 241.14 [M]+ C. Ethyl 2-(2-eth0xyflu0r0phenyl)—2,2-diflu0r0acetate. To a stirred solution of ethyl 2-(2-ethoxyfluorophenyl)oxoacetate (800 mg, 3.33 mmol) was added diethyl amino sulfur trifluoride (1.34 g, 8.33 mmol) and stirred for 16h at room temperature. The reaction mixture was neutralized with aqueous ted sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined c layers were washed with water (2 X 30 mL), brine (30 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(2-ethoxyfluorophenyl)-2,2- difluoroacetate (450 mg, 1.71 mmol, 51 % yield) as a brown liquid. GC-MS (ESI) m/z 262 [M]+ D. 2-(2-Eth0xyfluorophenyl)-2,2-diflu0r0acetic acid. To a stirred solution of ethyl 2-(2-ethoxyfluorophenyl)-2,2-difluoroacetate (1 g, 3.81 mmol) in tetrahydrofuran /Methanol/Water mixture (30 mL, 1:1:1) was added m hydroxide monohydrate (480 mg, 11.45 mmol) and stirred at room temperature for 4h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2-(2-ethoxyfluorophenyl)-2,2-difluoroacetic acid (600 mg, 2.56 mmol, 67% yield) as a brown semi solid. The crude compound used for next step without further purification.
E. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2-(2- ethoxyfluorophenyl)-2,2-diflu0r0acetamide. To a cold (0 oC) stirred solution of thoxyfluorophenyl)-2,2-difluoroacetic acid (181 mg, 0.776 mmol) in pyridine (10 mL) was added phosphoryl chloride (294 mg 1.93 mmol) and stirred at 0 0C-5 0C for 1h. To this reaction mixture was then added 3-(5-(aminomethyl)oxoisoindolin- 2-yl)piperidine-2,6-dione hydrochloride (200 mg, 0.647 mmol) at 0 oC and allowed to warm room temperature stirring over a period of 1h. The reaction mixture was neutralized with ted aqueous sodium onate (up to pH-8) and extracted with 2015/039926 ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X mL), brine (10 mL), dried over sodium sulphate and concentrated. The crude product was purified by ris C-18 reversed phase column using 45-55% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl) oxoisoindolinyl)methyl)(2-ethoxyfluorophenyl)-2,2-difluoroacetamide (80 mg, 0.163 mmol, 25% yield)as an offwhite solid. MS (ESI) m/z 489.95 [M+1]+. 1H NMR (300MHz 8 10.98 (s, 1H), 9.35 (br t, J=5.8 Hz, 1H), 7.71 , DMSO-d6) (d, J=7.7 Hz, 1H), 7.59 (dd, J=8.6, 6.8 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.05 (br d, J=11.0 Hz, 1H), 6.88 (td, J=8.5, 2.4 Hz, 1H), 5.11 (dd, J=13.3, 5.3 Hz, 1H), .26 (m, 4H), 4.00 (q, J=6.9 Hz, 2H), 3.00-2.85 (m, 1H), 2.67-2.55 (m, 1H), 2.44- 2.31 (m, 1H), 2.06-1.95 (m, 1H), 1.11 (t, J=6.9 Hz, 3H).
Example 58 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(2— isopr0poxyphenyl)acetamide o 0 : .x. WodboO A. 1-Iod0isopropoxybenzene. To a stirred on of 2-iodophenol (2 g, 9.09 mmol) in N,N—dimethylformamide (20 mL) was added 2-bromopropane (3.38 mL, 36.3 mmol) followed by potassium carbonate (3.76 g, 27.27 mmol) and stirred at 90 CC for 16h. The reaction mixture was diluted with ice water (25 mL) and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated to afford 1-iodoisopropoxybenzene (2.0 g, 7.63 mmol, 84% yield) as a colorless liquid. MS (ESI) m/Z 262.21 [Mr- B. Ethyl 2,2-difluoro-Z-(Z-isopr0p0xyphenyl)acetate. To a stirred solution of 1-iodoisopropoxybenzene (2 g, 7.6 mmol) in dimethylsulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate (1.5 mL, 11.45 mmol) followed by copper (1.26 g, 19.84 mmol) at RT and stirred at 55 CC for 6h. The reaction mixture was basified with s saturated sodium bicarbonate on and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude product was purified by flash chromatography (20% WO 07848 ethyl acetate in pet ether) to afford ethyl 2,2-difluoror(2-isopropoxyphenyl)acetate (1.3 g, 5.03 mmol, 66%) as a colorless liquid. MS (ESI) m/z 259.23 [M+1]+‘ C. 2,2-Diflu0r0(2-is0pr0poxyphenyl)acetic acid. To a stirred solution of ethyl fluoro(2-isopropoxyphenyl)acetate (1 g, 3.87 mmol) in tetrahydrofuran: methanol: water (15 mL, 1:1:1) was added lithium hydroxide rnonohydnfie(049 g,1162 rnnufl)andsfinedatnxnntmnpmaunefor4h.The volatiles were removed under reduced pressure and obtained crude was ved in water (15 mL), washed with ethyl acetate (2 X 10 mL). Aqueous layer was acidified with 1N hydrochloride aqueous solution and extracted with ethyl acetate (3 X 15 mL).
The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated to afford 2,2-difluoro(2-isopropoxyphenyl)acetic acid (600 mg, 2.60 mmol, 67% yield) as semi-solid compound. 1H NMR (300 MHz, CDC13)5 8.75 (brs, 1H), 7.65 (d, J: 7.2 Hz, 1H), 7.44 (dd, J: 8.0, 7.6 Hz, 1H), 7.03 (dd, J: 8.0, 7.2 Hz, 1H), 6.94 (d, J: 8.4 Hz, 1H), 4.66 (Sep, J: 6.0 Hz, 1H), 1.32 (d, ,F=60HL6H) D. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- difluor0(2-is0pr0p0xyphenyl)acetamide. To an ice cold solution of fluoro- 2-(2-isopropoxyphenyl)acetic acid (267 mg, 1.16 mmol) in pyridine (6 mL) was added phosphorus oxychloride (0.27 mL, 2.9 mmol) in drop wise and stirred at 0-5°C for 1h.
Then, 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hloride (300 mg, 0.97 mmol) was added and stirred at room temperature for 2h. The reaction e was d with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography (50-55% acetonitrile in 0.1% aqueous formic acid) to afford (2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)-2,2-difluoro(2- isopropoxyphenyl)acetamide (40 mg, 0.08 mol, 8% yield) as white solid. MS (ESI) m/z 485.98 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 10.99 (s, 1H), 9.26 (t, J: 581k,HD,770@LJ=781h,HD,755—7450n¢flD,712@LJ=84}h,MD, 7.02 (dd, J: 7.2, 7.0 Hz, 1H), 5.11 (dd, J: 13.2, 5.1 Hz, 1H), 4.46 (Sep, J: 6.0 Hz, 1H), 4.45 (d, J: 6.3 Hz, 2H), 4.44 (d, J: 17.2, 1H), 4.31 (d, J: 17.4 Hz, 1H), 2.98 — 2.86 (m, 1H), 2.57 — 2.49 (m, 1H), 2.43 — 2.30 (m, 1H), 2.04 — 1.94 (m, 1H), 1.13 (d, J: 6.0 Hz, 3H), 1.12 (d, J: 6.0 Hz, 3H).
Example 59 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2—diflu0r0(2— flu0r0is0pr0p0xyphenyl)acetamide /l\ 0 o F A. 1-(2-Flu0r0isopr0p0xyphenyl)ethanone. To a d solution of 1-(2-fluorohydroxyphenyl)ethanone (300 mg, 1.95 mmol) in N,N—dimethylformamide (3 mL) was added isopropyl iodide (397 mg, 2.33 mmol) followed by potassium carbonate (672 mg, 4.87 mmol) and d at 90 0C for 16h.
The on mixture was diluted with ice water (20 mL) and ted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford 1-(2-fiuoroisopropoxyphenyl)ethanone (300 mg, 1.53 mmol, 79% yield) as a colorless liquid. MS (ESI) m/z 197.2 [M+1]+.
B. Ethyl 2-(2-flu0r0isopropoxyphenyl)0x0acetate. To a stirred solution of 1-(2-fluoroisopropoxyphenyl)ethanone (300 mg, 1.63 mmol) in pyridine (3 mL) was added selenium dioxide (452 mg, 3.38 mmol) at room temperature. The on mixture was stirred at 100 0C for 16h. The reaction e was filtered through a Celite pad and washed thoroughly with dichloromethane (10 mL). Ethyl chloroformate (0.64 mL) was added to the filtrate at 0 0C and stirred at room temperature for 4h. The reaction mixture was quenched with ice water and ted with dichloromethane (3 X 10 mL). The combined organic layers were washed with 1N hydrochloride solution (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford ethyl 2-(2-fluoroisopropoxyphenyl)oxoacetate (200 mg, 0.787 mmol, 48% yield) as a colorless liquid. MS (ESI) m/z 255.28 [M+1]+.
C. Ethyl 2,2-diflu0r0(2-flu0r0is0pr0p0xyphenyl)acetate. Ethyl 2- (2-fiuoroisopropoxyphenyl)oxoacetate (200 mg, 0.787 mmol) was added into diethylamino sulfur trifluoride (0.4 mL) at 0 0C and stirred at room temperature for 16h. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl e (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated.
Obtained crude product was d by flash column chromatography (100-200 silica gel, 10% ethyl acetate in pet ether) to afford ethyl 2,2-difluoro(2-fluoro isopropoxyphenyl)acetate (200 mg, 0.72 mmol, 92% yield) as a less liquid. MS (ESI) m/Z 276.1 [M+1]+.
D. 2,2-Diflu0r0(2-flu0r0is0pr0p0xyphenyl)acetic acid. To a stirred solution of ethyl 2,2-difluoro(2-fluoroisopropoxyphenyl)acetate (200 mg, 0.72 mmol) in mixture of tetrahydrofuran: ol: water (10 mL, 1:1:1) was added lithium hydroxide monohydrate (91 mg, 2.17 mmol) and stirred at room temperature for 16h. The on mixture was concentrated under reduced pressure and the resultant residue was dissolved in water (10 mL) and washed with ethyl acetate (2 X mL). The aqueous layer was acidified with 1N hydrochloride aqueous solution and emmwflmemflmmMMSXKmm)flmmemdmgmdwmmme%Md with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford 2,2-difluoro(2-fluoroisopropoxyphenyl)acetic acid (160 mg, 0.65 mmol, 89% yield) as olid compound.
E. N-((2-(2,6-Di0x0piperidinyl)—1-0xois0ind01inyl)methyl)-2,2— difluoro-Z-(2-flu0r0is0pr0p0xyphenyl)acetamide. To an ice cold solution of 2,2-difluoro(2-fluoroisopropoxyphenyl)acetic acid (289 mg, 1.16 mmol) in pyridine (9 mL) was added phosphorus oxychloride (0.27 mL, 2.9 mmol) in drop wise and stirred at 0-5 0C for 1h. Then, 3-(5-(aminomethyl)oxoisoindolinyl) dine-2,6-dione hydrochloride (300 mg, 0.97 mmol) was added into the reaction e and stirred at room temperature for 1h. The reaction mixture was basif1ed with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X mL). The ed organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant crude product was purified by Reveleris C-18 reversed phase column chromatography (50-55% acetonitrile in 0.1% aqueous formic acid) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolin yl)methyl)-2,2-difluoro(2-fluoroisopropoxyphenyl)acetamide (60 mg, 0.12 mmol, 12% yield) as white solid. MS (ESI) m/Z 503.99 [M+1]+. 1H NMR (400 MHz, 6) 5 10.99 (s, 1H), 9.59 (d, J: 7.2 Hz, 1H), 7.70 (d, J: 7.6 Hz, 1H), 7.48 (dd, J: 8.8, 8.7 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J: 8.0 Hz, 1H), 6.96 (dd, J: 13.2, 2.0 Hz, 1H), 6.87 (dd, J: 8.3, 2.0 Hz, 1H), 5.11 (dd, J: 13.2, 5.2 Hz,1H), 4.71 (sep, J: 6.0 Hz, 1H), 4.48 (d, J: 6.4 Hz, 2H), 4.45 (d, J: 17.2 Hz, 1H), 4.31 (d, J: 18.0 Hz, 1H), 2.95 — 2.87 (m, 1H), 2.62 — 2.58 (m, 1H), 2.41 — 2.37 (m, 1H), 2.02 — 1.99 (m, 1H), 1.28 (d, J: 5.6 Hz, 6H).
Example 60 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolinyl)methyl)-2,2-diflu0r0(3- (morpholinomethyl)phenyl)acetamide A. Ethyl 2,2-diflu0r0(3-(morpholinomethyl)phenyl)acetate. To a stirred solution of ethyl 2,2-difluoro(3-formylphenyl)acetate (1.2 g, 5.26 mmol) in ethanol (25 mL) was added morpholine (0.91 g, 10.52 mmol), acetic acid (0.63 mL, .52 mmol) and stirred at 0 0C for 1h and then added sodium cyanoborohydride (0.661 g10.52 mmol) and stirred at room temperature for 3h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 X 50 mL). The combined c layers were washed with water (2 X 20 mL), brine (30 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(3- (morpholinomethyl)phenyl)acetate (0.8 g, 2.67 mmol, 51% yield) as brown .
LCMS (ESI) m/z 300.0.
B. 2,2-Diflu0r0(3-(morpholinomethyl)phenyl)acetic acid. To a cold (0 CC) stirred solution of ethyl 2,2-difluoro(3-(morpholinomethyl)phenyl)acetate (0.8 g, 2.67 mmol) in methanol/ tetrahydrofuran /water mixture (15 mL, 1:1:1) was added lithium hydroxide monohydrate (337 mg, 8.02 mmol) and stirred at room ature for 2h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous potassium hate (20 mL) and extracted with ethyl acetate (2 X 40 mL). The ed organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(3- (morpholinomethyl)phenyl)acetic acid (600 mg, 2.21 mmol, 82 % yield) as a brown solid. LCMS (ESI) m/z 272.
C. N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolinyl)methyl)-2,2- difluoro-Z-(3-(m0rph01in0methyl)phenyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(3 -(morpholinomethyl)phenyl)acetic acid acid (290 mg, 1.06 mmol) and 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.970 mmol) in N,N—dimethylformamide (20 mL) was added N,N—diisopropylethylamine (0.6 mL, 3.33 mmol) followed by l- [Bis(dimethylamino)methylene] - 1 H- 1 ,2,3 olo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate (553.3 mg, 1.45 mmol) and stirred at room temperature for 4h.
The reaction e was diluted with water (50 mL) and extracted with ethyl acetate (2 X 40 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulphate, concentrated and dried under vacuum. The product was purified by Reveleris C-l8 reversed phase column using 40% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)- 2,2-difluoro(3-(morpholinomethyl)phenyl) acetamide (40 mg, 0.06 mmol, 8% yield)as an off- white solid. LCMS (ESI) m/z 526.7 [M+1]+. 1H NMR (300 MHZ, TFA-d4) 8 = 8.03 - 7.92 (m, 2H), 7.83 (br s,lH), 7.72 (br s, 2H), 7.64 - 7.54 (m, 2H), .64-5.0 (m,lH), 4.80 (br s, 2H), 4.73 (br s,2H), 4.6 (br s,2H), 4.4(s,2H), 4.08 (t, J=ll.7 Hz, 2H), 3.73 (d, J=ll.7 Hz, 1H), 3.51 (d, J=l2.l Hz, 1H), 3.33 - 3.04 (m, 2H), 2.92 - 2.61 (m, 1H), 2.53 (s, 1H). e 61 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(4— fluor0(2,2,2-triflu0roeth0xy)phenyl)acetamide O O mNm{2:O NH F F H N O F i A. 1-(4-Flu0r0(2,2,2-trifluoroethoxy)phenyl)ethan0ne. To a stirred on of 1-(4-fluorohydroxyphenyl)ethanone (1 g, 6.48 mmol) in N,N—dimethylformamide (20 mL) was added 1,1,1-trifluoroiodoethane (0.64 mL, 6.48 mmol) followed by potassium carbonate (2.68 g, 19.46 mmol) and stirred at 90 CC for 16h. The reaction mixture was diluted with ice water (30 mL) and ted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered and solvent was concentrated to afford 1-(4-fluoro(2,2,2-trifluoroethoxy)phenyl)ethanone (325 mg, 1.36 mmol, 20% yield) as a colorless liquid. 1H NMR (400 MHz, CDClg) 8 7.90 (dd, J = 6.8, 6.8 Hz, 1H), 6.85 — 6.81 (m, 1H), 6.61 (dd, J: 2.0, 2.4 Hz, 1H), 4.42 — 4.38 (m, 2H), 2.61 (s, 3H).
WO 07848 B. Ethyl u0r0(2,2,2-triflu0r0eth0xy)phenyl)0x0acetate. To a stirred solution of 1-(4-fluoro(2,2,2-trifluoroethoxy)phenyl)ethanone (320 mg, 1.35 mmol) in pyridine (10 mL) was added selenium dioxide (376 mg, 3.38 mmol) at room temperature. The reaction mixture was stirred at 100 0C for 16h. The reaction mixture was filtered through celite pad and washed with dichloromethane (10 mL).
Ethyl chloroformate (0.64 mL) was added to the filtrate at 0 0C and stirred at room temperature for 4h. The reaction mixture was quenched with ice water and extracted with romethane (3 X 10 mL). The ed organic layers were washed with 1N hydrochloride solution (15 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford ethyl 2-(4-fluoro(2,2,2-trifiuoroethoxy)phenyl) oxoacetate (300 mg, 1.02 mmol, 75% yield) as a colorless liquid. 1H NMR (400 MHz,CDC13)5 7.99 — 7.95 (m, 1H), 6.94 — 6.89 (m, 1H), 6.66 (dd, J: 2.4, 9.6 Hz, 1H), 4.42 — 4.35 (m, 4H), 1.38 (t, J: 7.6 Hz, 3H).
C. Ethyl 2,2-diflu0r0(4-flu0r0(2,2,2- trifluoroethoxy)phenyl)acetate. Ethyl 2-(4-fluoro(2,2,2-trifluoroethoxy)phenyl) oxoacetate (300 mg, 1.02 mmol) was added into Diethylamino sulfur trifluoride (DAST, 0.9 mL) at 0 0C and stirred at room temperature for 16h. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. Obtained crude was purified by column chromatography (100-200 silica gel, 10% ethyl acetate in pet ether) to afford ethyl 2,2-difiuoro(4-fluoro(2,2,2-trifiuoroethoxy)phenyl)acetate (250 mg, 0.79 mmol, 77% yield) as a less liquid. 1H NMR (300 MHz, CDClg) 8 7.71 — 7.66 (m, 1H), 6.91 — 6.85 (m, 1H), 6.66 (d, J: 9.6 Hz, 1H), 4.39 — 4.28 (m, 4H), 1.33 (t, J: 4.2 Hz, 3H).
D. 2,2-Diflu0r0(4-flu0r0(2,2,2-triflu0r0eth0xy)phenyl)acetic acid.
To a stirred on of ethyl 2,2-difluoro(4-fluoro(2,2,2-trifluoro ethoxy) )acetate (390 mg, 1.23 mmol) in tetrahydrofuran: methanol: water (12 mL, 1:1:1) was added m hydroxide monohydrate (155 mg, 3.70 mmol) and stirred at room temperature for 16h. The reaction mixture was concentrated under reduced pressure and obtained crude was dissolved in water (10 mL) and washed with ethyl acetate (2 X 10 mL). Aqueous layer was acidified with 1N hloride aqueous solution and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and t was concentrated to afford 2,2-difluoro(4-fluoro(2,2,2-trifluoroethoxy)phenyl)acetic acid (280 mg, 0.98 mmol, 79% yield) as semi-solid compound. 1H NMR (400 MHz, CDC13)5 7.72 — 7.69 (m, 1H), 6.91 — 6.87 (m, 1H), 6.66 (d, J: 9.2 Hz, 1H), 6.57 (brs, 1H), 4.39 — 4.34 (m, 2H).
E. N-((2-(2,6-Di0x0piperidinyl)—1-0xois0ind01inyl)methyl)-2,2— difluor0(4-flu0r0(2,2,2-triflu0r0eth0xy)phenyl)acetamide. To an ice cold solution of 2,2-difluoro(4-fluoro(2,2,2-trifluoroethoxy)phenyl)acetic acid (280 mg, 0.97 mmol) in pyridine (9 mL) was added phosphorus oxychloride (0.27 mL, 2.9 mmol) drop wise and stirred at 0-5 0C for 1h. Then, 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) was added into the reaction mixture and stirred at room temperature for 1h. The reaction mixture was basified with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL). The ed organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was d by ris C-18 ed phase column chromatography (50-55% acetonitrile in 0.1% aqueous formic acid) to give N—((2-(2,6-dioxopiperidinyl)oxoisoindolin-5 -yl)methyl)-2,2-difluoro(4-fluoro(2,2,2- trifluoroethoxy)phenyl)acetamide (45 mg, 0.08 mmol, 8% yield) as white solid.
MS (ESI) m/z 544.03 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.99 (s, 1H), 9.44 (t, J: 5.7 Hz, 1H), 7.70 (d, J: 7.8 Hz, 1H), 7.64 (dd, J: 9.0, 6.6 Hz, 1H), 8.49 (s, 1H), 7.42 (d, J: 8.1 Hz, 1H), 7.26 (dd, J: 11.1, 0.6 Hz, 1H), 7.02 (ddd, J: 10.8, 8.7, 2.4 Hz, 1H), 5.11 (dd, J: 13.2, 5.1 Hz, 1H), 4.81 (q, J: 8.7 Hz, 2H), 4.45 (d, J: 7.2 Hz, 2H), 4.44 (d, J: 16.2 Hz, 1H), 4.31 (d, J: 17.1 Hz, 1H), 2.93 — 2.90 (m, 1H), 2.63 — 2.54 (m, 1H), 2.45 — 2.36 (m, 1H), 2.01 — 1.98 (m, 1H).
Example 62 (2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(4— isopropoxy-Z-methylphenyl)acetamide O O mNmHL—HNHFF H 0 A. 1-(4-Isopropoxy-Z-methylphenyl)ethanone. To a stirred solution of 1-(4-hydroxymethylphenyl)ethanone (2.0 g, 13.333mmol) in N,N— ylformamide (20 mL) was added potassium carbonate (5.5 g, 49.0 mmol) followed by isopropyl iodide (2 mL, 20.0 mmol) and stirred at 80 0C for 4h. The reaction mixture was filtered and water (20 mL) was added and extracted with ethyl X40nfl)TheammnwdmgmncbywswmewmflmdwflflmmeGOnfl) dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography (100-200 silica) using 0-10% ethyl acetate in hexanes to afford 1-(4-isopropoxymethylphenyl)ethanone (1.58 g, 8.229 mmol, 62% yield).
MS (ESI) m/Z 193.48[M+1]+.
B. Ethyl 2-(4-isopropoxy-Z-methylphenyl)—2-0xoacetate. To a stirred solution of sopropoxymethylphenyl)ethanone (1.58 g, 8.229 mmol mmol) in pyridine (30 mL) was added selenium e (1.82 g, 16.46 mmol) and d for 16 h at 100 CC. The reaction mixture was diluted with dichloromethane (40 mL) and filtered through Celite pad. To the filtrate was added ethyl chloroformate (3 mL) at 0 CC and stirred for 2h. The reaction mixture was neutralized with 1N aqueous lwmmMmkaddwpmpHAMmdemmdemmflmflMeGX50meme combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and trated. The resultant residue was purified by column chromatography (100-200 silica) using 10% ethyl acetate in pet ether to afford ethyl 2- (4-isopropoxymethylphenyl)oxoacetate (1.0 g, 4.01 mmol, 49 %) as a colorless liquid. MS (ESI) m/Z 251.40 [M+1]+.
] C. Ethyl 2,2-difluoro-Z-(4-is0propoxy-Z-methylphenyl)acetate. To a stirred solution of ethyl 2-(4-isopropoxymethylphenyl)oxoacetate (1.0 g, 4.01 mmol) was reacted with diethyl amino sulfur trifluoride (1.32 mL, 10.025 mmol) and stirred for 12h at room temperature. The reaction mixture was lized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (KXan)Hmmemdmymdwmw%w%MdewmflQX10mmimm (10 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro (4-isopropoxymethylphenyl)acetate (990 mg, 3.639 mmol, 91 %) as a liquid.
GC-MS (m/Z) 272.2 [M]+.
D. flu0r0(4-isopropoxy-Z-methylphenyl)acetic acid. To a cold (0 CC) stirred solution of ethyl 2,2-difluoro(4-isopropoxymethylphenyl)acetate (990 mg, 3.694 mmol ) in tetrahydrofuran: methanol:water e (1 : 1 :1, 10 mL) was added lithium hydroxide (916 mg, 21.838 mmol) and stirred at room temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and trated to afford fluoro(4-isopropoxymethylphenyl)acetic acid (719 mg, 2.618 mmol, 81% yield) as an brown solid. 1H NMR (400 MHz, CDClg) 5 ppm 9.59 (br s, 1 H) 7.49 (d, J=8.80 Hz, 1 H) 6.58 - 6.85 (m, 2 H) 4.41 - 4.67 (m, 1H) 2.41 (s, 3 H) 1.34 (m, , 6H).
E. N-((2-(2,6-Di0x0piperidinyl)—1-0xois0ind01inyl)methyl)-2,2— difluoro-Z-(4-is0propoxy-Z-methylphenyl)acetamide. To a d on of 2,2-difluoro(4-isopropoxymethylphenyl)acetic acid (236 mg, 0.968 mmol) in pyridine (25 mL) was added phosphoryl chloride (0.3 mL, 2.16 mmol) dropwise and stirred at 0-5°C for 1h and then added 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione hydrochloride (300 mg, 0.968 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined c layer was washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase Grace column chromatography using 40-50% acetonitrile in s formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl) oxoisoindolinyl)methyl)-2,2-difluoro(4-isopropoxymethylphenyl)acetamide (79 mg, 0.158 mmol, 16% yield)as an offwhite solid. MS (ESI) m/z 500.2329 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 ppm 10.98 (s, 1 H), 9.51 (br t, J=6.05 Hz, 1H), 7.69 (d, J=7.70 Hz, 1H), 7.51 - 7.28 (m, 3H), 6.83 (s, 2H), 5.11 (br dd, J=13.20, 5.14 Hz, 1 H), 4.66 (dt, J=12.10, 6.05 Hz, 1 H), 4.51 - 4.25 (m, 4 H), 2.99 — 2.82 (m, 1H), 2.67 — 2.54 (m, 1 H), 2.46 — 2.30 (m, 1 H), 2.28 (s, 3 H), 2.07 — 1.95 (m, 1 H), 1.26 (m, 6H).
Example 63 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(4— isoprop0xymethylphenyl)acetamide A O ] A. 1-(4-Is0pr0p0xymethylphenyl)ethanone.To a stirred solution of l- (4-hydroxymethylphenyl)ethanone (3.0 g, 19.97 mmol) in N,N—dimethyl ide (20 mL) was added potassium carbonate (8.3 g, 59.91 mmol), isopropyl iodide (4.0 g, 23.96 mmol) at room temperature and stirred at 100 CC for 4h. The on mixture was quenched with water (150 mL) and extracted with ethyl acetate (2 X 100 mL).
The combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and concentrated to afford l-(4-isopropoxy methylphenyl)ethanone (3.2 g, 16.66 mmol, 84% yield). LCMS (ESI) m/Z 193.3 [M+1]+.
B. Ethyl 2-(4-is0pr0p0xymethylphenyl)—2-0x0acetate. To a stirred solution of sopropoxymethylphenyl)ethanone (3.2 g, 16.66 mmol) in pyridine (15 mL) was added selenium dioxide (4.6 g, 41.66 mmol) and stirred at 100 0C for 16h. The reaction mixture was diluted with dichloromethane (30 mL) and filtered through Celite pad. To the filtrate was added ethyl chloroformate (9 mL) at 0 CC and stirred at room temperature for 3h.The reaction mixture was lized with 1N aqueous hydrochloric acid (up to pH-4) and extracted with ethyl e (2 X 100 mL).
The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(4-isopropoxy methylphenyl)oxoacetate (2.5 g, 10.0 mmol, 60% yield). LCMS (ESI) m/Z 251.28 [M+1]+.
C. Ethyl 2,2-difluoro-Z-(4-is0prop0xymethylphenyl)acetate. To a d solution of ethyl 2-(4-isopropoxymethylphenyl)oxoacetate (500 mg, 2.00 mmol) was reacted with diethyl amino sulfur trifluoride (2.5 g, 15.26 mmol) and stirred at room temperature for 16h. The reaction mixture was neutralized with aqueous ted sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 30 mL), brine (30 mL) and dried over sodium sulphate and was concentrated to give ethyl 2,2- difluoro(4-isopropoxymethylphenyl)acetate (450 mg, 1.65 mmol, 83% yield).
GCMS (m/Z) 272.2 [M]+.
D. 2,2-Diflu0r0(4-isopr0p0xymethylphenyl)acetic acid. To a stirred solution of ethyl fluoro(4-isopropoxymethylphenyl)acetate (450 mg, 1.65 mmol) in tetrahydrofuran -methanol-water (20 mL, 1:1:1) was added lithium hydroxide monohydrate (208 mg, 4.96 mmol) and stirred at room temperature for 2h.
The reaction mixture was concentrated and the residue was neutralized with 10% s hydrochloric acid (5 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium te and concentrated to give 2,2-difluoro(4-isopropoxymethylphenyl)acetic acid (200 mg, 0.81 mmol, 50% yield). LCMS (ESI) m/z 243.34 [M-1]+.
E. N-((2-(2,6-Di0x0piperidinyl)—1-0xois0ind0]inyl)methyl)-2,2— difluoro-Z-(4-is0prop0xymethylphenyl)acetamide. To a cold (0 oC) stirred solution of fluoro(4-isopropoxymethylphenyl)acetic acid (200 mg, 0.81 mmol) in pyridine (5 mL) was added phosphoryl chloride (0.3 mL, 2.45 mmol) and stirred at 0-5 CC for 1h. Then added 3-(5-(amino methyl)oxoisoindolin yl)piperidine-2,6-dione hydrochloride (253 mg, 0.81 mmol) and stirred at room temperature for 1h. The on mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (2 X 25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over sodium te and concentrated. The ant e was purified by Reveleris C-18 reversed phase column chromatography using 40-45% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolin yl)methyl)-2,2-difluoro(4-isopropoxymethylphenyl)acetamide (90 mg, 0.18 mmol, 22.0 % yield) as an offwhite solid. LCMS (ESI) m/z 500.57 [M+1]+. 1H NMR (400MHz, DMSO-d6) 5 = 10.98 (s, 1H), 9.52 (br t, J=6.1 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.44 — 7.26 (m, 2H), 7.06 (d, J=8.3 Hz, 1H), 5.11 (dd, J=4.9, 13.2 Hz, 1H), 4.72 — 4.60 (m, 1H), 4.50 — 4.20 (m, 4H), 3.00 — 2.83 (m, 1H), 2.67 — 2.54 (m, 1H), 2.44 — 2.29 (m, 1H), 2.14 (s, 3H), 2.05 — 1.95 (m, 1H), 1.29 (d, J=6.4 Hz, 6H).
Example 64 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(3- flu0r0is0pr0p0xyphenyl)acetamide A O A. 1-(3-Flu0r0isopr0p0xyphenyl)ethanone. To a stirred solution of 1- (3-fluoro- 4-hydroxyphenyl)ethanone (3.0 g, 19.46 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (8.0 g, 58.38 mmol), isopropyl iodide (3.9 g, 23.35 mmol) at room temperature and stirred at 100 CC for 4h. The reaction mixture was quenched with water (150 mL) and ted with ethyl acetate (2 X 100 mL).
The combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and concentrated to afford 1-(3-fluoro isopropoxyphenyl)ethanone (3.1 g, 15.81 mmol, 81% yield). LCMS (ESI) m/Z 197.3 [M+1]+.
B. Ethyl 2-(3-flu0r0is0propoxyphenyl)—2-oxoacetate. To a stirred solution of 1-(3-fluoroisopropoxyphenyl)ethanone (3.1 g, 15.81 mmol) in pyridine (15 mL) was added selenium dioxide (4.6 g, 39.54 mmol) and stirred at 100 0C for 16h. The reaction mixture was diluted with dichloromethane (30 mL) and filtered h Celite pad. To the filtrate was added ethyl chloroformate (9 mL) at 0 CC and stirred at room temperature for 3h. The reaction mixture was neutralized with 1N aqueous hydrochloric acid (up to pH-4) and extracted with ethyl e (2 X 100 mL).
The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(3-fluoro isopropoxyphenyl)oxoacetate (2.5 g, 9.84 mmol, 62% yield). LCMS (ESI) m/Z 255.28 [M+1]+.
C. Ethyl 2,2-diflu0r0(3-flu0r0is0pr0p0xyphenyl)acetate. To a stirred solution of ethyl 2-(3-fluoroisopropoxyphenyl)oxoacetate (1.2 g, 4.72 mmol) was added diethyl amino sulfur trifluoride (3.1 g, 19.23 mmol) and stirred at room temperature for 16h. The on mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 100 mL). The combined c layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro (3-fluoroisopropoxyphenyl)acetate (900 mg, 3.26 mmol, 69% . GCMS (m/z) 276.2 [Mi D. 2,2-Diflu0r0(3-flu0r0isopr0p0xyphenyl)acetic acid. To a stirred solution of ethyl 2,2-difluoro(3-fluoroisopropoxyphenyl)acetate (900 mg, 3.26 mmol) in tetrahydrofuran -methanol-water (20 mL, 1:1:1) was added lithium hydroxide monohydrate (410 mg, 9.78 mmol) and stirred at room temperature for 2h.
The reaction mixture was concentrated and the residue was neutralized with 10% aqueous hydrochloric acid (5 mL) and extracted with ethyl e (2 X 50 mL). The combined c layers were washed with brine (20 mL), dried over sodium sulphate WO 07848 2015/039926 and concentrated to afford 2,2-difluoro(3-fluoroisopropoxyphenyl)acetic acid (700 mg, 2.82 mmol, 87% yield). LCMS (ESI) m/z 247.52 [M-1]+.
E. N-((2-(2,6-Di0x0piperidinyl)—1-0xois0ind01inyl)methyl)-2,2— difluoro-Z-(3-flu0r0—4-is0pr0p0xyphenyl)acetamide. To a cold (0 °C) stirred solution of 2,2-difluoro(3-fluoroisopropoxyphenyl)acetic acid (300 mg, 1.20 mmol) in pyridine (10 mL) was added phosphoryl chloride (0.4 mL, 3.62 mmol) and stirred at 0-5 CC for 1h. Then added 3-(5-(amino methyl)oxoisoindolin yl)piperidine-2,6-dione hydrochloride (374 mg, 1.20 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (2 X 25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over sodium te and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 35-40% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolin yl)methyl)-2,2-difluoro(3-fluoroisopropoxyphenyl) acetamide (80 mg, 0.15 mmol, 13.0 % yield) as an offwhite solid. LCMS (ESI) m/z 504.56 . 1H NMR (400MHz, 6) 8 = 10.98 (s, 1H), 9.60 (br t, J=6.1 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.45 - 7.26 (m, 5H), 5.10 (dd, J=5.1, 13.5 Hz, 1H), 4.73 (m, 1H), 4.50 - 4.23 (m, 4H), 2.98 - 2.85 (m, 1H), 2.67 — 2.55 (m, 1H), 2.45 - 2.30 (m, 1H), 2.04 - 1.95 (m, 1H), 1.30 (d, J=5.9 Hz, 6H).
Example 65 2-(3-Chlor0is0propoxyphenyl)-N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin- -yl)methyl)—2,2-diflu0roacetamide A,ClfigfimNfio0o A. 1-(3-Chlor0is0pr0p0xyphenyl)ethanone. To a stirred solution of 1- (3-chlorohydroxyphenyl)ethanone (2.5 g, 14.62 mmol) in N,N-dimethylformamide (30 mL) was added 2-iodopropane (2.98 g, 17.54 mmol) followed by potassium ate (5.04 g, 36.55 mmol) and stirred at 90 0C for 16h. The reaction mixture was diluted with ice water (40 mL) and extracted with ethyl acetate (3 X 30 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate, filtered and concentrated to afford 1-(3-chloro isopropoxyphenyl)ethanone (2.3 g, 10.84 mmol, 74% yield) as a colorless liquid. MS (ESI) m/Z 213.23 [Mr- B. Ethyl 2-(3-chlor0is0pr0p0xyphenyl)0x0acetate. To a stirred solution of 1-(3-chloroisopropoxyphenyl)ethanone (2 g, 8.26 mmol) in pyridine (30 mL) was added selenium dioxide (2.69 g, 24.79 mmol) at room temperature. The reaction mixture was stirred at 100 0C for 16h. The reaction mixture was filtered h a Celite pad and washed with dichloromethane (30 mL). Ethyl chloroformate (6 mL) was added to the filtrate at 0 0C and stirred at room temperature for 4h. The reaction mixture was quenched with ice water and extracted with dichloromethane (3 X 30 mL). The combined organic layers were washed with 1N hydrochloride solution (30 mL), brine (30 mL), dried over sodium sulfate, filtered and concentrated to afford ethyl hloroisopropoxyphenyl)oxoacetate (1.8 g, 6.66 mmol, 80% yield) as a colourless liquid. 1H NMR (400 MHz, CDClg) 8 8.08 (d, J = 2.0 Hz, 1H), 7.92 (dd, J: 8.8, 2.8 Hz, 1H), 7.00 (d, J: 8.8 Hz, 1H), 4.71 (sep, J: 6.2 Hz, 1H), 4.44 (q, J: 6.8 Hz, 2H), 1.44 (d, J: 6.5 Hz, 6H), 1.38 (t, J: 7.2 Hz, 3H).
C. Ethyl 2-(3-chlor0isopropoxyphenyl)-2,2-difluoroacetate.
Diethylamino sulfur trifiuoride (1.47 mL) was added into ethyl 2-(3-chloro isopropoxyphenyl)oxoacetate (1 g, 3.7 mmol) at 0 0C and stirred at room temperature for 16h. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated. Obtained crude was d by column chromatography (100-200 silica gel, 10% ethyl acetate in pet ether) to afford ethyl 2-(3-chloroisopropoxyphenyl)- 2,2-difiuoroacetate (900 mg, 3.08 mmol, 89% yield) as a less liquid. MS (ESI) m/Z 293.1 [M+1]+‘ D. 2-(3-Chlor0is0prop0xyphenyl)—2,2-difluoroacetic acid. To a stirred solution of ethyl 2-(3-chloroisopropoxyphenyl)-2,2-difiuoroacetate (0.45 g, 1.54 mmol) in tetrahydrofuran: methanol: water (15 mL, 1:1:1) was added lithium ide monohydrate (195 mg, 4.54 mmol) and stirred at room temperature for 16h.
The volatiles were removed under reduced re and the obtained residue was dissolved in water (10 mL), washed with ethyl acetate (2 X 10 mL). s layer was acidified with 1N hydrochloride solution and ted with ethyl e (3 X mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford 2-(3-chloroisopropoxyphenyl)- 2,2-difluoroacetic acid (300 mg, 1.13 mmol, 74% yield) as semi-solid compound. 1H NMR (400 MHz, CDC13)5 8.41 (brs, 1H), 7.65 (d, J: 2.1 Hz, 1H), 7.47 (dd, J: 8.7, 2.1 Hz, 1H), 6.97 (dd, J: 5.1, 8.7 Hz, 1H), 4.62 (sep, J: 5.7 Hz, 1H), 1.40 (d, J: 6.3 Hz, 6H).
E. 2-(3-Chlor0isoprop0xyphenyl)—N-((2-(2,6-dioxopiperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To an ice cold solution of 2-(3-chloroisopropoxyphenyl)-2,2-difluoroacetic acid (235 mg, 0.89 mmol) in pyridine (6 mL) was added phosphorus oride (0.23 mL, 2.43 mmol) in dropwise and stirred at 0-5 0C for 1h. Then, 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione hloride (250 mg, 0.81 mmol) was added and stirred at room temperature for 2h. The reaction mixture was basif1ed with aqueous saturated sodium onate solution and extracted with ethyl acetate (3 X 15 mL). The combined c layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by ris C-18 reversed phase column chromatography (50-55% acetonitrile in 0.1% aqueous formic acid) to give 2-(3-chloroisopropoxyphenyl)-N-((2-(2,6- dioxopiperidinyl)oxoisoindolin—5-yl)methyl)-2,2-difluoro acetamide (60 mg, 0.11 mmol, 14% yield) as white solid. MS (ESI) m/Z 520.01 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 10.98 (s, 1H), 9.62 (t, J: 5.7 Hz, 1H), 7.68 (d, J: 7.8 Hz, 1H), 7.59 (d, J: 2.4 Hz, 1H), 7.49 (dd, J: 8.7, 2.1 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J: 8.1 Hz, 1H), 7.31 (d, J: 8.7 Hz, 1H), 5.11 (dd, J: 13.2, 5.4 Hz, 1H), 4.76 (sep, J = 6.3 Hz, 1H), 4.45 (d, J: 5.7 Hz, 2H), 4.42 (d, J: 18.0 Hz, 1H), 4.28 (d, J: 17.7, 1H), 2.93 — 2.87 (m, 1H), 2.63 — 2.57 (m, 1H), 2.40 — 2.30 (m, 1H), 2.04 — 1.94 (m, 1H), 1.31 (d, J: 5.7 Hz, 6H).
