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COMPOUNDS AND USES THEREOF

20230145003 · 2023-05-11

    Inventors

    Cpc classification

    International classification

    Abstract

    The present disclosure features compounds useful for the treatment of BAF complex-related disorders.

    Claims

    1. A compound having the structure: ##STR00679## wherein A is ##STR00680## m is 0, 1, 2, or 3; n is 1 or 2; o is 0 or 1; X is O, CH.sub.2, or NR.sup.7; X′ is N, CH, or CR.sup.X, wherein R.sup.X is a halogen; B is an optionally substituted 6-membered monocyclic heteroarylene or an optionally substituted 9- or 10-membered bicyclic heteroarylene; L is a covalent bond, optionally substituted C.sub.1-C.sub.3 alkylene, C.sub.2 alkynylene, optionally substituted C.sub.2 alkenylene, optionally substituted C.sub.2-C.sub.3 heteroalkylene, optionally substituted C.sub.3-C.sub.5 cycloalkylene, or optionally substituted 4- to 10-membered heterocyclylene; C is optionally substituted 3- to 10-membered cycloalkyl; optionally substituted 6- to 10-membered aryl; optionally substituted 5- to 10-membered heteroaryl; or optionally substituted 5- to 10-membered heterocyclyl; R.sup.1 and R.sup.7 are, independently, hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl; each R.sup.2 and R.sup.3 is independently, hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl; or optionally substituted C.sub.1-C.sub.6 heteroalkyl; R.sup.4 is cyano, fluoro, hydroxy, or —CH.sub.2OH; R.sup.5 is C.sub.1-C.sub.3 alkyl optionally substituted with one, two, three, four, five, six, or seven fluoro groups; and R.sup.6 is C.sub.1-C.sub.3 alkyl optionally substituted with one, two, three, four, five, six, or seven fluoro groups, or a pharmaceutically acceptable salt thereof.

    2. The compound of claim 1, wherein R.sup.1 is hydrogen.

    3. The compound of claim 1, wherein m is 1.

    4. The compound of claim 1, wherein R.sup.3 is hydrogen.

    5. The compound of claim 1, wherein R.sup.2 is hydrogen.

    6. The compound of claim 1, wherein R.sup.2 is optionally substituted C.sub.1-C.sub.6 heteroalkyl.

    7. (canceled)

    8. The compound of claim 1, wherein R.sup.2 is optionally substituted C.sub.1-C.sub.6 heteroalkyl.

    9. (canceled)

    10. (canceled)

    11. (canceled)

    12. The compound of claim 1, wherein A is ##STR00681##

    13.-26. (canceled)

    27. The compound of claim 12, wherein A is ##STR00682## ##STR00683##

    28. The compound of claim 1, wherein C is optionally substituted 3- to 10-membered cycloalkyl.

    29. (canceled)

    30. The compound of claim 1, wherein C is optionally substituted 6- to 10-membered aryl.

    31. The compound of claim 30, wherein C is phenyl, 3-difluoromethyl-phenyl, 4-dilfluoromethylphenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 3,5-difluorophenyl, 3-difluoromethylphenyl, 2-methoxy-5-methyl-phenyl, 2-methoxy-4-chloro-phenyl, 3-cyano-phenyl, 3-fluoro-5-methoxy-phenyl, 3-fluoro-5-azitidinyl-phenyl, 3-azetidyl-phenyl, 4-azetidyl-2-methoxy-phenyl, 4-morpholin-4-yl-2-methoxy-phenyl, 4-tert-butyl-2-methoxy-phenyl, 4-azetidyl-phenyl, 2-methoxy-4-oxetan-3-yl-phenyl, 2-azetidin-2-one-1-yl-phenyl, 3-(3-difluoromethyloxetan-3-yl)-phenyl, 3-(3-methoxyoxetan-3-yl)-phenyl, 3-(N-methyl-N-acetamido)-phenyl, 3-cyclopropylphenyl, 3-(N-methylazetidin-3-yl)-phenyl, 3-(N-methyl-N′-piperazinyl)-phenyl, 3-fluoro-5-azetidyl-phenyl, 3-methyl ester-phenyl, ##STR00684##