Example 66 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(2— methyl(trifluoromethoxy)phenyl)acetamide F NH FF>I\O O A. Ethyl flu0r0(2-methyl-4—(trifluoromethoxy)phenyl)acetate.
To a stirred solution of 1-iodomethyl(trifluoromethoxy)benzene (1.0 g, 3.31 —194— mmol) in dimethylsulfoxide (13 mL) was added copper (546 mg, 8.60 mmol) and ethyl 2-bromo-2,2-difluoroacetate (0.638 mL 4.96 mmol) at room temperature and d at 55 CC for 2h. The on mixture was neutralized with s ted ammonium chloride (50 mL) solution and extracted with ethyl e (2 X 100 mL). The combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(2-methyl (trifluoromethoxy)phenyl)acetate (900 mg, 3.02 mmol, 91%). 1H NMR (400MHz, CDClg) 5 7.65-7.58 (d, 1H), 7.18-7.02 (m, 2H), 4.41 — 4.25 (m, 2H), 2.43 (s, 3H), 1.36 — 1.29 (m, 3H). (Ethyl acetate traces indicated along with the product in the 1H NMR) B. 2,2-Diflu0r0(2-methyl(triflu0r0meth0xy)phenyl)acetic acid. To a stirred solution of ethyl 2,2-difluoro(2-methyl(trifluoromethoxy)phenyl)acetate (900 mg, 3.020 mmol) in tetrahydrofuran:methanol:water mixture (30 mL, 1:1:1) was added lithium hydroxide monohydrate (634 mg, 15.106 mmol) and stirred at room temperature for 4h. The reaction mixture was concentrated and the e was neutralized with saturated potassium bisulphate (25 mL) and extracted with ethyl acetate (2 X 50mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(2-methyl oromethoxy)phenyl)acetic acid (450 mg, 1.66 mmol, 55% . 1H NMR (400MHz, CDC13)5 7.65-7.49 (d, J: 9.2 Hz, 1H), 7.20-7.16 (m, 2H), 2.18 (s, 3H).
C. N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2- difluoro-Z-(2-methyl(triflu0r0methoxy)phenyl)acetamide. To a cold (0 oC) stirred on of 2,2-difluoro(2-methyl(trifluoromethoxy)phenyl)acetic acid (261 mg, 0.968 mmol) in pyridine was added phosphoryl chloride (0.27 mL, 2.906 mmol) drop wise and stirred at 0-5 0C for 1h. To this reaction mixture was then added 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.968 mmol) and stirred at room temperature for 30min. The reaction mixture was neutralized with s saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated.
The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 40-60% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)-2,2-difluoro(2- 2015/039926 methyl(trifluoromethoxy)phenyl)acetamide (60 mg, 0.114 mmol, 11% yield) as an te solid. MS (ESI) m/z 526.52 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.99 (s, 1H), 9.65 (t, J: 5.9 Hz, 1H), 7.73 — 7.63 (m, 2H), 7.46 (s, 1H), 7.43 — 7.38 (d, J: 8.0 Hz, 1H), 7.38 — 7.32 (m, 2H), 5.10 (dd, J: 13.2, 5.1 Hz, 1H), 4.52 — 4.28 (m, 4H), 2.96 — 2.85 (m, 1H), 2.68 — 2.53 (m, 1H), 2.47 — 2.31 (m, 4H), 2.08 — 1.94 (m, 1H).
Example 67 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(2— fluor0(triflu0r0methoxy)phenyl)acetamide FF NH F>|\O O A. 2-Flu0r0i0d0(trifluor0meth0xy)benzene. To a stirred solution of 1-bromofluoro(trifluoromethoxy)benzene (500 mg, 1.93 mmol) in 1,4-dioxane (10 mL) was added sodium iodide (579 mg, 3.86 mmol), copper iodide (18 mg, 0.09 mmol) and trans-N,N’-dimethylcyclohexane-1,2-diamine (30 mg, 0.11 mmol) at room temperature, then heated at 110 CC for 16h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford oiodo (trifluoromethoxy)benzene (400 mg, 1.3 mmol, 68% yield) as brown . 1H NMR (300 MHz,CDC13)8 7.78 (dd, J: 8.4, 6.9 Hz, 1H), 6.98 (dd, J: 8.1, 1.5 Hz, 1H), 6.84 (d, J: 8.3 Hz, 1H).
B. Ethyl fluoro-Z-(Z-fluor0(triflu0r0methoxy)phenyl)acetate.
To a stirred solution of 2-fluoroiodo(trifluoromethoxy)benzene (1 g, 3.27 mmol) in dimethylsulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate (0.6 mL, 4.9 mmol) followed by copper (0.54 g, 8.49 mmol) at RT and stirred at 60 0C for 6h.
The reaction mixture was ed with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude product was purified by flash chromatography (20% ethyl acetate in pet ether) to afford ethyl 2,2-difluoro(2-fluoro (trifluoromethoxy)phenyl)acetate (800 mg, 2.64 mmol, 81% yield) as a colorless liquid. MS (ESI) m/Z 302.1 [Mr- C. 2,2-Diflu0r0(2-flu0r0(triflu0r0meth0xy)phenyl)acetic acid. To a stirred on of ethyl 2,2-difluoro(2-fluoro(trifluoromethoxy)phenyl)acetate (800 mg, 2.64 mmol) in e of tetrahydrofuran: methanol:water (15 mL, 1:1:1) was added lithium hydroxide monohydrate (333 mg, 7.94 mmol) and stirred at room temperature for 4h. The volatiles were removed under d pressure and the obtained crude was dissolved in water (15 mL) and washed with ethyl acetate (2 X mL). Aqueous layer was acidified with 1N hydrochloride aqueous solution and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated to afford 2,2-difluoro(2-fluoro(trifluoromethoxy)phenyl)acetic acid (450 mg, 1.64 mmol, 62% yield) as olid compound. MS (ESI) m/z 298.1 [M]+‘ 1H NMR (400 MHz, CDC13)5 7.70 (dd, J: 9.6 Hz, 1.6 Hz, 1H), 7.14 (d, J: 7.9 Hz, 1H), 7.06 (dd, J: 7.8 Hz, 1.8 Hz, 1H), 5.02 (brs, 1H).
D. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- diflu0r0(2-fluor0(trifluor0meth0xy)phenyl)acetamide. To an ice cold stirred solution of 2,2-difluoro(2-fluoro(trifluoromethoxy) phenyl)acetic acid (274 mg, 155nnnoDinpyfidnw(6rnL)wasaddedphomfluuusoxydflofide(036rnL, 3.87 mmol) dropwise and stirred at 0-5 0C for 1h. Then, the reaction mixture was d with 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (400 mg, 1.29 mmol) and stirred at room temperature for 2h. The reaction mixture was basified with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column tography (50-55% acetonitrile in 0.1% aqueous formic acid to afford N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 thyl)-2,2-difluoro(2- fluoro(trifluoromethoxy)phenyl)acetamide (60 mg, 0.11 mmol, 9% yield) as white solid. MS (ESI) m/z 529.6 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 10.99 (s, 1H), 9.76 (t, J: 5.8 Hz, 1H), 7.82 (dd, J: 8.4, 8.3 Hz, 1H), 7.70 (d, J: 7.5 Hz, 1H), 7.63 (d, J: 11.4 Hz, 1H), 7.48 (s, 1H), 7.43 — 7.40 (m, 2H), 5.11 (dd, J: 12.9, 4.8 Hz, 1H), 4.50 (d, J: 6.3 Hz, 2H), 4.46 (t, J: 17.7 Hz, 1H), 4.31 (d, J: 17.4, 1H), 2.90 — 2.63 (m, 1H), 2.63 — 2.56 (m, 1H), 2.42 — 2.27 (m, 1H), 2.02 — 1.98 (m, 1H).
Example 68 2-(5-Chlor0pyridinyl)—N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)-2,2-diflu0roacetamide ] A. Ethyl 2-(5-chlor0pyridinyl)—2,2-diflu0roacetate. To a stirred solution of 5-chloroiodopyridine (1.0 g, 4.18 mmol) in dimethylsulfoxide (11 mL) was added copper (690 mg, 10.86 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.01 g, 5.01 mmol) at room temperature and stirred at 55 CC for 6h. The reaction e was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and trated to afford ethyl 2-(5-chloropyridinyl)-2,2-difluoroacetate (700 mg, 2.98 mmol, 70%). GCMS (m/Z) 235.1 [M]+.
B. hloropyridin-Z-yl)—2,2-diflu0r0acetic acid. To a stirred solution of ethyl hloropyridinyl)-2,2-difluoroacetate (800 mg, 3.40 mmol) in tetrahydrofiJran:methanol:water mixture (30 mL, 1:1:1) was added lithium hydroxide monohydrate (429 mg, 10.21 mmol) and stirred at room temperature for 4h. The reaction mixture was concentrated and the residue was neutralized with saturated potasiium hate (20 mL) and extracted with ethyl acetate (2 X 25 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulphate and concentrated to afford 2-(5-chloropyridinyl)-2,2-difluoroacetic acid (400 mg, 1.94 mmol, 57% yield). MS (ESI) m/Z 208.30 [M+1]+.
C. 2-(5-Chloropyridin-Z-yl)—N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a cold (0 oC) stirred solution of 2-(5 -chloropyridinyl)-2,2-difluoroacetic acid (200 mg, 0.96 mmol) in pyridine (20 mL) was added phosphoryl chloride (443mg, 2.89 mmol) dropwise and stirred at 0-5 °C for 30min. To this reaction mixture was then added aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.96 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 40-45% acetonitrile in aqueous formic acid (0.1%) to afford 2-(5-chloropyridinyl)-N-((2- (2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoroacetamide (65 mg, 0.14 mmol, 14% yield)as an off-white solid. MS (ESI) m/z 462.69 . 1H NMR (300MHz, DMSO-d6) 5 = 10.99 (s, 1H), 9.69 (t, J=5.9 Hz, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.19 (dd, J=2.6, 8.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J=7.7 Hz, 1H), 5.11 (dd, J=5.0, 13.0 Hz, 1H), 4.56 - 4.27 (m, 4H), 3.00 - 2.84 (m, 1H), 2.74 - 2.55 (m, 1H), 2.45 - 2.22 (m, 1H), 2.09 - 1.91 (m, 1H).
Example 69 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(5— fluor0pyridinyl)acetamide A. 5-Flu0r0i0d0pyridine. To a stirred solution of 2-bromo fluoropyridine (2.5 g, 14.2 mmol) in 1,4-dioxane (10 mL) was added sodium iodide (4.26 g, 28.4 mmol), copper iodide (135 mg, 0.71 mmol) followed by trans-N,N— dimethylcyclohexane-l,2-diamine (0.24 mL, 1.56 mmol) at room temperature and stirred at 110 CC for 16h. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 X 25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over sodium sulfate, ed and concentrated to afford 5-fluoroiodopyridine (2.2 g, 9.86 mmol, 71% yield) as brown liquid. LCMS (m/Z) 224.3 [M].
B. Ethyl 2,2-difluoro-Z-(S-fluor0pyridinyl)acetate. To a d solution of 5-fluoroiodopyridine (300 mg, 1.34 mmol) in dimethylsulfoxide (3.4 mL) was added ethyl 2-bromo-2,2-difluoroacetate (409 mg, 2.02 mmol) followed by copper (22 mg, 3.49 mmol) at RT and stirred at 60 CC for 6h. The reaction mixture was d with aqueous saturated sodium onate solution and ted with ethyl acetate (3 X 10 mL). The ed organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated. The ed crude was purified by silica gel column chromatography (20% ethyl acetate in pet ether) to afford ethyl fluoro(5 -fluoropyridinyl)acetate (200 mg, 072mmmL54%ymM)%acobfl%shmmiNB(E$)m&278mflfi C. 2,2-Diflu0r0(5-flu0r0pyridinyl)acetic acid. To a stirred solution of ethyl 2,2-difluoro(5-fluoropyridinyl)acetate (250 mg, 1.14 mmol) in mixtue of tetrahydrofuran: ol:water (10 mL, 1:1:1) was added lithium hydroxide monohydrate (144 mg, 3.42 mmol) and stirred at room temperature for 4h. The volatiles were removed under reduced pressure and the obtained crude was dissolved in water (10 mL), washed with ethyl e (2 X 10 mL). Aqueous layer was acidified with 1N hydrochloride aqueous solution and extracted with ethyl acetate (3 X 10 mL).
The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford 2,2-difluoro(5-fluoropyridinyl)acetic acid (150 mg, 0.78 mmol, 69% yield) as semi-solid compound. 1H NMR (400 MHz, CDOQ8856GJH)837®mJH)784@¢J=88HL44HL1HL764me J: 10.8 Hz, 8.8 Hz, 2.4 Hz, 1H).
] D. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- difluor0(5-flu0r0pyridinyl)acetamide. To an ice cold solution of 2,2-difluoro- 2-(5-fluoropyridinyl)acetic acid (221 mg, 1.16 mmol) in pyridine (6 mL) was added phosphorus oxychloride (0.27 mL, 2.91 mmol) dropwise and stirred at 0-5 0C for 1h.
Then, 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) was added and stirred at room temperature for 2h. The reaction mixture was basified with aqueous saturated sodium bicarbonate solution and emflmmmu3XUni)flmwmhmdmgmdwmmme%Md with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by ris C-18 reversed phase column chromatography (50-55% acetonitrile in 0.1% s formic acid to afford N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)-2,2-difluoro(5-fluoro pyridinyl)acetamide (60 mg, 0.11 mmol, 14% yield) as white solid. MS (ESI) m/Z 446.7 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 10.98 (s, 1H), 9.67 (t, J: 5.7 Hz, 1H), 8.76 (d, J: 2.4 Hz, 1H), 8.01 — 7.89 (m, 2H), 7.71 (d, J: 7.8 Hz, 1H), 7.52 (s, 1H), 7.45 (d, J: 8.1 Hz, 1H), 5.11 (dd, J: 13.5, 5.1 Hz, 1H), 4.50 (d, J: 5.4 Hz, 2H), 447QLJ=174}h,HD,432@LJ=171,HD,298—2840n,HD,266—2580n HD,243—2300n,HD,202—194(nn1H) Example 70 2-(2,4-Diflu0r0phenyl)-N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)-2,2-difluoroacetamide A. Ethyl 2-(2,4-difluorophenyl)—2,2-diflu0r0acetate. To a stirred solution of 2,4-difluoroiodobenzene (800 mg, 3.33 mmol) in dimethyl sulfoxide (10 mL) was added ethyl o-2,2-difluoroacetate (1.01 g, 4.99 mmol), copper (550 mg, 8.65 mmol) and d at 55 0C for 6h. The reaction e was neutralized with aqueous saturated ammonium chloride solution and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(2,4- difluorophenyl)-2,2-difluoroacetate (400 mg, 1.69 mmol, 51%) as a brown liquid.
GCMS: 236.1[M]+.
B. -Difluor0phenyl)-2,2-difluoroacetic acid. To a stirred solution of ethyl 2-(2,4-difluorophenyl)-2,2-difluoroacetate (400 mg, 1.69 mmol) in ethanol: tetrahydrofuran: water (10 mL, 1:1 :1) was added lithium hydroxide (214 mg, .08 mmol) and stirred at room temperature for 4h. The reaction mixture was concentrated and the residue was neutralized with sat.potasiium hydrozensulphate (20 mL) and extracted with ethyl acetate (2 X 50 mL). The ed organic layer was washed with brine (25 mL), dried over sodium sulphate and concentrated to give 2-(2,4-difluorophenyl)-2,2-difluoroacetic acid (250 mg, 1.20 mmol, 71% yield). MS (ESI) m/Z 207.43 [M—i]+ C. 2-(2,4-Diflu0r0phenyl)—N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a d cold (0 oC) on of 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) in N,N—dimethylformamide (10 mL) was added 2-(2,4- difluorophenyl)-2,2-difluoroacetic acid (202 mg, 0.97 mmol) followed by diisopropylethylamine (0.52 mL, 2.91 mmol), 1-[Bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (480 mg, 1.26 mmol) and stirred at room temperature for 16h. The reaction mixture was diluted with water (100 mL) and the solid obtained was filtered, washed with diethyl ether (20 mL), dried and purified by column chromatography (100-200 silica) using 4% methanol in dichloromethane as eluent to afford 2-(2,4-difluorophenyl)-N—((2-(2,6-dioxopiperidin- 3-yl)oxoisoindolinyl)methyl)-2,2-difluoroacetamide (60 mg, 0.129 mmol, 13% yield) as an off white solid. MS (ESI) m/z 463.68 [M+1]+. 1H NMR (400 MHz, DMSO-d6) 5 = 10.98 (s, 1H), 9.72 (br t, J=5.9 Hz, 1H), 7.78 - 7.65 (m, 2H), 7.55 - 7.34 (m, 3H), 7.29 - 7.18 (m, 1H), 5.11 (br dd, J=5.1, 13.2 Hz, 1H), 4.56 - 4.16 (m, 4H), 3.08 - 2.80 (m, 1H), 2.75 - 2.59 (m, 1H), 2.44 - 2.32 (m, 1H), 2.06 - 1.92 (m, 1H).
Example 71 2-(4-Br0mophenyl)—N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)— 2,2-difluoroacetamide N§fONHF F H A. Ethyl 2-(4-br0m0phenyl)—2,2-difluoroacetate. To a stirred solution of 1-bromoiodobenzene (300 mg, 2.81 mmol) in dimethyl ide (3 mL) was added ethyl 2-bromo-2,2-difluoroacetate (324 mg, 1.6 mmol) followed by copper powder (175 mg, 2.75 mmol) at room temperature and stirred at 55 CC for 6h. The reaction mixture was basified with s sodium bicarbonate on and ted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was purified by silica gel column chromatography (20% ethyl acetate in pet ether) to afford ethyl 2-(4-bromophenyl)-2,2-difluoroacetate (200 mg, 0.72 mmol, 25% yield) as a colorless liquid. GCMS (ESI) m/z 278.1 [M]+ B. 2-(4-Br0m0phenyl)-2,2-difluoroacetic acid. To a stirred solution of ethyl 2-(4-bromophenyl)-2,2-difluoroacetate (200 mg, 0.72 mmol) in mixture of tetrahydrofuran: methanol: water (15 mL, 1:1:1) was added lithium hydroxide monohydrate (90 mg, 2.15 mmol) and stirred at room temperature for 4h. The les were removed under reduced pressure and obtained residue was dissolved in water (15 mL), washed with ethyl acetate (2 X 10 mL). Aqueous layer was acidified with 1N hydrochloride aqueous solution and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and solvent was concentrated to afford 2-(4-bromophenyl)-2,2-difluoroacetic acid (150 mg, 0.60 mmol, 84% yield) as olid compound. MS (ESI) m/z 251.43 [M-HT C. 2-(4-Br0m0phenyl)-N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin- -yl)methyl)-2,2-difluoroacetamide. To an ice cold on of 2-(4-bromophenyl)- 2,2-difluoroacetic acid (291 mg, 1.16 mmol) in pyridine (6 mL) was added phosphorus oxychloride (0.27 mL, 2.9 mmol) in dropwise and stirred at 0-5 0C for 1h. Then, 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) was added into the reaction mixture and stirred at room temperature for 2h. The reaction mixture was basified with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography (50-55% 0.1% acetonitrile in aqueous formic acid) to afford 2-(4-bromophenyl)-N-((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoroacetamide (50 mg, 0.098 mmol, 10% yield) as white solid. MS (ESI) m/z 505.6 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.99 (s, 1H), 9.68 (t, J: 5.8 Hz, 1H), 7.77 (d, J: 8.4 Hz, 2H), 7.68 (d, J: 7.8 Hz, 1H), 7.54 (d, J: 8.7 Hz, 2H), 7.39 (s, 1H), 7.36 (d, J: 8.1 Hz, 1H), 5.10 (dd, J: 13.2, 4.8 Hz, 1H), 4.45 (d, J: 6.0 Hz, 2H), 4.43 (d, J: 18.1 Hz, 1H), 4.28 (d, J: 17.4 Hz, 1H), 2.96 — 2.86 (m, 1H), 2.63 — 2.49 (m, 1H), 2.41 — 2.30 (m, 1H), 2.07 — 1.94 (m, 1H).
Example 72 N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0indolinyl)methyl)-2,2—diflu0r0(2-(2- yeth0xy)phenyl)acetamide O O @waNHFFH N O A. 1-Iod0(2-methoxyethoxy)benzene. To a d solution of 2-iodophenol (1 g, 4.54 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (1.88 g, 13.64 mmol) followed by potassium iodide (0.07 g, 0.45 mmol) and omethoxyethane (0.46 mL, 4.99 mmol) at room ature and stirred at 70 CC for 16h. The reaction mixture was ed with water (15 mL) and ted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, d and concentrated to afford 1-iodo(2-methoxy ethoxy)benzene (0.8 g, 2.87 mmol, 84% yield) as colorless liquid. GCMS (m/z) 278.1 [M+].
B. Ethyl 2,2-diflu0r0(2-(2-meth0xyeth0xy)phenyl)acetate. To a stirred solution of (2-methoxyethoxy)benzene (800 mg, 2.87 mmol) in dimethyl sulfoxide (15 mL) was added ethyl 2-bromo-2,2-difluoroacetate (0.42 mL, 4.31 mmol) followed by copper powder (470 mg, 7.46 mmol) at RT and stirred at 60 °C for 6h. The reaction mixture was quenched with water and filtered through a Celite pad. The filtrate was basified with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was ed by flash column tography (20% ethyl acetate in pet ether) to afford ethyl 2,2-difluoro(2-(2- methoxyethoxy)phenyl)acetate (460 mg, 1.37 mmol, 24% yield) as a colorless liquid.
MS (ESI) m/Z 274.2 [Mr- C. 2,2-Diflu0r0(2-(2-meth0xyeth0xy)phenyl)acetic acid. To a stirred solution of ethyl 2,2-difluoro(2-(2-methoxyethoxy)phenyl)acetate (450 mg, 1.64 mmol) in tetrahydrofuran: methanol:water mixture (15 mL, 1:1:1) was added lithium hydroxide monohydrate (206 mg, 4.92 mmol) and stirred at room temperature for 4h. The les were removed under d pressure and the obtained crude was dissolved in water (10 mL), washed with ethyl acetate (2 X 10 mL). Aqueous layer was acidified with 1N hydrochloride aqueous solution and ted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford 2,2-difluoro(2-(2- methoxyethoxy)phenyl)acetic acid (290 mg, 1.17 mmol, 72% yield) as semi-solid compound. MS (ESI) m/Z 247.28 ~ D. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- difluoro-Z-(2-(2-meth0xyeth0xy)phenyl)acetamide. To an ice cold solution of 2,2-difluoro(2-(2-methoxyethoxy)phenyl)acetic acid (262 mg, 1.07 mmol) in pyridine (9 mL) was added phosphorus oxychloride (0.27 mL, 2.9 mmol) in dropwise and stirred at 0-5 CC for 1h. Then, the reaction mixture was treated with 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hloride (300 mg, 0.97 mmol) and stirred at room temperature for 2h. The reaction mixture was basif1ed with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate —204— (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and solvent was concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography (50-55% itrile in 0.1% aqueous formic acid to afford N—((2- (2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 thyl)-2,2-difluoro(2-(2- methoxyethoxy)phenyl)acetamide (60 mg, 0.12 mmol, 12% yield) as white solid.
MS (ESI) m/z 502.34 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 10.99 (s, 1H), 9.23 (t, J: 5.6 Hz, 1H), 7.71 (d, J: 8.1 Hz, 1H), 7.55 (dd, J: 9.6, 1.5 Hz, 1H), 7.52 — 7.48 (m, 2H), 7.45 (d, J: 8.1 Hz, 1H), 7.15 (d, J: 8.4 Hz, 1H), 7.07 (dd, J: 7.8, 7.2 Hz, 1H), 5.11 (dd, J: 13.5, 5.1 Hz, 1H), 4.47 (d, J: 6.3 Hz, 2H), 4.45 (d, J: 15.9 Hz, 1H), 4.31 (d, J: 17.4 Hz, 1H), 4.05 (t, J: 4.8 Hz, 2H), 3.45 (t, J: 5.1 Hz, 2H), 3.24 (s, 3H), 2.96 — 2.86 (m, 1H), 2.66 — 2.57 (m, 1H), 2.45 — 2.30 (m, 1H), 2.04 — 1.94 (m, 1H).
Example 73 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(1- hydroxycyclohexyl)acetamide A. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2- diflu0r0(1-hydr0xycyclohexyl)acetamide. 3 minomethyl)oxoisoindolin- 2-yl)piperidine-2,6-dione, Mesylic acid (0.050 g, 0.135 mmol) (0.050 g, 0.113 mmol) was placed in a vial with 2,2-difluoro(1-hydroxycyclohexyl)acetic acid (0.026 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol) and N,N—dimethylformamide (1.0 mL).
The reaction mixture was stirred at 40 CC for 18 h. The reaction mixture was taken up in dimethylsulfoxide and purified using reverse-phase semi preparatory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min). ons containing desired product were combined and volatile cs were removed under reduced re to give N—((2-(2,6-dioxopiperidin-3 -yl) oxoisoindolinyl)methyl)-2,2-difluoro(1-hydroxycyclohexyl)acetamide (0.041 g, 0.091 mmol, 67.4 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.97 (s, 1H), 9.04 (t, .1: 6.15 Hz, 1H), 7.68 (d, .1: 7.88 Hz, 1H), 7.50 (s, 1H), 7.43 (d, .1: 7.88 Hz, 1H), 5.19 (s, 1H), 5.10 (dd, .1: 5.04, 13.24 Hz, 1H), 4.40 - 4.47 (m, 3H), 4.27 - 4.34 (m, 1H), 2.86 - 2.96 (m, 1H), 2.57 - 2.63 (m, 1H), 2.40 (qd, .1: 4.57, 13.19 Hz, 1H), 2.00 (dtd, .1: 2.05, 5.28, 12.61 Hz, 1H), 1.70 (d, .1: 12.30 Hz, 2H), 1.45 - 1.61 (m, 5H), 1.34 - 1.43 (m, 2H), 1.00 - 1.13 (m, 1H). MS (ESI) m/z 450.2 [M+1]+.
Example 74 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)—2,2-diflu0r0(1- hydroxycyclopentyl)acetamide A. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- diflu0r0(1-hydr0xycyclopentyl)acetamide. 3 -(5-(Aminomethyl)oxoisoindolin- 2-yl)piperidine-2,6-dione, Mesylic acid (0.050 g, 0.135 mmol) (0.050 g, 0.113 mmol) was placed in a vial with 2,2-difluoro(1-hydroxycyclopentyl)acetic acid (0.024 g, 0.135 mmol), diisopropylethylamine (0.071 mL, 0.406 mmol), 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 olo [4,5-b]pyridinium 3-oxid hexafluorophosphate (0.057 g, 0.149 mmol) and N,N—Dimethylformamide (1.0 mL).
The reaction mixture was stirred at 40 CC for 18 h. The reaction mixture was taken up in dimethylsulfoxide and purified using reverse-phase semi atory HPLC (5-100 % acetonitrile + 0.1% formic acid in water + 0.1% formic acid, over 20 min).
Fractions containing desired product were combined and volatile organics were d under reduced pressure to give N—((2-(2,6-dioxopiperidin-3 -yl) oxoisoindolinyl)methyl)-2,2-difluoro(1-hydroxycyclopentyl)acetamide (0.044 g, 0.101 mmol, 74.7 % yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) 8 10.97 (s, 1H), 9.10 (t, .1: 6.15 Hz, 1H), 7.68 (d, .1: 7.57 Hz, 1H), 7.49 (s, 1H), 7.43 (d, .1: 7.88 Hz, 1H), 5.35 (s, 1H), 5.10 (dd, .1: 5.20, 13.40 Hz, 1H), 4.40 - 4.49 (m, 3H), 4.27 - 4.33 (m, 1H), 2.91 (ddd, .1: 5.36, 13.79, 17.42 Hz, 1H), 2.57 - 2.63 (m, 1H), 2.39 (qd, .1: 4.57, 13.29 Hz, 1H), 2.00 (dtd, .1: 2.36, 5.26, 12.65 Hz, 1H), 1.88 - 1.96 (m, 2H), 1.62 - 1.76 (m, 4H), 1.52 - 1.60 (m, 2H). MS (ESI) m/z 436.2 .
Example 75 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(3- methyl(trifluoromethoxy)phenyl)acetamide F NH FF>|\O 0 A. 4-Iod0methyl(trifluor0meth0xy)benzene. To a stirred solution of omethyl(trifluoromethoxy)benzene (1 g, 3.92 mmol) in 1,4-dioxane (10 mL) was added sodium iodide (1.17 g, 7.84 mmol), copper iodide (37.3 mg, 0.19 mmol), N,N’-dimethylcyclohexane-1,2-diamine (61.3 mg, 0.43 mmol) at room temperature and stirred at 110 CC for 16h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layer was washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford methyl(trifluoromethoxy)benzene (1.0 g, 3.31 mmol, 84%) as brown liquid. GCMS (m/z) 302[M+].
B. Ethyl 2,2-diflu0r0(3-methyl(triflu0r0meth0xy)phenyl)acetate.
To a stirred solution of 4-iodomethyl(trifluoromethoxy)benzene (1.0 g, 3.31 mmol) in dimethylsulfoxide (10 mL) was reacted with ethyl 2-bromo-2,2- difluoroacetate (802 mm, 3.97 mmol), copper (547 mg, 8.61 mmol) and stirred at 55 °C for 6h. The reaction mixture was neutralized with aqueous ted ammonium chloride solution and extracted with ethyl acetate (3 X 50 mL). The combined organic layer was washed with water (2 X 50 mL), brine (50 mL) and dried over sodium sulphate and was concentrated to afford ethyl 2,2-difluoro(3-methyl (trifluoromethoxy)phenyl)acetate (700 mg, 2.35 mmol, 70%) as a brown .
GCMS (m/Z) 298.1[M]+.
C. 2,2-Diflu0r0(3-methyl(trifluor0meth0xy)phenyl)acetic acid. To a stirred solution of ethyl 2,2-difluoro(3 -methyl(trifluoromethoxy)phenyl)acetate (700 mg, 2.35 mmol) in ethanol: tetrahydrofuran: water (15 mL, 1:1:1) was added lithium hydroxide (296 mg, 7.05 mmol) and stirred at room temperature for 4h. The reaction mixture was concentrated and the residue was neutralized with saturated potasiium bisulphate (20 mL) and extracted with ethyl acetate (2 X 25 mL). The combined organic layer was washed with brine (25 mL), dried over sodium te and concentrated to afford 2,2-difluoro(3-methyl(trifluoromethoxy)phenyl)acetic acid (400 mg, 1.48 mmol, 63% yield). MS (ESI) m/z 269.45 [M-1]+.
D. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2— difluoro-Z-(3-methyl(trifluoromethoxy)phenyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(3-methyl(trifluoromethoxy)phenyl) acetic acid (200 mg, 0.74 mmol) in pyridine (20 mL) was added phosphoryl chloride (340mg, 2.22 mmol) dropwise and stirred at 0-5 0C for 1h and then added 3-(5-(aminomethyl)- 1-oxoisoindolinyl)piperidine-2,6-dione hydrochloride (229 mg, 0.74 mmol) and stirred at room temperature for 30min. The reaction mixture was lized with aqueous saturated sodium bicarbonate (up to pH-8) and ted with ethyl acetate (3 X 50 mL). The ed organic layer was washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column tography using 40-50% acetonitrile in aqueous formic acid (0.1%) to afford N—((2—(2,6-dioxopiperidinyl) indolinyl)methyl)-2,2-difluoro(3-methyl (trifluoromethoxy)phenyl)acetamide (80 mg, 0.15 mmol, 20% yield)as a white solid.
MS (ESI) m/z 526.26 . 1H NMR (400MHz, DMS)-d6) 5 = 10.98 (s, 1H), 9.68 (t, J=6.1 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.62 (s, 1H), 7.57 - 7.47 (m, 2H), 7.42 (s, 1H), 7.37 (d, J=7.9 Hz, 1H), 5.10 (dd, J=5.2, 13.4 Hz, 1H), 4.49 - 4.25 (m, 4H), 2.98 - 2.85 (m, 1H), 2.69 - 2.55 (m, 1H), 2.44 - 2.34 (m, 1H), 2.33 (s, 3H), 2.05 - 1.94 (m, 1H).
Example 76 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)(3-eth0xypyridin-2— yl)—2,2—difluoroacetamide A. 3-Eth0xy-2—i0d0pyridine. To a stirred solution of 2-iodopyridinol (1 g, 4.52 mmol) in N,N-dimethyl formamide (20 mL) was added potassium carbonate (0.936 g, 6.78 mmol) at room temperature, and stirred for 10 min. To this reaction mixture was added ethyl iodide (1.41 g, 9.04 mmol) at room temperature and stirred for 2h at 80 CC. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column tography (silica-gel 100-200) 100% hexane as eluent to afford xyiodopyridine (1 g, 4.0 mmol, 88.8% yield) as brown liquid. LCMS (ESI) m/Z 251.1 [Mi B. Ethyl 2-(3-eth0xypyridinyl)—2,2-diflu0r0acetate. To a stirred solution of 3-ethoxyiodopyridine (1.0 g, 4.01 mmol) in dimethyl sulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate (1.6 mL, 8.03 mmol), copper (0.66 g, .44 mmol) and stirred at 55 CC for 16h. The reaction mixture was neutralized with aqueous ted ammonium chloride on and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with water (2 X 100 mL), brine (10 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(3- ethoxypyridinyl)-2,2-difluoroacetate (800 mg, 3.26 mmol, 81 %) as a brown liquid.
LCMS (ESI) m/Z 246.1[M]+.
C. 2-(3-Eth0xypyridinyl)—2,2-difluoroacetic acid. To a cold (0 CC) stirred solution of ethyl 2-(3-ethoxypyridinyl)-2,2-difluoroacetate (800 mg, 3.26 mmol) in in Mthanol: tetrahydrofuran:water (9 mL, 1:1:1) was added lithium ide monohydrate (410 mg, 9.78mmol) and stirred at room temperature for 2h.
The reaction mixture was concentrated, the residue was neutralized with 10% aqueous potassium bisulphate (10 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2-(3-ethoxypyridinyl)-2,2-difluoroacetic acid (500 mg, 2.13 mmol, 88 % yield) as a brown semi solid. The reaction mixture was taken to the next step without further purification.
D. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2-(3- ethoxypyridin-Z-yl)—2,2-diflu0r0acetamide. To a cold (0 oC) stirred solution of 2-(3-ethoxypyridinyl)-2,2-difluoroacetic acid (252 mg, 1.16 mmol) in pyridine (20 mL) was added phosphoryl chloride mg, 2.91 mmol) drop wise and d at 0-5 CC for 30min. To this reaction e was then added 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 2h. The reaction mixture was neutralized with aqueous saturated sodium onate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase Grace column tography using 45-50% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6- dioxopiperidin-3 -oxoisoindolin-5 -yl)methyl)(3 -ethoxypyridinyl)-2,2- difluoroacetamide (60 mg, 0.12 mmol, 13% yield)as an off-white solid. LCMS (ESI) m/z 473.29 [M+1]+.1H NMR z, DMSO-d6) 5 = 10.98 (s, 1H), 9.41 (br t, J=6.3 Hz, 1H), 8.22 (dd, J=1.1, 4.4 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.66 - 7.61 (m, 1H), 7.59 - 7.53 (m, 2H), 7.48 (d, J=7.9 Hz, 1H), 5.12 (dd, J=5.6, 13.2 Hz, 1H), 4.53 - 4.27 (m, 4H), 4.08 (q, J=7.2, 2H), 2.99 - 2.86 (m, 1H), 2.70 - 2.56 (m, 1H), 2.47 - 2.32 (m, 1H), 2.05 - 1.96 (m, 1H), 1.19 (t, J=7.2 Hz, 3H).
Example 77 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(3- methylpyridin-Z-yl)acetamide A. Ethyl 2,2-diflu0r0(3-methylpyridin-Z-yl)acetate. To a stirred solution of 2-iodomethylpyridine (0.7 g, 3.19 mmol) in dimethyl sulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate (0.8 mL, 6.39 mmol), copper (0.52 g, 8.29 mmol) and stirred for 16h at 50 CC. The reaction e was neutralized with aqueous ted ammonium chloride solution and extracted with ethyl e (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL) and dried over sodium sulphate and was concentrated to afford ethyl 2,2- difluoro(3-methylpyridinyl)acetate (500 mg, 2.32 mmol, 73 %) as a brown liquid. GCMS (m/Z) 215.2.
B. 2,2-Diflu0r0(3-methylpyridin-Z-yl)acetic acid. To a cold (0 oC) stirred solution of ethyl 2,2-difluoro(3 -methylpyridinyl)acetate (500 mg, 2.32 mmol) in methanol/ tetrahydrofuran /water mixture (9 mL, 1:1:1) was added lithium ide monohydrate (327 mg, 6.97mmol) and stirred at room temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with % aqueous potassium hate (10 mL) and extracted with ethyl acetate (2 X 30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(3-methylpyridin yl)acetic acid (400 mg, 2.13 mmol, 88 % yield) as a brown semi solid. MS (ESI) m/z 1 8 8 .3 1 . 2015/039926 C. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- diflu0r0(3-methylpyridin-Z-yl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(3-methylpyridinyl)acetic acid (300 mg, 1.60 mmol) in pyridine (20 mL) was added phosphoryl chloride (735 mg, 4.80 mmol) dropwise and stirred at 0-5 °C for 30min. To the reaction mixture was then added 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (395 mg, 1.60 mmol) and stirred at room temperature for 2h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL) and dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 ed phase column chromatography using 45-50% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl) indolinyl)methyl)-2,2-difluoro(3 -methylpyridinyl)acetamide (40 mg, 0.09 mmol, 7% yield) as an off-white solid. MS (ESI) m/z 443.30 . 1H NMR (300 MHz, DMSO-d6) 5 10.99 (s, 1H), 9.45 (br t, J=6.1 Hz, 1H), 8.51 (br d, J=3.9 Hz, 1H), 7.84 (br d, J=7.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.63 (s, 1H), 7.51 (br d, J=7.8 Hz, 2H), 5.19 - 5.03 (m, 1H), 4.58 - 4.28 (m, 4H), 2.92 — , 1H), 2.68 - 2.54 (m, 1H), 2.45 - 2.30 (m, 4H), 2.10 - 1.92 (m, 1H).
Example 78 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(5— pyridin-Z-yl)acetamide A. 2-Iod0methylpyridine. To a stirred solution of 2-bromo methylpyridine (2 g, 11.63 mmol) in 1,4-dioxane (30 mL) was added sodium iodide (3.4 g, 23.24 mmol), copper iodide (110 mg,0.58 mmol), trans-N,N’- dimethylcyclohexane-l,2-diamine (180 mg, 1.26 mmol) at room ature and stirred at 110 CC for 16 h in sealed tube. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 X 30 mL). The combined organic layers were washed with water (2 X 20 mL), brine (20 mL), dried over sodium sulphate and concentrated to afford 2-iodomethylpyridine (1.3 g, 5.93 mmol, 52% WO 07848 yield) as brown liquid. 1H NMR (300MHz, CDClg) 5 8.2 (s, 1H), 7.6 — 7.56 (d, J=8.1 Hz, 1H), 7.18 - 7.12 (m, 1H), 2.3 — 2.25(s, 1H).
B. Ethyl 2,2-diflu0r0(5-methylpyridin-Z-yl)acetate. To a stirred solution of 2-iodomethylpyridine (1 g, 4.56 mmol) in dimethyl sulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate (1.2 mL, 9.13 mmol), copper (0.75 g, 11.85 mmol) and stirred for 16h at 50 CC. The reaction mixture was neutralized with aqueous saturated um chloride solution and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated to afford ethyl ethyl 2,2- difluoro(5-methylpyridinyl)acetate (600 mg, 2.72 mmol, 60 %) as a brown liquid. GCMS (m/z) 215.0 C. 2,2-Diflu0r0(5-methylpyridin-Z-yl)acetic acid. To a cold (0 oC) d solution of ethyl 2,2-difluoro(5 -methylpyridinyl)acetate (500 mg, 2.32 mmol) in in ol/ tetrahydrofuran /water mixture (9 mL, 1:1:1) was added lithium hydroxide monohydrate (327 mg, 6.97mmol) and stirred at room temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with % aqueous potassium bisulphate (10 mL) and extracted with ethyl acetate (2 X 30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate and trated to afford 2,2-difluoro(5-methylpyridin yl)acetic acid (350 mg, 1.87 mmol, 87 % yield) as a brown semi solid. MS (ESI) m/z 1 8 8 .3 9.
] D. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- diflu0r0(5-methylpyridin-Z-yl)acetamide. To a cold (0 oC) d solution of 2,2-difluoro(5-methylpyridinyl)acetic acid (180 mg, 0.97 mmol) in pyridine (20 mL) was added phosphoryl chloride (0.2 mL, 2.91 mmol) dropwise and stirred at 0-5 °C for 30min. To this reaction mixture was then added 3-(5-(aminomethyl) oxoisoindo1inyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 2h. The reaction mixture was lized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL) and dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 45-50% acetonitrile in s formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl) oxoisoindolinyl)methyl)-2,2-difluoro(5 -methylpyridinyl)acetamide (64 mg, 0.14 mmol, 13% as an off-white solid. MS (ESI) m/z 443.30 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.99 (s, 1H), 9.60 (br t, J=5.9 Hz, 1H), 8.55 (bs, 1H), 7.88 - 7.98 (m, 1H), 7.69-7.63 (t, J=8.6 Hz, 2H), 7.52 (s, 1H), 7.49 - 7.40 (m, 1H), 5.11 (dd, J=5.1, 13.5 Hz, 1H), 4.59 - 4.21 (m, 4H), 2.98 - 2.85 (m, 1H), 2.68 - 2.53 (m, 1H), 2.45 - 2.39 (m, 4H), 2.06 - 1.97 (m, 1H).
Example 79 N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0indolinyl)methyl)(2-eth0xy fluor0phenyl)—2,2-difluoroacetamide ] A. 1-Eth0xyflu0r0i0dobenzene. To a stirred solution of 2-bromo ethoxyfluorobenzene (1 g, 4.58 mmol) in 1,4-dioxane (30 mL) was added sodium iodide (1.37 g, 9.17 mmol), copper iodide (43.6 mg,0.22 mmol), trans-N,N’- dimethylcyclohexane-l,2-diamine (71.2 mg, 0.504 mol) at room temperature and stirred at 110 CC for 16h in sealed tube. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford 1-ethoxyfluoroiodobenzene (1 g, 5.93 mmol, 52% yield) as brown liquid. GC-MS (ESI) m/z 266.
B. Ethyl 2-(2-eth0xyfluorophenyl)-2,2-diflu0r0acetate. To a stirred solution of 1-ethoxyfluoroiodobenzene (1 g, 3.17 mmol) in dimethyl sulfoxide (20 mL) was added ethyl o-2,2-difluoroacetate (1.53 g, 7.54 mmol), copper (0.62 g, 9.80 mmol) and stirred for 16h at 50 oC. The reaction mixture was lized with aqueous saturated ammonium de solution and ted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 20 mL), brine (20 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(2- ethoxyfluorophenyl)-2,2-difluoroacetate (800 mg, 3.05 mmol, 81 %) as a brown liquid. GC- MS (ESI) m/z 262.2 C. 2-(2-Eth0xyfluor0phenyl)—2,2-diflu0r0acetic acid. To a cold (0 CC) stirred solution of and was concentrated to give ethyl 2-(2-ethoxyfluorophenyl)-2,2- difluoroacetate (500 mg, 2.32 mmol) in in ethanol/ tetrahydrofuran /water mixture (9 mL, 1:1:1) was added lithium hydroxide monohydrate (327 mg, 6.97mmol) and stirred at room temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous potassium hate (10 mL) and extracted with ethyl acetate (2 X 30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate and concentrated to afford thoxy fluorophenyl)-2,2-difluoroacetic acid (400 mg, 1.70 mmol, 56 % yield) as a brown semi solid. LCMS (ESI) m/z 233.4 [M-1]'.
D. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- diflu0r0(5-methylpyridin-Z-yl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(5-methylpyridinyl)acetic acid (272 mg, 1.16 mmol) in ne (20 mL) was added phosphoryl de (0.3 mL, 2.91 mmol) dropwise and stirred at 0-5 °C for 30min. To this reaction mixture was then added aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) and stirred at room temperature for 2h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL) and dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase Grace column chromatography using 45-50% acetonitrile in s formic acid (0.1%) to afford N—((2-(2,6- dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)-2,2-difluoro(5 lpyridin yl)acetamide (60 mg, 0.12 mmol, 12% yield)as an off-white solid. LCMS (ESI) m/z 490.3 [M+1]+.1H NMR (400MHz, 6) 8 = 10.98 (s, 1H), 9.36 (br t, J=6.1 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.54 - 7.47 (m, 3H), 7.45 (d, J=7.6 Hz, 1H), 7.00 - 6.84 (m, 1H), 5.11 (br dd, J=5.0, 13.3 Hz, 1H), 4.52 - 4.27 (m, 4H), 3.99 (q, J=7.0 Hz, 1H), 3.04 - 2.82 (m, 1H), 2.71 - 2.54 (m, 1H), 2.46 - 2.28 (m, 1H), 2.04 - 1.94 (m, 1H), 1.14 (t, J=7.0 Hz, 1H).
Example 80 N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)-2,2-diflu0r0(4'- fluorobiphenylyl)acetamide —214— A. Fluorobiphenylyl)ethan0ne. To a solution of l-(4- bromophenyl)ethanone (2 g, 10.05 mmol) in toluene/ethanol ((10 mL, 2:1) was added 4-fluorophenylboronic acid (1.68 g, 12.06 mmol) ed by potassium carbonate (3.46 g, 25.12 mmol) and degassed for 10min. The reaction mixture was further d with tetrakis(triphenylphosphine)palladium(0) (1.16 mg, 1.005 mmol) and degassed for additional 10min and heated at 80 CC in a sealed tube for 6h. The reaction mixture was cooled to room temperature, d through the celite pad. The filtrate was diluted with cold water and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, d and concentrated. The obtained residue was purified by column chromatography (100-200 silica gel, 30% ethyl acetate in hexane) to afford l-(4'- iphenylyl)ethanone (l g, 4.67 mmol, 48% yield) as an off-white solid. MS (ESI) m/Z 215.27 .
B. Ethyl 2-(4'-flu0robiphenylyl)0xoacetate. To a stirred solution of l-(4'-fluorobiphenylyl)ethanone (1.5 g, 7.009 mmol) in pyridine (10 mL) was added selenium dioxide (1.94 g, 17.52 mmol) at room temperature. The reaction mixture was stirred at 100 CC for 16h. The reaction mixture was filtered through celite pad and washed with dichloromethane (15 mL). Ethyl chloroformate (15 mL) was added to the filtrate at 0 CC and stirred at room temperature for 4h. The reaction mixture was quenched with ice water and extracted with dichloromethane (3 X 10 mL). The combined organic layers were washed with 1N hydrochloride (15 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford ethyl 2-(4'- fluorobiphenylyl)oxoacetate (900 mg, 3.308 mmol, 47% yield) as a colorless liquid. MS (ESI) m/Z 273.51 [M+1]+.
C. Ethyl 2,2-diflu0r0(4'-flu0r0biphenylyl)acetate. Ethyl 2-(4'- fluorobiphenylyl)oxoacetate (l g, 3.676 mmol) was added in portion into diethylaminosulfur trifiuoride (1.4 mL) at 0 CC and stirred at room ature for 16h. The reaction mixture was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was purified by column tography [using (100-200) silica gel, 10% ethyl acetate in pet ether] to afford ethyl fluoro(4'-fluorobiphenylyl)acetate (800 mg, 2.72 mmol, 80% yield) as a colorless liquid. GCMS (ESI) m/z 294 [M+l]+.
D. 2,2-Diflu0r0(4'-flu0r0biphenylyl)acetic acid. To a stirred solution of ethyl 2,2-difluoro(4'-fluorobiphenylyl)acetate (900 mg, 3.06 mmol) in tetrahydrofilran: methanol: water e (12 mL, 1:1:1) was added lithium hydroxide monohydrate (385 mg, 9.18 mmol) and stirred at room temperature for 4h.
The reaction mixture was concentrated under reduced pressure and the residue obtained was dissolved in water (10 mL), washed with ethyl acetate (2 X 10 mL). The aqueous layer was ed with 1N hydrochloride aqueous solution and extracted MmdMHmmmGX1WMJTmamMmdmgmdwflmwmw%Mdmmmme (10 mL), dried over sodium e, filtered and concentrated to afford 2,2-difiuoro (4'-fluorobiphenylyl)acetic acid (400 mg, 2.91 mmol, 44% yield) as semi-solid compound. The crude was used to next step without purification.
E. N-((2-(2,6-Di0x0piperidinyl)—1-0xoisoindolinyl)methyl)-2,2— difluoro-Z-(4'-flu0r0biphenyl—4-yl)acetamide. To an ice cold on of 2,2- difluoro(4'-fiuorobiphenylyl)acetic acid (266 mg, 1.16 mmol) in pyridine (15 mL) was added phosphorus oxychloride (445 mL, 2.91 mmol) drop wise and stirred at 0-5 CC for 1h. Then, 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) was added into the reaction mixture and d at room temperature for 1h. The reaction mixture was basified with aqueous saturated wwmeMMmmwmmnmdammwmemflmmmm3XUnm)flw combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was d by Reveleris C-18 reversed phase column chromatography (50-55% acetonitrile in 0.1% aqueous formic acid) to afford (2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoro(4'-fluorobiphenylyl) ide (60 mg, 0.114 mmol, 11% yield) as white solid. MS (ESI) m/z 522.46 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 ppm 1098(s11D,968G"]=58Ikg11D,786—7720n¢flD,772—762(nn3H) 7.43 — 7.28 (m, 4H), 5.09 (dd, J: 13.2, 5.1 Hz, 1H), 4.47 (d, J: 5.7 Hz, 2H), 4.38 (d, J: 17.1 Hz, 1H), 4.24 (d, J: 17.1 Hz, 1H), 3.00 — 2.81 (m, 1H), 2.64 — 2.53 (m, 1H), 2.38 — 2.20 (m, 1H), 2.03— 1.90 (m, 1H).
Example 81 N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0indolinyl)methyl)(2-eth0xy fluor0phenyl)—2,2-difluoroacetamide A. 1-(2-Eth0xyflu0r0phenyl)ethan0ne. To a stirred solution of 1-(5-fluorohydroxyphenyl)ethanone (500 mg, 3.24 mmol) in N,N-dimethylformamide (15 mL) was added ethyl bromide (607 mg, 3.89 mmol) followed by potassium ate (1.11 g, 8.10 mmol) and stirred at 90 0C for 16h. The on mixture was diluted with ice water (15 mL) and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford 1-(2-ethoxy fluorophenyl)ethanone (350 mg, 1.36 mmol, 20% yield) as a colorless liquid. MS (ESI) m/Z 183.34 [M+1]+.
B. Ethyl 2-(2-eth0xyflu0r0phenyl)—2-0x0acetate. To a stirred solution of 1-(2-ethoxyfluorophenyl)ethanone (2 g, 10.99 mmol) in pyridine (10 mL) was added selenium dioxide (3.05 g, 27.47 mmol) at room temperature heated at 100 0C for 16h. The on mixture was filtered through a Celite pad and washed with romethane (15 mL). 4 mL of ethyl chloroformate was added to the filtrate at 0 0C and stirred at room temperature for 4h. The reaction mixture was ed with ice water and extracted with dichloromethane (3 X 30 mL). The combined c layers were washed with 1N hydrochloride solution (30 mL), brine (30 mL), dried over sodium sulfate, filtered and concentrated to afford ethyl 2-(2-ethoxyfluorophenyl)- 2-oxoacetate (1.7 g, 7.08 mmol, 75% yield) as a colorless liquid. Without further purification used for next step.
C. Ethyl 2-(2-eth0xyflu0r0phenyl)—2,2-diflu0r0acetate. Ethyl 2-(2- ethoxyfluorophenyl)oxoacetate (1 g, 4.16 mmol) was added into diethylamino sulfur trifluoride (2 mL) at 0 CC and stirred at room temperature for 16h. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and trated. ed crude was purified by column chromatography (100-200 silica gel, 10% ethyl acetate in pet ether) to afford ethyl 2-(2-ethoxyfluorophenyl)-2,2-difluoroacetate (800 mg, 3.05 mmol, 73% yield) as a colourless liquid. MS (ESI) m/z 262.2 [M]+.
D. 2-(2-Eth0xyfluorophenyl)-2,2-diflu0r0acetic acid. To a stirred solution of ethyl 2-(2-ethoxyfluorophenyl)-2,2-difluoroacetate (600 mg, 2.29 mmol) in mixture of ydrofuran: methanol: water (12 mL, 1:1:1) was added lithium hydroxide monohydrate (288 mg, 6.87 mmol) and stirred at room temperature for 16h. The volatiles were d under reduced pressure and obtained e was dissolved in water (10 mL) and washed with ethyl acetate (2 X 10 mL). Aqueous layer was acidified with 1N hloride aqueous solution and ted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, ed and solvent was concentrated to afford 2-(2-ethoxy fluorophenyl)-2,2-difluoroacetic acid (310 mg, 1.32 mmol, 87% yield) as semi-solid compound. 1H NMR (400 MHz, CDClg) 8 7.38 (dd, J: 8.8, 3.2 Hz, 1H), 7.16 (ddd, J = 11.2, 8.8, 3.2 Hz, 1H), 6.91 (dd, J: 9.2, 4.4 Hz, 1H), 4.08 (q, J: 7.2 Hz, 2H), 2.68 (brs, 1H), 1.39 (t, J: 6.8 Hz, 3H).
E. N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0ind01inyl)methyl)(2- ethoxy-S-fluorophenyl)-2,2-diflu0r0acetamide. To an ice cold solution of 2-(2-ethoxyfluorophenyl)-2,2-difluoroacetic acid (151 mg, 0.65 mmol) in pyridine (9 mL) was added phosphorus oxychloride (0.18 mL, 1.94 mmol) in drop wise and stirred at 0 — 5 0C for 1h. Then, 3-(5-(aminomethyl)oxoisoindolinyl)piperidine- 2,6-dione hydrochloride (200 mg, 0.65 mmol) was added into the reaction mixture and d at room temperature for 1h. The reaction mixture was basified with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL).
The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by Reveleris C-18 mwnmdmmmcdmmumnmmmgqmy6069%awmmnmfln01%ammmmfimmc acid) to give N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)(2- ethoxyfluorophenyl)-2,2-difluoro ide (55 mg, 0.11 mmol, 17% yield) as white solid. MS (ESI) m/z 490.1 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 10.98 (s, 1HL938GVJ=56fh,HD,770@LJ=75I£;1H)750(s1HL744@LJ= 8.4 Hz, 1H), 7.39 — 7.34 (m, 2H), 7.19 — 7.11 (m, 1H), 5.11 (dd, J: 13.2, 5.1 Hz, 1H), 4.47 (d, J: 6.6 Hz, 2H), 4.45 (d, J: 16.5 Hz, 1H), 4.31 (d, J: 17.7, 1H), 3.97 (q, J = 6.9 Hz, 2H), 2.96 — 2.85 (m, 1H), 2.67 — 2.55 (m, 1H), 2.45 — 2.30 (m, 1H), 2.04 — 1.94 (m, 1H), 1.11 (t, J: 7.2 Hz, 3H).
Example 82 2-Cyclopentyl—N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2- difluoroacetamide A. Ethyl flu0r0(1-hydr0xycyclopentyl)acetate. To a stirred solution of entanone (1 g, 11.90 mmol) in ydrofuran (20 mL) was added anhydrous cerium(III) chloride (0.06 g, 0.24 mmol) followed by activated zinc dust (0.93 g, 14.28 mmol) and ethyl 2-bromo-2,2-difiuoroacetate (2.01 mL, 15.47 mmol) at 0 CC and stirred at room temperature for 16h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered and solvent was concentrated and obtained crude was d by silica gel column chromatography (30% ethyl acetate in pet ether) to afford ethyl 2,2-difiuoro (1-hydroxycyclopentyl)acetate (0.55 g, 2.40 mmol, 22% yield) as a colorless liquid. 1H NMR (300 MHz, DMSO-d6) 5 5.48 (s, 1H), 4.27 (q, .1: 6.9 Hz, 2H), 1.87 — 1.81 (m, 2H), 1.75 — 1.57 (m, 6H), 1.26 (t, J: 6.9 Hz, 3H).
B. Ethyl 2-cyclopentenyl—2,2-diflu0r0acetate. To a stirred solution of ethyl 2,2-difluoro(1-hydroxycyclopentyl)acetate (50 mg, 0.24 mmol) in pyridine (1.7 mL) was added thionyl chloride (0.17 mL, 2.40 mmol) at 0 CC and d at room temperature for 16h. The reaction mixture was diluted with water (4 mL) and basified with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 X 4 mL).
The combined organic layers were washed with water (4 mL), brine (4 mL), dried over sodium sulfate, filtered and concentrated. The ed crude product was d by silica gel column chromatography (30% ethyl acetate in pet ether) to afford ethyl 2- cyclopentenyl-2,2-difiuoroacetate (25 mg, 0.13 mmol, 45% yield) as a colorless liquid.
MS (ESI) m/Z 190.1 [M]+.
C. Ethyl 2-cyclopentyl-2,2-difluoroacetate. To a stirred solution of ethyl 2-cyclopentenyl-2,2-difiuoroacetate (100 mg, 0.52 mmol) in ethyl e (10 mL) was added slurry of 10% palladium hydroxide (30 mg) in ethyl acetate under nitrogen stream and stirred under hydrogen balloon pressure at room temperature for 4h. The hydrogen atmosphere was evacuated and on mixture was filtered through a Celite pad, filtrate was concentrated to afford ethyl 2-cyclopentyl-2,2-difluoroacetate (60 mg, 0.31 mmol, 59% yield) as a colorless liquid. 1H NMR (300 MHz, CDClg) 5 4.32 (q, J: 7.2 Hz, 2H), 2.67 — 2.57 (m, 1H), 1.79 — 1.55 (m, 8H), 1.35 (t, J: 6.9 Hz, 3H).
D. 2-Cyclopentyl-2,2-diflu0roacetic acid. To a d solution of ethyl 2- cyclopentyl-2,2-difluoroacetate (450 mg, 2.34 mmol) in tetrahydrofuran: methanol: water mixture (15 mL, 1:1:1) was added lithium hydroxide monohydrate (295 mg, 7.03 mmol) and stirred at room temperature for 4h. The volatiles were d under reduced pressure and the resultant residue was dissolved in water (10 mL) and washed with ethyl acetate (2 X 10 mL). s layer was acidified with 1N hydrochloride aqueous on and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford 2-cyclopentyl-2,2-difluoroacetic acid (280 mg, 1.70 mmol, 72% yield) as semi-solid compound. 1H NMR (300 MHz, DMSO-d6) 8 8.68 (brs, 1H), 2.69 — 2.59 (m, 1H), 1.84 — 1.59 (m, 8H).
E. 2-Cyclopentyl—N-((2-(2,6-dioxopiperidinyl)—1-oxoisoindolin yl)methyl)—2,2-diflu0r0acetamide. To an ice cold solution of 2-cyclopentyl-2,2- oacetic acid (159 mg, 0.97 mmol) in pyridine (9 mL) was added phosphorus oxychloride (0.27 mL, 2.9 mmol) drop wise and d at 0-5 0C for 1h. Then, 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) was added into the reaction mixture and stirred at room temperature for 2h. The reaction mixture was basified with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and trated.
The resultant residue was purified by Reveleris C-18 reversed phase column chromatography (50-55% acetonitrile in 0.1% aqueous formic acid) to afford 2-cyclopentyl-N—((2-(2,6-dioxopiperidin-3 -oxoisoindolin-5 -yl)methyl)-2,2- difluoroacetamide (50 mg, 0.12 mmol, 12 % yield) as white solid. MS (ESI) m/Z 420.17 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.98 (s, 1H), 9.36 (t, J: 6.3 Hz, 11D,770(dflfi=78lfiz11D,747(s11D,740(d"]=8JQHz,H1L511(ddfll=135, .1 Hz, 1H), 4.46 (d, J: 17.1 Hz, 1H), 4.44 (d, J: 6.0 Hz, 2H), 4.31 (d, J: 17.7 Hz, 1H), 2.92 — 2.87 (m, 1H), 2.73 — 2.57 (m, 2H), 2.40 — 2.36 (m, 1H), 2.02 — 1.98 (m, 1H), 1.70 — 1.53 (m, 8H).
Example 83 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(3- methyl(trifluoromethoxy)phenyl)acetamide O O F F "mh‘{fo ClOm A. r0i0d0(triflu0r0meth0xy)benzene. To a cold (0 °C) stirred solution of 3-chloro(trifluoromethoxy)aniline (2.5 g, 11.79 mmol) in aq H2S04 (10 mL) was added sodium nitrite (894 mg, 12.96 mmol) urea (106 mg, 1.768 mmol) and potassium iodide (4.1 g, 24.75 mmol) at 0 OC and stirred at 50 0C for 2h. The reaction mixture was quenched with aqueous sodium bicarbonate solution (40 mL) and extracted with ethyl e (3 X 50 mL). The combined c layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated to afford 2-chloroiodo(trifluoromethoxy)benzene and crude (2 g, 6.23 mmol, 52% yield) as colorless liquid which was used to next step without any ation.
B. Ethyl 2-(3-chlor0(trifluor0meth0xy)phenyl)-2,2-diflu0r0acetate.
To a stirred solution of 2-chloroiodo(trifluoromethoxy)benzene (1.5 g, 4.56mmol) in ylsulfoxide (12 mL) was reacted with ethyl 2-bromo-2,2- difluoroacetate (138 g 6.84 mmol), copper (753 mg, 11.85 mmol) and stirred for 6h at 55 CC. The reaction mixture was neutralized with aqueous saturated ammonium chloride on and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(3-chloro(trifluoromethoxy)phenyl)-2,2- difluoroacetate (1.1 g, 3.45 mmol, 78% yield) as a brown liquid. MS (ESI) m/z 318 [M+1]+.
C. 2-(3-Chlor0(triflu0r0methoxy)phenyl)-2,2-difluoroacetic acid. To a cold (0 oC) stirred solution of ethyl 2-(3-chloro(trifluoromethoxy)phenyl)-2,2- difluoroacetate (2 g, 6.289 mmol) in in methanol/ tetrahydrofuran /water mixture (10 mL, 1:1:1) was added lithium hydroxide monohydrate (792 mg, 18.86 mmol) and stirred at room temperature for 16h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous hydrochloric acid (10 mL) in 1,4-dioxane and extracted with ethyl acetate (2 X 30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate and concentrated to afford 2-(3-chloro(trifluoromethoxy)phenyl)-2,2-difluoroacetic acid and crude (800 mg, 2.75 mmol, 44% yield) as a brown semi solid which was used to next step without any purification D. 2-(3-Chlor0(triflu0r0meth0xy)phenyl)—N-((2-(2,6-di0x0piperidin- 3-yl)—1-oxoisoindolinyl)methyl)—2,2-difluoroacetamide. To a cold (0 oC) stirred solution of 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (250 mg, 0.809 mmol) and 2-(3-chloro(trifluoromethoxy)phenyl)- 2,2-difluoroacetic acid (234 mg, 0.970 mmol) in N,N—dimethylformamide (10 mL) was added N,N—diisopropylethylamine (0.4 mL, 2.42 mmol) followed by 1- [Bis(dimethylamino)methylene] - 1 H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid hexafluorophosphate (614 mg, l.6lmmol) and d at room temperature for 16h.
The reaction e was diluted with water (30 mL) and ted with ethyl acetate (2 X 40 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated dried under vacuum. The product was purified by Reveleris C-l8 reversed phase column using 60% acetonitrile in aqueous formic acid (0.1%) to afford (2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)- 2,2-difluoro(2-(2-hydroxyethoxy)phenyl)acetamide (35 mg, 0.064 mmol, 8% yield)as an off-white solid. MS (ESI) m/z 546.26 [M+1]+. 1H NMR z , DMSO-d6,) 5 10.98 (s, 1H), 9.75 (br t, J=5.9 Hz, 1H), .90 (m, 1H), 7.82 -7.64 (m, 3H), 7.47-7.34 (m, 2H), 5.10 (dd, J=13.2, 5.1 Hz, 1H), 4.51-4.24 (m, 4H), 2.99- 2.84 (m, 1H), 2.67-2.55 (m, 1H), 2.45-2.25 (m, 1H), 2.05-1.93 (m, 1H).
Example 84 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(4- meth0xy(trifluoromethyl)phenyl)acetamide A. 1-Br0m0meth0xy(trifluoromethyl)benzene. To a d solution of o(trifluoromethyl)phenol (2 g, 8.29 mmol) in N,N—dimethyl formamide (20 mL) was added portion wise sodium hydride (398 mg, 16.59 mmol) at 0 oC, and d for 30min at room temperature. To this reaction mass was added methyl iodide (671 mg, 10.78 mmol) at 0 CC and stirred at room temperature for 1h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl e (2 X 200 mL). The combined organic layers were washed with water (2 X 100 mL), bfine(1001nL),dnedoversodnnnsuhfluueandconcmnnfied.Thereaflfinfiremdue was purified by column chromatography (silica-gel 100-200) 100% hexane as a eluent to afford 1-bromomethoxy(trifluoromethyl)benzene (1.2 g, 4.72 mmol, 57% yield) as an off-white solid. MS (ESI) m/z 254.1 [M]+.
B. 1-Iod0methoxy-Z-(triflu0r0methyl)benzene. To a d solution of 1-bromomethoxy(trifluoromethyl)benzene (1 g, 3.93 mmol) in 1,4-dioxane (10 mL) was added sodium iodide (1.76 g, 11.79 mmol), copper iodide (150 mg, 0.786 mmol) followed by trans-N,N’-dimethylcyclohexane-1,2-diamine (168 mg, 1.18 mmol) at room temperature and stirred at 110 CC for 2 h in microwave. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 X 200 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afforde 1-iodo methoxy(trifluoromethyl)benzene (800 g, 2.65 mmol, 68% yield) as brown liquid.
MS (ESI) m/Z 302.0 [M]+.
C. Ethyl 2,2-diflu0r0(4-methoxy-Z-(trifluoromethyl)phenyl)acetate.
To a stirred solution of 1-iodomethoxy(trifluoromethyl)benzene (800 mg, 2.65 mmol) in dimethyl sulfoxide (20 mL) was added ethyl 2-iodo-2,2-difluoroacetate (0.62 mL, 3.97 mmol), copper (438 g, 6.89 mmol) and stirred for 16h at room ature. The reaction mixture was neutralized with aqueous saturated ammonium chloride solution and extracted with ethyl acetate (3 X 50 mL). The combined c layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(4-methoxy (trifluoromethyl)phenyl)acetate (600 mg, 2.01 mmol, 76 %) as a brown liquid. MS (ESI) m/Z 298.1 [M]+.
D. flu0r0(4-meth0xy(triflu0r0methyl)phenyl)acetic acid. To a cold (0 oC) stirred solution of ethyl 2, 2-difluoro(4-methoxy(trifluoromethyl) phenyl) acetate (600 mg, 2.01 mmol) in in methanol/ tetrahydrofuran /water (9 mL, 1:1:1) was added lithium hydroxide monohydrate (253 mg, 6.03mmol) and stirred at room temperature for 4h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous potassium bisulphate (10 mL) and extracted with ethyl acetate (2 X 30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(4-methoxy (trifluoromethyl)phenyl)acetic acid (450 mg, 1.66 mmol, 83 % yield) as a brown semi solid. MS (ESI) m/Z 269.30 [M-1]+.
E. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluoro-Z-(4-meth0xy(triflu0r0methyl)phenyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(4-methoxy(trifluoromethyl)phenyl)acetic acid (314 mg, 1.16 mmol) in pyridine (20 mL) was added phosphoryl chloride (0.7 mL, 2.91 mmol) dropwise and stirred at 0-5 0C for 30min. To this, 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) was added and stirred at room temperature for 1h. The reaction mixture was lized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column tography using 50-55% itrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)-2,2-difluoro(4- methoxy(trifluoromethyl)phenyl)acetamide (35 mg, 0.07 mmol, 7% yield) as an ite solid. MS (ESI) m/z 526.21 [M+1]+. 1H NMR (300 MHz, 6) 5 ppm .97 (br s, 1 H), 9.59 (br t, J=5.87 Hz, 1 H), 7.81 —7.60 (m, 2 H), 7.56 —7.20 (m, 4 H), .11 (br dd, J=13.39, 4.95 Hz, 1 H), 4.56 —4.14 (m, 4 H), 3.89 (s, 3 H), 3.02 — 2.85 (m, 1 H), 2.67 — 2.55 (m, 1 H), 2.46 — 2.30 (m, 1 H), 2.06 — 1.94 (m, 1 H).
Example 85 (2,6-Di0x0piperidinyl)—1-0x0is0indolinyl)methyl)-2,2—diflu0r0(2-(2- hydroxyethoxy)phenyl)acetamide —224— WO 07848 A. (2-Br0m0ethoxy)(tert—butyl)dimethylsilane. To a stirred solution of oethanol (10 g, 80 mmol) in dichloromethane (100 mL) was added tert—butylchlorodimethylsilane (14.5 g, 96.77 mmol) and imidazole (10 g,161.2 mmol) at 0 CC and stirred at room temperature for 16h. The reaction mixture was quenched with aqueous sodium bicarbonate solution (40 mL) and extracted with ethyl e (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated to afford (2-bromoethoxy)(tert-butyl)dimethylsilane (8 g, 33.61 mmol, 42% yield) as colorless liquid.
B. Tert—butyl(2-(2-i0dophenoxy)ethoxy)dimethylsilane. To a stirred solution of 2-iodophenol (3 g, 13.6 mmol) in N,N-dimethylformamide (20 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (3.89 g, 16.36 mmol), tert—butyl ammonium iodide (1 g 2.72 mmol) and potassium carbonate (4.69 g 34 mmol) at 0 °C and stirred at 80 CC for 16h. The reaction mixture was quenched with water (40 mL) and ted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated to afford tert-butyl(2-(2-iodophenoxy)ethoxy)dimethylsilane (2.5 g, 6.613 mmol, 49% yield) as colorless liquid.
C. Ethyl 2,2-diflu0r0(2-(2-hydr0xyeth0xy)phenyl)acetate. To a stirred solution of tert—buty1(2-(2-iodophenoxy)ethoxy)dimethylsilane (3 g, 7.936mmol) in dimethyl sulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate (2.41 g 11.90 mmol), copper powder (1.3. g, 20.63 mmol) and stirred at 50 0C for 6h. The reaction mixture was lized with aqueous saturated ammonium chloride solution and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium te and concentrated to afford ethyl fluoro(2-(2-hydroxyethoxy)phenyl)acetate (900 mg, 3.406 mmol, 45 %) as a brown liquid.
D. 2,2-Diflu0r0(2-(2-hydr0xyeth0xy)phenyl)acetic acid. To an ice cold solution of ethyl 2,2-difluoro(2-(2-hydroxyethoxy)phenyl)acetate (1.2 g, 3.20 mmol) in ethanol/ ydrofuran /water mixture (15 mL, 1:1:1) was added lithium hydroxide monohydrate (404 mg, 9.62 mmol) and stirred at room temperature for 6h. The reaction mixture was concentrated and the resultant residue was lized with 10% aqueous hloric acid in1,4-dioxane (10 mL) and extracted with ethyl acetate (2 X 30 mL). The combined organic layer was washed with brine (10 mL), dried over sodium te and concentrated to afford 2,2-difluoro(2-(2- hydroxyethoxy)phenyl)acetic acid (650 mg, 2.82mmol, 65% yield) as a brown semi solid. 1H NMR (300 MHz, DMSO-d6) 8 7.68 (d, J: 7.2 Hz, 1H), 7.46 (dd, J: 8.1 Hz, 7.8 Hz, 1H), 7.09 (dd, J: 8.0, 7.8 Hz, 1H), 6.91 (d, J: 8.4 Hz, 1H), 6.38 (brs, 1H), 4.12 (t, J: 5.4 Hz, 2H), 3.99 (t, J: 3.9 Hz, 2H).
E. N-((2-(2,6-Di0x0piperidinyl)—1-0xois0ind01inyl)methyl)-2,2— difluoro-Z-(2-(2-hydr0xyeth0xy)phenyl)acetamide. To an ice cold solution of 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.970 mmol) and 2,2-difluoro(2-(2-hydroxyethoxy)phenyl)acetic acid (225 mg, 0.970 mmol) in methylformamide (10 mL) was added N,N—diisopropylethylamine (0.5 mL, 2.91 mmol) ed by 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (737 mg, 1.94mmol) and stirred at room temperature for 12h.
The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 X 40 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated dried under vacuum. The product was purified by Reveleris C-18 reversed phase column (60% acetonitrile in 0.1% aqueous formic acid) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoro(2-(2-hydroxyethoxy) phenyl)acetamide (40 mg, 0.082 mmol, 8% yield)as an off-white solid. MS (ESI) m/z 488.12. 1H NMR (300MHz, DMSO-d6): 8 = 10.98 (s, 1H), 9.29 (t, J: 5.7 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.60 — 7.39 (m, 4H), 7.16 (br d, J: 8.1 Hz, 1H), 7.10 — 7.01 (m, 1H), 5.11 (dd, J: 13.0, 5.0 Hz, 1H), 4.72 (t, J: 5.5 Hz, 1H), 4.51 — 4.27 (m, 4H), 3.98 (t, J: 5.3 Hz, 1H), 3.60 (q, J: 5.3 Hz, 1H), 3.00 — 2.82 (m, 1H), 2.63 — 2.54 (m, 1H), 2.45 — 2.32 (m, 1H), 2.06 — 1.94 (m, 1H).
Example 86 2-(4-Chloro-Z-ethoxyphenyl)-N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)—2,2-diflu0roacetamide O O WNQEWEONHFF H CI 0 A. hlor0eth0xyphenyl)ethan0ne. To a d solution of 1-(4-chlorohydroxyphenyl)ethanone (2 g, 11.76 mmol) in N,N—dimethylformamide (15 mL) was added ethyl iodide (2.8 mL, 29.4 mmol) followed by potassium carbonate (4.87 g, 35.29 mmol) and stirred at 90 0C for 16h. The reaction e was diluted with ice water (20 mL) and ted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated to afford 1-(4-chloro ethoxyphenyl)ethanone (1.7 g, 8.58 mmol, 73% yield) as a colorless liquid. MS (ESI) m/Z 199.41 [M+1]+.
B. Ethyl 2-(4-chloro-Z-ethoxyphenyl)0x0acetate. To a d solution of 1-(4-chloroethoxyphenyl)ethanone (1.7 g, 8.58 mmol) in pyridine (10 mL) was added selenium dioxide (2.38 g, 21.46 mmol) at room temperature and stirred at 100 0C for 16h. The on mixture was filtered through a Celite pad and washed with dichloromethane (15 mL). Ethyl chloroformate (3.4 mL) was added to the filtrate at 0 0C and stirred at room temperature for 4h. The reaction mixture was quenched with ice water and extracted with dichloromethane (3 X 20 mL). The combined organic layers were washed with 1N hydrochloride solution (20 mL), brine (20 mL), dried over sodium sulfate, filtered and trated to afford ethyl 2-(4-chloro ethoxyphenyl)oxoacetate (1.2 g, 4.68 mmol, 54% yield) as a colorless liquid. MS (ESI) m/Z 256.1 [M]+.
C. Ethyl 2-(4-chlor0eth0xyphenyl)-2,2-diflu0r0acetate. Ethyl 2-(4- chloroethoxyphenyl)oxoacetate (1 g, 3.9 mmol) was added into diethylamino sulfur ride (1.89 g, 11.72 mmol) at 0 0C and stirred at room temperature for 16h. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated.
Obtained crude was ed by flash chromatography (100-200 silica gel, 10% ethyl acetate in pet ether) to afford ethyl 2-(4-chloroethoxyphenyl)-2,2-difluoroacetate (570 mg, 2.05 mmol, 52% yield) as a colourless liquid. 1H NMR (400 MHz, CDClg) 5 7.56 (d, J: 8.4 Hz, 1H), 7.03 (dd, J: 8.4, 1.6 Hz, 1H), 6.91 (s, 1H), 4.31 (q, J: 7.6 Hz, 2H), 4.05 (q, J: 6.8 Hz, 2H), 1.37 (t, J: 7.2 Hz, 3H), 1.31 (t, J: 7.2 Hz, 3H).
D. 2-(4-Chloro-Z-eth0xyphenyl)—2,2-difluoroacetic acid. To a stirred solution of ethyl 2-(4-chloroethoxyphenyl)-2,2-difluoroacetate (470 mg, 1.69 mmol) in tetrahydrofuran: methanol: water (12 mL, 1:1:1) was added lithium ide drate (213 mg, 5.07 mmol) and stirred at room temperature for 16h. The les were removed under reduced pressure and obtained crude was dissolved in water (10 mL) and washed with ethyl acetate (2 X 10 mL). Aqueous layer was acidified with 1N hydrochloride aqueous solution and ted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and solvent was concentrated to afford hloro phenyl)-2,2-difluoroacetic acid (260 mg, 1.04 mmol, 61% yield) as semi-solid lewMKGOOMHL(XXHQS758QLJ=87HL1HL705w, J=81HL1HL694GJEQ409QLJ=72HL2HL1390NF=69HL3H) E. 2-(4-Chloro-Z-ethoxyphenyl)—N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To an ice cold solution of 2-(4 chloroethoxyphenyl)-2,2-difluoroacetic acid (178 mg, 0.71 mmol) in pyridine (9 mL) was added phosphorus oxychloride (0.18 mL, 1.94 mmol) in drop wise and stirred at 0-5 0C for 1h. Then, 3-(5-(aminomethyl)oxoisoindolinyl)piperidine- 2,6-dione hydrochloride (200 mg, 0.64 mmol) was added into the reaction e and stirred at room temperature for 1h. The reaction mixture was basif1ed with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL).
The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by ris C-18 reversed phase column chromatography (50-55% acetonitrile in 0.1% aqueous formic acid) to give 2-(4-chloroethoxyphenyl)-N-((2-(2,6-dioxopiperidinyl) oxoisoindolinyl)methyl)-2,2-difluoroacet amide (58 mg, 0.11 mmol, 18% yield) as white solid. MS (ESI) m/z 506.1 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 10.98 (s, 1HL938GVI=56}h,HD,771fiLJ=78}h,HD,756@LJ=81}h,HD,750 (s, 1H), 7.44 (d, J: 7.5 Hz, 1H), 7.22 (s, 1H), 7.12 (dd, J: 7.8, 1.8 Hz, 1H), 5.11 (dd, J: 13.2, 5.1 Hz, 1H), 4.46 (d, J: 17.2 Hz, 1H), 4.46 (d, J: 5.7 Hz, 2H), 4.31 (d, J: 174,HD,403abJ=69Ihg2HL298—2850n,HD,267—255(nn1H)243— 2.30 (m, 1H), 2.04 — 1.93 (m, 1H), 1.11 (t, J: 6.9 Hz, 3H).
Exanqfle87 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(2— hydroxyphenyDacetanfide A. 1-Iod0(methoxymethoxy)benzene. To a stirred solution of 2-iodophenol (3 g, 13.63 mmol) in dichloro methane (30 mL) was added ropyl ethyl amine (7.2 mL, 40.89 mmol) followed by chloro methyl methyl ether (1.63 g, .45 mol) at 0 CC and stirred at room temperature for 16h. The reaction e was ed with ice water (30 mL) and extracted with ro methane (3 X mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate, d and concentrated. The resultant crude product was purified by silica gel column chromatography (20% ethyl acetate in pet ether) to afford 1-iodo(methoxymethoxy)benzene (2.5 g, 9.61 mmol, 72% yield) as a brown liquid. 1H NMR (400 MHz, CDClg) 5 7.78 (dd, J: 8.0, 1.6 Hz, 1H), 7.28 (ddd, J: 8.5, 7.4, 1.6 Hz, 1H), 7.07 (dd, J: 8.4, 1.6 Hz, 1H), 6.76 (ddd, J: 8.8, 7.2, 0.8 Hz, 1H), 5.24 (s, 2H), 3.52 (s, 3H).
B. Ethyl 2,2-diflu0r0(2-(methoxymethoxy)phenyl)acetate. To a stirred solution of 1-iodo(methoxymethoxy)benzene (3 g, 8.24 mmol) in dimethylsulfoxide (11.5 mL) was added ethyl 2-bromo-2,2-difiuoroacetate ( 2.67 g, 13.18 mmol) followed by copper powder (1.31 g, 20.6 mmol) at 0 OC and stirred at 60 0C for 5h. The reaction mixture was quenched with ice water (30 mL) and filtered through a Celite pad. The filtrate was extracted with ethyl acetate (3 X 30 mL) and the combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude product was purified by flash chromatography (20% ethyl acetate in pet ether to afford ethyl 2,2-difluoro(2- (methoxymethoxy)phenyl)acetate (1.3 g, 5.0 mmol, 62% yield) as a colorless liquid.
MS (ESI) m/Z 260.2 [M]+.
C. flu0r0(2-(meth0xymeth0xy)phenyl)acetic acid. To a d solution of ethyl 2,2-difluoro(2-(methoxymethoxy)phenyl)acetate (2 g, 7.69 mmol) in mixture of methanol: tetrahydrofi1ran:water (20 mL, 1:1:1) at 0 °C was added lithium hydroxide monohydrate (970 mg, 23.07 mmol) and stirred at room temperature for 4h. The volatiles were removed under reduced pressure and the obtained crude was diluted with water (20 mL) and washed with ethyl acetate (2 X 15 mL). Aqueous layer was acidified with s potassium bisulfate solution and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to afford 2,2-difiuoro(2- (methoxymethoxy)phenyl)acetic acid (1.2 g, 4.87 mmol, 63% yield) as a brown semi solid. MS (ESI) m/Z 246.3 [Mi D. N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2- difluoro-Z-(2-hydroxyphenyl)acetamide. To an ice cold solution of 2,2-difluoro (2-(methoxymethoxy)phenyl)acetic acid (258 mg, 1.16 mmol) in pyridine (9 mL) was added orus oxychloride (0.27 mL, 2.9 mmol) drop wise and stirred at 0-5 0C for 1h. Then, 3 -(5 -(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) was added into the reaction mixture and stirred at room temperature for 1h. The reaction mixture was ed with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was d by Reveleris C-18 ed phase column chromatography (50-55% acetonitrile in 0.1% aqueous formic acid) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- o(2-hydroxyphenyl) acetamide (33 mg, 0.07 mmol, 8% yield) as white solid.