    32. The compound of claim 1, wherein C is optionally substituted 5- to 10-membered heteroaryl.

    33. The compound of claim 32, wherein C is ##STR00685## ##STR00686## ##STR00687## ##STR00688## ##STR00689## ##STR00690## ##STR00691## ##STR00692## ##STR00693## ##STR00694## ##STR00695## ##STR00696##

    34. The compound of claim 32, wherein C is ##STR00697##

    35. The compound of claim 1, wherein C is optionally substituted 5- to 10-membered heterocyclyl.

    36. The compound of claim 35, wherein C is ##STR00698## ##STR00699## or N-pyrrolidinyl.

    37. The compound of claim 35, wherein C is ##STR00700##

    38. The compound of claim 1, wherein B is an optionally substituted 6-membered monocyclic heteroarylene.

    39. The compound of claim 38, wherein B has the structure: ##STR00701## wherein R.sup.a is hydrogen or fluoro; R.sup.b is hydrogen, fluoro, or C.sub.1-C.sub.3 alkyl; and X.sup.a is N or CH.

    40.-47. (canceled)

    48. The compound of claim 39, wherein B is ##STR00702##

    49. (canceled)

    50. (canceled)

    51. The compound of claim 1, wherein B has the structure: ##STR00703## wherein D is an optionally substituted 5- or 6-membered heteroaryl or optionally substituted 5- or 6-membered heterocyclyl.

    52. The compound of claim 51, wherein B is ##STR00704##

    53. (canceled)

    54. The compound of claim 1, wherein L is optionally substituted C.sub.1-C.sub.3 alkylene.

    55. (canceled)

    56. (canceled)

    57. The compound of claim 1, wherein L is optionally substituted C.sub.2 alkenylene.

    58. The compound of claim 57, wherein L is ##STR00705##

    59. The compound of claim 1, wherein L is optionally substituted C.sub.2-C.sub.3 heteroalkylene.

    60. (canceled)

    61. The compound of claim 1, wherein L is optionally substituted C.sub.3-C.sub.5 cycloalkylene.

    62. The compound of claim 61, wherein L is ##STR00706##

    63. The compound of claim 1, wherein L is optionally substituted 4- to 10-membered heterocyclylene.

    64. The compound of claim 63, wherein L is ##STR00707##

    65. The compound of claim 1, wherein the compound is any one of compounds 1-48 in Table 1, compounds 49-84 in Table 2, and compounds 85-126 in Table 3.

    66. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

    67.-76. (canceled)

    77. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1.

    78. The method of claim 77, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small-cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, Adrenocortical carcinoma, appendiceal cancer, small bowel cancer, or penile cancer.

    79. The method of claim 78, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, soft tissue sarcoma, or penile cancer.

    80. The method of claim 79, wherein the cancer is non-small cell lung cancer.

    81. The method of claim 79, wherein the cancer is soft tissue sarcoma.

    82. (canceled)

    83. (canceled)

    84. A method of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1.

    85.-89. (canceled)

    90. The method of claim 84, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cancer is metastatic.

    91.-115. (canceled)

    Description

    BRIEF DESCRIPTION OF THE DRAWINGS

    [0138] FIG. 1 is a graph illustrating inhibition of cell proliferation of several cancer cell lines by a BRG1/BRM inhibitor (Compound A).

    [0139] FIG. 2A is a graph illustrating inhibition of cell proliferation of uveal melanoma cell line 92-1 by a BRG1/BRM inhibitor (Compound A), a MEK inhibitor (Selumetinib), and a PKC inhibitor (LXS196).

    [0140] FIG. 2B is a graph illustrating inhibition of cell proliferation of uveal melanoma cell line MP41 by a BRG1/BRM inhibitor (Compound A), a MEK inhibitor (Selumetinib), and a PKC inhibitor (LXS196).

    [0141] FIG. 3 is a graph illustrating inhibition of cell proliferation of several cancer cell lines by a BRG1/BRM inhibitor (Compound B).