MS (ESI) m/z 444.35 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 11.00 (s, 1H), 10.24 (bs, 1H), 9.38 (bs, 1H), 7.68 (d, J: 7.8 Hz, 1H), 7.51 (s, 1H), 7.47 — 7.44 (m, 2H), 7.34 (dd, J: 7.8, 7.5 Hz, 1H), 6.91 — 6.87 (m, 2H), 5.11 (dd, J: 13.5, 5.1 Hz, 1H), 4.48 (d, J: 4.5 Hz, 2H), 4.46 (d, J: 18.0 Hz, 1H), 4.32 (d, J: 17.4 Hz, 1H), 2.96 — 2.86 (m, 1H), 2.58 — 2.49 (m, 1H), 2.42 — 2.27 (m, 1H), 2.07 — 1.98 (m, 1H).
Example 88 N-((2-(2,6-Dioxopiperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—difluoro(2— (methylamino)phenyl)acetamide A. Benzyl 2-i0d0phenylcarbamate. To a stirred solution of 2-iodoaniline (3 g, 13.69 mmol) in 4N sodium s hydroxide (3 mL), water (10 mL) was added benzyl chloroformate (2.79 g, 16.43 mmol) at 0 CC and stirred at room temperature for 3h. The reaction mixture was diluted with water (30 mL) and ted with ethyl acetate (3 X 30 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate and concentrated to afford benzyl 2- iodophenylcarbamate (3 g, 8.49 mmol, 62% yield) as a colorless liquid. 1H NMR (400 MHz, CDClg) 5 8.08 (d, J: 8.8 Hz, 1H), 7.76 (dd, J: 11.8 Hz, 1.8 Hz, 1H), 7.48 — 7.32 (m, 6H), 7.02 (brs, 1H), 6.79 (ddd, J: 8.0, 7.7, 1.8 Hz, 1H), 5.23 (s, 2H).
B. Benzyl 2-i0d0phenyl(methyl)carbamate. To a d solution of benzyl phenylcarbamate (1.5 g, 4.24 mmol) in N,N-dimethylformamide (15 mL) was added cesium carbonate (4.13 g ,12.72 mmol) ed by iodo methane (0.9 g, 6.37 mmol) at 0 oC and stirred at 60 0C for 5 h. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 X 25 mL). The ed organic layers were washed with water (25 mL), brine (25 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was purified by silica gel column chromatography using 30% ethyl acetate in pet ether to afford benzyl 2- iodophenyl(methyl)carbamate (1.2 g, 3.26 mmol, 80% yield) as a colorless liquid. MS (ESI) m/Z 368.01 [M+1]+ C. Ethyl (benzyloxycarbonyl)(methyl)amin0)phenyl)-2,2- difluoroacetate. To a stirred solution of benzyl 2-iodophenyl(methyl)carbamate (1 g, 2.72 mmol) in dimethylsulfoxide (20 mL) was added ethyl 2-bromo-2,2- difiuoroacetate (0.83 g, 4.08 mmol) followed by copper (0.45 g, 7.08 mmol) at 0 oC and stirred at 60 CC for 5h. The reaction mixture was quenched with ice water and filtered through a Celite pad. The filtrate was extracted with ethyl acetate (3 X 15 mL) and the combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was purified by flash chromatography (20% ethyl acetate in pet ether to afford ethyl 2-(2- ((benzyloxycarbonyl) l)amino)phenyl)-2,2-difiuoroacetate (0.72 g, 1.98 mmol, 73% yield) as a colorless liquid. MS (ESI) m/z 363.1 [M]+.
D. 2-(2-((Benzyloxycarbonyl)(methyl)amino)phenyl)—2,2-diflu0r0acetic acid. To a cold (0 CC) stirred solution of ethyl 2-(2-((benzyloxycarbonyl) (methyl) amino)phenyl)-2,2-difiuoroacetate (700 mg, 1.9 mmol) in mixture of methanol: tetrahydrofuran: water mixture (15 mL, 1:1 :1) was added lithium hydroxide monohydrate (242 mg, 5.78 mmol) and stirred at room temperature for 4h. The les were removed under reduced pressure and the obtained residue was ved in water (10 mL), washed with ethyl acetate (2 X 10 mL). Aqueous layer was acidified with aqueous potassium bisulfate solution and ted with ethyl acetate (3 X mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and trated to afford 2-(2- ((benzyloxycarbonyl)(methyl)amino)phenyl)-2,2-difiuoroacetic acid (620 mg, 1.85 mmol, 97% yield) as a semi solid. MS (ESI) m/z 336.4 [M+1]+.
E. Benzyl 2-(2-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methylamin0)—1,1-diflu0r00x0ethyl)phenyl(methyl)carbamate. To an ice cold solution of 2-(2-((benzyloxycarbonyl)(methyl)amino)phenyl)-2,2-difiuoroacetic acid (325 mg, 0.97 mmol) in pyridine (9 mL) was added phosphorus oxychloride (0.27 mL, 2.9 mmol) in drop wise and stirred at 0-5 0C for 1h. Then, 3-(5-(aminomethyl) oxoisoindo1inyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) was added into the on mixture and stirred at room temperature for 2h. The reaction mixture was basified with aqueous saturated sodium bicarbonate on and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, d and concentrated. The ant residue was purified by Reveleris C-18 ed phase column chromatography % acetonitrile in 0.1% aqueous formic acid) to afford benzyl 2-(2-((2-(2,6- dioxopiperidin-3 -yl)oxoisoindolinyl)methylamino)- 1 ,1-difiuoro oxoethyl)phenyl(methyl)carbamate (150 mg, 0.25 mmol, 26% yield) as white solid.
MS (ESI) m/Z 591.62 [M+1]+.
F. N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- diflu0r0(2-(methylamin0)phenyl)acetamide. To a stirred solution of benzyl 2-(2- ((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolinyl)methylamino)- 1 ,1-difiuoro oxoethyl)phenyl(methyl)carbamate (0.1 g, 0.169 mmol) in methanol (15 mL) was added a slurry of 10% palladium hydroxide (10 mg) in ol under nitrogen stream and stirred under 60 psi hydrogen pressure at room temperature for 6h. The hydrogen atmosphere was evacuated and reaction mixture was filtered through a Celite pad and the e was concentrated. The resultant residue was purified by Reveleris C-18 mwxmdmmmcdmmumnmmmgqmy6069%awmmfimfln01%ammmmfimmc acid) to afford to afford N-((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)- 2,2-difiuoro(2-(methyl amino)phenyl)acetamide (62 mg, 0.13 mmol, 80% yield) as a white solid. MS (ESI) m/Z 457.23 [M+H]+. 1H NMR (300 MHz, DMSO-d6) 5 10.98 (s1HL956(LJ=60}h,HD,767@LJ=87}R,HD,742@,HD,739—7280m 3H), 6.70 — 6.65 (m, 2H), 5.43 (q, .1: 4.2 Hz, 1H), 5.10 (dd, J: 13.5, 5.1 Hz, 1H), 4.47 (d, J: 6.0 Hz, 2H), 4.42 (d, J: 17.9 Hz, 1H), 4.28 (d, J: 17.1 Hz, 1H), 2.91 — 2.85 (m, 1H), 2.74 (d, J: 4.8 Hz, 3H), 2.62 — 2.50 (m, 1H), 2.43 — 2.34 (m, 1H), 2.01 — 1.99 (m, 1H).
Example 89 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(4— isoprop0xy(triflu0r0methyl)phenyl)acetamide FF" N o A 0 A. 0is0pr0p0xy(trifluoromethyl)benzene. To a stirred solution of 4-bromo(trifluoromethyl)phenol (5 g, 20.83 mmol) in N,N— dimethylformamide (20 mL) was added potassium carbonate (8.6 g, 62.49 mmol) followed by pyl iodide (3.1 mL, 31.24 mmol) and d at 80 0C for 4h. The reaction mixture was filtered and water (50 mL) was added and extracted with ethyl e (2 X 60 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography (100-200 silica) using 0-10% ethyl acetate in hexanes to afford 1-bromoisopropoxy(trifluoromethyl)benzene (3.5 g, 12.41 mmol, 59% yield). LCMS (ESI) m/Z 284.38 .
B. 1-Iod0is0prop0xy(trifluoromethyl)benzene. To a stirred on of 1-bromoisopropoxy(trifluoromethyl)benzene (3.5 g, 12.41 mmol) in 1,4-dioxane (30 mL) was added sodium iodide (5.58 g, 37.23 mmol), copper iodide (471 mg, 2.48 mmol), trans-N,N’-dimethylcyclohexane-1,2-diamine (529 mg, 3.72 mmol) at room temperature and stirred at 110 CC for 16 h in sealed tube. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 X 300 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford 1-iodo isopropoxy(trifluoromethyl)benzene (3 g, 9.09 mmol, 73% yield) as brown liquid.
MS (ESI) m/Z 331.0 [M]+.
C. Ethyl 2,2-diflu0r0(2-methyl-4—(trifluoromethoxy)phenyl)acetate.
To a stirred solution of 1-iodoisopropoxy(trifluoromethyl)benzene (3 g, 9.09 mmol) in dimethyl sulfoxide (25 mL) was added copper (1.5 g, 23.63 mmol) and ethyl 2-ido-2,2-difluoroacetate (2.005 mL, 13.63 mmol) at room temperature and d at 55 CC for 2h. The reaction mixture was neutralized with aqueous saturated ammonium chloride (50 mL) solution and extracted with ethyl acetate (2 X 100 mL).
The ed organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(4- isopropoxy(trifluoromethyl)phenyl)acetate (2.5 g, 7.66 mmol, 84%). GCMS (ESI) m/Z 326.2.
D. 2,2-Diflu0r0(4-isopropoxy-Z-(trifluor0methyl)phenyl)acetic acid.
To a cold (0 oC) stirred solution of ethyl ethyl 2,2-difluoro(4-isopropoxy oromethyl)phenyl)acetate (2.5 g, 7.66 mmol) in tetrahydrofilran:Methanol:water (30 mL, 1:1:1) was added lithium hydroxide (1.6 g, 38.34 mmol) and stirred at room temperature for 6h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous hydrochloric acid (10 mL) and extracted with ethyl e (2 X 20 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(4-isopropoxy oromethyl)phenyl)acetic acid (1.8 g, 6.04 mmol, 78% yield) as a brown liquid.
The crude was taken to the next step without fiarther purification.
E. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluor0(4-isoprop0xy(triflu0r0methyl)phenyl)acetamide. To a cold (0 oC) d solution of 2,2-difluoro(4-isopropoxy(trifluoromethyl)phenyl)acetic acid (380 mg, 1.165 mmol) in ne was added POC13 (0.27 mL, 2.91 mmol) se and stirred at 0-5 CC for 1h and then added 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione hydrochloride (300 mg, 0.968 mmol) and continued ng at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 40-60% acetonitrile in aqueous formic acid (0.1%) to give N-((2-(2,6-dioxopiperidinyl) oxoisoindolinyl)methyl)-2,2-difluoro(4-isopropoxy (trifluoromethyl)phenyl)acetamide (48 mg, 0.086 mmol, 10% yield) as an off white solid. MS (ESI) m/z 554.03 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.99 (s, 1H), 9.58 (t, J: 5.6 Hz, 1H), 7.73 — 7.64 (m, 2H), 7.47 (s, 1H), 7.41 (d, J: 7.6 Hz, 1H), 7.36 (d, J: 8.8 Hz,1H), 7.32 — 7.28 (m, 1H), 5.11(dd, J: 13.2, 5.1 Hz, 1H), 5.00 — —234— 4.25 (m, 4H), 3.00 — 2.85 (m, 1H), 2.69 — 2.55 (m, 1H), 2.44 — 2.35 (m, J: 2.0 Hz, 1H), 2.05 — 1.95 (m, 1H), 1.35 — 1.25 (m, 6H).
Example 90 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(4— methylcyclohexyl)acetamide A. Ethyl 2,2-diflu0r0(1-hydr0xymethylcyclohexyl)acetate. To a stirred solution of 4-methylcyclohexanone (1 g, 8.92 mmol) in tetrahydrofuran (20 mL) was added catalytic amount of anhydrous cerium(IH) chloride (0.22 g, 0.89 mmol), followed by activated zinc dust (0.75 g, 11.6 mmol) and ethyl 2-bromo- 2,2-difluoroacetate (1.13 mL, 11.6 mmol) at 0 CC and stirred at room temperature for 16h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated. The ed crude was purified by silica gel column chromatography (30% ethyl acetate in pet ether) to afford ethyl 2,2-difluoro(1-hydroxymethylcyclohexyl)acetate (0.9 g, 3.81 mmol, 41% yield) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6) 8 5.33 (d, J: 13.2 Hz, 1H), 4.27 (q, J: 7.2 Hz, 2H), 2.37 (dt, .1: 13.3, 7.8 Hz, 1H), 2.18 — 2.13 (m, 1H), 1.94 — 1.86 (m, 1H), 1.78 — 1.70 (m, 4H), 1.48 — 1.39 (m, 2H), 1.26 (t, J: 7.3 Hz, 3H), 0.91 (dt, .1: 18.8, 5.6 Hz, 3H).
B. Ethyl 2,2-diflu0r0(4-methylcyclohexenyl)acetate. To a stirred solution of ethyl 2,2-difluoro(1-hydroxymethylcyclohexyl)acetate (1.8 g, 7.62 mmol) in pyridine (18 mL), was added thionyl chloride (9 mL, 76.27 mmol) at 0 CC and stirred at room temperature for 16h. The reaction mixture was diluted with water (20 mL) and d with aqueous sodium onate solution and extracted with ethyl e (3 X 20 mL). The combined c layers were washed with water (20 mL), brine (20 mL), dried over sodium e, filtered and concentrated. The obtained crude product was purified by silica gel column chromatography using 20% ethyl acetate in pet ether to afford ethyl 2,2-difluoro(4-methylcyclohex enyl)acetate (1 g, 4.23 mmol, 62% yield) as a colorless liquid. MS (ESI) m/Z 218.2 [MT- C. Ethyl fluoro-Z-(4-methylcyclohexyl)acetate. To a stirred solution of ethyl 2,2-difluoro(4-methylcyclohexenyl)acetate (700 mg, 3.21 mmol) in ethyl acetate (15 mL) was added a slurry of 10% palladium hydroxide (200 mg) in ethyl acetate under en stream and stirred under hydrogen balloon re at room temperature for 4h. The hydrogen atmosphere was evacuated and reaction mixture was filtered through a Celite pad, e was concentrated to afford ethyl 2,2-difiuoro(4-methylcyclohexyl)acetate (500 mg, 1.3 mmol, 37% yield) as a colorless liquid. MS (ESI) m/Z 220.2 [Mi D. 2,2-Diflu0r0(4-methylcyclohexyl)acetic acid._To a stirred solution of ethyl 2,2-difluoro(4-methylcyclohexyl)acetate (500 mg, 2.27 mmol) in mixture of tetrahydrofuran: methanol: water (15 mL, 1:1:1) was added lithium ide monohydrate (286 mg, 6.81 mmol) and stirred at room temperature for 4h. The volatiles were removed under d re and the obtained residue was dissolved in water (10 mL) and washed with ethyl acetate (2 X 10 mL). s layer was acidified with 1N hydrochloride and ted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and solvent was concentrated to afford 2,2-difluoro(4- methylcyclohexyl)acetic acid (280 mg, 1.45 mmol, 64% yield) as semi-solid compound. 1H NMR (300 MHz, CDClg) 5 8.26 (brs, 1H), 2.04 — 2.02 (m, 1H), 1.85 -1.78 (m, 3H), 1.60 — 1.52 (m, 2H), 1.36 — 1.24 (m, 2H), 1.01 — 0.87 (m, 2H), 0.90 (d, J: 6.3 Hz, 3H).
E. N-((2-(2,6-Di0x0piperidinyl)—1-0xoisoindolin-S-yl)methyl)-2,2- difluor0(4-methylcyclohexyl)acetamide. To an ice cold solution of 2,2-difluoro- 2-(4-methylcyclohexyl)acetic acid (186 mg, 0.97 mmol) in pyridine (9 mL) was added phosphorus oxychloride (0.27 mL, 2.9 mmol) drop wise and stirred at 0-5 0C for 1h.
Then, 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) was added into the reaction mixture and stirred at room temperature for 2h. The reaction mixture was basified with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography (50-55% acetonitrile in 0.1% aqueous formic acid) to afford N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)-2,2-difluoro(4- methylcyclohexyl) acet amide (45 mg, 0.1 mmol, 10% yield) as white solid. MS (ESI) m/z 448.19 . 1H NMR (300 MHz, DMSO-d6) 5 10.98 (s, 1H), 9.35 (t, J: 6.0 Hz, 1H), 7.70 (d, J: 7.5 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J: 8.1 Hz, 1H), 5.11 (dd, J: 13.2, 5.4 Hz, 1H), 4.45 (d, J: 16.5 Hz, 1H), 4.44 (d, J: 6.6 Hz, 2H), 4.31 (d, J: 17.4 Hz, 1H), 2.92 — 2.87 (m, 1H), 2.63 — 2.57 (m, 1H), 2.41 — 2.36 (m, 1H), 2.02 — 1.98 (m, 2H), 1.68 — 1.65 (m, 3H), 1.48 — 1.42 (m, 3H), 1.24 — 1.15 (m, 2H), 0.99 — 0.86 (m, 1H), 0.87 (dd, J: 6.9, 6.3 Hz, 3H).
Example 91 N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0indolinyl)methyl)-2,2—diflu0r0(3-(2- isopropoxyeth0xy)phenyl)acetamide O O /L F F "m'kbo O/\/o A. Ethyl 2,2-diflu0r0(3-(2-is0pr0p0xyeth0xy)phenyl)acetate. To a stirred solution of ethyl fluoro(3 -hydroxyphenyl)acetate (200 mg, 0.92 mmol) in tetrahydrofuran (10 mL) was added diisopropyl azodicarboxylate (373 mg, 1.85 mmol) followed by triphenylphosphine (485 mg, 1.85 mmol) and 2-isopropoxyethanol (96.2 mg, 0.92 mmol) at 0 CC and stirred at room temperature for 16h. The reaction mixture was quenched with ice water and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was d by flash chromatography (20% ethyl acetate in pet ether) to afford ethyl fiuoro(3-(2-isopropoxyethoxy)phenyl)acetate (100 mg, 0.33 mmol, 36% yield) as a colorless liquid. GCMS (ESI) m/z 302.6 [M]+.
B. 2,2-Diflu0r0(3-(2-is0propoxyethoxy)phenyl)acetic acid. To an ice cold stirred solution of ethyl 2,2-difluoro(3-(2-isopropoxy ethoxy) phenyl)acetate (210 mg, 0.69 mmol) in mixture of methanol: tetrahydrofuran:water (10 mL, 1:1 :1) was added lithium hydroxide monohydrate (87 mg, 2.086 mmol) and stirred at room temperature for 4h. The volatiles were removed under reduced pressure and the obtained residue was dissolved in water (10 mL), washed with ethyl acetate (2 X 6 mL). s layer was acidified with aqueous potassium bisulfate solution and extracted with ethyl acetate (3 X 10 mL). The ed organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and trated to afford 2,2-difiuoro(3-(2-isopropoxyethoxy)phenyl)acetic acid (180 mg, 0.65 mmol, 95% yield) as a semi solid. 1H NMR (300 MHz, CDClg) 8 7.29 (dd, J: 8.2, 7.5 Hz, 1H), 7.18 (d, J: 7.8 Hz, 1H), 7.11 (s, 1H), 6.99 (d, J: 7.5 Hz, 1H), 4.11 (t, J: 5.4 Hz, 2H), 3.82 (t, J: 5.1 Hz, 2H), 3.75 (sep, .1: 6.0 Hz, 1H), 1.23 (d, J: 5.7 Hz, 6H).
C. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- difluor0(3-(2-is0pr0p0xyeth0xy)phenyl)acetamide. To an ice cold on of 2,2-difluoro(3-(2-isopropoxyethoxy)phenyl)acetic acid (221 mg, 0.81 mmol) in pyridine (9 mL) was added phosphorus oxychloride (371 mg, 2.47 mmol) in drop wise and stirred at 0-5 CC for 1h. Then, 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione hydrochloride (250 mg, 0.81 mmol) was added into the reaction mixture and d at room temperature for 1h. The reaction mixture was basified with s saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography (50-55% acetonitrile in 0.1% aqueous formic acid) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolin- -yl)methyl)-2,2-difluoro(3-(2-isopropoxy ethoxy)phenyl)acetamide (62 mg, 0.116 mmol, 15% yield) as white solid. MS (ESI) m/z 529.9 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 10.98 (s, 1H), 9.60 (t, J: 6.0 Hz, 1H), 7.67 (d, J: 7.5 Hz, 1H), 7.45 (d, J: 8.1 Hz, 1H), 7.40 (s, 1H), 7.36 (d, J: 7.5 Hz, 1H), 7.15 — 7.12 (m, 3H), .10 (dd, J: 13.5, 5.1 Hz, 1H), 4.45 (d, J: 5.7 Hz, 2H), 4.42 (d, J: 18.0 Hz,1H), 4.27 (d, J: 17.4 Hz, 1H), 4.08 (t, J: 4.5 Hz, 2H), 3.69 (t, J: 4.8 Hz, 2H), 3.62 (sep, .1: 5.7 Hz, 1H), 2.98 — 2.87 (m, 1H), 2.66 — 2.56 (m, 1H), 2.45 — 2.30 (m, 1H), 2.04 — 1.94 (m, 1H), 1.09 (d, J: 6.3 Hz, 6H).
Example 92 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(3- hydroxyphenyl)acetamide A. 1-Iod0(methoxymethoxy)benzene. To a stirred solution of 3-iodophenol (1 g, 4.54 mmol) in romethane (10 mL) was added N,N-diisopropyl ethyl amine (2.4 mL, 13.63 mmol) followed by chloro methyl methyl emmf05mh68lnmmDm0°CmmmfimdMKmmemMMMemrflLflmrwdmn mixture was quenched with ice water and extracted with romethane (2 X 100 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford l-iodo (methoxymethoxy)benzene (1.0 g, 3.78 mmol, 83% yield). GC MS (m/z) 264.0 [M]+.
B. Ethyl 2,2-diflu0r0(3-(methoxymethoxy)phenyl)acetate. To a stirred solution of l-iodo(methoxymethoxy)benzene (800 mg, 3.03 mmol) in dimethylsulfoxide (10 mL) was added ethyl 2-bromo-2,2-difiuoroacetate (738 mg, 3.97 mmol) followed by copper (501mg, 7.88 mmol) and stirred at 55 0C for 5h. The reaction mixture was quenched with aqueous ammonium chloride solution and was extracted with ethyl acetate (3 X 50 mL). The ed organic layers were washed with water (50 mL), brine (50 mL), dried over sodium e, filtered and concentrated to afford ethyl 2,2-difluoro(3-(methoxymethoxy)phenyl)acetate (700 mg, 2.69 mmol, 89% yield). GC MS (m/z) 260.2 [M]+.
C. 2,2-Diflu0r0(3-(meth0xymeth0xy)phenyl)acetic acid. To a stirred solution of ethyl 2,2-difiuoro(3-(methoxymethoxy)phenyl)acetate (700 mg, 2.69 mmol) in methanol- tetrahydrofuran -water mixture (15 mL, l:l:l) was added lithium hydroxide monohydrate (339 mg, 8.07 mmol) and stirred at room temperature for 2h. The reaction e was diluted with water (50 mL) and acidified with mmmmpd%wmflmMfimwmmmmMemeflmemflawmeGXSOmU.
The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, d and concentrated to afford 2,2-difiuoro(3- (methoxymethoxy)phenyl)acetic acid (400 mg, 1.72 mmol, 64% yield). LCMS (ESI) m/Z 23l.3l [M-l]'.
] D. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- mmmmJfiHmaMQmaMQmmmflMwmmM&RmamHWTflmmdwmmn of 2,2-difiuoro(3-(methoxymethoxy)phenyl)acetic acid (300 mg, 1.29 mmol) in pyridine (5 mL) was added phosphoryl chloride (0.4 mL, 3.87 mmol) dropwise and stirred at 0-5 CC for lh, and then added 3-(5-(aminomethyl)-l-oxoisoindolin yl)piperidine-2,6-dione hydrochloride (400 mg, 1.29 mmol) and stirred at room temperature for lh. The on mixture was neutralized with aqueous saturated sodium onate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 30 mL), brine (30 mL), dried WO 07848 over sodium sulphate and concentrated to afford N—((2-(2,6-dioxopiperidinyl) oxoisoindolinyl)methyl)-2,2-difluoro(3-(methoxymethoxy)phenyl)acetamide (250 mg, 0.51 mmol, 40% yield). LCMS (ESI) m/z 488.39 [M+1]+.
E. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluoro-Z-(3-hydr0xyphenyl)acetamide. To a cold (0 oC) stirred solution of N—((2- (2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)-2,2-difluoro(3 - (methoxymethoxy)phenyl)acetamide (250 mg, 0.51 mmol) in 1,4-dioxane (5 mL) was added 1,4-dioxane.HCl (2.0 mL)dropwise and stirred at room temperature for 1h. The reaction e was neutralized with s saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layer was washed with water (2 X 30 mL), brine (30 mL) and dried over sodium sulphate and was concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 45-50% itrile in aqueous formic acid (0.1%) to afford N-((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoro(3-hydroxyphenyl)acetamide (75 mg, 0.16 mmol, 33.0% yield) as an off- white solid. LCMS (ESI) m/z 444.13 [M+1]+. 1H NMR z, dmso) 8 = 10.98 (s, 1H), 9.87 (s, 1H), 9.62 - 9.53 (m, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.42 - 7.27 (m, 4H), 7.02 - 6.68 (m, 3H), 5.10 (br dd, J=5.0, 13.4 Hz, 1H), 4.50 - 4.22 (m, 4H), 2.96 - 2.82 (m, 1H), 2.68 - 2.54 (m, 1H), 2.44 - 2.30 (m, 1H), 2.05 - 1.93 (m, 1H).
Example 93 N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)-2,2—diflu0r0(3-((4- methylpiperazinyl)methyl)phenyl)acetamide A. Ethyl 2,2-diflu0r0(3-f0rmylphenyl)acetate. To a stirred solution of 4-iodobenzaldehyde (5g, 21.55 mmol) in dimethylsulfoxide (50 mL) was added ethyl 2-bromo-2,2-difluoroacetate (6.0 mL, 43.11 mmol), copper (4.0 g, 56.03 mmol) and stirred for 4h at 55 CC. The on mixture was neutralized with s saturated ammonium chloride solution and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(3- formylphenyl)acetate (3.5 g, 15.35 mmol, 71 %). GC MS (m/Z) 228.2. —240— B. Ethyl 2,2-diflu0r0(3-((4-methylpiperazin yl)methyl)phenyl)acetate. To a stirred solution of ethyl 2,2-difluoro(3- formylphenyl)acetate (1.0 g, 4.38 mmol) in ethanol (25 mL) was added 1-methylpiperazine (878 mg, 8.77 mmol), acetic acid (526 mg, 8.77 mmol) and stirred at 0 0C for 1h. To this reaction mixture was then added sodium cyanoborohydride (551 mg, 8.77 mmol) and stirred at room ature for 3h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and concentrated to afford ethyl fluoro(3-((4- methylpiperazin-l-yl)methyl)phenyl)acetate (1.0 g, 3.20 mmol, 74% yield). LCMS (ESI) m/Z 313.53[M+1]+ C. 2,2-Diflu0r0(3-((4-methylpiperazinyl)methyl)phenyl)acetic acid. To a cold (0 CC) stirred solution of ethyl 2,2-difluoro(3-((4-methylpiperazin- 1-yl)methyl)phenyl)acetate (1.0 g, 3.20 mmol) in ydrofuran:methanol:water e (1 :1 :1, 30 mL) was added lithium hydroxide monohydrate (403 mg, .01 mmol) and stirred at room temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with 10% s potassium bisulphate (10 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to give 2,2-difluoro(3-((4-methylpiperazinyl)methyl)phenyl)acetic acid (750 mg, 2.64 mmol, 82 % yield). LCMS (ESI) m/z 284.9[M+1]+.
D. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- diflu0r0(3-((4-methylpiperazinyl)methyl)phenyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(3-((4-methylpiperazinyl)methyl)phenyl)acetic acid (350 mg, 1.23 mmol) in pyridine (5 mL) was added phosphoryl chloride (0.3 mL, 3.69 mmol) and stirred at 0-5 0C for 1h. Then added 3-(5-(aminomethyl) indolinyl)piperidine-2,6-dione hydrochloride (381 mg, 1.23 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with s saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (2 X mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulphate and trated. The resultant e was purified by Reveleris C-18 reversed phase column chromatography using 45-50% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl) —241— oxoisoindolinyl)methyl)-2,2-difluoro(3-((4-methylpiperazin yl)methyl)phenyl)acetamide (40 mg, 0.26 mmol, 6% yield) as a pale yellow solid.
LCMS (ESI) m/z 540.40 [M+1]+. 1H NMR (300MHz, DMSO-d6) 510.99 (s, 1H), 9.67 (t, J=5.8 Hz, 1H), 7.87 (br s, 2H), 7.67 - 7.55 (m, 3H), 7.45 - 7.33 (m, 2H), 5.10 (dd, J=4.9, 13.3 Hz, 1H), 4.48 - 4.24 (m, 6H), 3.65 - 3.03 (m, 8H), 3.01 - 2.82 (m, 4H), 2.66 - 2.54 (m, 1H), 2.48 - 2.30 (m, 1H), 2.29 - 1.82 (m, 1H).
Example 94 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(4- methyl-Z-(trifluoromethyl)phenyl)acetamide F 00 H N O A. 1-Iod0methyl-Z-(triflu0r0methyl)benzene. To a stirred solution of 1-bromomethyl(trifluoromethyl)benzene (1.0 g, 4.18 mmol) in 1,4-dioxane (10 mL) was added sodium iodide (1.3 g, 8.36 mmol), copper iodide (40 mg,0.20 mmol), trans-N,N’-dimethylcyclohexane-1,2-diamine (66 mg, 0.46 mmol) at room temperature and stirred at 110 CC for 16 h in sealed tube. The reaction e was quenched with water (100 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium te and concentrated to give methyl (trifluoromethyl)benzene (900 mg, 3.14 mmol, 75% yield). GCMS (m/Z) 286.
B. Ethyl 2,2-diflu0r0(4-methyl(triflu0r0methyl)phenyl)acetate. To a stirred solution of 1-iodomethyl(trifluoromethyl)benzene (900 mg, 3.14 mmol) in dimethylsulfoxide (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate (1.3 g, 6.29 mmol), copper (520 mg, 8.18 mmol) and stirred at 55 0C for 16h. The reaction mixture was neutralized with s saturated ammonium chloride on and extracted with ethyl e (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(4-methyl(trifluoromethyl)phenyl)acetate (800 mg, 2.83 mmol, 90 %). GCMS (m/z) 282.1.
C. 2,2-Diflu0r0(4-methyl(trifluor0methyl)phenyl)acetic acid. To a cold (0 oC) stirred solution of ethyl 2,2-difluoro(4-methyl (trifluoromethyl)phenyl)acetate (800 mg, 2.83 mmol) in tetrahydrofuran - Methanol- —242— water (15 mL, 1:1:1) was added lithium hydroxide monohydrate (357 mg, 8.51 mmol) and stirred at room temperature for 2h. The reaction mixture was concentrated and the residue was lized with 10% aqueous ium bisulphate (10 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(4- methyl(trifluoromethyl)phenyl)acetic acid (400 mg, 1.57 mmol, 56 % yield). LCMS (ESI) m/z 253.32 [M-1]'.
D. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- diflu0r0(4-methyl(triflu0r0methyl)phenyl)acetamide. To a cold (0 oC) d on of 2,2-difluoro(4-methyl(trifluoromethyl)phenyl)acetic acid (400 mg, 1.57 mmol) in pyridine (5 mL) was added phosphoryl de (0.4 mL, 4.72 mmol) drop wise and stirred at 0-5 CC for 1h. To this reaction mixture was added 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (487 mg, 1.57 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous ted sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The ed organic layers were washed with water (2 X mL), brine (30 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 45-50% itrile in aqueous formic acid (0.1%) to afford N—((2-(2,6- dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)-2,2-difluoro(4-methyl (trifluoromethyl)phenyl)acetamide (50 mg, 0.09 mmol, 6.0% yield)as an off-white solid. LCMS (ESI) m/z 510.28 [M+1]+. 1H NMR (400MHz, DMSO-d6) 8 = 10.98 (s, 1H), 9.62 (br t, J=6.1 Hz, 1H), 7.78 — 7.60 (m, 4H), 7.75 (s, 1H), 7.41 (d, J=7.6 Hz, 1H), 5.11 (dd, J=5.1, 13.5 Hz, 1H), 4.51 — 4.21 (m, 4H), 2.98 - 2.85 (m, 1H), 2.65 — 2.54 (m, 1H), 2.47 — 2.31 (m, 4H), 2.04 — 1.96 (m, 1H).
Example 95 N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0indolinyl)methyl)-2,2-diflu0r0(3-(2- (2-methoxyethoxy)ethoxy)phenyl)acetamide O O /O\/\O/\/o\©)«'rN0 A. 1-Iod0(methoxymethoxy)benzene. To a stirred solution of 3-iodophenol (1 g, 4.54 mmol) in dichloromethane (10 mL) was added —243— N,N—diisopropyethylamine (2.4 mL, 13.63 mmol) followed by chloro methyl methyl ether (0.5 mL, 6.81 mmol) at 0 CC and stirred at room temperature for 2h. The reaction mixture was quenched with ice water and extracted with romethane (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated to afford 1-iodo (methoxymethoxy)benzene (1.0 g, 3.78 mmol, 83% yield). MS (ESI) m/Z 264.0 [M]+.
B. Ethyl 2,2-diflu0r0(3-(methoxymethoxy)phenyl)acetate. To a stirred solution of 1-iodo(methoxymethoxy)benzene (800 mg, 3.03 mmol) in dimethyl sulfoxide (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate (738 mg, 3.97 mmol) followed by copper (501mg, 7.88 mmol) and stirred at 55 0C for 5h. The reaction mixture was quenched with aqueous ammonium de solution and was ted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated to afford ethyl 2,2-difluoro(3-(methoxymethoxy)phenyl)acetate (700 mg, 2.69 mmol, 89% yield). MS (ESI) m/z 260.2 [M]+.
C. Ethyl 2,2-diflu0r0(3-hydr0xyphenyl)acetate. To an ice cold solution of ethyl 2,2-difluoro(3-(methoxymethoxy)phenyl)acetate (1 g, 3.84 mmol) in 1,4-dioxane (5 mL) was added 1,4-dioxane°HCl (5 mL) at 0 CC and stirred at room temperature for 3h. The volatiles were removed under reduced pressure and ed crude was purified by flash column chromatography (20% ethyl acetate in pet ether) to afford ethyl 2,2-difluoro(3-hydroxyphenyl)acetate (0.7 g, 3.24 mmol, 84% yield) as colorless liquid. MS (ESI) m/Z 216.1 [M]+.
D. Ethyl 2,2-diflu0r0(3-(2-(2-meth0xyeth0xy)eth0xy)phenyl)acetate.
To a d solution of ethyl 2,2-difluoro(3-hydroxyphenyl)acetate (1 g, 4.63 mmol) in tetrahydrofuran (10 mL) were sequentially added ropyl azodicarboxylate (1.87 g, 9.26 mmol), triphenylphosphine (2.42 g, 9.26 mmol) and 2-(2-methoxyethoxy)ethanol (0.55 g, 4.63 mmol) at 0 CC and stirred at room temperature for 16h. The reaction mixture was ed with ice water and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was purified by flash column chromatography (20% ethyl acetate in pet ether) to afford ethyl 2,2-difluoro(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetate (0.5 g, 1.57 mmol, 34% yield) as a ess liquid. GCMS (ESI) m/z 318.6 [M]+. —244— 2015/039926 ] E. flu0r0(3-(2-(2-meth0xyeth0xy)eth0xy)phenyl)acetic acid. To an ice cold solution of ethyl 2,2-difluoro(3-(2-(2-methoxyethoxy) ethoxy) phenyl) acetate (500 mg, 1.57 mmol) in mixture of methanol: ydrofuran:water (15 mL, 1:1:1) was added lithium hydroxide monohydrate (198 mg, 4.71 mmol) and stirred at room temperature for 4h. The volatiles were removed under reduced pressure and the obtained crude product was dissolved in water (10 mL), washed with ethyl acetate (2 X 8 mL). Then, the aqueous layer was acidified with aqueous potassium ate solution and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford 2,2-difluoro(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetic acid (300 mg, 0.65 mmol, 84% yield) as a semi solid. MS (ESI) m/z 289.36 [M-1]+.
F. (2,6-Di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluoro-Z-(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetamide. To an ice cold solution of 2,2-difluoro(3-(2-(2-methoxyethoxy)ethoxy)phenyl)acetic acid (375 mg, 1.29 mmol) in pyridine (9 mL) was added phosphorus oxychloride (593 mg, 3.88 mmol) in drop wise and stirred at 0-5 0C for 1h. Then, 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (400 mg, 1.29 mmol) was added into the reaction mixture and stirred at room temperature for 2h. The reaction mixture was d with aqueous saturated sodium onate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography (50-55% acetonitrile in 0.1% aqueous formic acid) to afford N—((2-(2,6- dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)-2,2-difluoro(3 -(2-(2- methoxyethoxy)ethoxy)phenyl)acetamide (46 mg, 0.08 mol, 7% yield) as white solid. MS (ESI) m/z 546.06 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 10.99 (bs, 1H), 9.60 (t, J: 6.3 Hz, 1H), 7.67 (d, J: 7.5 Hz, 1H), 7.44 (dd, J: 8.1, 7.8 Hz, 1H), 7.40 (s, 1H), 7.37 (d, J: 7.8 Hz, 1H), 7.16 — 7.12 (m, 3H), 5.10 (dd, J: 13.2, 5.1 Hz, 1H), 4.45 (d, J: 5.7 Hz, 2H), 4.41 (d, J: 18.2 Hz, 1H), 4.27 (d, J: 17.7 Hz, 1H), 4.11 (t, J: 4.2 Hz, 2H), 3.73 (t, J: 4.5 Hz, 2H), 3.58 (t, J: 4.5 Hz, 2H), 3.45 (t, J: 5.1Hz, 2H), 3.24 (s, 3H), 2.98 — 2.83 (m, 1H), 2.67 — 2.53 (m, 1H), 2.44 — 2.30 (m, 1H), 2.05 — 1.94 (m, 1H).
Example 96 —245— 2015/039926 2-(3-(2-(Dimethylamino)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide hydrochloride . . wow \N/\/O N | HCI m 0 A. odophenoxy)-N,N-dimethylethanamine. To a stirred solution of 3-iodophenol (2g, 9.09 mmol) in acetone (20 mL) was added ro-N,N— dimethylethanamine hydrochloride (1.57 0 mmol), ium carbonate (5.07 g, 36.36 mmol) and stirred for 16h at 55 oC. The reaction e was quenched with water (50 mL) and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography (silica-gel 100-200) 100% hexane as a eluent to afford 2-(3-lodophenoxy)-N,N-dimethylethanamine (1.5 g, 5.22 mmol, 57 % yield) as brown liquid. MS (ESI) m/Z 291[M]+.
B. Ethyl 2-(3-(2-(dimethylamino)ethoxy)phenyl)-2,2-difluoroacetate. To a stirred solution of 2-(3-lodophenoxy)-N,N—dimethylethanamine (1.5 g, 5.22 mmol) in dimethyl sulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate (1.36 mL, .45 mmol) followed by copper (0.86 g, 13.58 mmol) and stirred for 16h at 50 oC.
The reaction mixture was neutralized with aqueous saturated um chloride solution and ted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with water (2 X 100 mL), brine (10 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(3-(2-(dimethylamino)ethoxy)phenyl)-2,2- difluoroacetate (1.5 g crude) as a brown liquid. MS (ESI) m/z 288.4[M]+.
C. 2-(3-(2-(Dimethylamino)ethoxy)phenyl)-2,2-difluoroacetic acid. To a cold (0 oC) stirred solution of ethyl 2-(3-(2-(dimethylamino)ethoxy)phenyl)-2,2- difluoroacetate (1.0 g, 3.48 mmol) in in methanol/ tetrahydrofuran /water (20 mL, 1:1:1) was added lithium hydroxide monohydrate (438.4 mg, 10.44 mmol) and stirred at room temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous potassium bisulphate (10 mL) and ted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2-(3-(2- (dimethylamino)ethoxy)phenyl)-2,2-difluoroacetic acid (600 mg ) as a brown semi solid which was taken to the next step t further purification.
D. 2-(3-(2-(Dimethylamin0)eth0xy)phenyl)-N-((2-(2,6-di0x0piperidin yl)0x0is0indolin-S-yl)methyl)-2,2-difluoroacetamide hloride. To a cold (0 CC) stirred solution of 2-(3-ethoxypyridinyl)-2,2-difluoroacetic acid (252 mg, 1.16 mmol) in pyridine (20 mL) was added phosphoryl chloride (446.4mg, 2.91 mmol) dropwise and d at 0-5°C for 30 min. and then added 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) and d at room temperature for 2h. The reaction mixture was neutralized with s saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The ant residue was purified by Reveleris C-18 reversed phase column chromatography using 45-50% acetonitrile in aqueous formic acid (0.1%) to afford 2-(3-(2- (dimethylamino)ethoxy)phenyl)-N-((2-(2,6-dioxopiperidin-3 -yl)— 1 -oxoisoindolin-5 - yl)methyl)-2,2-difluoroacetamide hydrochloride (50 mg, 0.07 mmol, 7.5% yield) as an off-white solid. MS (ESI) m/z 515.13 [M+11H NMR (400MHz, DMSO-d6) 5ppm .99 (s, 1H), 10.31 (br s, 1H), 9.68 (br t, J=5.9 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.43 — 7.33 (m, 3H), 7.26 — 7.13 (m, 3H), 5.11 (dd, J=4.9, 13.2 Hz, 1H), 4.50 — 4.34 (m, 4H), 4.33 — 4.23 (m, 2H), 3.00 — 2.87 (m, 1H), 2.83 — 2.70 (br s, 2H), 2.67— 2.55 (m, 1H), 2.45 — 2.25 (m, 7H), 2.05 — 1.94 (m, 1H).
Example 97 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(5- isopropylpyridin-Z-yl)acetamide A. 5-(Pr0penyl)pyridinamine. To a stirred and degassed solution of 5-bromopyridinamine (3.5 g, 20.34 mmol) in oxane.water (1 :1, 40 mL) was added potassium phosphate (12.94 g, 61.04 mmol), and continued degassing for 10min. Then, 4,4,5,5-tetramethyl(propenyl)-1,3,2-dioxaborolane (5.21 g, .51 mmol) followed by [1,1’-bis(diphenylphosphino) ferrocene] —247— dichloropalladium(II) (1.47 mg, 2.014 mmol) was added, degassed 10min with stirring and heated to 100 CC for 2h. The reaction mixture was cooled to room ature, filtered h the Celite pad. To the filtrate was added cold water and extracted with ethyl acetate (3 X 200 mL). The organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by silicagel (100-200 mesh) column chromatography using 40% of ethylacetate in petroleum ether to afford 5-(propenyl) pyridinamine (2.5 g, 18.65 mmol, 91% yield) as brown colored solid. MS (ESI) m/z 135.18 [M+1]+.
B. 5-Isopropylpyridin-Z-amine. To slurry of 20% palladium hydroxide (1 g) in ethyl acetate (50 mL) was added 5-(propenyl) pyridinamine (2.5 g, 18.65 mmol) and stirred at room temperature for 2h under hydrogen balloon (1 atrn).
The reaction mixture was filtered through Celite pad, dried over sodium sulphate and concentrated to afford the 5-isopropylpyridinamine (2 g, 14.70 mmol, 79% yield) as a brown liquid. MS (ESI) m/Z 137.15 [M+1]+.
C. 2-Br0m0is0pr0pylpyridine. To a cold (0 °C) stirred solution of -isopropylpyridinamine (2 g, 14.70 mmol ) in 47% aqueous hydrobromic acid (20 mL) was added a solution of sodium e (2.63 g, 38.23 mmol, in 5mL water) and d at the same temperature for 30min. To this reaction mixture bromine (2.27 mL, 44.1 mmol) was drop wise at -5 CC and stirred at room temperature for 4h.
The on mixture was neutralized with aqueous sodium hydroxide solution and extracted with dichloromethane (2 X 50mL). The combined organic layers were washed with saturated s sodium thiosulphate solution (100 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford 2-bromoisopropylpyridine (1.8 g, 9.04 mmol, 62% yield) as a brown colored liquid. MS (ESI) (m/z) 200.23 [M+1]+.
D. 2-Iod0is0pr0pylpyridine. To a stirred solution of 2-bromo isopropylpyridine (1.8 g, 9.04 mmol ) in acetonitrile (20 mL) was added potassium iodide (3.75 g, 22.61 mmol) and acetyl chloride (1.42 g, 18.08 mmol) at room ature and stirred at 85 CC for 16h. The reaction e was neutralized with aqueous sodium onate solution and extracted with dichloromethane (2 X 50mL).
The combined organic layers were washed with saturated aqueous sodium thiosulphate solution (100 mL) brine (50 mL) and dried over sodium sulphate and concentrated.
The ant residue was d by Silicagel (100-200 mesh) column chromatography using 5% of ethylacetate in pet.ether as eluent to afford 2-bromo isopropylpyridine (850 mg, 3.44 mmol, 39% yield). MS (ESI) (m/z) 248.24 [M+l]+.
E. Ethyl flu0r0(5-isopr0pylpyridin-Z-yl)acetate. To a stirred solution of 2-iodoisopropylpyridine (800 mg, 3.23 mmol) in dimethyl sulfoxide (15 mL) was added ethyl o-2,2-difluoroacetate (0.62 mL, 4.845 mmol) followed by copper (534 g, 8.39 mmol) and stirred for 16h at 50 oC. The reaction mixture was neutralized with aqueous saturated ammonium chloride on and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(5 -isopropylpyridinyl)acetate (650 mg, 2.67 mmol, 82 %) as a brown liquid. MS (ESI) m/z 244.28 [M+l]+.
] F. Ethyl 2,2-difluoro-Z-(5-isopr0pylpyridinyl)acetic acid. To a cold (0 CC) stirred solution of ethyl 2,2-difluoro(5-isopropylpyridinyl)acetate (600 mg, 2.46 mmol) in in methanol/ tetrahydrofuran /water mixture (9 mL, l:l : l) was added lithium hydroxide monohydrate (310 mg, 7.40 mmol) and d at room temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous potassium bisulphate (10 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(5- isopropylpyridinyl)acetic acid (450 mg, 2.09 mmol, 85 % yield) as a brown semi solid. MS (ESI) m/Z 216.30 [M-l]+.
G. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2- o-Z-(5-is0propylpyridin-Z-yl)acetamide. To a cold (0 oC) stirred solution of ethyl 2,2-difluoro(5-isopropylpyridinyl)aceticacid (333 mg, 1.54 mmol) in pyridine (10 mL) was added oryl chloride (0.4 mL, 3.87 mmol) drop wise and stirred at 0-5 °C for 30min. To this was added 3-(5-(aminomethyl)-l-oxoisoindolin yl)piperidine-2,6-dione hydrochloride (400 mg, 1.29 mmol) and stirred at room temperature for 2h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column tography using 3-4% of methanol in dichloromethane as a eluent to afford N—((2-(2,6-dioxopiperidinyl)- l oindolin-5 -yl)methyl)-2,2-difluoro(5- —249— isopropylpyridinyl)acetamide (65 mg, 0.138 mmol, 11% yield) as an off-white solid. MS (ESI) m/z 471.10 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 ppm 10.99 (s, 1 H), 9.61 (br t, J=6.05 Hz, 1 H), 8.62 (s, 1 H), 7.91 (dd, , 1.83 Hz, 1 H), 7.71 (d, J=8.07 Hz, 2 H), 7.52 (s, 1 H), 7.46 (br d, J=7.70 Hz, 1 H), 5.11 (br dd, J=13.57, .14 Hz, 1 H), 4.55 — 4.27 (m, 4 H), 3.10 — 3.00 (m, 1 H), 2.95 — 2.85 (m, 1 H), 2.75 — 2.67 — 2.54 (m, 1 H), 2.44 — 2.30 (m, 1 H), 2.07 — 1.93 (m, 1 H), 1.30 — 1.20 (m, 6 H).
Example 98 N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2-diflu0r0(3-(2- (methylsulfonyl)eth0xy)phenyl)acetamide A. (2-(3-10dophenoxy)ethyl)(methyl)sulfane. To a stirred solution of phenol (5 g, 22.72 mmol) in tetrahydrofuran (60 mL) was added diisopropyl azodicarboxylate (8.9 mL, 45.45 mmol) followed by triphenylphosphine (11.9 g, 45.45 mmol) and 2-(methylthio)ethanol (1.97 mL, 22.72 mmol) at 0 CC and stirred at room temperature for 3h. The reaction mixture was ed with ice water (50 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was purified by flash chromatography (1% ethyl acetate in pet ether) to afford (2-(3 -Iodophenoxy)ethyl)(methyl)sulfane (2.5 g, 8.503 mmol, 37% yield) as a colorless liquid. 1H NMR z, DMSO-d6) 5 (ppm) 7.33 — 7.24 (m, 1H), 7.04 — 6.95 (m, 1H), 6.90 — 6.83 (m, 1H), 4.12 (t, J=6.8 Hz, 1H), 2.87 (t, J=6.8 Hz, 1H), 2.21 (s, 1H).
B. 1-I0d0(2-(methylsulfonyl)ethoxy)benzene. To a stirred solution of (2-(3-Iodophenoxy)ethyl)(methyl)sulfane (2.5 g, 8.503 mmol) in dichloromethane (25 mL) was added m-chloroperbenzoicacid (4.4 g, 25.5 mmol) at 0 OC and stirred at room temperature for 3h. The reaction mixture was ed with aq.NaHCOg (200 mL) and extracted with dichloromethane (3 X 50 mL), washed with brine (50 mL) and dried over sodium sulphate, organic phase was concentrated. ed residue was purified by column chromatography (100-200 silica) using 5% ethyl e in hexanes to give the 1-iodo(2-(methylsulfonyl)ethoxy)benzene (1.2 g, 3.68 mmol, 43% yield) as an off white solid. MS (ESI) m/z 349.26 [M+Na]+.
C. Ethyl 2,2-difluoro-Z-(3-(2-(methylsulfonyl)ethoxy)phenyl)acetate. To a stirred solution of 1-iodo(2-(methylsulfonyl)ethoxy)benzene (1.2 g, 3.68 mmol) in dimethyl sulfoxide (12 mL) was added copper (708 mg, 11.04 mmol) and ethyl 2-iodo- 2,2-difluoroacetate (1.1 g, 4.42 mmol) at room temperature and stirred at room temperature for 16h. To the reaction mixture was added aqueous saturated um chloride (50 mL) on and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(3-(2- (methylsulfonyl)ethoxy)phenyl)acetate (720 mg, 2.23 mmol, 61% yield). MS (ESI) m/Z 345.4 [M+Na]+.
D. 2,2-Diflu0r0(3-(2-(methylsulfonyl)eth0xy)phenyl)acetic acid. To a stirred solution of ethyl fluoro(3 ethylsulfonyl)ethoxy)phenyl)acetate (720 mg, 2.23 mmol) in oxane (30 mL) was added 4M aqueous hydrochloric acid (15 mL) at room temperature and stirred at room temperature for 16h. The rwamnmmmmwweflmddvflhdbdmdfiMBX50mLwadeMflMm (50 mL) and dried over sodium sulphate, organic phase was concentrated to give the 2,2-difluoro(3-(2-(methylsulfonyl)ethoxy)phenyl)acetic acid (550 mg, 1.87 mmol, 84% yield) as an off white solid. MS (ESI) m/Z 293.21 [M+H]+.
] E. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- 0(3-(2-(methylsulf0nyl)eth0xy)phenyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(3-(2-(methylsulfonyl)ethoxy)phenyl)acetic acid (250 mg, 0.85 mmol) in pyridine (10 mL) was added phosphoryl chloride (0.2 mL, 2.55 mmol) drop wise and stirred at 0 0C for 1h and then added 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (394 mg, 1.02 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 50-55% itrile in aqueous formic acid (0.1%) to give N-((2-(2,6-dioxopiperidin-3 -yl) oxoisoindolinyl)methyl)-2,2-difluoro(3-(2- (methylsulfonyl)ethoxy)phenyl)acetamide (50 mg, 0.091 mmol, 11% yield) as a white solid. MS (ESI) m/z 549.81 [M+1]+. 1H NMR z, DMSO-d6) 8 (ppm) 10.98 (s, 1H), 9.63 (br t, J=5.9 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.52 — 7.44 (m, 1H), 7.41 — 7.34 (m, 2H), 7.23 — 7.13 (m, 3H), 5.10 (dd, J=5.1, 13.5 Hz, 1H), 4.45 (br d, J=6.4 Hz, 2H), 4.40 — 4.22 (m, 4H), 3.64 (t, J=5.4 Hz, 1H), 2.97 — 2.84 (m, 1H), 2.63 — 2.57 (m, 1H), 2.44 — 2.33 (m, 1H), 2.04 — 1.95 (m, 1H). e 99 N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0indolinyl)methyl)-2,2—diflu0r0(3-(3- (methylsulfonyl)pr0pyl)phenyl)acetamide ] A. Ethyl 2,2-diflu0r0(3-f0rmylphenyl)acetate. To a stirred solution of 3-iodobenzaldehyde (4 g, 17.24 mmol) in dimethylsulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate (5.25 g, 25.86 mmol) followed by copper powder (2.84 g, 44.82 mmol) at room temperature and stirred at 60 CC for 5h. The reaction mixture was basified with aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 40 mL). The combined organic layers were washed with water (40 mL), brine (40 mL), dried over sodium sulfate, filtered and solvent was trated and obtained crude was purified by flash column chromatography (20% ethyl acetate in pet ether) to afford ethyl 2,2-difluoro(3-formylphenyl)acetate (2.3 g, 8.27 mmol, 58%) as a ess liquid. MS (ESI) m/z 228.1 [M]+.
B. Ethyl 2,2-diflu0r0(3-Vinylphenyl)acetate. To a stirred solution of methyltriphenylphosphonium bromide (1.58 g, 4.4 mmol) in tetrahydrofuran/ diethyl ether e (30 mL, 2:1), was added n-butyl lithium (1 mL, 2.49 mmol) at -78 CC and stirred the same temperature for 30min. Then, ethyl 2,2-difluoro(3- formylphenyl)acetate (0.5 g, 2.27 mmol) was added into the reaction mixture at -78 CC and stirred at 0 0C for 3h. The reaction mixture was quenched with aqueous saturated ammonium chloride solution and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered and solvent was concentrated and obtained crude was purified by flash column chromatography (20% ethyl acetate in pet ether) to afford ethyl 2,2- difluoro(3-Vinylphenyl)acetate (0.32 g, 1.41 mmol, 64% yield) as a ess liquid. 1H NMR (400 MHz, CDC13) 5 7.63 (s, 1H), 7.53 — 7.48 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), 6.73 (dd,.]= 17.6, 10.4 Hz, 1H), 5.81 (d,J= 17.6 Hz, 1H), 5.33 (d, J = 10.8 Hz, 1H), 4.30 (q, J: 7.2 Hz, 2H), 1.31 (t, J: 7.2 Hz, 3H).
C. 3-(Methylsulf0nyl)pr0p-l-ene. To a stirred on of dWKmdMfimmam(5g5681mmd)mdempmdee60nfl)wwa¢bd hloroperoxybenzoic acid (19.65 g, 113.63 mmol) at 0 OC and stirred at room temperature for 16h. The reaction mixture was d with saturated sodium wmmmmm@MWmdmmmwbmmmMm%3Xmni)wamMmd organic layers were washed with water (40 mL), brine (40 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was purified by flash column chromatography (20% ethyl acetate in pet ether) to afford 3-(methylsulfonyl)prop ene (2.5 g, 20.83 mmol, 36% yield) as a white solid. 1H NMR (400 MHz, CDC13) 5 .98 (ddt, J: 17.2, 14.8, 7.2 Hz, 1H), 5.48 (dd, J: 17.2, 1.2 Hz, 2H), 3.74 (d, J: 7.6 Hz, 2H), 2.88 (s, 3H).
D. hyl 2,2-diflu0r0(3-(3-(methylsulf0nyl)pr0p enyl)phenyl)acetate. To a stirred solution of ethyl 2,2-difluoro(3- Vinylphenyl)acetate (100 mg, 0.44 mmol) in dichloromethane (10 mL) was added 3-(methylsulfonyl)propene (265 mg, 2.21 mmol) followed by Grubbs' II generation catalyst (19 mg, 0.02 mmol) at room temperature and refluxed at 40 CC for 16h. The volatiles were remove under reduced re and obtained residue was purified by flash column chromatography (30% ethyl acetate in pet ether) to afford (E)—ethyl 2,2- difluoro(3-(3-(methylsulfonyl)propenyl)phenyl)acetate (60 mg, 0.18 mmol, 42% yield) as a colorless . 1H NMR (300 MHZ, CDClg) 5 7.64 (s, 1H), 7.59 — 7.42 (m, 3H), 6.76 (d, J: 16.2 Hz, 1H), 6.41 — 6.31 (m, 1H), 4.31 (q, J: 6.9 Hz, 2H), 3.91 (d, J: 7.2 Hz, 2H), 2.92 (s, 3H), 1.31 (t, J: 6.9 Hz, 3H).
E. Ethyl 2,2-diflu0r0(3-(3-(methylsulfonyl)pr0pyl)phenyl)acetate.To a stirred solution of (E)-ethyl 2,2-difluoro(3-(3-(methylsulfonyl)prop enyl)phenyl)acetate (220 mg, 0.69 mmol) in ethyl acetate (10 mL) was added slurry of % palladium hydroxide (50 mg) in ethyl acetate under nitrogen stream. The on mixture was stirred under hydrogen balloon pressure at room temperature for 16h. The hydrogen atmosphere was ted and reaction mixture was filtered through a Celite pad, filtrated and concentrated obtained residue was purified by flash column chromatography (20% ethyl acetate in pet ether) to afford ethyl 2,2-difluoro(3-(3- (methylsulfonyl)propyl)phenyl)acetate (120 mg, 0.37 mmol, 54% yield) as a colorless 2015/039926 liquid. 1H NMR (300 MHz, CDClg) 5 7.48 (d, J: 7.8 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J: 7.5 Hz, 1H), 7.32 (dd, J: 8.1, 7.9 Hz, 1H), 4.31 (q, .1: 6.9 Hz, 2H), 2.99 (t, J: 7.5 Hz, 2H), 2.89 (s, 3H), 2.66 (t, J: 7.5 Hz, 2H), 2.23 — 2.15 (m, 2H), 1.32 (t, J: 6.9 Hz, 3H).
] F. 2,2-Diflu0r0(3-(3-(methylsulfonyl)pr0pyl)phenyl)acetic acid. To a stirred solution of ethyl 2,2-difiuoro(3 -(3-(methylsulfonyl)propyl)phenyl)acetate (150 mg, 0.47 mmol) in tetrahydrofuran: methanol: water mixture (10 mL, 1:1:1) was added lithium hydroxide monohydrate (59 mg, 1.41 mmol) and stirred at room temperature for 4h. The volatiles were rmoved under d pressure and the obtained crude product was dissolved in water (15 mL), washed with ethyl acetate (2 X 6 mL). The aqueous layer was acidified with 1N hydrochloride aqueous solution and extracted with ethyl acetate (3 X 8 mL). The combined organic layers were washed with brine (8 mL), dried over sodium sulfate, filtered and concentrated to afford 2,2-difiuoro(3-(3-(methylsulfonyl)propyl)phenyl)acetic acid (130 mg, 0.44 mmol, 94% yield) as semi-solid compound. 1H NMR (300 MHz, DMSO-d6) 8 7.50 — 7.41 (m, 4H), 3.32 (brs, 1H), 3.12 — 3.09 (m, 2H), 3.04 (s, 3H), 2.78 (t, J: 7.8 Hz, 2H), 2.04 — 1.96 (m, 2H).
G. N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2- difluor0(3-(3-(methylsulf0nyl)pr0pyl)phenyl)acetamide. To an ice cold solution of 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (180 mg, 0.58 mmol) and 2,2-difiuoro(3-(3-(methylsulfonyl)propyl)phenyl)acetic acid (136 mg, 0.46 mmol) in N,N-dimethylformamide (10 mL) was added N,N—diisopropylethylamine (0.3 mL, 1.74 mmol) followed by 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafiuorophosphate (442 mg, 1.16 mmol) and stirred at room temperature for 4h.
The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 X 10 mL). The combined c layers were washed with brine (10 mL), dried over sodium sulphate, filtered and concentrated. The obtained crude t was purified by ris C-18 reversed phase column (50% acetonitrile in 0.1% aqueous formic acid) to afford (2,6-dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)- 2,2-difiuoro(3-(3-(methylsulfonyl)propyl)phenyl)acetamide (40 mg, 0.07 mmol, 12% yield) as an off-white solid. MS (ESI) m/z 472.11 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.98 (s, 1H), 9.63 (t, J: 5.6 Hz, 1H), 7.68 (d, J: 7.8 Hz, 1H), —254— 7.44 - 7.36 (m, 6H), 5.10 (dd, J: 13.2, 5.1 Hz, 1H), 4.45 (d, J: 5.1 Hz, 2H), 4.42 (d, J: 17.9 Hz, 1H), 4.28 (d, J: 17.7, 1H), 3.11 (t, J: 8.1 Hz, 2H), 2.96 (s, 3H), 2.91 - 2.85 (m, 1H), 2.76 (t, J: 7.8 Hz, 2H), 2.67 — 2.55 (m, 1H), 2.45 — 2.30 (m, 1H), 2.06 — 1.92 (m, 3H).
Example 100 N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0indolinyl)methyl)-2,2—diflu0r0(4-(2- fluoropropan-Z-yl)phenyl)acetamide O O HN\/©:l Example 101 2-(1-Benzyl0x0-1,6-dihydropyridinyl)-N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-diflu0roacetamide ©/\N\ NH / 0 A. 1-Benzyli0d0pyridin-2(1H)-0ne. To a stirred solution of -iodopyridinol (5 g, 22.62 mmol) in dry methylformamide (50 mL) was added potassium carbonate (9.36 g, 67.86 mmol) followed by benzylbromide (2.95 mL, 24.88 mmol) at room temperature and stirred at 70 CC for 4h.The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and trated. The resultant residue was purified by column chromatography (100-200 silica) using 30% cetate in hexanes as elunt to afford 1-benzyliodopyridin-2(1H)-one (4.5 g, 14.46 mmol, 64% yield) as an off white solid. MS (ESI) m/Z 311.98 [M+l]+.
B. ylbenzylpyridin-2(1H)-one. To a stirred solution of l-benzyl- -iodopyridin-2(1H)—one (1.2 g, 3.858 mmol) in N,N—dimethylformamide (12 mL) was added l-(Vinyloxy)butane (1.93 g, 19.29 mmol) ed by 3M aqueous potassium carbonate (2.4 mL, 11.57 mmol), Pd(OAc)2 (400 mg, 0.192 mmol) was added followed by 1, 3-bis (diphenylphosphino) propane (477 mg, 1.157 mmol) and stirred at 80 CC for 3h. The reaction mixture was cooled to room temperature and 1N aqueous hydrochloric acid (12 mL) was added and stirred at 40 CC for 2h. The reaction mixture was cooled to room temperature and water (40 mL) was added and extracted with ethyl acetate (3 X 50 mL), washed with water (2 X 50 mL), brine (50 mL) and dried over sodium sulphate, c phase was concentrated. Obtained residue was purified by column chromatography (100-200 ) using 30% ethyl acetate in hexanes to give the 5-acetyl-l-benzylpyridin-2(1H)—one (700 mg, 3.08 mmol, 80% yield) as yellow syrup. MS (ESI) m/Z 228.24 [M+H]+.
C. Ethyl 2-(1-benzyl0x0-1,6-dihydr0pyridinyl)—2-oxoacetate. To a stirred on of 5-acetylbenzylpyridin-2(1H)-one (700 mg, 3.08 mmol) in ne (7 mL) was added selenium dioxide (855 mg, 7.709 mmol) and stirred at 100 °C for 3h. The reaction mixture was diluted with dichloromethane (14 mL) and filtered through celite pad. To the filtrate was added ethylchloroformate (2.1 mL) at 0 CC and stirred at room temperature for 16h.The reaction mixture was neutralized with 1N aqueous hloric acid (up to pH-4) and extracted with ethyl e (2 X 50 mL). The combined organic layer was washed with water (2 X 50 mL), brine (50 mL) and dried over sodium sulphate and was concentrated to give ethyl 2-(1- benzyloxo-1,6-dihydropyridinyl)—2-oxoacetate (500 mg, 1.75 mmol, 57% yield) as yellow syrup. MS (ESI) m/Z 286.12 [M+H]+.
D. Ethyl enzyl—6-0x0-1,6-dihydr0pyridinyl)—2,2- difluoroacetate. To ethyl 2-(1-benzyloxo-1,6-dihydropyridinyl)oxoacetate (500 mg, 1.75 mmol) was added l amino sulfur trifluoride (1.5 mL) at 0 OC and stirred at room ature for 16h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl e (3 X 50 mL). The combined organic layers were washed with water (2 X 25 mL), brine (25 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(1- oxo-1,6-dihydropyridinyl)-2,2-difluoroacetate (450 mg, 1.46 mmol, 84% yield). MS (ESI) m/Z 265.07 [M+1]+.
E. 2-(1-Benzyl—6-0x0-1,6-dihydr0pyridinyl)—2,2-difluoroacetic acid.
To a stirred solution of ethyl 2-(1-benzyloxo-1,6-dihydropyridinyl)-2,2- difluoroacetate (400 mg, 1.302 mmol) in tetrahydrofilran:methanol:water mixture (10 mL, 1:1:1) was added lithium hydroxide monohydrate (112 mg, 3.906 mmol) and stirred at room temperature for 2h. The reaction e was concentrated and the residue was lized with saturated potassium bisulphate (20 mL) and extracted with ethyl acetate (2 X 25 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulphate and concentrated to afford 2-(1-benzyloxo- 1,6-dihydropyridinyl)-2,2-difluoroacetic acid (350 mg, 1.254 mmol, 96% yield).
MS (ESI) m/Z 280.32 [M+1]+.
F. 2-(1-Benzyl—6-0x0-1,6-dihydr0pyridinyl)-N-((2-(2,6- dioxopiperidinyl)—1-0x0isoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a cold (0 oC) stirred solution of 2-(1-benzyloxo-1,6-dihydropyridinyl)-2,2- difluoroacetic acid (279 mg, 1.294 mmol) in pyridine (10 mL) was added phosphoryl chloride (0.36 mL, 3.894 mmol) drop wise and stirred at 0 0C for 1h and then added 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (400 mg, 1.294 mmol) and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 50-55% acetonitrile in aqueous formic acid (0.1%) to afford 2-(1-benzyloxo-1,6- dihydropyridinyl)-N-((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)- 2,2-difluoroacetamide (80 mg, 0.148 mmol, 11% yield) as an off white solid. MS (ESI) m/z 535.09 [M+1]+.1H NMR z, DMSO-d6) 8 (ppm) 10.99 (s, 1H), 9.62 (br t, J=5.9 Hz, 1H), 8.18 (br s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.56 (dd, J=2.7, 9.5 Hz, 1H), 7.44 (s, 1H), 7.40 — 7.24 (m, 6H), 5.16 (s, 1H), 5.10 (br dd, J=4.9, 13.2 Hz, 1H), 4.46 (br d, J=5.9 Hz, 1H), 4.41 (br d, J=17.6 Hz, 1H), 4.27 (br d, J=17.6 Hz, 1H), 2.97 — 2.85 (m, 1H), 2.69 — 2.56 (m, 1H), 2.43 — 2.30 (m, 1H), 2.02 — 1.98 (m, 1H).
Example 102 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(5— meth0xypyridinyl)acetamide ] A. 2-Iod0meth0xypyridine. To a stirred solution of 2-bromo methoxypyridine (2 g, 10.63 mmol) in 1,4-dioxane (20 mL) was added sodium iodide (3.3 g, 21.27 mmol), copper iodide (100 mg,0.53 mmol), trans-N,N’- dimethylcyclohexane-1,2-diamine (150 mg, 1.16 mmol) at room temperature and stirred at 110 CC for 16h in sealed tube. The reaction e was quenched with water (20 mL) and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium te and trated to afford 2-iodomethoxypyridine (1.1 g, 4.46 mmol, 47% yield) as brown liquid. GCMS (m/Z) 235.0 [M]+.
B. Ethyl 2,2-diflu0r0(5-meth0xypyridinyl)acetate. To a stirred solution of 2-iodomethoxypyridine (1 g, 4.32 mmol) in dimethyl sulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate (1.1 mL, 8.65 mmol), copper (0.73 g, 11.20 mmol) and stirred for 16h at 50 CC. The reaction mixture was neutralized with s saturated ammonium chloride solution and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro (5-methoxypyridinyl)acetate (700 mg, 3.03 mmol, 71 %) as a brown liquid. GCMS (méfl2311.
C. 2,2-Diflu0r0(5-meth0xypyridinyl)acetic acid. To a cold (0 CC) stirred solution of ethyl 2,2-difluoro(5 -methoxypyridinyl)acetate (600 mg, 2.59 mmol) in ethanol/ tetrahydrofuran /water mixture (9 mL, 1:1:1) was added lithium hydroxide monohydrate (327 mg, 7.79mmol) and d at room temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with % s ium bisulphate (10 mL) and extracted with ethyl acetate (2 X mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(5-methoxypyridin yl)acetic acid (450 mg, 2.21 mmol, 85% yield) as a brown semi solid. MS (ESI) m/z 204.23 [M+1]+.
D. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- diflu0r0(5-methoxypyridin-Z-yl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(5-methoxypyridinyl)acetic acid (300 mg, 1.47 mmol) and 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (360 mg, 1.18 mmol) in methylformamide (20 mL) was added N,N—diisopropylethylamine (0.8 mL, 2.20 mmol) followed by (dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (670 mg, 4.41 mmol) and stirred at room temperature for 16h.
The reaction mixture was diluted with water (70 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column using 57% acetonitrile in s formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoro(5-methoxypyridinyl)acetamide (58 mg, 0.12 mol, 8% yield) as an off- white solid. MS (ESI) m/z 459.20 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.99 (s, 1H), 9.61 - 9.53 (m, 1H), 8.41 (br d, J=2.9 Hz, 1H), 7.72 (dd, J=8.3, 11.2 Hz, 2H), 7.57 (dd, J=2.9, 8.8 Hz, 1H), 7.52 (s, 1H), 7.45 (br d, J=8.3 Hz, 1H), 5.11 (br dd, J=4.9, 13.2 Hz, 1H), 4.53 - 4.27 (m, 4H), 3.89 (s, 3H) 2.98 - 2.85 (m, 1H), 2.69 - 2.56 (m, 1H), 2.44 - 2.31 (m, 1H), 2.06 - 1.95 (m, 1H). e 103 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(1- methyl0x0-1,6-dihydr0pyridinyl)acetamide A. 6-Hydr0xy-N-meth0xy-N-methylnicotinamide.To a stirred solution of 6-hydroxynicotinic acid (10 g, 45.24 mmol) in ydrofuran (100 mL) was added EDC.HCl (13.01 g, 67.87 mmol), HOBT (10.39 g, 67.87 mmol), N,O-dimethyl hydroxylamine HCl (5.29 g, 67.87 mmol), N,N—diisopropylethylamine (3 l .55 mL, 180.99 mmol) sequentially and stirred at room temperature for 16h. The reaction mixture was d with water (100 mL) and extracted with ethyl acetate (3 X 500 mL). The combined organic layers were washed with brine (50 mL), dried over sodium te and trated. The resultant residue was purified by column chromatography (100-200 silica) using 5% methanol:dichloromethane to afford 6-hydroxy-N-methoxy-N-methylnicotinamide (8 g, 43.95 mmol, 96% yield). LCMS (ESI) m/Z 183.0 [M+1]+.
B. N-Methoxy-N,1-dimethyl0x0-1,6-dihydr0pyridine—3- carboxamide. To a stirred solution of 6-hydroxy-N-methoxy-N-methylnicotinamide (8 g, 43.95 mmol) in N,N-dimethylformamide was added methyl iodide (3.01 mL, 48.35 mmol), potassium carbonate (l8. 19 g, 13 l .86 mmol) at room temperature and stirred for 3h.The reaction mixture was d with water (100 mL) and extracted with ethyl acetate (3 X 500 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography (100-200 silica) using 4% methanol:dichloromethane to afford N-methoxy-N, l -dimethyloxo- l ,6- dihydropyridinecarboxamide (6 g, 30.61 mmol, 69% yield). LCMS (ESI) m/z 197.29 [M+1]+.
C. 5-Acetylmethylpyridin-2(1H)-0ne. To a stirred solution ofN- methoxy-N, l -dimethyloxo- l ,6-dihydropyridinecarboxamide (6 g, 30.61 mmol) in dry tetrahydrofuran (50 mL) was added methyl lithium 1.6 M in diethyl ether (2.67 mL), at 0 CC for 3h.The reaction e was quenched with saturated ammonium de solution and extracted with ethyl acetate (2 X 500 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and concentrated The resultant residue was purified by column chromatography (100-200 silica) using 7-10% methanol:dichloromethane to afford 5-acetyl methylpyridin-2(lH)-one (4 g, 26.49 mmol, 86% yield). MS (ESI) m/z 152.14 [M+1]+.
D. Ethyl 2-(1-methyl0x0-1,6-dihydropyridinyl)—2-0x0acetate. To a stirred solution of 5-acetylmethylpyridin-2(1H)-one (4 g, 26.49 mmol) in pyridine (50 mL) was added selenium dioxide (7.35 g, 66.22 mmol) and stirred for 16h at 100 CC. The reaction mixture was diluted with dichloromethane (50 mL) and filtered through Celite pad. To the filtrate was added ethyl chloroformate (12 mL) at 0 CC and stirred for 2h.To the resultant reaction mixture was added water (30 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and trated. The resultant residue was d by column tography 00 silica) using -20% ethyl acetate in pet ether to afford ethyl 2-(1-methyloxo-1,6- dihydropyridinyl)oxoacetate (2 g, 9.56 mmol, 36% yield). LCMS (ESI) m/z 210.29 [M+1]+.
E. Ethyl 2,2-diflu0r0(1-methyl0x0-1,6-dihydr0pyridin yl)acetate. To ethyl 2-(1-methyloxo-1,6-dihydropyridinyl)oxoacetate (2 g, 9.56 mmol) was added diethylaminosulfur trifluoride (3.2 mL, 23.92 mmol) and stirred for 12h at room temperature. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined c layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro (1-methyloxo-l,6-dihydropyridinyl)acetate (lg, 4.32 mmol, 45 %) as a liquid.
LCMS (ESI) m/Z 232.33[M+1]+.
F. 2,2-Diflu0r0(1-methyl0x0-1,6-dihydropyridinyl)acetic acid.
To a cold (0 oC) d solution of ethyl 2,2-difluoro(l-methyloxo-l,6- dihydropyridinyl)acetate (1 g, 4.32 mmol) in tetrahydrofi1ran:Methanol:water mixture (30 mL, 1:1:1) was added lithium hydroxide (0.909 g, 21.64 mmol) and d at room temperature for 6h. The on mixture was concentrated and the e was neutralized with 10% aqueous hydrochloric acid (10 mL) and ted with ethyl acetate (2 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(l-methyloxo- WO 07848 1,6-dihydropyridinyl)acetic acid (500 g, 2.46 mmol, 56% yield) as off white solid.
LCMS (ESI) m/z 204.35 [M+1]+.
G. N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2- o(1-methyloxo-1,6-dihydropyridinyl)acetamide. To a cold (0 °C) stirred solution of 2,2-difluoro(1-methyloxo-1,6-dihydropyridin-3 -yl)acetic acid (196.6 mg, 0.968 mmol) in pyridine was added phosphoryl chloride (0.27 mL, 2.906 mmol) dropwise and stirred at 0-5 0C for 1h. To this reaction e was added 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hloride (300 mg, 0.968 mmol) and stirred at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodium onate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated.
The ant residue was purified by Reveleris C-18 reversed phase Grace column chromatography using 40-60% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidin-3 -oxoisoindolin-5 -yl)methyl)-2,2-difluoro( 1 - methyloxo-1,6-dihydropyridinyl)acetamide (60 mg, 0.131 mmol, 13% yield)as an off white solid. MS (ESI) m/Z 459.16 [M+1]+. 1H NMR (300 MHZ, DMSO-d6) 5 ppm 10.98 (s, 1 H), 9.58 (br t, J=5.85 Hz, 1 H), 8.05 (s, 1 H), 7.70 (d, J=7.68 Hz, 1 H), 7.58 — 7.35 (m, 3 H), 6.49 (d, J=9.50 Hz, 1 H), 5.11 (dd, J=13.16, 5.12 Hz, 1 H), 4.5 - 4.35 (m, 3 H), 4.35 — 4.25 (d, 1H), 3.53 — 3.45 (s, 3H), 2.98 — 2.82 (m, 1 H), 2.67 — 2.52 (m, 1 H), 2.45 — 2.30 (m, 1 H), 2.05 — 1.95 (m, 1 H).
Example 104 2-(5-Tert—butylpyridin-Z-yl)—N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)—2,2-difluoroacetamide O O H N N 4%:N2H:0 A. tert—Butyl 5-bromopyridin-Z-ylcarbamate. To a cold (0 CC) stirred solution of 5-bromopyridinamine (20 g, 116.30 mmol) in dichloromethane (200 mL) was added triethylamine (34 mL, 255.87 mmol), di-tert-butyl dicarbonate (35 mL, 151.19 mmol) followed by 4-dimethylaminopyridine (1.4 g, 11.63 mmol) and stirred at room temperature for 2h. The reaction mixture was quenched with water and extracted with dichloromethane (2 X 200 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over sodium sulfate and concentrated. The resultant residue was purified by column chromatography with 5% ethyl acetate in pet ether as eluent to afford tert—butyl 5-bromopyridinylcarbamate (25.0 g, 91.91 mmol, 79% yield). LCMS (ESI) m/z 219.08 [M+1]+.
B. utyl 5-tert-butylpyridin-Z-ylcarbamate. To a cold (-78 OC) stirred solution of copper e (33 g, 367.64 mmol) in dry ydrofuran (1200 mL) was added tert—butyl magnesium chloride (2.0M in tetrahydrofuran) (362 mL, 735.29 mmol) slowly and stir for 1h. To this reaction mixture was added tert—butyl 5-bromopyridinylcarbamate (25.0 g, 91.91 mmol) at -78 CC, stirred for 2h and d to stir at room temperature for 16h. The reaction mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (3 X 200 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over sodium e and concentrated. The resultant residue was purified by column chromatography with the eluent of 10% ethyl acetate in pet ether to afford tert—butyl 5-tert—butylpyridinylcarbamate (15.0 g, 60.00 mmol, 65% .
LCMS (ESI) m/Z 251.48 [M+1]+.
C. 2-Br0mo-S-tert—butylpyridine. To a cold (0 °C) stirred solution of tert- butyl 5-tert-butylpyridinylcarbamate (13.0 g, 52.00 mmol) in aqueous hydrobromic acid (150 mL) was added sodium nitrite (9.3 g, 135.2 mmol) slowly and stir for 15min.
To this on mixture was added liquid bromine (8.0 mL, 156.00 mmol) and stirred at room temperature for 4h. The reaction mixture was quenched with aqueous sodium hydroxide solution and was extracted with ethyl acetate (3 X 150 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate and concentrated. The resultant e was purified by column chromatography with the eluent of 5% ethyl acetate in pet ether to afford 2-bromo tert-butylpyridine (3.2 g, 15.02 mmol, 29% . LCMS (ESI) m/z 214.11 [M+1]+.
D. 5-tert—Butyl—2-i0dopyridine. To a stirred solution of 2-bromotert- butylpyridine (3.2 g, 15.02 mmol) in 1,4-dioxane (10 mL) was added sodium iodide (4.5 g, 30.04 mmol), copper iodide (145 mg,0.75 mmol), trans-N,N’- dimethylcyclohexane-l,2-diamine (235 mg, 1.65 mmol) at room temperature and stirred at 100 CC for 16 h in sealed tube. The reaction mixture was quenched with water (100 mL) and extracted with ethyl e (3 X 100 mL). The combined organic 2015/039926 layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford 5-tert—butyl—2-iodopyridine (3.5 g, 13.40 mmol, 89% yield). GCMS (m/z) 261.0.
E. Ethyl 2-(5-tert-butylpyridin-Z-yl)—2,2-diflu0roacetate. To a stirred solution of 5-tert—butyl—2-iodopyridine (3.5 g, 13.40 mmol) in dimethylsulfoxide (30 mL) was added ethyl 2-bromo-2,2-difluoroacetate (5.4 g, 26.81 mmol) followed by copper (2.2 g, 34.86 mmol) and stirred at 55 0C for 5h. The reaction mixture was quenched with aqueous ammonium chloride solution and was extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford ethyl ert—butylpyridinyl)-2,2-difluoroacetate (2.8 g, 10.89 mmol, 81% yield). LCMS (ESI) m/Z 258.17 [M+1]+.
F. 2-(5-tert-Butylpyridin-Z-yl)—2,2-difluoroacetic acid. To a stirred solution of ethyl ert-butylpyridinyl)-2,2-difluoroacetate (2.8 g, 10.89 mmol) in methanol- tetrahydrofuran -water mixture (15 mL, 1:1:1) was added lithium hydroxide monohydrate (1.4 g, 32.68 mmol) and stirred at room temperature for 2h.
The reaction mixture was diluted with water (50 mL) and acidified with aqueous potassium bisulfate solution and extracted with ethyl e (3 X 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered was concentrated to afford 2-(5 -tert-butylpyridinyl)-2,2-difluoroacetic acid (2.0 g, 8.73 mmol, 80% yield). LCMS (ESI) m/Z 230.32 [M+1]+.