    [0142] FIG. 4 is a graph illustrating the area under the curves (AUCs) calculated from dose-response curves for cancer cell lines treated with a BRG1/BRM inhibitor.

    [0143] FIG. 5 is a graph illustrating inhibition of cell proliferation of uveal melanoma and non-small cell lung cancer cell lines by a BRG1/BRM inhibitor (Compound B).

    [0144] FIG. 6A is a graph illustrating inhibition of cell proliferation of uveal melanoma cell line 92-1 by a BRG1/BRM inhibitor (Compound B), a MEK inhibitor (Selumetinib), and a PKC inhibitor (LXS196).

    [0145] FIG. 6B is a graph illustrating inhibition of cell proliferation of uveal melanoma cell line MP41 by a BRG1/BRM inhibitor (Compound B), a MEK inhibitor (Selumetinib), and a PKC inhibitor (LXS196).

    [0146] FIG. 7A is a graph illustrating inhibition of cell proliferation of parental and PKC-inhibitor refractory uveal melanoma cell lines by a PKC inhibitor (LXS196).

    [0147] FIG. 7B is a graph illustrating inhibition of cell proliferation of parental and PKC-inhibitor refractory uveal melanoma cell lines by a BRG1/BRM inhibitor (Compound B).

    [0148] FIG. 8A is a graph illustrating inhibition of tumor growth in mice engrafted with uveal melanoma cell lines by a BRG1/BRM inhibitor (Compound C).

    [0149] FIG. 8B is an illustration of the size of tumors from mice engrafted with uveal melanoma cell lines and dosed with a BRG1/BRM inhibitor (Compound C).

    [0150] FIG. 8C is a graph illustrating body weight change of mice engrafted with uveal melanoma cell lines and dosed with a BRG1/BRM inhibitor (Compound C).

    DETAILED DESCRIPTION

    [0151] The present disclosure features compounds useful for the inhibition of BRG1 and/or BRM. These compounds may be used to modulate the activity of a BAF complex, for example, for the treatment of a BAF-related disorder, such as cancer. Exemplary compounds described herein include compounds having a structure according to Formula I:

    ##STR00561##

    [0152] wherein

    ##STR00562##

    [0153] A is or

    [0154] m is 0, 1, 2, or 3;

    [0155] n is 1 or 2;

    [0156] o is 0 or 1;

    [0157] X is O, CH.sub.2, or NR.sup.7;

    [0158] X′ is N, CH, or CR.sup.x, wherein R.sup.x is a halogen;

    [0159] B is an optionally substituted 6-membered bicyclic heteroarylene or an optionally substituted 9- or 10-membered bicyclic heteroarylene;

    [0160] L is a covalent bond, optionally substituted C.sub.1-C.sub.3 alkylene, C.sub.2 alkynylene, optionally substituted C.sub.2 alkenylene, optionally substituted C.sub.2-C.sub.3 heteroalkylene, optionally substituted C.sub.3-C.sub.5 cycloalkylene, or optionally substituted 4- to 10-membered heterocyclylene;

    [0161] C is optionally substituted 3- to 10-membered cycloalkyl; optionally substituted 6- to 10-membered aryl; optionally substituted 5- to 10-membered heteroaryl; or optionally substituted 5- to 10-membered heterocyclyl;

    [0162] R.sup.1 and R.sup.7 are, independently, hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl;

    [0163] each R.sup.2 and R.sup.3 is independently, hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl; or optionally substituted C.sub.1-C.sub.6 heteroalkyl;

    [0164] R.sup.4 is cyano, fluoro, hydroxy, or —CH.sub.2OH;

    [0165] R.sup.5 is C.sub.1-C.sub.3 alkyl optionally substituted with one, two, three, four, five, six, or seven fluoro groups; and

    [0166] R.sup.6 is C.sub.1-C.sub.3 alkyl optionally substituted with one, two, three, four, five, six, or seven fluoro groups,

    [0167] or a pharmaceutically acceptable salt thereof.