G. 2-(5-Tert—butylpyridin-Z-yl)—N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a cold (0 oC) stirred on of 2-(5-tert-butylpyridinyl)-2,2-difluoroacetic acid (2.0 g, 8.73 mmol (300 mg, 1.31 mmol) in pyridine (5 mL) was added phosphoryl chloride (0.4 mL, 3.87 mmol) dropwise and stirred at 0-5 0C for 1h, and then added 3-(5-(aminomethyl) oxoisoindolinyl)piperidine-2,6-dione hydrochloride (404 mg, 1.31 mmol) and stirred at room ature for 1h. The reaction mixture was lized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The ed organic layers were washed with water (2 X 30 mL), brine (30 mL) and dried over sodium sulphate and was trated to afford 2-(5 -tert- butylpyridinyl)-N-((2-(2,6-dioxopiperidinyl)oxoisoindolin-5 -yl)methyl)-2,2- difluoroacetamide (75 mg, 0.15 mmol, 12% yield) as an off white solid. LCMS (ESI) m/z 485.17 [M+1]+.1H NMR (400MHz, DMSO-d6) 8 = 10.98 (br s, 1H), 9.62 (br t, J=6.1 Hz, 1H), 8.78 (d, J=2.4 Hz, 1H), 8.02 (dd, J=2.4, 8.3 Hz, 1H), 7.71 (dd, J=2.2, 8.1 Hz, 1H), 7.52 (s, 1H), 7.46 (d, J=7.8 Hz, 1H), 5.11 (dd, J=4.9, 13.2 Hz, 1H), 4.53 - 4.28 (m, 4H), 2.99 - 2.84 (m, 1H), 2.69 - 2.55 (m, 1H), 2.45 - 2.30 (m, 1H), 2.06 - 1.94 (m, 1H), 1.35 (s, 9H).
Example 105 2-(5-Cyclopr0pylpyridinyl)—N-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)-2,2-diflu0roacetamide A. 5-Cyclopropylpyridin-Z-amine. To a stirred and degassed on of -bromopyridinamine (5 g, 28.90 mmol) in 10% water: toluene mixture (100 mL) was added cyclopropylboronic acid (3.73 g, 43.35 mmol) followed by ium phosphate (12.25 g, 57.80 mmol), tricyclohexylphosphine(794 mg, 2.89 mmol) and continued degassing for 10min. Then, palladium(II) acetate (650 mg, 2.89 mmol) was added, degassed for additional 10min and heated at 110 0C for 3h. The reaction mixture was cooled to room temperature and filtered through the Celite pad. To the filtrate was added cold water (100 mL) and extracted with ethyl acetate (3 X 100 mL).
The combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and trated to afford 5-cyclopropylpyridinamine (3.0 g, 22.39 mmol, 77% yield). GCMS (m/z) 134.1 [M]+.
B. 2-Br0mocyclopr0pylpyridine. To a cold (0 °C) stirred solution of -cyclopropylpyridinamine (3.0 g, 22.39 mmol) in 47% aqueous hydrobromic aicd (25mL) was added a solution of sodium nitrite (4.0 g, 58.21 mmol) and stirred at the same ature for 30min. To this reaction e was then added bromine (10.75 g, 67.16 mmol) and stirred at room tempareture for 2h. The reaction mixture poured into water (100 mL) and extracted with ethyl acetate (3 X 100mL). The combined organic layers were washed with brine (100 mL), dried over sodium te and concentrated. The resultant residue was purified by combi-column chromatography, using 15-20% ethyl acetate in pet ether to afford 2-bromo cyclopropylpyridine (1.2 g, 6.09 mmol, 27% yield). GCMS (m/z) 197.0 [M]+.
C. 5-Cyclopr0pyl—2-i0dopyridine. To a stirred on of 2-bromo cyclopropylpyridine (1.2 g, 6.09 mmol) in 1,4-dioxane (25 mL) was added sodium iodide (1.83 g, 12.18 mmol), copper iodide (58 mg, 0.30 mmol), trans-N,N’- dimethylcyclohexane-l,2-diamine (95 mg, 0.67 mmol) at room temperature and stirred at 110 CC for 16h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium te and concentrated to afford 5-cyclopropyliodopyridine (1.2 g, 4.90 mmol, 81%). GCMS (m/Z) M]+.
] D. Ethyl 2-(5-cyclopr0pylpyridinyl)—2,2-diflu0r0acetate. To a stirred solution of 5-cyclopropyliodopyridine (1.2 g, 4.90 mmol) in dimethyl sulfoxide (12 mL) was added copper (809 mg, 12.73 mmol) and ethyl 2-bromo-2,2- mflumbamfime(148g,735nnnoDeuromntmnpmauneandsfinedat55°Clbr2h.To the reaction mixture was added aqueous saturated ammonium chloride (50 mL) solution and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and concentrated to afford ethyl 2-(5-cyclopropylpyridinyl)-2,2-difluoroacetate (1.0 g, 4.15 mmol, 85%). 1H NMR (400MHz, CDC13)5 8.44 (br s, 1H), 7.61(br s, 1HL743(¢J=80fh,HD,442—430@m2HL204—191Gm1HL140—1240n 3H), 1.12 — 1.09 (m, 2H), 0.84 — 0.77 (m, 2H).
E. 2-(5-Cyclopr0pylpyridinyl)—2,2-difluoroacetic acid. To a stirred solution of ethyl 2-(5-cyclopropylpyridinyl)-2,2-difluoroacetate (1.0 g, 4.15 mmol) in tetrahydrofuran:methanol:water mixture (30 mL, 1:1:1) was added lithium hydroxide drate (523 mg, 12.45 mmol) and stirred at room temperature for 4h.
The reaction mixture was trated and the residue was neutralized with saturated ium bisulphate (25 mL) and extracted with ethyl acetate (2 X 50mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and concentrated to afford 2-(5 -cyclopropylpyridinyl)-2,2-difluoroacetic acid (500 mg, 2.35 mmol, 50% yield). MS (ESI) m/z 214.3 Ve.
F. 2-(5-Cyclopr0pylpyridinyl)—N-((2-(2,6-di0x0piperidinyl) oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a cold (0 oC) stirred solution of 2-(5-cyclopropylpyridinyl)-2,2-difluoroacetic acid (300 mg, 1.41 mmol) in pyridine (20 mL) was added phosphoryl chloride (646 mg, 4.22 mmol) dropwise and stirred at 0-5 0C for 30min. To this on mixture was then added 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (435 mg, 1.41 mmol) and stirred at room ature for 1h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (2 X 100 mL). The combined c layers were washed with water (100 mL), brine (100 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 60-65% acetonitrile in aqueous formic acid (0.1%) to afford 2-(5-cyclopropylpyridin- 2-yl)-N-((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)-2,2- difluoroacetamide (140 mg, 0.30 mmol, 21% yield) as an off-white solid. MS (ESI) m/Z 469.06 [M+1]+. 1H NMR z, DMSO-d6) 5 10.99 (s, 1H), 9.58 (t, J=6.1 Hz, 1H), 8.53 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.66 - 7.60 (m, 2H), 7.51 (s, 1H), 7.46 (d, J=8.3 Hz, 1H), 5.11 (dd, J=4.9, 13.2 Hz, 1H), 4.56 - 4.28 (m, 4H), 3.08 - 2.85 (m, 1H), 2.67 - 2.56 (m, 1H), 2.45 - 2.32 (m, 1H), 2.10 - 1.96 (m, 2H), 1.13 - 1.03 (m, 2H), 0.89 - 0.79 (m, 2H).
Example 106 (2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(5— isoprop0xypyridin-Z-yl)acetamide AownmN%L—fo A. 2-Br0m0isopropoxypyridine. To a stirred on of 6-bromopyridinol (2 g, 11.49 mmol) in N,N—dimethylformamide (20 mL) was added 2-iodopropane (1.4 mL, 13.79 mmol), potassium carbonate (4.7 g, 34.47 mmol) and stirred at 80 CC for 6h. The reaction mixture was quenched with water and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 20 mL), brine (20 mL), dried over sodium sulphate and concentrated to afford 2-bromoisopropoxypyridine (1.4 g, 6.48 mmol, 58 %) as a pale yellow solid. MS (ESI) m/z 216.20 B. 2-Iod0is0propoxypyridine. To a stirred solution of 2-bromo isopropoxypyridine (1.4 g, 6.48 mmol) in 1,4-dioxane (30 mL) in a sealed tube, was added sodium iodide (1.9 g, 12.96 mmol), copper iodide (61 2 mmol), trans-N,N’-dimethylcyclohexane-1,2-diamine (101 mg, 0.71 mmol) at room temperature and stirred at 110 CC for 16h. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 X 30 mL). The combined organic layers were washed with water (2 X 20 mL), brine (20 mL), dried over sodium sulphate and concentrated to afford 2-iodoisopropoxypyridine (1 g, 3.83 mmol, 58% yield) as brown solid. GCMS (m/z) 263.0.
C. Ethyl 2,2-diflu0r0(5-is0prop0xypyridinyl)acetate. To a stirred solution of 2-iodoisopropoxypyridine (1 g, 3.80 mmol) in dimethyl sulfoxide (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate (1 mL, 7.60 mmol), copper (0.6 g, 10.09 mmol) and d for 16h at 50 oC. The reaction mixture was neutralized with aqueous ted ammonium chloride solution and extracted with ethyl acetate (3 X 40 mL). The combined organic layers were washed with water (2 X 20 mL), brine (20 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2- difluoro(5-isopropoxypyridinyl)acetate (500 mg, 2.30 mmol, 60 %) as a brown liquid. MS (m/z) 259.1.
D. 2,2-Diflu0r0(5-isopr0p0xypyridinyl)acetic acid. To a cold (0 CC) stirred solution of 2,2-difluoro(5 -isopropoxypyridinyl)acetate (500 mg, 2.32 mmol) in methanol/ tetrahydrofuran /water e (9 mL, 1:1:1) was added lithium ide monohydrate (280 mg, 6.91mmol) and d at room temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with % aqueous ium bisulphate (10 mL) and extracted with ethyl acetate (2 X mL). The ed organic layers were washed with brine (10 mL), dried over sodium sulphate, concentrated to afford 2,2-difluoro(5-isopropoxypyridin yl)acetic acid (350 mg, 1.51 mmol, 79 % yield) as a brown semi solid. MS (ESI) m/z 232.24 E. N-((2-(2,6-Di0x0piperidinyl)—1-0xois0ind01inyl)methyl)-2,2— difluoro-Z-(5-is0prop0xypyridinyl)acetamide. To a cold (0 oC) stirred solution of 3 -(6-((methylamino)methyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (400 mg, 1.29 mmol) and 2,2-difluoro(5-isopropoxypyridinyl)acetic acid (300 mg, 1.29 mmol) in methylformamide (20 mL) was added N,N—diisopropylethylamine (0.7 mL, 3.86 mmol) followed by 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (735 mg, 1.93 mmol) and stirred at room temperature for 16h.
The reaction mixture was diluted with water (70 mL) and extracted with ethyl acetate (2 X 40 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by ris C-18 reversed phase column using 58% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoro(5-isopropoxy pyridinyl)acetamide (70 mg, 0.14 mmol, 11% yield) as an offwhite solid. MS (ESI) m/z 487.20 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 10.99 (s, 1H), 9.55 (br t, J=6.1 Hz, 1H), 8.36 (d, J=2.6 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.60 - 7.50 (m, 2H), 7.45 (d, J=8.1 Hz, 1H), 5.11 (dd, J=4.8, 13.2 Hz, 1H), 4.80 - 4.75 (m, 1H), 4.65 - 4.26 (m, 4H), 3.02 - 2.83 (m, 1H), 2.75 - 2.54 (m, 1H), 2.46 - 2.305 (m, 1H), 2.06 - 1.94 (m, 1H), 1.31 (m, 6H).
Example 107 2-(5-Br0mopyridin-Z-yl)—N-((2-(2,6-di0x0piperidinyl)0x0isoindolin yl)methyl)—2,2-difluoroacetamide ] A. Ethyl 2-(5-br0m0pyridinyl)—2,2-diflu0r0acetate. To a stirred solution of 5-bromoiodopyridine (3 g, 10.56 mmol) in dimethylsulfoxide (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate (3.13 g, 15.84 mmol) followed by copper powder (1.74 g, 27.46 mmol) at room temperature and stirred at 55 CC for 6h. The reaction mixture was basified with aqueous saturated sodium bicarbonate solution and extracted with ethyl e (3 X 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated. The obtained crude was purified by silica gel column chromatography (20% ethyl acetate in pet ether) to afford ethyl 2-(5 -bromopyridinyl)-2,2-difluoroacetate (1.5 g, .35 mmol, 60%) as a colorless liquid. MS (ESI) m/z 280.2 [M+1]+.
B. 2-(5-Br0m0pyridinyl)—2,2-difluoroacetic acid. To a stirred on of ethyl romopyridinyl)-2,2-difluoroacetate (1.5 g, 5.37 mmol) in mixture of tetrahydrofuran: methanol:water (15 mL, 1:1:1) was added lithium hydroxide monohydrate (677 mg, 16.13 mmol) and stirred at room temperature for 4h. The volatiles were removed under reduced pressure and the resultant crude product was dissolved in water (15 mL), washed with ethyl acetate (2 X 10 mL). s layer was ied with 1N hydrochloride aqueous solution and extracted with ethyl acetate (3 X 15 mL). The combined c layers were washed with brine (15 mL), dried over sodium sulfate and concentrated to afford 2-(5-bromopyridinyl)-2,2- difluoroacetic acid (900 mg, 3.57 mmol, 69% yield) as semi-solid compound. MS (ESI) m/Z 252.2 [M+H]+' C. 2-(5-Br0m0pyridinyl)—N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a cold solution of 2-(5- bromopyridinyl)-2,2-difluoroacetic acid (243 mg, 0.97 mmol) in pyridine (6 mL) was added phosphorus oxychloride (1.8 mL, 2.9 mmol) in drop wise and stirred at 0-5 CC for 1h. Then, 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) was added and stirred at room temperature for 2h.
The reaction mixture was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium e, filtered and trated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography (50-55% acetonitrile in 0.1% s formic acid (to afford 2-(5 -bromopyridinyl)-N-((2-(2,6-dioxopiperidin-3 -oxoisoindolin-5 - yl)methyl)-2,2-difluoroacetamide (33 mg, 0.065 mmol, 7% yield) as white solid. MS (ESI) m/z 507.8 [M+1]+. 1H NMR (400 MHz, DMSO-d6) 8 10.99 (s, 1H), 9.68 (t, J: 4.5 Hz, 1H), 8.89 (d, J: 1.6 Hz, 1H), 8.31 (dd, J: 8.4, 2.4 Hz, 1H), 7.78 (d, J: 8.4 Hz, 1H), 7.72 (d, J: 8.0 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J: 8.0 Hz, 1H), 5.11 (dd, J: 13.2, 5.2 Hz, 1H), 4.50 (d, J: 6.4 Hz, 2H), 4.46 (d, J: 17.9 Hz, 1H), 4.32 (d, J: 17.6 Hz, 1H), 2.95 — 2.87 (m, 1H), 2.66 — 2.55 (m, 1H), 2.45 — 2.30 (m, 1H), 2.05 — 1.96 (m, 1H).
Example 108 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(4- fluor0(triflu0r0methoxy)phenyl)acetamide A. (2-Flu0r0(triflu0r0meth0xy)phenyl)trimethylsilane. To a cold(- 78 oC) stirred solution of 1-fluoro(trifluoromethoxy)benzene (2.0 g, 11.11 mmol) and TMEDA (1.3 mL, 11.11 mmol) in dry tetrahydrofuran (20 mL) was added sec-butyl lithium (1.4M in cyclohexane, 8 mL) and stirred for 2h. To this reaction mixture was added hylsilyl chloride (1.81 g, 16.66 mmol) at -78 °C and stirred for 1h at room temperature. The reaction e was quenched with aqueous ammonium chloride solution and extracted with diethylether (2 X 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium e and concentrated to afford (2-fluoro (trifluoromethoxy)phenyl)trimethylsilane (1.8 g, 7.14 mmol, 64% yield). 1H NMR (400MHz, CDClg) 5 (ppm) 7.35 (dt, J=6.6, 8.2 Hz, 1H), 7.05 — 7.00 (m, 1H), 6.92 (t, JE8313L11D,041—033(HL9H) B. (6-Flu0r0i0d0(triflu0r0meth0xy)phenyl)trimethylsilane. To a cold (-78 oC) stirred solution of 2,2,6,6-tetramethylpiperidine (897 mg, 6.34 mmol) in dry tetrahydrofuran (20 mL) was added n-butyl lithium (2.5M in n-hexane, 2.5 mL, 6.34 mmol) slowly, followed by (2-fluoro(trifluoromethoxy)phenyl)trimethylsilane (1.6 g, 6.34 mmol) in ydrofuran (5 mL) and stirred for 2h at same temperature.
Iodine (2.4 g, 9.52 mmol) in dry tetrahydrofuran (10 mL) was added to this reaction mn78°Candaflwmdtosfirat0°Clbr1h.Therawfionnnxunewmsqumnmed with aqueous ammonium chloride solution and extracted with diethyl ether (2 X 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate and trated to afford (6-fluoro-3 -iodo (trifluoromethoxy)phenyl)trimethylsilane (2.0 g, 5.29 mmol, 84% yield). GCMS (m/Z) 3781.
C. Ethyl 2,2-diflu0r0(4-flu0r0(trifluoromethoxy)phenyl)acetate.
To a stirred solution of (6-fluoroiodo(trifluoromethoxy)phenyl)trimethylsilane (20g529mmd)mdmmmflsMfimMeGOnflJmswhdumewwammddMAl bromo-2,2-difluoroacetate (2.1 g, 10.58 mmol) followed by copper (874 mg, 13.76 mmol) and stirred at 55 CC for 16h. The reaction mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (3 X 100 mL).
The combined organic layers were washed with water (100 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford ethyl 2,2-difluoro(4-fluoro- 2-(trifluoromethoxy)phenyl)acetate (1.5 g, 4.96 mmol, 94% yield). GCMS (m/Z) 3021.
D. 2,2-Diflu0r0(4-flu0r0(triflu0r0meth0xy)phenyl)acetic acid. To a d solution of ethyl 2,2-difluoro(4-fluoro(trifluoromethoxy)phenyl)acetate (1.5 g, 4.96 mmol) in methanol: ydrofilran:water mixture (15 mL, 1:1:1) was added lithium hydroxide monohydrate (1.4 g, 14.90 mmol) and stirred at room ature for 2h. The reaction mixture was diluted with water (50 mL), ed with aqueous potassium bisulfate solution and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered was concentrated to afford 2,2-difluoro(4-fluoro (trifluoromethoxy)phenyl)acetic acid (1.0 g, 3.64 mmol, 73% yield). LCMS (ESI) m/Z 273.26 [M-1]'.
E. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- 0(4-fluor0(trifluor0meth0xy)phenyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(4-fluoro(trifluoromethoxy)phenyl)acetic acid (300 mg, 1.09 mmol) in pyridine (5 mL) was added phosphoryl chloride (0.3 mL, 3.28 mmol) dropwise and stirred at 0-5 0C for 1h. 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione hydrochloride (338 mg, 1.09 mmol) was added to this reaction mixture and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl e (3 X 50 mL). The ed organic layers were washed with water (2 X mL), brine (30 mL) and dried over sodium sulphate and was concentrated to afford N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)-2,2-difluoro(4- fluoro(trifluoromethoxy)phenyl)acetamide(37 mg, 0.06 mol, 6% yield) as an off white solid. LCMS (ESI) m/z 530.07 [M+1]+. 1H NMR (300MHz, DMSO-d6) 8 (ppm) .98 (s, 1H), 9.78 (br t, J=5.9 Hz, 1H), 7.82 (t, J=8.6 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.63 (br d, J=11.4 Hz, 1H), 7.51 — 7.38 (m, 3H), 5.11 (br dd, J=5.1, 13.2 Hz, 1H), 4.56 — 4.40 (m, 3H), 4.31 (d, J=17.6 Hz, 1H), 3.00 — 2.83 (m, 1H), 2.66 — 2.54 (m, 1H), 2.44 — 2.30 (m, 1H), 2.08 — 1.93 (m, 1H).
Example 109 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(4— fluor0cyclohexyl)acetamide A. 8-Flu0r0-1,4-di0xaspir0[4.5]dec—7—ene. To a stirred solution of 1,4-dioxaspiro[4.5]decanone (12 g, 76.92 mmol) in pyridine (120 mL) was added diethylamino sulfur trifiuoride (37 g, 230 mmol) at 0 CC and stirred at room temperature for 48h. The on mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated. Obtained crude was purified by column chromatography (100- 200 silica gel, 10% ethyl acetate in pet ether) to afford o-1,4- dioxaspiro[4.5]decene (6.5 g, 41 mmol, 54% yield) as a colourless liquid. MS (ESI) m/Z 158.1 [M]+.
B. 8-Flu0r0-1,4-di0xaspir0[4.5]decane. To a stirred solution of 8-fluoro- oxaspiro[4.5]decene (l g, 3.53 mmol) in ethyl acetate (15 mL) was added a slurry of 10% palladium on charcoal (200 mg) in ethyl acetate under en stream.
The reaction mixture was stirred at room ature for 4h under hydrogen atmosphere. The hydrogen atmosphere was evacuated and the reaction mixture was filtered through a Celite pad, filtrate was concentrated to afford to afford 8-fluoro-1,4- dioxaspiro[4.5]decane (500 mg, 1.3 mmol, 37% yield) as a colorless liquid. MS (ESI) m/Z 160.1 [M]+.
C. 4-Flu0r0cyclohexan0ne. To a d solution of 8-fluoro-l,4- piro[4.5]decane (3.5 g, 21.87 mmol) in tetrahydrofuran (20 mL) was added mL of 4N aqueous hydrochloric acid at 0 CC and stirred at room temperature for 6h.
The reaction mixture was diluted with water (10 mL) and basified with aqueous sodium bicarbonate on and extracted with ethyl e (3 X 30 mL). The ed organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulfate and concentrated to afford ocyclohexanone (1.2 g, 10.34 mmol, 48% yield) as a colorless liquid. MS (ESI) m/z 116.1 [M]+ D. Ethyl 2,2-diflu0r0(4-flu0r0hydr0xycyclohexyl)acetate. To a stirred solution of 4-fiuorocyclohexanone (1.6 g, 13.7 mmol) in tetrahydrofuran (20 mL) was added cerium(III) chloride heptahydrate (340 mg 1.37 mmol) followed by zinc (1.07 g, 16.55 mmol) and ethyl 2-bromo-2,2-difiuoroacetate (3.35 g, 16.55 mmol) at 0 CC and stirred at room temperature for 16h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude t was purified by flash chromatography (30% ethyl acetate in pet ether) to afford ethyl 2,2-difluoro(4- fluorohydroxycyclohexyl)acetate (1.1 g, 4.58 mmol, 34% yield) as a colorless liquid. 1H NMR (300 MHz, DMSO-d6) 8 5.60 (s, 1H), 4.83 (dt, J: 49.2, 2.7 Hz, 1H), 4.29 (q, J: 7.2 Hz, 2H), 1.82 — 1.64 (m, 8H), 1.26 (t, J: 7.0 Hz, 3H).
E. Ethyl 2,2-diflu0r0(4-flu0r0cyclohexenyl)acetate. To a stirred solution of ethyl 2,2-difluoro(4-fluorohydroxycyclohexyl)acetate (0.75 g, 3.12 mmol) in pyridine (22.6 mL) was added thionyl de (3.72 g, 31.25 mmol) at 0 CC and stirred at room temperature for 16h. The reaction mixture was diluted with water (10 mL), basified with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was purified by silica gel column tography (5% ethyl acetate in pet ether) to afford ethyl 2,2-difluoro(4-fluorocyclohexenyl)acetate (0.3 g, 1.35 mmol, 43% yield) as a ess liquid. MS (ESI) m/z 221.9 [M]+.
F. Ethyl 2,2-diflu0r0(4-flu0r0cyclohexyl)acetate. To a stirred solution of ethyl 2,2-difluoro(4-fluorocyclohexenyl)acetate (200 mg, 0.9 mmol) in ethyl acetate (10 mL) was added a slurry of 10% platinum oxide (20 mg) in ethyl acetate under nitrogen stream. The reaction mixture was stirred under 60 psi hydrogen re at room temperature for 16h. The hydrogen atmosphere was evacuated and reaction e was ed through a Celite pad, filtrated and concentrated to afford ethyl 2,2-difluoro(4-fluorocyclohexyl)acetate (100 mg, 0.44 mmol, 50% yield) as a colourless liquid. 1H NMR (300 MHz, CDClg) 8 4.83 (dt, J: 49.2, 2.7 Hz, 1H), 4.34 (q, J: 7.2 Hz, 2H), 2.16 — 1.98 (m, 4H), 1.70 — 1.57 (m, 4H), 1.51 — 1.41 (m, 1H), 1.26 (t, J: 6.6 Hz, 3H).
G. 2,2-Diflu0r0(4-flu0r0cyclohexyl)acetic acid. To a stirred solution of ethyl 2,2-difluoro(4-fluorocyclohexyl)acetate (100 mg, 0.446 mmol) in mixture of tetrahydrofuran: methanol: water (6 mL, 1:1:1) was added lithium hydroxide monohydrate (56 mg, 1.34 mmol) and d at room temperature for 4h. The volatiles were removed under reduced pressure and the obtained crude was dissolved in water (5 mL), washed with ethyl acetate (2 X 5 mL). Aqueous layer was ied with 1N hydrochloride aqueous solution and extracted with ethyl acetate (3 X 5 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, —274— filtered and concentrated to afford fluoro(4-fluorocyclohexyl)acetic acid (50 mg, 0.255 mmol, 59% yield) as semi-solid compound. 1H NMR (300 MHz, CDC13)5 4.82 (dt, J: 42.2, 6.6 Hz, 1H), 2.18 — 1.20 (m, 10H).
H. N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2- diflu0r0(4-fluor0cyclohexyl)acetamide. To an ice cold solution of 2,2-difluoro (4-fluorocyclohexyl)acetic acid (190 mg, 0.97 mmol) in pyridine (9 mL) was added phosphorus oxychloride (445 mg, 2.91 mmol) drop wise and stirred at 0-5 0C for 1h.
Then, 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride was added into the reaction mixture and stirred at room temperature for 2h. The reaction mixture was basified with s saturated sodium bicarbonate and ted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium e, filtered and concentrated. The resultant residue was purified by ris C-18 reversed phase column chromatography (50-55% acetonitrile in 0.1% aqueous formic acid) to afford N—((2-(2,6- dioxopiperidin-3 -yl)oxoisoindolin-5 thyl)-2,2-difluoro(4- fluorocyclohexyl)acetamide (33 mg, 0.073 mmol, 7% yield) as white solid. MS (ESI) m/z 452.15 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 10.98 (s, 1H), 9.56 (t, J: 5.6 Hz, 1H), 7.70 (d,.]= 8.1 Hz, 1H), 7.47 (s, 1H), 7.41 (d,.]= 8.1 Hz, 1H), 5.11 (dd, J: 13.2, 5.4 Hz, 1H), 4.84 (d, J: 48.6 Hz, 1H), 4.45 (d, J: 17.1 Hz, 1H), 4.44 (d, J: 6.3 Hz, 2H), 4.31 (d, J: 17.4 Hz, 1H), 2.96 — 2.72 (m, 1H), 2.62 — 2.51 (m, 1H), 2.40 — 2.21 (m, 2H), 2.07 — 1.90 (m, 4H), 1.62 — 1.41 (m, 6H).
Example 110 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(4- (methylsulfonyl)phenyl)acetamide A. 1-Iod0(methylsulfonyl)benzene. To a stirred on of 1-bromo (methylsulfonyl)benzene (2 g, 8.506 mmol) in 1,4-dioxane (15 mL) was added sodium iodide (2.55 g, 17.01 mmol), copper iodide (80 mg,0.42 mmol), trans-N,N’- dimethylcyclohexane-1,2-diamine (133 mg, 0.93 mmol) at room temperature and stirred at 110 CC for 16h in sealtube. The reaction mixture was quenched with water WO 07848 (50 mL) and extracted with ethyl acetate (3 X 200 mL). The combined organic layers waewwkflwfihwfimf2X50mL)mmeGOmLLmmdowrwmmnmmmMemm concentrated to afford 1-iodo-3 -(methylsulfonyl)benzene (1.8 g, 6.38 mmol, 75% yield) as a brown solid. LCMS (ESI) m/Z 283.16 [M+H]+.
B. Ethyl 2,2-diflu0r0(4-(methylsulf0nyl)phenyl)acetate. To a stirred solution of 1-iodo(methylsulfonyl)benzene (500 mg, 1.77 mmol) in dimethyl sulfoxide (5 mL) was added ethyl 2-iodo-2,2-difluoroacetate (0.32 mL, 2.313mmol), copper (107 mg, 1.68 mmol) and stirred for 16h at room temperature. The reaction mixture was neutralized with aqueous saturated ammonium de solution and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed whhwfimf2X50nflmbnne60nflo¢hmd0VflsomumsumhMemmcmmmnmmd The ant residue was purified by silica-gel 00 mesh, 20% ethyl acetate in hexanes) to afford to afford ethyl 2,2-difluoro(4-(methylsulfonyl)phenyl)acetate (250 mg, 0.899 mmol, 50 %) as an off-white solid. MS (ESI) m/z 279.26 [M+1]+.
C. 2,2-Diflu0r0(4-(methylsulf0nyl)phenyl)acetic acid. To a cold (0 CC) stirred solution of ethyl 2,2-difluoro(4-(methylsulfonyl)phenyl)acetate (250 mg, 0.899 mmol) in in methanol/ tetrahydrofuran /water (6 mL, 1:1:1) was added lithium hydroxide monohydrate (75 mg, 0.798 mmol) and stirred at room temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with % aqueous potassium bisulphate (10 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium te and concentrated to afford 2,2-difluoro(4- (methylsulfonyl)phenyl)acetic acid (180 mg, 0.72 mmol, 80 % yield) as a gummy solid. MS (ESI) m/Z 249.26 [M—lr.
D. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- difluor0(4-(methylsulf0nyl)phenyl)acetamide. To a cold (0 oC) stirred solution of 2 2,2-difluoro(4-(methylsulfonyl)phenyl)acetic acid (194 mg, 0.776 mmol) in pyridine (10 mL) was added oryl chloride (0.18 mL, 1.94 mmol) drop wise and stirred at 0-5 CC for 30min.To this, 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione hydrochloride (200 mg, 0.64 mmol) was added and stirred at room temperature for 2h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The ed organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by grace column chromatography using 52% ACN in 0.1% aqueous formic acid solution as a eluent to afford (2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoro(4-(methylsulfonyl)phenyl)acetamide (70 mg, 0.138 mmol, 21% yield) as an off-white solid. MS (ESI) m/Z 506.06 [M+1]+. 1H NMR (400MHz, DMSO-d6) 5 .98 (s, 1H), 9.78 (br t, J=6.1 Hz, 1H), 8.11 (d, J=8.3 Hz, 2H), 7.88 (d, J=8.3 Hz, 2H), 7.69 (d, J=7.8 Hz, 1H), 7.42 — 7.34 (m, 2H), 5.10 (dd, J=4.9, 13.2 Hz, 1H), 4.53— 4.37 (m, 3H), 4.28 (d, J=17.2 Hz, 1H), 3.29 (s, 3H), 2.98 — 2.87 (m, 1H), 2.68 — 2.55 (m, 1H), 2.46 — 2.31 (m, 1H), 2.06 — 1.94 (m, 1H).
Example 111 N-((2-(2,6-di0x0piperidinyl)—1-0x0is0indolin-S-yl)methyl)-2,2-diflu0r0(3- (methylsulfonyl)phenyl)acetamide A. 1-Iod0(methylsulfonyl)benzene. To a stirred solution of 1-bromo (methylsulfonyl)benzene (1 g, 4.25 mmol) in 1,4-dioxane (15 mL) was added sodium iodide (1.92 g, 12.76 mmol), copper iodide (81 25 mmol), trans-N,N’- dimethylcyclohexane-l,2-diamine (90 mg, 0.63 mmol) at room temperature and stirred at 110 CC for 16h in sealtube. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 X 200 mL). The combined organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford 1-iodo-3 -(methylsulfonyl)benzene (900 g, 3.19 mmol, 75% yield) as a brown solid. LCMS (ESI) m/Z 282.85 .
B. Ethyl 2,2-diflu0r0(3-(methylsulf0nyl)phenyl)acetate. To a stirred solution of 1-Iodo(methylsulfonyl)benzene (900 mg, 3.19 mmol) in dimethylsulfoxide (15 mL) was added ethyl 2-iodo-2,2-difluoroacetate (0.56 mL, 4.147 mmol), copper (527 mg, 8.29 mmol) and stirred for 16h at room temperature.
The reaction mixture was neutralized with s saturated ammonium chloride solution and extracted with ethyl acetate (2 X 100 mL). The ed organic layers were washed with water (2 X 50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant e was purified by silica-gel (100-200 mesh, 12% ethyl acetate in hexane) to afford ethyl 2,2-difluoro(3- (methylsulfonyl)phenyl)acetate (850 mg, 3.05 mmol, 95 %) as an off-white solid. MS (ESI) m/Z 320.32 [M+1]+ (ACN (+41) adduct) C. 2,2-Diflu0r0(3-(methylsulf0nyl)phenyl)acetic acid. To a cold (0 CC) stirred solution of ethyl 2,2-difluoro(3-(methylsulfonyl)phenyl)acetate (800 mg, 2.87 mmol) in in methanol/ tetrahydrofuran /water (10 mL, 1:1:1) was added lithium hydroxide monohydrate (361 mg, 8.61 mmol) and stirred at room ature for 2h. The reaction mixture was concentrated and the residue was neutralized with % aqueous potassium bisulphate (20 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and concentrated to afford fluoro(3- (methylsulfonyl)phenyl)acetic acid (650 mg, 1.74 mmol, 70 % yield) as an gummy solid. MS (ESI) m/Z 251.07 [M+1]+.
D. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- 0(3-(methylsulf0nyl)phenyl)acetamide. To a cold (0 oC) stirred solution of 2 2,2-difluoro(3-(methylsulfonyl)phenyl)acetic acid (291 mg, 1.16 mmol) in ne (10 mL) was added phosphoryl chloride (0.27 mL, 2.91 mmol) dropwise and stirred at 0-5 CC for 30min. To this reaction mixture was then added 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.97 mmol) and d at room temperature for 2h. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and ted with wwmwmmGX5MMJTmamMmdmgmdwmmwmw%MdmmwmflQX 50 mL), brine (50 mL), dried over sodium te and concentrated. The resultant residue was purified by grace column chromatography using 52% ofACN-0. 1% formic acid in water as a eluent to afford N-((2-(2,6-dioxopiperidinyl) oxoisoindolinyl)methyl)-2,2-difluoro(3-(methylsulfonyl)phenyl)acetamide (72 mg, 0.142 mmol, 15% yield) as an off-white solid. MS (ESI) m/Z 506.01 [M+l]+. 1H NMR (300 MHz, DMSO-d6) 5 ppm 10.98 (s, 1 H) 9.80 (br t, J=5.85 Hz, 1 H), 812——8090n,2fD,796@LJ=84}h,1fD,790—¥I800n,1fD,7670LJ=768HZ, 1 H), 7.41 (s, 1 H), 7.36 (d, J=7.8 Hz, 1 H), 5.10 (dd, J=13.16, 5.12 Hz, 1 H), 4.54 - 4.20 (m, 4 H), 3.30 (d, J=8.04 Hz, 3 H), 3.01 - 2.79 (m, 1 H), 2.67 — 2.55 (m, 1 H), 2.47 — 2.30 (m, 1 H), 2.06 — 1.92 (m, 1 H).
ExanqflellZ 2-(2-Aminopyrimidinyl)—N-((2-(2,6-di0x0piperidinyl)-l-oxoisoindolin-S- yl)methyl)-2,2-difluoroacetamide O O WN 0 A. Ethyl 2-(2-amin0pyrimidinyl)—2,2-diflu0r0acetate. To a stirred on of 5-iodopyrimidinamine (1 g, 4.52 mmol) in dimethylsulfoxide (20 mL) was reacted with ethyl 2-bromo-2,2-difluoroacetate (1.1 mL, 9.04 mmol), copper (0.75 g, 11.76 mmol) and stirred for 16h at 50 oC. The reaction mixture was neutralized with aqueous saturated ammonium de solution and extracted with ethyl acetate (3 X 50 mL). The combined organic layer was washed with water (2 X mL), brine (10 mL) and dried over sodium sulphate and was concentrated to give ethyl minopyrimidinyl)—2,2-difluoroacetate (600 mg, 2.76 mmol, 61 %) as a brown liquid. GCMS (m/z) 217.1.
B. 2-(2-Amin0pyrimidinyl)—2,2-diflu0roacetic acid. To a cold (0 oC) stirred solution of ethyl 2-(2-aminopyrimidinyl)—2,2-difluoroacetate (500 mg, 2.30 mmol) in in ethanol/ tetrahydrofuran /water (12 mL, 1:1:1) was added lithium hydroxide monohydrate (290 mg, 6.91mmol) and stirred at room ature for 2h.
The reaction mixture was concentrated and the residue was neutralized with 10% s potassiumbisulphate (10 mL) and extracted with ethyl acetate (2 X 30 mL).
The combined organic layer was washed with brine (10 mL), dried over sodium sulphate and concentrated to afford 2-(2-aminopyrimidinyl)-2,2-difluoroacetic acid (300 mg, 1.58 mmol, 69 % yield) as a brown semi solid. MS (ESI) m/z 190.22.
[M+1]+.
C. 2-(2-Amin0pyrimidinyl)—N-((2-(2,6-di0x0piperidinyl)—1- oxoisoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a cold (0 oC) stirred solution of 2-(2-aminopyrimidinyl)-2,2-difluoroacetic acid (800 mg, 4.23 mmol) and 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (915 mg, 2.96 mmol) in N,N—dimethylformamide (30 mL) was added N,N—diisopropylethylamine (2.3 mL, 12.69 mmol) followed by (dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (2.4 g, 6.34 mmol) and stirring at room temperature for 16h. The on mixture was diluted with water (70 mL) and and extracted with ethyl e (2 X 20 mL) and the combined organic layer was washed with brine (30 mL), dried over sodium sulphate and concentrated dried under vacuum. The product was purified by Reveleris C-18 reversed phase column using 40% acetonitrile in aqueous formic acid (0.1%) to afford 2-(2-aminopyrimidinyl)-N-((2-(2,6-dioxopiperidin-3 -yl) oxoisoindolinyl)methyl)-2,2-difluoroacetamide (45 mg, 1.01 mmol, 15% yield)as an off-white solid. MS (ESI) m/Z 445.44 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 5 .96 (s, 1H), 9.59 (br t, J=5.8 Hz, 1H), 8.36 (s, 2H), 7.67 (d, J=7.7 Hz, 1H), 7.43 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.26 (s, 2H), 5.10 (dd, J: 5.2, 13.4 Hz, 1H), 4.65 — 4.24 (m, 4H), 3.02 — 2.83 (m, 1H), 2.67 — 2.54 (m, 1H), 2.46 — 2.30 (m, 1H), 2.01 — 1.95 (m, 1H).
Example 113 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(5— (trifluor0methylthi0)pyridinyl)acetamide O O pomF A. tert-Butyl 6-br0m0pyridinylcarbamate. To a d solution of opyridinamine (7 g, 40.46 mmol) in dichloromethane (70 mL) was added di-tert—butyl onate (10.58 mL, 48.55 mmol) followed by 4- dimethylaminopyridine (0.99 g, 8.09 mmol), triethyl amine (0.99 g, 8.09 mmol) at 0 CC and stirred at room temperature for 6h. The reaction e was diluted with water (50 mL) and extracted with dichloromethane (3 X 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was purified by silica gel column chromatography (5% ethyl acetate/pet-ether) to afford utyl 6-bromopyridinylcarbamate (6 g, 22.05 mmol, 54% yield) as a colorless liquid. MS (ESI) m/z 273.22 [M+1]+‘ B. Ethyl tert—but0xycarb0nylamin0)pyridinyl)—2,2- difluoroacetate. To a stirred solution of tert—butyl 6-bromopyridinylcarbamate (6 g, 16.08 mmol) in dimethyl sulfoxide (40 mL) was added ethyl 2-bromo-2,2- difluoroacetate (4.89 mL, 24.12 mmol) followed by copper powder (2.65 g, 41.73 mmol) at room temperature and stirred at 60 CC for 6h. The reaction mixture was diluted with water and filtered through a Celite pad. Filtrate was extracted with ethyl 2015/039926 e (3 X 50 mL) and the ed organic layers were washed with brine (50 mL), dried over sodium sulfate, d and concentrated. The obtained crude was purified by silica gel column chromatography (5% ethyl acetate/pet-ether) to afford ethyl 2-(5- (tert—butoxycarbonylamino)pyridinyl)-2,2-difluoroacetate (4 g, 12.65 mmol, 57% yield) as a colorless liquid. 1H NMR (300 MHz, CDClg) 5 8.42 (d, J = 2.1 Hz, 1H), 816QLJ=69fh,HD,766@LJ=901h,HD,667GB,HD,436@LJ=7JPR, 2H), 1.53 (s, 9H), 1.32 (t, J: 7.2 Hz, 3H).
C. Ethyl 2,2-diflu0r0(5-thi0cyanatopyridin-Z-yl)acetate. A stirred solution of ethyl 2-(5-(tert—butoxycarbonylamino)pyridinyl)-2,2-difluoroacetate (4 g, 12.65 mmol) in 6N HCl (80 mL) at 0 CC and stirred at room temperature for 30min. Then, sodium nitrite (0.87 g, 12.65 mmol) was added into the reaction mixture followed by copper(I) thiocyanate (0.77 g, 6.32 mmol), potassium thiocyanate (0.99 g, 8.09 mmol) at -5 CC and d at room temperature for 1h. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl mama}X40mmfmememdmgmchwmwmewwmflvmhmmeMOmm, dried over sodium e, filtered and concentrated. The obtained crude was purified by silica gel column chromatography (5% ethyl acetate/ pet-ether) to afford ethyl 2,2- difluoro(5-thiocyanatopyridinyl)acetate (0.7 g, 2.71 mmol, 21% yield) as a colourless liquid. MS (ESI) m/Z 259.23 [M+l]+~ D. Ethyl 2,2-diflu0r0(5-(trifluoromethylthi0)pyridinyl)acetate. To a stirred solution of ethyl 2,2-difiuoro(5 -thiocyanatopyridinyl)acetate (700 mg, 2.71 mmol) in tetrahydrofuran (10 mL) was added trifluoromethyltrimethylsilane (770 mg, 5.42 mmol) followed by tetra-n-butylammonium fluoride (1.08 mL, 1.08 mmol) at 0 CC and stirred at room temperature for 16h. The reaction mixture was quenched with s sodium bicarbonate solution and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was d by flash column chromatography 00 silica gel, 2% ethyl acetate/pet-ether) to afford ethyl 2,2-difluoro(5-(trifluoromethylthio)pyridinyl)acetate (170 mg, 0.56 mmol, 21% yield) as a colourless liquid. MS (ESI) m/Z 302.27 [M+l]+- E. 2,2-Diflu0r0(5-(triflu0r0methylthi0)pyridinyl)acetic acid. To a stirred solution of ethyl 2,2-difluoro(5 -(trifluoromethylthio)pyridinyl)acetate (170 mg, 0.56 mmol) in tetrahydrofuran: ethanol: water (5 mL, 1:1:1) was added lithium hydroxide monohydrate (71 mg, 1.69 mmol) and stirred at room temperature for 4h. The volatiles were removed under reduced pressure and obtained crude was dissolved in water (5 mL) and washed with ethyl acetate (2 x 4 mL). The aqueous layer was ed with aqueous ium bisulphate on and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated to afford 2,2-difluoro(5- (trifluoromethylthio)pyridinyl)acetic acid (140 mg, 0.51 mmol, 91% yield) as a semi-solid compound. MS (ESI) m/z 274.18 [M+1]+‘ ] F. N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- diflu0r0(5-(trifluor0methylthi0)pyridinyl)acetamide. To an ice cold solution of 2,2-difluoro(5-(trifluoromethylthio)pyridinyl)acetic acid (220 mg, 0.81 mmol) in pyridine (5 mL) was added orus oxychloride (371 mg, 2.42 mmol) drop wise and d at 0-5 CC for 1h. Then, 3-(5-(aminomethyl)oxoisoindolin yl)piperidine-2,6-dione hydrochloride (250 mg, 0.81 mmol) was added into the reaction mixture and stirred at room temperature for 1h. The reaction mixture was neutralized with aqueous saturated sodium onate and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate, filtered and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column chromatography (50-55% itrile/0.1% aqueous formic acid) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolin yl)methyl)-2,2-difluoro(5-(trifiuoromethylthio) pyridineyl)acetamide (45 mg, 0.08 mmol, 10% yield) as an off-white solid. MS (ESI) m/z 529.03 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 10.99 (s, 1H), 9.77 (t, J: 5.4 Hz, 1H), 9.01 (s, 1H), 8.44 (dd, J=78J18HLlHL798fiLJ=84fh,HD,771@LJ=75I£;1HL750(&1H) 7.44 (d, J: 7.5 Hz, 1H), 5.11 (dd, J: 12.9, 5.1 Hz, 1H), 4.51 (d, J: 6.3 Hz, 2H), 4.46 fiLJ=179fh,HD,431@LJ=176P&,HD,292—2880n,HD,263—2570n HD,241—2360n,HD,202—2(M(nn1H) Exanqfle114 N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0indolinyl)methyl)-2,2—diflu0r0(3-(2- (methylamin0)eth0xy)phenyl)acetamide hydrochloride H N O \N/\/OHCI N 4% H O A. Ethyl 2-(3-(2-(tert-but0xycarb0nyl(methyl)amin0)eth0xy)phenyl)— 2,2-diflu0roacetate. To a stirred solution of ethyl 2,2-difluoro(3- hydroxyphenyl)acetate (2 g, 9.25 mmol) in tetrahydrofuran (20 mL) was added tert- butyl 2-hydroxyethyl(methyl)carbamate (2.43 g 13.88 mmol), N,N—diisopropyl azodicarboxylate (1.87 g 9.25 mmol) ed by triphenyl phosphine (2.4 g, 9.25 mmol) at room temperature and stirred at 50-55 CC for 16h. The reaction mass was directly concentrated. The resultant residue was purified by column tography (silica-gel 100-200) 30% ethylacetate - hexanes as a eluent to afford ethyl 2-(3 ert-butoxycarbonyl (methyl)amino)ethoxy)phenyl)-2,2-difluoroacetate (1 g, 4.0 mmol, 29% yield) as brown liquid. MS (ESI) m/Z 274.2 ]+.
B. 2-(3-(2-(tert-But0xycarb0nyl(methyl)amin0)eth0xy)phenyl)-2,2- difluoroacetic acid. To a cold (0 CC) stirred solution of ethyl 2-(3-(2-(tert— butoxycarbonyl(methyl)amino)ethoxy)phenyl)-2,2-difluoroacetate (1.0 g, 2.67 mmol) in Methanol/Tetrahydrofuran/water (15 mL, 1:1:1) was added lithium hydroxide monohydrate (224.5 mg, 5.64 mmol) and d at room temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous potassium bisulphate (10 mL) and extracted with ethyl e (2 X 50 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulphate and concentrated to give ethyl 2-(3-(2-(tert-butoxycarbonyl (methyl)amino)ethoxy)phenyl)-2,2-difluoroaceticacid (600 mg, 1.73 mmol, 65 % yield) as a brown semi solid. MS (ESI) m/z 343.8 [M-1]+.
] C. tert-Butyl 2-(3-(2-((2-(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methylamin0)—1,1-diflu0r00x0ethyl)phen0xy)ethyl(methyl)carbamate. To a solution of ethyl 2-(3 -(2-(tert-butoxycarbonyl(methyl)amino)ethoxy)phenyl)-2,2- difluoroaceticacid (447.8 mg, 1.44 mmol) in N,N—dimethylformamide (20 mL) was added (3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (500 mg, 1.44 mmol) was added sub sequentially diisopropylethylamine (561.8 mg, 4.34 mmol) and 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (825.9 g, 2.17 mmol) at room temperature and reaction was continued to room for 2h. The reaction mixture was poured in ice cold water (40 mL) to observed off-white solid. The resultant residue was purified by Reveleris C-18 reverse phase column tography using 45-50% acetonitrile in s formic acid (0.1%) to give tert—butyl 2-(3-(2-((2-(2,6-dioxopiperidinyl) oxoisoindolinyl)methylamino)- 1 ,1-difluoro oxoethyl)phenoxy)ethyl(methyl)carbamate (200 mg, 0.33 mmol, 20% yield)as an off-white solid. MS (ESI) m/z 501 [M-100]+ (De Boc mass).
D. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)-2,2- difluor0(3-(2-(methylamin0)eth0xy)phenyl)acetamide hydrochloride. To tert- butyl 2-(3 -(2-((2-(2,6-dioxopiperidin-3 -oxoisoindolinyl)methylamino)- 1 ,1- difluorooxoethyl)phenoxy)ethyl(methyl)carbamate (160 mg, 0.26 mmol), 4M hloric acid in dioxane was (5 mL) was added and stirred at room temperature for 4h. The on was distilled off under reduced pressure and washed with diethylether to afford 3-(5 -(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (60 mg, ol, 42% yield) as an off white solid. MS (ESI) m/z 501.59 [M+1]+. 1H NMR (400MHz, 6) 5 ppm 10.99 (s, 1H), 9.87 — 9.58 (m, 1H), 8.98 (br s, 2H), 7.68 (d, J=7.8 Hz, 1H), 7.53 — 7.46 (m, 1H), 7.44 — 7.40 (m, 1H), 7.39 — 7.34 (m, 1H), 7.46 — 7.32 (m, 1H), 7.24 — 7.16 (m, 3H), 5.11 (dd, J=5.1, 13.5 Hz, 1H), 4.48 — 4.39 (m, 3H), 4.33 — 4.24 (m, 3H), 3.40 — 3.25 (m, 2H), 2.97 — 2.85 (m, 1H), 2.67 — 2.55 (m, 4H), 2.39 (dq, J=4.4, 13.2 Hz, 4H), 2.05 — 1.94 (m, 1H).
Example 115 N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(1- methyl0x0-1,6-dihydr0pyridazinyl)acetamide A. 1-tert-Butyl 3-ethyl 2-(6-ch10r0pyridazinyl)malonate. 1-Tert—butyl ethyl malonate (26.6 mL, 140.54 mmol) was added drop wise to a sion of sodium hydride (12.9 g, 324.32 mmol) in dioxane at 10 CC. The reaction was stirred at CC for 1h and then allowed to warm to room temperature. 3,6-dichloropyridazine (20 g, 135.13 mmol) was then added portion wise to the on at 25 OC and refluxed for 2 hr. The reaction mixture was diluted with ice cold water (500 mL) extracted with ethyl acetate (5 X 500 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography (100-200 silica) using 6% EtoAc:Hexene to afford 1-tert-butyl 3-ethyl 2-(6-chloropyridazinyl)malonate (16 g,53.33 mmol, 39% yield). LCMS (ESI) m/Z 301.31 [M+1]+.
B. -Butyl 3-ethyl 2-(6-chlor0pyridazinyl)—2-fluoromalonate. To a solution of —butyl 3-ethyl hloropyridazinyl)malonate (16 g, 53.33 mmol) in tetrahydrofuran (200 mL) was added sodium hydride (2.31 g, 58.133 mmol) at 0 oC and stirred for 15min. A cloudy solution of SelectFluor (20.5 g, 58.13 mmol) in dry N,N-dimethylformamide (40 mL) was added drop wise at 0 oC overapefiodof20nnnandthmiflwreadnniwasaflowwdtosfiratnxnntmnpmauue for 2h. The reaction was quenched with ammonium chloride (200 mL) and extracted with ethyl acetate (5 X 500 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography 00 silica) using 5% EtoAc:Hexene to afford 1-tert—butyl 3-ethyl 2-(6-chloropyridazinyl)fluoromalonate (11 g, 34.59 mmol, 64% yield). LCMS (ESI) m/Z 219.27 [M+1]+.
C. Ethyl 2-(6-chloropyridazinyl)flu0r0acetate. A solution of 1-tert— butyl 3-ethyl 2-(6-chloropyridazinyl)fluoromalonate (11 g, 34.54 mmol) in tfifluonxweficaddxfidflonnnmhanennxuue(L1,6an)wmssfinedat25°C1br2h and then concentrated to dryness over rotary evaporator. The resulting residue was dissolved in ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate on, dried over sodium sulphate and then concentrated to dryness to afford ethyl 2-(6-chloropyridazinyl)fluoroacetate (6 g, 27.52 mmol 79% , LCMS (ESI) m/z 219.06 [M+1]+. The material was taken to the next step without findwrpufificafion.
D. Ethyl 2-flu0r0(6-hydr0xypyridazinyl)acetate. To a stirred on of ethyl 2-(6-chloropyridazinyl)fluoroacetate (6 g, 27.52 mmol) in acetic acid (20 mL) was added sodium acetate (22.56 g, 275.52 mmol) and d for 16h at 100 CC. The reaction mixture was diluted with ice cold water (500 mL) extracted with ethyl acetate (5 X 500 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography (100-200 silica) using 30% ethyl acetate in hexanes to afford ethyl 2-fluoro(6-hydroxypyridazinyl)acetate (4 g, 20.00 mmol, 72% yield). LCMS (ESI) m/Z 201.22 [M+1]+.
E. Ethyl 2-flu0r0(1-methyl0x0-1,6-dihydr0pyridazinyl)acetate.
To a stirred solution of ethyl 2-fluoro(6-hydroxypyridazinyl)acetate (4 g, .00 mmol) in N,N-dimethylformamide (20 mL) was added methyl iodide (1.86 mL, .00 mmol), potassium carbonate (8.28 g, 60.00 mmol) at room temperature and stirred for 3h.The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 X 100 mL). The ed organic layers were washed with brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography (100-200 ) using 40% ethyl acetate in hexanes to afford ethyl o(1-methyloxo-1,6-dihydropyridazinyl)acetate (3 g, 14.01 mmol, 70% yield). LCMS (ESI) m/z 215.66 [M+1]+.
F. Ethyl 2,2-diflu0r0(1-methyl0x0-1,6-dihydr0pyridazin yl)acetate. To a solution of ethyl 2-fluoro(1-methyloxo-1,6-dihydropyridazin yl)acetate (3 g 14.01 mmol) in dry tetrahydrofuran (30 mL) was added lithium hexamethyldisilazide (14 mL ,16.82 mmol) drop wise at -78 oC and stirred for minutes. To this, a suspension of SelectFluor (5.9 g, 16.8 mmol) in dry N,N-dimethylformamide (10 mL) was added drop wise over a period of 10min. Upon completion addition, the reaction was d to warm to room ature over a period of 30min. The reaction was quenched with saturated ammonium chloride (50 mL) and the organic fractions were distilled off. The residue obtained was diluted with ice cold water (500 mL) and extracted with ethyl acetate (5 X 500 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate and trated. The resultant residue was purified by Flash column chromatography (100-200 silica) using 42% ethyl acetate in hexanes to afford ethyl 2,2-difluoro(1-methyloxo-1,6-dihydropyridazinyl)acetate (1.2 g, 5.17 mmol, 36% yield). LCMS (ESI) m/Z 233.33 [M+1]+.
G. 2,2-Diflu0r0(1-methyl0x0-1,6-dihydr0pyridazinyl)acetic acid. To a cold (0 oC) stirred solution of ethyl 2,2-difluoro(1-methyloxo-1,6- dihydropyridazin-3 etate (1.2g, 5.17 mmol) in tetrahydrofilran:Methanol:water mixture (30 mL, 1:1:1) was added lithium hydroxide monohydrate (1.08 g, .86 mmol) and stirred at room temperature for 6h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous hydrochloric acid and extracted with ethyl acetate (2 X 50 mL). The ed organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(1-methyloxo-1,6-dihydropyridazinyl)acetic acid (700 mg, 3.43 mmol, 66% yield) as an off white solid. LCMS (ESI) m/z 205.31[M+1]+.
H. N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2- difluoro-Z-(l-methyl0x0-1,6-dihydr0pyridazinyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(1-methyloxo-1,6-dihydropyridazinyl)acetic acid (197.6 mg, 0.968 mmol) in ne was added oryl chloride (0.27 mL, 2.906 mmol) dropwise and d at 0-5°C for 1h. To this reaction e was added aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (300 mg, 0.968 mmol) and continued stirring at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated.
The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 40-60% acetonitrile in aqueous formic acid (0.1%) to afford N- ((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)-2,2-difluoro(1-methyl- 6-oxo-1,6-dihydropyridazinyl)acetamide (70 mg, 0.152 mmol, 15% yield) as an off white solid. MS (ESI) m/z 460.52 [M+1]+. 1H NMR (300MHz, DMSO-d6) 8 = 10.98 (s, 1H), 9.68 (br t, J=5.8 Hz, 1H), 7.79 — 7.69 (m, 2H), 7.51 (s, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.12 (d, J=9.5 Hz, 1H), 5.11 (dd, J=4.9, 13.3 Hz, 1H), 4.58 — 4.27 (m, 4H), 3.66 (s, 3H), 2.99 — 2.83 (m, 1H), 2.67 — 2.56 (m, 1H), 2.45 — 2.29 (m, 1H), 2.08 — 1.93 (m, 1H).
Example 1 16 2-(2-amin0pyrimidin-4—yl)—N-((2—(2,6-di0x0piperidinyl)—l-oxoisoindolin-S- yl)methyl)—2,2-difluoroacetamide HZNYN@fiN A. 4-Iod0pyrimidinamine. To an ice cold on of 4-chloropyrimidinamine (5 g, 38.5 mmol) in hydroiodic acid (100 mL) was added sodium iodide (17.2 g, 115.7 mmol) at 0 CC and stirred at room temperature for 2h.
The reaction mixture was quenched cautiously with aqueous sodium bicarbonate solution at 0 CC and extracted with dichloromethane (3 X 150 mL). The combined organic layers were washed water (150 mL), brine (150 mL), dried over sodium sulphate, filtered and trated to afford 4-iodopyrimidineamine (1.55 g, 7.01 mmol, 18% yield) as a colourless liquid. MS (ESI) m/z 222 [M+H]+‘ 2015/039926 ] B. Ethyl 2-(2-amin0pyrimidinyl)—2,2-diflu0roacetate. To a d solution of pyrimidineamine (5 g, 22.60 mmol) in dimethyl sulfoxide (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate (4.53 mL, 33.92 mmol) followed by copper powder (3.7 g, 58.75 mmol) and stirred at 50 0C for 4h. The reaction mixture was neutralized with aqueous saturated ammonium chloride solution and extracted with ethyl acetate (3 X 150 mL). The combined organic layers were washed with water (2 X50 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford Ethyl 2-(2-aminopyrimidinyl)-2,2-difluoroacetate (1.4 mg, 6.45 mmol, 28 %) as a brown liquid. MS (ESI) m/z 218 [M+H]+' C. 2-(2-aminopyrimidinyl)—2,2-diflu0roacetic acid. To a cold (0 oC) stirred solution of ethyl 2-(2-aminopyrimidinyl)-2,2-difluoroacetate (700 mg, 3.22 mmol) in tetrahydrofuran was added 1N hydrochloric acid and stirred at room temperature for 12h. The on mixture was concentrated and the obtained residue was co-distilled with toluene to afford 2-(2-aminopyrimidinyl)-2,2-difluoroacetic acid (550 mg, 2.91 mmol, 82 % yield) as a white solid. MS (ESI) m/z 188 [M-H]+‘ D. 2-(2-aminopyrimidinyl)—N-((2-(2,6-di0x0piperidinyl)—1- "MmmmMmSflmwmflyLfimmmnmwmmMeToawMGWCfldmmnfi 3 -(6-((methylamino)methyl)oxoisoindolinyl)piperidine-2,6-dione°hydrochloride (683 mg, 2.21 mmol) and 2-(2-aminopyrimidinyl)-2,2-difluoroacetic acid (500 mg, 2.21 mmol) in N,N—dimethylformamide (10 mL) was added N,N—diisopropylethylamine (1.15 mL, 6.63 mmol) followed by 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (1 g, 2.65 mmol) and stirred at room temperature for 16h. The reaction mixture was diluted with water (70 mL) and extracted with ethyl acetate (2 X 50 mL). The combined c layers were washed with brine (30 mL), dried over sodium te and concentrated. The resultant residue was purified by Reveleris C-18 reversed phase column using 58% acetonitrile in aqueous formic acid (0.1%) to afford 2-(2-aminopyrimidinyl)-N-((2-(2,6-dioxopiperidinyl)oxoisoindolin-5 - yl)methyl)-2,2-difluoroacetamide (52 mg, 11.6 mmol, 5% yield) as an off white solid.
MS (ESI) m/z 445.1 [M+H]+. 1H NMR (400 MHz, 6) 5 10.99 (s, 1H), 9.57 (t, J: 6.0 Hz, 1H), 8.46 (d, J: 4.8 Hz, 1H), 7.71(d, J: 8.0 Hz, 1H), 7.48 (s, 1H), 7.60 (d, J: 7.6 Hz, 1H), 7.07 (s, 1H), 6.86 (d, J: 4.8 Hz, 1H), 5.11 (dd, J: 13.2, 4.8 Hz, 2015/039926 1H), 4.48 (d, J: 5.2 Hz, 2H), 4.46 (d, J: 16.9 Hz, 1H), 4.31 (d, J: 17.2 Hz, 1H), 2.93 — 2.89 (m, 1H), 2.67 — 2.58 (m, 1H), 2.40 — 2.33 (m, 1H), 2.01 — 1.98 (m, 1H).
Example 117 (2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)-2,2—diflu0r0 (pyrimidinyl)acetamide O O MNH N 0 NVN 0 A. Ethyl flu0r0(2-(methylthi0)pyrimidinyl)acetate. To a stirred solution of 4-chloro(methylthio)pyrimidine (5 g, 21.55 mmol) in dimethylsulfoxide (50 mL) was added ethyl 2-bromo-2,2-difluoroacetate (8 mL, 62.2 mmol) followed by copper powder (5.93 g, 93.4 mol) at RT and d at 60 0C for 6h. The reaction mixture was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with water (40 mL), brine (40 mL), dried over sodium sulfate, filtered and t was concentrated and obtained crude was purified by silica gel column chromatography using 20% ethyl acetate in pet ether to afford ethyl 2,2-difluoro(3- formylphenyl)acetate (3 g, 12.00 mmol, 38%) as a colorless liquid. MS (ESI) m/z 249.66 [M+1]+.
B. Ethyl 2,2-diflu0r0(pyrimidinyl)acetate. Ethyl 2,2-difluoro(2- (methylthio)pyrimidinyl)acetate (2.8 g, 11.29 mmol) in tetrahydrofuran was added to trimethylsilane (5.3 mL) at 0 CC and added 10% Pd/C (622 mg) then stirred at room temperature for 5 h. The reaction mixture was filtered through celite pad The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The obtained crude was purified by flash column chromatography (100-200 silica gel, 10% ethyl acetate in pet ether) to affordethyl 2,2- difluoro(pyrimidinyl)acetate (800 mg, 3.96 mmol, 36% yield) as a colourless liquid MS (ESI) m/Z 203.65 [M+1]+.
C. 2,2-Diflu0r0(pyrimidinyl)acetic acid. To a stirred solution of ethyl 2,2-difiuoro(pyrimidinyl)acetate (1 g, 4.95 mmol) in tetrahydrofuran: ethanol: water (15 mL, 1:1:1) was added lithium hydroxide drate (624 mg, 14.85 mmol) and d at room temperature for 16h. The volatiles were removed under reduced pressure and obtained crude was dissolved in water (15 mL) and washed with ethyl e (2 x 10 mL). The aqueous layer was acidified with 1N hydrochloride solution and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to fluoro(pyrimidinyl)acetic acid (800 mg, 4.59 mmol, 92% yield) as semi-solid compound. MS (ESI) m/z 175 [M+1]+’ D. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- difluoro-Z-(pyrimidinyl)acetamide. To an ice cold solution of 2,2-difluoro (pyrimidinyl)acetic acid (203 mg, 1.16 mmol) in pyridine (10 mL) was added orus oxychloride (0.27 mL, 2.91 mmol) drop wise and stirred at 0-5 0C for 1h and then added 3-(6-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hloride (300 mg, 0.97 mmol) and stirred at room temperature for 30 min. The on mixture was neutralized with aqueous saturated sodium bicarbonate and extracted with ethyl acetate (3 X 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over sodium sulphate, filtered and concentrated. The resultant residue was purified by ris C-18 reversed phase column tography (50-55% acetonitrile in 0.1% aqueous formic acid to afford N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)-2,2-difluoro (pyrimidinyl)acetamide (55 mg, 0.12 mmol, 12% yield) as an off-white solid. MS (ESI) m/z 430.47 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 10.99 (s, 1H), 9.81 (t, J: 6.0 Hz, 1H), 9.41 (s, 1H), 9.12 (d, J=5.1 Hz ,1H) 7.95 (dd, J: 5.1,1.5 Hz,1H) 7.71 (d, J: 7.5 Hz ,1H), 7.52(s, 1H),7.44 (d, J: 7.5 Hz, 1H), 5.11 (dd, J: 13.2, .1 Hz, 1H), 4.51 (d, J: 6.3 Hz, 2H), 4.47 (d, J: 17.6 Hz, 1H), 4.32 (d, J: 17.4 Hz, 1H) 2.96 — 2.88 (m, 1H), 2.63 — 2.57 (m, 1H), 2.43 — 2.38 (m, 1H), 2.07 — 1.98 (m, 1H).
Example 118 N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2-diflu0r0(3-(2- (piperidinyl)ethoxy)phenyl)acetamide O O N/\/ A. Methyl 2,2-difluoro-Z-(3-hydr0xyphenyl)acetate. To a stirred solution of ethyl 2,2-difluoro(3-(methoxymethoxy)phenyl)acetate (13.0 g, 49.98 mmol) in dichloromethane (130 mL) was added trifluoroacetic acid (65 mL) at 0 °C and stirred at room temperature for 5h. The reaction mixture was quenched with water (200 mL) and extracted with romethane (3 X 200 mL). The combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over sodium sulphate and concentrated to afford methyl 2,2-difluoro(3-hydroxyphenyl)acetate (8.0 g 37.03 mmol, 74% yield). GCMS (m/z) 216.1.
B. 1-(2-Chloroethyl)piperidine. To a stirred solution of 2-(piperidin yl)ethanol (4.0 g, 30.95 mmol) in dichloromethane (40 mL) was added l de (7.0 mL, 92.87) at 0 °C and stirred at room temperature for 3h. The reaction mixture wasmmndwdwfihwaerOnfl)mflefinwmdwmthMomnwmmm(3X50mL) Theammnwdogmncbywswmewaflwdwfihwfimf2X50nfl)bfimfl50mLL dried over sodium sulphate and concentrated to afford 1-(2-chloroethyl)piperidine (1.8 g 12.24 mmol, 40% yield). GCMS (m/z) 147.1.
C. Ethyl 2,2-diflu0r0(3-(2-(piperidinyl)eth0xy)phenyl)acetate. To a stirred solution of methyl 2,2-difluoro(3-hydroxyphenyl)acetate (1.0 g, 4.62 mmol) in acetone (15 mL) was added 1-(2-chloroethyl)piperidine (885 mg, 6.01 mmol), potassium carbonate (1.9 g, 13.88 mmol) and stirred at 55 0C for 4h. The mmmmmmmmwwfiMmdmmwMMWQmmwwhmmdemmmGX5mfl) The filtrate was dried over sodium sulphate and concentrated to afford ethyl 2,2- difluoro(3-(2-(piperidinyl)ethoxy)phenyl)acetate (1.4 g, 4.28 mmol, 93% yield).
LCMS (ESI) m/z 328.0.
D. 2,2-Diflu0r0(3-(2-(piperidinyl)eth0xy)phenyl)acetic acid. To a cold (0 oC) stirred solution of ethyl 2,2-difluoro(3-(2-(piperidin yl)ethoxy)phenyl)acetate (1.4 g, 4.28 mmol) in methanol- tetrahydrofiaran-water mixture (20 mL, 1:1:1) was added lithium hydroxide monohydrate (539 mg, 12.84 mmol) and d at room temperature for 2h.The on mixture was concentrated and the residue was neutralized with 10% aqueous potassium bisulphate (20 mL) and ted with ethyl acetate (2 X 40 mL).The combined c layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(3-(2-(piperidinyl)ethoxy)phenyl)acetic acid (700 mg, 2.34 mmol, 55 % . LCMS (ESI) m/Z 300.0.
E. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- dmmnm%34%mmumm4yMMmmmmmflnwmmMeToawMGWCflmmd solution of 2,2-difluoro(3-(2-(piperidinyl)ethoxy)phenyl)acetic acid (300 mg, 1.00 mmol) and 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (310 mg, 1.00 mmol) in N,N—dimethylformamide (20 mL) was added isopropylethylamine (389 mg, 3.01 mmol) followed by 1- [Bis(dimethylamino)methylene]-1H-1 ,2,3 olo [4,5-b]pyridinium 3-oxid hexafluorophosphate (572 mg, 1.50 mmol) and stirred at room ature for 4h.
The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 X 40 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulphate, concentrated and dried under vacuum. The product was purified by Reveleris C-18 reversed phase column using 40% itrile in s formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolin—5-yl)methyl)- 2,2-difluoro(3-(2-(piperidinyl)ethoxy)phenyl)acetamide (56 mg, 0.09 mmol, 9% yield) as an off- white solid. LCMS (ESI) m/Z 555.23 [M+1]+. 1H NMR (300 MHz, DMSO-d6) 8 (ppm) 10.99 (s, 1H), 9.66 (br t, J=5.9 Hz, 1H), 9.47 (br s, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.51 (t, J=8.1 Hz, 1H), 7.42 (s, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.27 — 7.12 (m, 3H), 5.11 (br dd, J=5.1, 13.2 Hz, 1H), 4.56 — 4.21 (m, 6H), 3.61 — 3.45 (m, 4H), 3.10 — 2.83 (m, 3H), 2.68 — 2.55 (m, 1H), 2.44 — 2.30 (m, 1H), 2.08 — 1.91 (m, 1H), 1.90 — 1.60 (m, 5H), 1.50 — 1.30 (m, 1H).
Example 119 N-((2-(2,6-Di0x0piperidinyl)—1-0x0is0indolinyl)methyl)-2,2—diflu0r0(3-(2- m0rpholinoethoxy)phenyl)acetamide Wm"Nm2))": A. Ethyl 2,2-diflu0r0(3-(2-m0rpholin0eth0xy)phenyl)acetate. To a stirred solution of methyl 2,2-difluoro(3-hydroxyphenyl)acetate (2.0 g, 9.25 mmol) in acetone (25 mL) was added 4-(2-chloroethyl)morpholine hydrochloric acid (2.23 g, 12.03 mmol), potassium carbonate (3.83 g 27.77 mmol) and stirred at 55 0C for 16h.
The reaction e was quenched with water (50 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with water (2 X mL), brine (30 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2-difluoro(3-(2-morpholinoethoxy)phenyl)acetate (1.5 g, 4.55 mmol, 49% yield) as brown liquid. LCMS (ESI) m/Z 330.0 [M+1]+.
B. 2,2-Diflu0r0(3-(2-m0rpholin0eth0xy)phenyl)acetic acid. To a cold (0 CC) stirred solution of ethyl 2,2-difluoro(3-(2-morpholinoethoxy)phenyl)acetate (1.5 g, 4.55 mmol) in methanol/tetrahydrofuran/water mixture (20 mL, 1:1:1) was addedlfihnnnhydnnddernonohydnfie(382rng,911rnnufl)andsfined2firoon1 temperature for 2h. The reaction mixture was concentrated and the residue was neutralized with 10% aqueous potassium bisulphate (20 mL) and extracted with ethyl acetate (2 X 40 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(3- (morpholinoethoxy)phenyl)acetic acid (600 mg, 1.99 mmol, 44 % yield) as a brown solid. LCMS (ESI) m/Z 302.0 [M+1]+.
] C. N-((2-(2,6-Di0x0piperidinyl)—1-0x0isoindolin-S-yl)methyl)—2,2- difluoro-Z-(3-(2-m0rph01in0eth0xy)phenyl)acetamide. To a cold (0 oC) stirred solution of 2,2-difluoro(3-(morpholinoethoxy)phenyl)acetic acid (513 mg, 1.66 mmol) and 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (500 mg, 1.66 mmol) in N,N—dimethylformamide (20 mL) was added N,N—diisopropylethylamine (643.8 mg, 4.98 mmol) followed by 1-[Bis(dimethylamino)methylene]-1H-1 ,2,3 -triazolo [4,5-b]pyridinium 3-oxid hexafluorophosphate (946.4 mg, 2.49 mmol) and stirred at room temperature for 4h.
The reaction e was diluted with water (50 mL) and ted with ethyl acetate (2 X 40 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulphate, concentrated and dried under vacuum. The product was purified by Reveleris C-18 ed phase column using 40% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)- 2,2-difluoro(3-(morpholinoethoxy)phenyl)acetamide hydrochloride salt (40 mg, 0.07 mmol, 4.4% yield)as an off- white solid. LCMS (ESI) m/z 557.2 [M+1]+. 1H NMR (400MHz, 6) 8 ppm 10.99 (s, 1H), 10.17 (br s, 1H), 9.66 (br t, J=6.1 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.51 (t, J=8.1 Hz, 1H), 7.42 (s, 1H), 7.36 (d, J=781h,HD,725—7J5(nn3H)511(mLJ:4%132fh,HD,448—4370n 5H), 4.28 (d, J=17.2 Hz, 1H), 3.98 (br d, J=12.2 Hz, 2H), 3.73 (br t, J=11.7 Hz, 2H), 3.64 — 3.49 (m, 5H), 3.48 — 3.22 (m, 2H), 2.98 — 2.84 (m, 1H), 2.68 — 2.56 (m, 1H), 2.45 — 2.31 (m, 1H), 2.05 — 1.95 (m, 1H).
Exanqfle120 2-(3-(2-(4,4-Diflu0r0piperidinyl)eth0xy)phenyl)-N-((2-(2,6-di0x0piperidin yl)—1-oxoisoindolin-S-yl)methyl)—2,2-diflu0r0acetamide O O Foven"O A. Ethyl 2-(4,4-diflu0r0piperidinyl)acetate. To a stirred solution of 4,4-difluoropiperidine°hydrogenchloride (2 g, 12.048 mmol) in tetrahydrofuran (45 mL) was added ethyl 2-bromoacetate (2.83 g, 18.07 mmol), triethyl amine (6.51 mL, 48.19 mmol) followed by tetrabutylammonium iodide (2.2 g, 6.024 mmol) at room ature and allowed to stir at the same temperature for 16h. The reaction was quenched with ice water and extracted with ethyl acetate (3 X 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated to afford ethyl -difluoropiperidinyl)acetate (1.5 g, 7.2 mmol, 60% yield) as a colourless liquid.GCMS (ESI) m/z 207 [M]+’ B. -Diflu0r0piperidinyl)ethanol: To a stirred on of ethyl 2- (4,4-difluoropiperidinyl)acetate (2 g, 9.66 mmol) in tetrahydrofuran (15 mL) was added lithium alluminiumhydride (9.6 mL, 19.32 mmol) at 0 CC and stirred at room temperature for 3h. The reaction mixture was cooled to 0 oC and quenched with Celite/sodium sulphate°hydrate (4: 1) and stirred at room temperature for 1h. The white slurry was filtered through a Celite pad and washed with thoroughly dichloromethane (60 mL). The filtrate was dried over sodium sulphate and concentrated to afford 2-(4,4-difluoropiperidin-l-yl)ethanol (l g, 6.06 mmol, 62% yield) as a colourless . 1H NMR (300 MHz, DMSO-d6) 8 4.45 (bs, 1H), 3.50 (t, J: 5.6 Hz, 2H), 2.54-2.43 (m, 6H), 2.00 — 1.87 (m, 4H).
] C. 2-(4,4-Diflu0r0piperidinyl)ethyl methanesulfonate. To a on of 2-(4,4-difluoropiperidinyl)ethanol (1 g, 4.8 mmol) in tetrahydrofuran was added methane sulphonyl chloride (0.706 mL) at 0 CC and stirred at room temperature for 1 h. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium e, filtered and concentrated to afford 2- (4,4-difluoropiperidinyl)ethyl methanesulfonate (800 mg, 3.27 mmol, 54% yield) —294— as a colourless liquid. Crude compound was used to the next step without fiarther purification.
D. tert—Butyl(3-i0dophenoxy)dimethylsilane. To a stirred solution of 3-iodophenol (5 g, 22.7 mmol) in methylformamide (15 mL, 1:1:1) was added tert—butyldimethyl silyl chloride (8.2 mL, 27.24 mol) at 0 CC and d at room temperature for 16h. The reaction mixture was poured into ice water (15 mL) and extracted with ethyl e (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford tert—butyl(3-iodophenoxy)dimethylsilane (10 g, 17.96 mmol, 80% yield) as semi-solid compound which was taken to next step without filrther purification.
E. Ethyl 2,2-diflu0r0(3-hydr0xyphenyl)acetate. To a d solution of utyl(3-iodophenoxy)dimethylsilane (10 g, 22.33 mmol) in dimethylsulfoxide (75 mL) was added Copper powder (3.5 g, 55.82 mmol) followed by ethyl 2-bromo- 2,2-difiuoroacetate (4.3 mL 33.49 mmol) at room temperature and stirred at 55 CC for 16h. The reaction mixture was poured into water (20 mL) and filtered through a Celite pad. The filtrate was extracted with ethylacetate (3 X 30 mL) and the combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to afford ethyl 2,2-difiuoro(3-hydroxyphenyl)acetate (3.5 g, 16.20 mmol, 54% yield) as a colourless liquid. MS (ESI) m/z [M-1]+' F. Ethyl 2-(3-(2-(4,4-difluoropiperidinyl)eth0xy)phenyl)—2,2- difluoroacetate. To a stirred on of ethyl 2,2-difiuoro(3-hydroxyphenyl)acetate (700 mg, 2.86 mmol) in toluene (20 mL) was added 2-(4,4-difiuoropiperidinyl)ethyl esulfonate (619 mg, 2.86 mmol) followed by potassium carbonate (1.59 g, 11.47 mmol), utylammonium iodide(30 mg) at room temperature and allowed to stir at 110 CC for 16h. The reaction mixture was poured into ice water and extracted with ethylacetate (3 X 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to afford ethyl 2-(3 -(2- (4,4-difiuoropiperidinyl)ethoxy)phenyl)-2,2-difiuoroacetate (600 mg, 1.65 mmol, 60% yield) as a colourless liquid. MS (ESI) m/z 364.14 [M+1]+‘ G. 2-(3-(2-(4,4-Diflu0r0piperidinyl)ethoxy)phenyl)-2,2-diflu0r0acetic acid. To a stirred solution of ethyl 2-(3-(2-(4,4-difiuoropiperidinyl)ethoxy)phenyl)- 2,2-difiuoroacetate (1 g, 2.75 mmol) in tetrahydrofuran: ol: water (15 mL, 1:1:1) was added lithium hydroxide monohydrate (348 mg, 8.26 mmol) and stirred at room temperature for 3h. The volatiles were removed under reduced pressure and ed crude was dissolved in water (15 mL) and washed with ethyl acetate (2 x mL). The aqueous layer was ed with 1N hydrochloride solution and extracted whhdhdmdfieax15mL)Hmcmmmmdmgwmhwmswmewwkflwflhmme (10 mL), dried over sodium sulfate, filtered and concentrated to afford 2-(3 ,4- difluoropiperidin-l-yl)ethoxy)phenyl)-2,2-difluoroacetic acid (800 mg, 2.38 mmol, 86% yield) as semi-solid compound. MS (ESI) m/z 334.04 [M]+‘ H. 2-(3-(2-(4,4-Diflu0r0piperidinyl)ethoxy)phenyl)-N-((2-(2,6- dioxopiperidinyl)—1-0x0isoindolin-S-yl)methyl)-2,2-difluoroacetamide. To a cold (0 CC) stirred solution of 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6- dione hydrochloride (276 mg, 0.895 mmol) and 2-(3-(2-(4,4-difluoropiperidin yl)ethoxy)phenyl)-2,2-difluoroacetic acid (300 mg, 0.895 mmol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (0.3 mL, 1.79 mmol) followed by 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (408 mg, 1.074mmol) and stirred at room ature for 2h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 X 40 mL). The ed organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated. The crude compound was purified by Reveleris C-18 reversed phase column (60% acetonitrile/0.1% aqueous formic acid) to afford 2-(3-(2-(4,4-difluoropiperidinyl)ethoxy)phenyl)-N- ((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolinyl)methyl)-2,2-difluoroacetamide (45 mg, 0.076 mmol, 8% as an off-white solid. MS (ESI) m/z 591.17. 1H NMR (400 MHz, DMSO-d6) 8 10.98 (s, 1H), 9.61 (t, J: 5.6 Hz, 1H), 7.67 (d, J: 8.0 Hz, 1HL744(&LJ=80,76PH,HD,740(s1HL736QLJ=76fh,HD,716—711 (m, 3H), 5.10 (dd, J: 13.2, 5.6 Hz, 1H), 4.45 (d, J: 6.0 Hz, 2H), 4.42 (d, J: 17.8 Hz, 1H), 4.28 (d, J: 17.2 Hz, 1H), 4.09 (t, J: 5.6 Hz, 2H), 2.95 — 2.87 (m, 1H), 2.78 (t, J: 5.6 Hz, 2H), 2.65 — 2.59 (m, 5H), 2.45 — 2.35 (m, 1H), 2.03 — 1.88 (m, 5H).
ExanqflelZl N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2—diflu0r0(1- methyl0x0-1,6-dihydr0pyridazinyl)acetamide O O A. 4,5-Dichlor0methylpyridazin-3(2H)—0ne. To a stirred solution of 4,5-dichloropyridazinol (20 g, 0.121 mol) in N,N—dimethylformamide (100 mL) was added potassium carbonate (42 g, 0.303 mol) followed by methyl iodide (18.9 g, 0.133 mol) and stirred at room temperature for 2h. The on mixture was filtered, to the filtrate was added water (100 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography (100-200 silica) using 10-20% ethyl acetate in hexanes to afford 4,5-dichloromethylpyridazin-3(2H)—one (15 g, 0.0837 mol, 69% yield). MS (ESI) m/Z 179.03 .
B. 5-I0d0methylpyridazin-3(2H)—0ne. To 4,5-dichloro methylpyridazin-3(2H)-one (15 g, 83.79 mmol) was added 47% of aqueous hydroiodic add(l85rnL)andsfinedfor24hat1400C.Tothmieacfionnfixuuewmsadded s saturated sodium thiosulphate and ted with ethyl acetate (3 X 100 mL).
Theammnwdogmncbywswmewaflwdwfihwfimf2X50nfl)bfimfl50mLL dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography (100-200 silica) using 30-40% ethyl acetate in hexanes to afford 5-iodomethylpyridazin-3(2H)-one (8.5 g, 36.016 mmol, 43% yield). MS (ESI) m/Z 237.22 [M+l]+.
C. 1-tert-Butyl 3-ethyl 2-(1-methyl0x0-1,6-dihydr0pyridazin yl)malonate. To a suspension of sodium hydride (2.07 g, 86.44 mmol) in 1,4-dioxane (85 mL) at 10 0C was added drop wise tert-butylethyl malonate (7 g, 37.45 mmol) and d to warm to 25 CC over lh with stirring. 5-Iodomethylpyridazin-3(2H)-one (8.5 g, 36.016 mmol) was then added n wise at 25 OC and refluxed for 2h. The reaction mixture was diluted with ice cold water (100 mL) and extracted with ethyl mmmm(3X100mL)Theammnwdmgmncbywswmewaflwdwfihwfimfi50mL) brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography 00 silica) using 20-30% ethyl acetate in hexanes to afford 1-tert—butyl 3-ethyl 2-(1-methyloxo-1,6-dihydropyridazin yl)malonate (7 g, 23.64 mmol, 65% yield). MS (ESI) m/Z 296.97 [M+1]+.
D. 1-tert-Butyl 3-ethyl 2-flu0r0(1-methyl0x0-1,6- 0pyridazinyl)malonate. To a on of l-tert—butyl 3-ethyl 2-(6- pyridazinyl)malonate (7 g, 23.64 mmol) in tetrahydrofuran (100 mL) at 0 CC was added sodium hydride (1.2 g, 25.77 mmol). The reaction was stirred for 15min. A cloudy on of Fluor (9.12 g, 25.77 mmol) in N,N-dimethylformamide (dry mL) was added drop wise at 0 0C over a period of 10min and allowed stir at room temperature for 2h. The reaction was quenched with ammonium chloride (50 mL) and extracted with ethyl acetate (3 X 70 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography (100-200 silica) using -35% ethyl acetate in hexanes to afford 1-tert—butyl l 2-fluoro(1-methyl oxo-1,6-dihydropyridazinyl)malonate (5 g, 15.92 mmol, 67% yield). LCMS (ESI) m/Z 315.40 [M+1]+.
E. Ethyl 2-flu0r0(1-methyl0x0-1,6-dihydr0pyridazinyl)acetate.
A solution of 1-tert—butyl 3-ethyl 2-fluoro(1-methyloxo-1,6-dihydropyridazin yl)malonate (5 g, 15.92 mmol) in 25 mL trifluoroacetic acid/dichloromethane(1 :1) was stirred at room temperature for 4h. To this reaction mixture was added aqueous ted sodium bicarbonate solution and extracted with ethyl acetate (3 X 70 mL).
The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulphate and concentrated. The resultant residue was purified by column chromatography (100-200 silica) using 25-35% ethyl acetate in hexanes to afford ethyl 2-fluoro(1-methyloxo-1,6-dihydropyridazinyl)acetate (3 g, 32.71 mmol, 88% yield). LCMS (ESI) m/Z 215.13 [M+1]+.
F. Ethyl 2,2-diflu0r0(1-methyl0x0-1,6-dihydr0pyridazin yl)acetate. To a solution of ethyl 2-fluoro(1-methyloxo-1,6-dihydropyridazin yl)acetate (3 g, 32.71 mmol) in dry tetrahydrofuran (30 mL) was added lithium thyldisilylazide (16.8 mL, 39.25 mmol) drop wise at -78 0C over a period of 10min. After stirring for 15min at same temperature, a solution of SelectFluor (5.9 g, 16.8 mmol) in dry N,N-dimethylformamide (10 mL) was added drop wise over 10min.
Upon complete on, the reaction was allowed to warm to room temperature for 30min with stirring and ed with saturated ammonium chloride (50 mL). After evaporation of the organic fractions rotary evaporator, the on mixture was diluted with ice cold water (50 mL) and extracted with ethyl e (5 X 50 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over sodium sulphate and trated. The resultant residue was purified by CombiFlash column chromatography (100-200 silica) using 20-30% ethyl acetate in hexanes to afford ethyl 2,2-difluoro(1-methyloxo-1,6-dihydropyridazinyl)acetate (1.2 g, .17 mmol, 36% yield). LCMS (ESI) m/Z 233.39 [M+1]+.
G. 2,2-Diflu0r0(1-methyl0x0-1,6-dihydropyridazinyl)acetic acid. To a cold (0 oC) stirred solution of ethyl 2,2-difluoro(1-methyloxo-1,6- dihydropyridazinyl)acetate (1 .2g, 5.17 mmol) in 1,4-dioxane (36 mL) was added 3NammmmhwhmmbncmMsdman4mLyn5WhmdmnmdMHmm temperature for 16h. The reaction e was diluted with water (20 mL) and extracted with ethyl acetate (2 X 30 mL). The ed organic layers were washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated to afford 2,2-difluoro(1-methyloxo-1,6-dihydropyridazinyl)acetic acid (700 mg, 3.43 mmol, 66% yield) as off white solid. LCMS (ESI) m/z 205.02 .
H. N-((2-(2,6-Di0x0piperidinyl)—1-oxoisoindolin-S-yl)methyl)—2,2- difluoro-Z-(l-methyl0x0-1,6-dihydr0pyridazinyl)acetamide. To a cold (0 oC) stirred solution of fluoro(1-methyloxo-1,6-dihydropyridazinyl)acetic acid (197.6 mg, 0.968 mmol) in pyridine was added phosphoryl chloride (0.27 mL, 2.906 mmol) drop wise and stirred at 0-5 0C for 1h. To this reaction mixture was then added 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hloride (300 mg, 0.968 mmol) and stirred at room temperature for 30min. The reaction mixture was neutralized with aqueous saturated sodium bicarbonate (up to pH-8) and extracted with ethyl acetate (3 X 50 mL). The ed organic layers were washed with water (2 X 10 mL), brine (10 mL), dried over sodium sulphate and concentrated.
The resultant residue was purified by Reveleris C-18 reversed phase column chromatography using 40-60% acetonitrile in aqueous formic acid (0.1%) to afford N—((2-(2,6-dioxopiperidin-3 -yl)oxoisoindolin-5 -yl)methyl)-2,2-difluoro( 1 - methyloxo-1,6-dihydropyridazinyl)acetamide (70 mg, 0.152 mmol, 15% yield)as an off white solid. MS (ESI) m/Z 459.16 [M+1]+.1H NMR (300 MHZ, DMSO-d6) 5 ppm 10.98 (s, 1 H) 9.80 (br t, J=5.66 Hz, 1 H) 8.06 (d, J=2.19 Hz, 1 H) 7.70 (d, J=768HZ,1H)747@,1H)7400LJ=804HZ,1H)715@,1H)511@M, J=13J6,512Eb,1H)455—4230n¢4H)369@,1H)301—2820n,1H) 2.68 -2.45 (m, 1 H) 2.46 — 2.31 (m, 1 H) 2.06 — 1.93 (m, 1 H). elZl N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2-diflu0r0(3-(4- methylpiperazinyl)phenyl)acetamide A. Methyl 2—(3-br0mophenyl)acetate. To a solution of 2-(3- bromophenyl)acetic acid (25 g, 116.27 mmol) in dichloromethane (60 mL) were added oxalyl chloride (20 mL, 232.25 mmol) followed by N,N-dimethylformamide (1 mL) at 0 CC and stirred at room ature for 1h. The reaction mixture was concentrated, to this resulting residue was added ol (250 mL) and stirred at room temperature for 1h. The reaction mass was concentrated, the resulting e was quenched with saturated aqueous sodium bicarbonate (250 mL) and extracted with ethyl acetate (3 X 200 mL). The ed organic layers were washed with water (2 X 100 mL), brine (200 mL), dried over sodium sulphate and trated methyl 2-(3- bromophenyl)acetate (20 g, 87.71 mmol, 76 % yield) as a colorless liquid. LCMS (ESI) m/Z 270.29[M+42] +.(ACN adduct).
B. Ethyl 2-(3-(4-methylpiperazinyl)phenyl)acetate. To a degassed solution of methyl 2-(3-bromophenyl)acetate (20 g, 87.71 mmol) in toulene (250 mL) was added 1-methylpiperazine (10.52 g, 105.52 mmol), cesium carbonate (40 g, 122.79 mmol) and ed for 30min. To this reaction mixture was then added 2,2’-bis(diphenylphosphino)—1,1’-binaphthalene (818 mg, 1.31 mmol), Palladium(II) acetate (590 mg, 0.877 mmol) and stirred at 110 0C for 16h. The reaction mixture was filtered through Celite pad, filtrate was concentrated, diluted with water (300 mL) and extracted with ethyl acetate (3 X 200 mL). The combined organic layers were washed with water (200 mL) and brine (150 mL), dried over sodium te, the organic layer was concentrated under reduced pressure to get crude residue which was purified by CombiFlash column chromatography (100-200 silica) using 21-24 % methanol in dichloromethane to afford ethyl 2-(3-(4-methylpiperazinyl)phenyl)acetate (4.0 g, 16.12 mmol, 19% yield) as a brown colour solid. LCMS (ESI) m/z 249.26[M+1] +.
C. Ethyl 2,2-diflu0r0(3-(4-methylpiperazinyl)phenyl)acetate. To a solution of ethyl 2-(3 -(4-methylpiperazinyl)phenyl)acetate (4 g, 16.12 mmol) in dry tetrahydtofuran (80 mL) was added m hexamethyldisilamide (1M in tetrahydrofuran) (24 mL, 24.18 mmol) dropwise at -78 CC and stirred for 15min. To this a solution ofN—fluorodibenzenesulfonimide (7.6 g, 24.18 mmol) in dry tetrahydrofuran (20 mL) was added drop wise over a period of 10min. Upon completion addition, the reaction was allowed to warm to room temperature over a period of 30 min and stirred for 1h at room temperature. The reaction was quenched with saturated ammonium chloride (50 mL) diluted with ice cold water (100 mL) and extracted with ethyl acetate (2 X 200 mL). The ed organic layers were washed with brine (100 mL), dried over sodium sulphate and concentrated to afford ethyl 2,2- difluoro(3-(4-methylpiperazinyl)phenyl)acetate (2.2 g, 8.87 mmol) as a light brown color solid. LCMS (ESI) m/Z 285.40 [M+1]+.
D. 2,2-Diflu0r0(3-(4-methylpiperazinyl)phenyl)acetic acid. To a cold (0 oC) stirred solution of ethyl 2,2-difluoro(3-(4-methylpiperazin yl)phenyl)acetate (2.0 g, 7.04 mmol) in tetrahydrofuran : methanol : water mixture (1 : 1 :1, 30 mL) was added m hydroxide monohydrate (504 mg, 21.12 mmol) and stirred at room temperature for 2h. The reaction e was concentrated and the mmmwwasmmwdwfihwmmrQOnflJmmwmflwdwfihdmmybmmf2X50mL) Aqueous layer neutralized with 10% aqueous potassium bisulphate (15 mL) and put the lyophillization to give 2,2-difluoro(3-(4-methylpiperazinyl)phenyl)acetic acid (1.2 g, 4.44 mmol). LCMS (ESI) m/Z 270.11[M+1]+.
E. N-((2-(2,6-di0x0piperidinyl)—1-oxoisoindolinyl)methyl)—2,2- diflu0r0(3-(4-methylpiperazinyl)phenyl)acetamide. To a cold (0 oC) d on of 2,2-difluoro(3-(4-methylpiperazinyl)phenyl)acetic acid (524 mg, 1.94 mmol) in pyridine (10 mL) was added phosphoryl chloride (0.45 mL, 4.83 mmol) at 0-5 CC and stirred at same temperature for 1h. Then added 3-(5-(aminomethyl)oxoisoindolinyl)piperidine-2,6-dione hydrochloride (500 mg, 1.61 mmol) and stirred at room temperature for 1h. The reaction mixture was trated. The resultant residue was purified by PREP-HPLC ((Atlantz's-T3 column) using acetonitrile — 0.1% of ammonium onate in water as eluent). After lyophillization LCMS indicated 84% of desired m/z, 16% of ring opended m/z was observed, which was further d by CombiFlash column chromatography using 6-7% methanol in romethane to afford N—((2-(2,6-dioxopiperidinyl) oxoisoindolinyl)methyl)-2,2-difluoro(3-((4-methylpiperazin medMfimmm®mmmmMe65ngJHm7nmmL4%ymMflmamfwmwde.
LCMS (ESI) m/z 526.39 [M+1]+. 1H NMR (300MHz, DMSO-d6) 5 = 11.00 (s, 1H), 9.59 (br t, J=6.1 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.45 — 7.29 (m, 3H), 7.11 (br d, J=8.4 Hz, 1H), 7.04 (s, 1H), 6.97 (br d, J=7.7 Hz, 1H), 5.11 (br dd, J=5.1, 13.2 Hz, 1H), 4.53 — 4.34 (m, 3H), 4.33 — 4.21 (m, 1H), 3.42 - 3.26 (m, 4H), 3.14 (br s, 4H), 3.00 — 2.84 (m, 1H), 2.66 — 2.66 (m, 1H), 2.42 — 2.33 (br dd, J=4.2, 13.0 Hz, 1H), 2.27 (br s, 3H), 2.06 — 1.92 (m, 1H).
Example 123 EFFECT OF TEST COMPOUNDS ON KG-l CELL PROLIFERATION The anti-proliferative activity of the test compound was evaluated on KG-l cell line (American Type Culture Collection [ATCC]: catalogue number ATCC® CCL- 246TM) at 72 hours reatment. The seeding density for KG-l was optimized to ensure assay linearity in 384-well plates.
Increasing concentrations of the test compound (0.5 nM to 10 uM) were spotted in a 10-point serial dilution fashion d dilution) in duplicate Via an acoustic dispenser (EDC 0) into an empty 384-well plate. The yl sulfoxide (DMSO) concentration was kept constant for a final assay concentration of 0.1% DMSO. Prior to testing, KG-l cells were grown in RPMI-1640 ll Park Memorial Institute — 1640) medium with 10% FBS (fetal bovine serum: HyClone) and expanded in culture flasks to provide sufficient amounts of ng material. Cells were then diluted to 5000 cells per well, in a 50 [LL volume and added directly to the compound-spotted 384-well plates.
Cells were allowed to grow for 72 hours in 5% C02 at 37°C. At the time when exposure of cells to compound began (to), initial viable cell number was assessed via Cell Titer- Glo® Luminescent Cell Viability Assay at a 1 vol: 2 vol ratio according to manufacturer’s instructions (Promega Corporation, Madison, WI) by quantifying the level of luminescence generated by adenosine-5’-triphosphate (ATP) present in viable cells. After 72 hours, cell Viability of t -treated cells was ed Via Cell Titer-Glo® and read for luminescence. IC50 values for exemplary nds are provided in Table 1. 2015/039926 In Table l, IC50 values as provided as below: A: < 0.01 HM; B: 0.01 to 0.05 HM; C: > 0.05 HM to 01 0M; and D: > 0.1 "M to HM.
Table 1 Compound FCA Prolif Cell TiterGlo KG-l 72h 2-(3-chloromethylphenyl)- N—((2-(2,6-dioxopiperidin-3 - yl)oxoisoindolin yl)methyl)-2,2- difluoroacetamide 2-(4-chlorophenyl)-N—((2-(2,6- 462.0 dioxopiperidin-3 -yl) indolin-S-yl)methyl)-2,2- difluoroacetamide N—((2-(2,6-dioxopiperidin 45 8 2 yl)oxoisoindolin yl)methyl)-2,2-difluoro(4- methoxyphenyl)acetamide 2-(3-chlorophenyl)-N—((2-(2,6- 462.2 dioxopiperidin-3 -yl) oxoisoindolin-S-yl)methyl)-2,2- difluoroacetamide Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(4- fluorophenyl)acetamide N-((2-(2,6-di0x0piperidin y1)0x0isoind01in-5 - hyl)-2,2-difluoro-Z-p- tolylacetamide 2-(3,4-dich10r0phenyl)-N-((2- (2,6-di0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide 2-(2-ch10r0phenyl)-N—((2-(2,6- 462.0 dioxopiperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide N—((2-(2,6-di0x0piperidin-3 - y1)- 1 oind01in-5 - yl)methyl)-2,2-diflu0r0(2- (trifluoromethyl)phenyl)acetam —304_ Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) 2-(4-tert-butylphenyl)-N-((2— (2,6-di0x0piperidin-3 - oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide (2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methy1)-2,2—difluoro-Z- phenylacetamide 2-(3 -ch10r0flu0r0phenyl)-N- ((2-(2,6-di0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(4- (trifluoromethylthi0)phenyl)ace tamide 2-(2,6-diflu0r0pheny1)-N—((2- (2,6-di0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) N-((2-(2,6-di0x0piperidin y1)- 1 oind01in-5 - y1)methy1)-2,2-difluoro-Z-otolylacetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - hyl)-2,2-diflu0r0(2- fluorophenyl)acetamide N-((2-(2,6-di0x0piperidin y1)0x0isoind01in-5 - yl)methyl)(2-ethoxyphenyl)- 2,2-diflu0r0acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(2- (trifluoromethoxy)pheny1)aceta mide 2-(3-br0m0 (trifluoromethoxy)phenyl)-N- ((2-(2,6-di0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) 2-(3-chlor0meth0xypheny1)- 492.5 N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methy1)-2,2— difluoroacetamide N-((2-(2,6-di0x0piperidin y1)0x0isoind01in-5 - yl)methy1)-2,2—difluoro-Z-m- tolylacetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(4- isopropoxyphenyl)acetamide 2-(3,4-diflu0r0pheny1)-N-((2- (2,6-di0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- oacetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - hy1)-2,2—diflu0r0(3 - fluorophenyl)acetamide Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2—diflu0r0(3 - (trifluoromethyl)pyridin yl)acetamide (2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(4- isopropylphenyl)acetamide 2-(2,4-dich10r0phenyl)-N-((2- (2,6-di0x0piperidin-3 - oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(2- methoxyphenyl)acetamide 2-(4-cyclopr0pylpheny1)-N-((2- 468.1 (2,6-di0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide Compound Name MH+ FCA Prolif Cell TiterGlo KG-l 72h (ICso) 2-(4-ch10r0flu0r0pheny1)-N— 480.1 ((2-(2,6-di0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide 2-(4-ch10r0-3 -flu0r0pheny1)-N— 480.1I ((2-(2,6-di0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- oacetamide N-((2-(2,6-di0x0piperidin 4601I y1)- 1 oind01in-5 - y1)methy1)-2,2-diflu0r0-2—(3- flu0r0 methylphenyl)acetamide 2-(3-ch10r0methylphenyl)- 4761 N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methy1)-2,2— difluoroacetamide (2,6-di0x0piperidin 514.1I y1)0x0isoind01in-5 - yl)methyl)-2,2—diflu0r0(4- flu0r0 (trifluoromethyl)phenyl)acetam Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) 2-(4-ch10r0methylphenyl)- N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methy1)-2,2— difluoroacetamide (2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - hyl)-2,2-diflu0r0(4- flu0r0 methylphenyl)acetamide 2-(4-ch10r0 (trifluoromethyl)pheny1)-N-((2- (2,6-di0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide 2-cyclohexy1-N-((2-(2,6- dioxopiperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide 2-(4-ch10r0 (trifluoromethoxy)phenyl)-N- ,6-di0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide Compound Name FCA Prolif Cell TiterGlo KG-l 72h (ICso) N-((2-(26-dioxopiperidin 502O y1)- 1- oxoisoindolin yl)methy1)-2,2-diflu010(3- methoxyethoxy)pheny1)acetami (2,6-diox0piperidin 488.1 y1)0xoisoindolin yl)methy1)-2,2-diflu010(3- hydroxyethoxy)phenyl)acetami N—((2-(2,6-diox0piperidin 502.1 y1)0xoisoindolin yl)methyl)-2,2-difluoro(4- yethoxy)pheny1)acetami N—((2-(2,6-diox0piperidin 472.1 y1)0xoisoindolin y1)methyl)-2,2-difluoro(3 - hydroxyethyl)phenyl)acetamide 2-(3 -(dimethy1amin0)phenyl)- 470. 8 N—((2-(2,6-diox0piperidin-3 - y1)0xoisoindolin yl)methy1)-2,2- difluoroacetamide Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2—diflu0r0(3 - (piperidin yl)pheny1)acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2—diflu0r0(3 - linophenyl)acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(4- flu0r0 isopropoxyphenyl)acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(2- (2,2,2- trifluoroethoxy)pheny1)acetami N—((2-(2,6-di0x0piperidin-3 - y1)- 1 oind01in-5 - yl)methy1)-2—(2—ethoxy fluoropheny1)-2,2- difluoroacetamide Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(2- poxyphenyl)acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(2- flu0r0 isopropoxyphenyl)acetamide N-((2-(2,6-di0x0piperidin y1)0x0isoind01in-5 - y1)methy1)-2,2-diflu0r0-2—(3- (morpholinomethy1)pheny1)acet amide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(4- flu0r0(2,2,2- trifluoroethoxy)pheny1)acetami N—((2-(2,6-di0x0piperidin-3 - y1)- 1 oind01in-5 - yl)methyl)-2,2-diflu0r0(4- isoprop0xy methylphenyl)acetamide nd FCA Prolif Cell TiterGlo KG-l 72h (ICso) N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(4- isopropoxy-3 - methylphenyl)acetamide N-((2-(2,6-di0x0piperidin y1)0x0isoind01in-5 - y1)methy1)-2,2-diflu0r0(3- flu0r0 poxyphenyl)acetamide 2-(3-ch10r0 isopropoxyphenyl)-N-((2-(2,6- dioxopiperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(2- methyl (trifluoromethoxy)phenyl)aceta mide N-((2-(2,6-di0x0piperidin y1)- 1 oind01in-5 - yl)methyl)-2,2—diflu0r0(2- flu0r0 (trifluoromethoxy)phenyl)aceta mide —314— Compound Name FCA Prolif Cell TiterGlo KG-l 72h (ICso) 2-(5-chloropyridiny1)-N-((2- 4627 (26-dioxopiperidin-3 --y1) 1- oxoisoindoliny1)methy1) difluoroacetamide N—((2-(2,6-diox0piperidin 4467 y1)0xoisoindolin-5 - y1)methy1)-2,2-difluoro(5- fluoropyridiny1)acetamide 2-(2,4-diflu010pheny1)-N-((2- 463.7 (2,6-diox0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide 2-(4-brom0pheny1)-N—((2-(2,6- 505.6 C dioxopiperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide (2,6-diox0piperidin 502.3 y1)0xoisoindolin-5 - hyl)-2,2-difluoro(2- methoxyethoxy)pheny1)acetami Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) N—((2-(2,6-di0x0piperidin-3 - y1)- 1 oind01in-5 - y1)methyl)-2,2-diflu0r0-2—(1 - hydroxycyclohexyl)acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methyl)-2,2-diflu0r0-2—(1 - ycyclopentyl)acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2—diflu0r0(3 - methyl (trifluoromethoxy)phenyl)aceta mide N—((2-(2,6-di0x0piperidin-3 - y1)oxoisoindolin-S - yl)methyl)(3 -ethoxypyridin- 2-y1)-2,2-diflu0r0acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2—diflu0r0(3 - methylpyridin-Z-yl)acetamide Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2—diflu0r0(5 - methylpyridin-Z-yl)acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methy1)-2—(2—ethoxy fluoropheny1)-2,2- oacetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methyl)-2,2-diflu0r0(4'- fluorobiphenyly1)acetamide N—((2-(2,6-di0x0piperidin-3 - y1)oxoisoindolin-S - hy1)-2—(2—ethoxy-S - fluoropheny1)-2,2- difluoroacetamide 2-cyclopentyl-N-((2-(2,6- dioxopiperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide nd FCA Prolif Cell TiterGlo KG-l 72h (ICso) 2-(3-ch10r0 (trifluoromethoxy)phenyl)-N- ((2-(2,6-di0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide N-((2-(2,6-di0x0piperidin y1)0x0isoind01in-5 - yl)methyl)-2,2—diflu0r0(4- methoxy-Z- oromethyl)phenyl)acetam N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(2- hydroxyethoxy)phenyl)acetami 2-(4-ch10r0eth0xyphenyl)- N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methy1)-2,2— difluoroacetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(2- hydroxyphenyl)acetamide Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(2- (methylamin0)pheny1)acetamid N—((2-(2,6-di0x0piperidin-3 - y1)- 1 oind01in-5 - yl)methyl)-2,2-diflu0r0(4- isoprop0xy (trifluoromethyl)phenyl)acetam N-((2-(2,6-di0x0piperidin y1)0x0isoind01in-5 - yl)methyl)-2,2—diflu0r0(4- methylcyclohexyl)acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - hy1)-2,2-diflu0r0(3 - isopropoxyethoxy)phenyl)aceta mide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2—diflu0r0(3 - hydroxyphenyl)acetamide nd FCA Prolif Cell TiterGlo KG-l 72h (ICso) (2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2—diflu0r0(3 - ((4-methylpiperazin yl)methyl)pheny1)acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(4- methyl (trifluoromethyl)phenyl)acetam N-((2-(2,6-di0x0piperidin y1)0x0isoind01in-5 - y1)methy1)-2,2-diflu0r0-2—(3- (2-(2- methoxyethoxy)ethoxy)pheny1) acetamide 2-(3 - (2- (dimethylamino)ethoxy)pheny1) -N-((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methy1)-2,2— difluoroacetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2-diflu0r0(5 - isopropylpyridin-Z- yl)acetamide Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2—diflu0r0(3 - (methylsulfonyl)ethoxy)phenyl) acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2—diflu0r0(3 - (3 - (methylsulfonyl)pr0pyl)phenyl) acetamide (2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methyl)-2,2-diflu0r0(4- (2-flu0r0pr0pan yl)pheny1)acetamide 2—(1-benzy10x0-1,6- dihydropyridin-3 -y1)-N-((2— i0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - hy1)-2,2—diflu0r0(5 - methoxypyridin-Z-y1)acetamide Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) N-((2-(2,6-di0x0piperidin y1)0x0isoind01in-5 - y1)methyl)-2,2-diflu0r0-2—(1 - 0x0-1,6- opyridin-3 -y1)acetamide 2-(5-tert-buty1pyridiny1)-N- ((2-(2,6-di0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide 2-(5-cyc10pr0py1pyridiny1)- N—((2-(2,6-di0x0piperidin-3 - y1)- 1 oind01in-5 - yl)methy1)-2,2— difluoroacetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2-diflu0r0(5 - isopropoxypyridin-Z- yl)acetamide 2-(5-br0m0pyridiny1)-N—((2- 507.8 (2,6-di0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide nd Name FCA Prolif Cell TiterGlo KG-l 72h (ICso) N-((2-(26-dioxopiperidin 530. 1 y1)- 1- oxoisoindolin y1)methyl)difluoro(4- (trifluoromethoxy)pheny1)aceta mide N—((2-(2,6-diox0piperidin 452.2 y1)0xoisoindolin yl)methyl)-2,2-difluoro(4- fluorocyc10hexy1)acetamide N—((2-(2,6-diox0piperidin 506.1 y1)0xoisoindolin yl)methyl)-2,2-difluoro(4- (methylsulfonyl)phenyl)acetam N—((2-(2,6-diox0piperidin 506.0 y1)0xoisoindolin y1)methyl)-2,2-difluoro(3 - (methylsulfonyl)phenyl)acetam 2-(2-amin0pyrimidiny1)-N- 445.4 ((2-(2,6-diox0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) N—((2-(2,6-di0x0piperidin-3 - y1)- 1 oind01in-5 - y1)methy1)-2,2—diflu0r0(5 - oromethylthio)pyridin-Z- yl)acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2-diflu0r0(3 - (methylamino)ethoxy)phenyl)a cetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methyl)-2,2-diflu0r0-2—(1 - methyl0x0-1,6- dihydropyridazin-3 - yl)acetamide 2-(2—amin0pyrimidiny1)-N- ((2-(2,6-di0x0piperidin-3 -y1) oxoisoindolin-S-y1)methy1)-2,2- difluoroacetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - yl)methy1)-2,2—difluoro-Z- (pyrimidiny1)acetamide —324— Compound FCA Prolif Cell TiterGlo KG-l 72h (ICso) N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2—diflu0r0(3 - (2-(piperidin— 1 - yl)eth0xy)phenyl)acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - hy1)-2,2—diflu0r0(3 - morpholinoethoxy)pheny1)aceta mide 2-(3 -(2-(4,4-diflu0r0piperidiny1)ethoxy)phenyl)-N—((2- (2,6-di0x0piperidin-3 -y1) indolin-S-y1)methy1)-2,2- difluoroacetamide (2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methyl)-2,2-diflu0r0-2—(1 - methyl0x0-1,6- dihydropyridazin yl)acetamide N—((2-(2,6-di0x0piperidin-3 - y1)0x0isoind01in-5 - y1)methy1)-2,2—diflu0r0(3 - (4-methylpiperazin- 1- yl)pheny1)acetamide ] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine mentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.
Compounds of the ion are for use in medicine.
Compounds of the invention are for use in the methods of treatment provided herein.

Claims (33)

What we claim is:
1. A compound of Formula I: or an enantiomer or a mixture of enantiomers thereof, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: R1 is optionally substituted monocyclic C3-10 cycloalkyl, optionally substituted monocyclic C6-18 aryl, ally substituted monocyclic heteroaryl, or optionally substituted monocyclic heterocyclyl; R2 and R3 are each halo; where the substituents on R1, when present, are one to three groups Q, where each Q is independently C1-6 alkyl, halo, halo C1-6 alkyl, oxo, optionally substituted monocyclic C3-10 cycloalkyl, optionally substituted monocyclic C3-10cycloalkylC1-6 alkyl, optionally substituted monocyclic heterocyclyl, optionally substituted monocyclic heterocyclyl C1-6 alkyl, optionally substituted monocyclic C6-18 aryl, optionally substituted monocyclic heteroaryl, -R4OR5, - R4O-R4OR5, -R4N(R6)(R7), -R4SR5, - R4OR4N(R6)(R7), -R4OR4C(J)N(R6)(R7), -C(J)R9 or R4S(O)tR8; where the substituents on Q, when present are one to three groups Qa, where each Qa is independently C1-6 alkyl, halo, halo C1-6 alkyl, C1-6 alkoxy C1-6 alkyl, oxo, hydroxyl or C1-6 alkoxy; each R4 is independently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is ndently hydrogen, C1-6 alkyl, halo C1-6 alkyl, hydroxy C1-6 alkyl, C1-6 alkoxy C1-6 alkyl, monocyclic C3-10 cycloalkyl, monocyclic C6-18 aryl, clic aryl, monocyclic cyclyl or monocyclic heterocyclyl C1-6 alkyl, where y C1- 6 alkyl, C1-6 alkoxy C1-6 alkyl, C3-10 cycloalkyl, C6-18 aryl, aryl, heterocyclyl or heterocyclyl C1-6 alkyl groups in R5 are each independently optionally tuted with 1-3 Q1 groups, where each Q1 is independently C1-6 alkyl, halo C1-6 alkyl or halo; where the heterocyclyl in R1, Q and R5 is a 3 to 15 ed heterocyclyl containing one to five heteroatoms selected from a group consisting of en, oxygen and sulfur; and the heteroaryl in R1, Q and R5 is a 5 to 15 membered aryl containing one to five heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur; R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or C1-6 alkyl; or ii) R6 and R7 er with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, C1-6 alkyl or halo C1-6 alkyl; R8 is C1-6 alkyl, halo C1-6 alkyl, or hydroxy C1-6 alkyl; R9 is C1-6 alkyl or C6-18 aryl; J is O or S; and t is 1 or 2.
2. The compound of claim 1, wherein R1 is ally substituted monocyclic C6- 18 aryl.
3. The compound of claim 1 having Formula II: or an enantiomer or a mixture of enantiomers f, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: R1 is optionally substituted monocyclic C3-10 lkyl, ally substituted monocyclic C6-18 aryl, optionally substituted monocyclic heteroaryl or optionally substituted monocyclic heterocyclyl; the heterocyclyl in R1 is a 3 to 15 membered heterocyclyl containing one to five heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur; and the heteroaryl in R1 is a 5 to 15 membered heteroaryl ning one to five heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur where the substituents on R1, when present, are one to three groups Q, where each Q is independently C1-6 alkyl, halo, halo C1-6 alkyl, optionally substituted clic C3-10 cycloalkyl, optionally substituted monocyclic C3-10 cycloalkyl C1-6 alkyl, optionally substituted monocyclic C6-18 aryl, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl or hydroxy C1-6 alkyl; R6 and R7 are selected as follows: i) R6 and R7 are each ndently hydrogen or C1-6 alkyl; or ii) R6 and R7 er with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, C1-6 alkyl or halo C1-6 alkyl.
4. The compound of claim 1, wherein R1 is optionally substituted monocyclic C6-18 aryl; where the tuents on R1, when t, are one to three groups Q, where each Q is independently C1-6 alkyl, halo, halo C1-6 alkyl, optionally tuted monocyclic C3-10 cycloalkyl, optionally substituted monocyclic C3-10 cycloalkyl C1-6 alkyl, optionally tuted monocyclic C6-18 aryl, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl or hydroxy C1-6 alkyl; R6 and R7 are selected as s: i) R6 and R7 are each independently hydrogen or C1-6 alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, C1-6 alkyl or halo C1-6 alkyl.
5. The compound of claim 1, wherein R1 is ally substituted phenyl, optionally substituted cyclohexyl, optionally substituted piperidinyl, or optionally substituted pyridyl, where the substituents on R1, when present, are one to three groups Q, where each Q is independently halo, C1-6 alkyl, -R4OR5 or -R4N(R6)(R7); each R4 is independently a direct bond or C1-8 alkylene; each R5 is independently hydrogen, C1-6 alkyl, or halo C1-6 alkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or C1-6 alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl ring.
6. The nd of claim 1, wherein R1 is ally substituted phenyl, where the substituents on R1, when present, are one to three groups Q, where each Q is ndently fluoro, chloro, , tert butyl, -R4OR5, -R4SR5 or R4OR4C(J)N(R6)(R7); each R4 is independently a direct bond or methylene; each R5 is independently hydrogen, methyl, ethyl or oromethyl; and R6 and R7 are each independently hydrogen or methyl.
7. The compound of claim 1, wherein the compound has formula III or an enantiomer or a mixture of enantiomers thereof, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, ate, or polymorph thereof, wherein: each Q1 is independently C1-6 alkyl, halo, halo C1-6 alkyl, optionally substituted monocyclic C3-10 cycloalkyl, optionally substituted monocyclic C3-10 cycloalkylalkyl, optionally substituted monocyclic C6-18 aryl, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl or y C1-6 alkyl; R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or C1-6 alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, C1-6 alkyl or halo C1-6 alkyl; and n is 0-3.
8. The compound of claim 1, wherein the compound has formula IV or an enantiomer or a mixture of enantiomers thereof, a pharmaceutically able salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: Q2 is hydrogen, C1-6 alkyl, halo, haloalkyl, optionally substituted monocyclic C3-10 cycloalkyl, optionally substituted clic C3-10 cycloalkyl C1-6 alkyl, optionally substituted monocyclic C6-18 aryl, -R4OR5, , -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl or hydroxy C1-6 alkyl; R6 and R7 are each independently hydrogen or C1-6 alkyl.
9. The compound of claim 1, wherein the compound has formula V or an enantiomer or a mixture of enantiomers thereof, a ceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph f, wherein: Q3 and Q4 are each independently hydrogen, C1-6 alkyl, halo, halo C1-6 alkyl, optionally substituted monocyclic C3-10 cycloalkyl, optionally substituted monocyclic C3-10 cycloalkylalkyl, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or (J)N(R6)(R7); J is O or S; each R4 is independently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl, hydroxy C1-6 alkyl,or C1-6 alkoxy C1-6 alkyl; and R6 and R7 are each independently hydrogen or C1-6 alkyl.
10. The nd of claim 1, wherein the nd has formula VI or an enantiomer or a mixture of enantiomers thereof, a pharmaceutically acceptable salt, solvate, e, co-crystal, clathrate, or polymorph thereof, wherein: Q4 and Q5 are each ndently hydrogen, C1-6 alkyl, halo, halo C1-6 alkyl, optionally tuted monocyclic C3-10 cycloalkyl, optionally substituted monocyclic C3-10 cycloalkyl C1-6 alkyl, -R4OR5, -R4SR5, -R4N(R6)(R7), R4OR4N(R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is independently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy C1-6 alkyl or hydroxy C1-6 alkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or C1-6 alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, C1-6 alkyl or halo C1-6 alkyl.
11. The compound of claim 10, wherein Q4 and Q5 are each ndently hydrogen, halo, C1-6 alkyl, -R4N(R6)(R7), or -R4OR5; R4 is a direct bond or C1-8 alkylene; R5 is hydrogen, C1-6 alkyl or halo C1-6 alkyl; and R6 and R7 together with the nitrogen atom on which they are substituted form a ered heterocyclyl.
12. The compound of claim 1, wherein the compound has formula VII or an enantiomer or a e of enantiomers thereof, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: Q5 is hydrogen, C1-6 alkyl, halo, halo C1-6 alkyl, ally substituted monocyclic C3- 4OR5, -R4SR5, - 10 cycloalkyl, optionally substituted monocyclic C3-10cycloalkylC1-6alkyl, -R R4N(R6)(R7), (R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is ndently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy C1-6 alkyl or hydroxy C1-6 alkyl; and R6 and R7 are selected as follows: i) R6 and R7 are each independently hydrogen or C1-6 alkyl; or ii) R6 and R7 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two halo, C1-6 alkyl or halo C1-6 alkyl.
13. The compound of claim 11, wherein Q5 is hydrogen, halo, C1-6 alkyl, - )(R7) or -R4OR5; R4 is a direct bond or C1-8 alkylene; and R5 is hydrogen, C1-6 alkyl or halo C1-6 alkyl; and R6 and R7 together with the nitrogen atom on which they are tuted form a 6-membered heterocyclyl.
14. The nd of claim 1, wherein the compound has formula VIII VIII or an enantiomer or a mixture of enantiomers thereof, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein: Q2 and Q5 are each independently hydrogen, C1-6 alkyl, halo, halo C1-6 alkyl, optionally substituted monocyclic C3-10 cycloalkyl, optionally substituted monocyclic C3-10 cycloalkyl C1-6 alkyl, optionally substituted C6-18 aryl, -R4OR5, -R4SR5, -R4N(R6)(R7), (R6)(R7) or R4OR4C(J)N(R6)(R7); J is O or S; each R4 is ndently C1-8 alkylene, C2-8 alkenylene or a direct bond; each R5 is independently hydrogen, C1-6 alkyl, halo C1-6 alkyl or hydroxy C1-6 alkyl; R6 and R7 are each independently hydrogen or C1-6 alkyl, or R6 and R7 together with the nitrogen atom on which they are substituted form a 6-membered heterocyclyl.
15. The compound claim 14, wherein Q2 and Q5 are each independently hydrogen, halo, C1-6 alkyl, optionally substituted C6-18 aryl, or -R4OR5; R4 is a direct bond or C1-8 alkylene; and R5 is en, C1-6 alkyl or halo C1-6 alkyl.
16. The compound of claim 1, wherein the compound is selected from Table 1.
17. The compound of claim 1, wherein the nd is selected from N-((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoro(4- methoxyphenyl)acetamide; 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoroacetamide; 2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- difluoroacetamide; N-((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoro(4- fluorophenyl)acetamide; and 2-(2-chlorophenyl)-N-((2-(2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2- roacetamide; or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
18. The compound of claim 1, wherein the compound is (2,6- dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoro(4- methoxyphenyl)acetamide.
19. The compound of claim 1, wherein the compound is 2-(4-chlorophenyl)-N-((2- (2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoroacetamide.
20. The compound of claim 1, wherein the nd is 2-(3-chlorophenyl)-N-((2- (2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoroacetamide.
21. The nd of claim 1, wherein the compound is N-((2-(2,6- dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoro(4-fluorophenyl)acetamide.
22. The compound of claim 1, wherein the compound is hlorophenyl)-N-((2- (2,6-dioxopiperidinyl)oxoisoindolinyl)methyl)-2,2-difluoroacetamide.
23. A pharmaceutical composition sing a therapeutically effective amount of a nd of any one of claims 1-22 and a pharmaceutically acceptable excipient,
24. Use of the compound of any one of claims 1-22 in the manufacture of a medicament for the ent of cancer.
25. The use of claim 24, wherein the cancer is leukemia.
26. The use of claim 25, wherein the leukemia is chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia or acute myeloid leukemia.
27. The use of claim 25, wherein the ia is an acute myeloid ia.
28. The use of claim 25, wherein the leukemia is relapsed, refractory or resistant to conventional therapy.
29. The use of claim 24, wherein the medicament is for administering in combination with another second active agent or a t care therapy.
30. The use of claim 29, wherein the other second active agent is a therapeutic antibody that specifically binds to a cancer antigen, hematopoietic growth factor, cytokine, anti-cancer agent, antibiotic, cox-2 tor, immunomodulatory agent, immunosuppressive agent, corticosteroid or a pharmacologically active mutant or derivative thereof.
31. A compound of any one of claims 1-22 for use as a medicament.
32. A compound according to claim 1 substantially as herein described or exemplified.
33. A use according to claim 24 substantially as herein described or exemplified.
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