    [0168] Preferably, when B is optionally substituted 6-membered bicyclic heteroarylene, L is a covalent bond, optionally substituted C.sub.1-C.sub.3 alkylene, C.sub.2 alkynylene, optionally substituted C.sub.2 alkenylene, optionally substituted C.sub.2-C.sub.3 heteroalkylene, optionally substituted C.sub.3-C.sub.5 cycloalkylene, or optionally substituted 4- to 10-membered heterocyclylene. Also preferably, when B is an optionally substituted 9- or 10-membered bicyclic heteroarylene, L is a covalent bond, e.g., the compound of Formula I is a compound of Formula Ia:

    ##STR00563##

    or a pharmaceutically acceptable salt thereof, where all variables are as described herein.

    [0169] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, has the structure of any one of compounds 1-48 in Table 1, compounds 49-84 in Table 2, or compounds 85-126 in Table 3.

    [0170] Other embodiments, as well as exemplary methods for the synthesis of production of these compounds, are described herein.

    Pharmaceutical Uses

    [0171] The compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their ability to modulate the level, status, and/or activity of a BAF complex, i.e., by inhibiting the activity of the BRG1 and/or BRM proteins within the BAF complex in a mammal. BAF complex-related disorders include, but are not limited to, BRG1 loss of function mutation-related disorders.

    [0172] An aspect of the present invention relates to methods of treating disorders related to BRG1 loss of function mutations such as cancer (e.g., non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer) in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to result in one or more (e.g., two or more, three or more, four or more) of: (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, (i) increased progression free survival of subject.

    [0173] Treating cancer can result in a reduction in size or volume of a tumor. For example, after treatment, tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. For example, the size of a tumor may be measured as a diameter of the tumor.

    [0174] Treating cancer may further result in a decrease in number of tumors. For example, after treatment, tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to number prior to treatment. Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2×, 3×, 4×, 5×, 10×, or 50×).

    [0175] Treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic nodules may be measured by any reproducible means of measurement. For example, the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2×, 10×, or 50×).

    [0176] Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the invention. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.

    [0177] Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of the invention. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.

    [0178] Exemplary cancers that may be treated by the invention include, but are not limited to, non-small cell lung cancer, small-cell lung cancer, colorectal cancer, bladder cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, Adrenocortical carcinoma, appendiceal cancer, small bowel cancer and penile cancer.

    Combination Formulations and Uses Thereof

    [0179] The compounds of the invention can be combined with one or more therapeutic agents. In particular, the therapeutic agent can be one that treats or prophylactically treats any cancer described herein.

    Combination Therapies

    [0180] A compound of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat cancer or symptoms associated therewith, or in combination with other types of treatment to treat cancer. In combination treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, dosages of the compounds when combined should provide a therapeutic effect.

    [0181] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., Taxol® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABraxane®, cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, III), and Taxotere® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; Gemzar® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the first therapeutic agent described herein. Suitable dosing regimens of combination chemotherapies are known in the art and described in, for example, Saltz et al. (1999) Proc ASCO 18:233a and Douillard et al. (2000) Lancet 355:1041-7.

    [0182] In some embodiments, the second therapeutic agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (Avastin®). In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer. Such agents include Rituxan (Rituximab); Zenapax (Daclizumab); Simulect (Basiliximab); Synagis (Palivizumab); Remicade (Infliximab); Herceptin (Trastuzumab); Mylotarg (Gemtuzumab ozogamicin); Campath (Alemtuzumab); Zevalin (Ibritumomab tiuxetan); Humira (Adalimumab); Xolair (Omalizumab); Bexxar (Tositumomab-I-131); Raptiva (Efalizumab); Erbitux (Cetuximab); Avastin (Bevacizumab); Tysabri (Natalizumab); Actemra (Tocilizumab); Vectibix (Panitumumab); Lucentis (Ranibizumab); Soliris (Eculizumab); Cimzia (Certolizumab pegol); Simponi (Golimumab); Ilaris (Canakinumab); Stelara (Ustekinumab); Arzerra (Ofatumumab); Prolia (Denosumab); Numax (Motavizumab); ABThrax (Raxibacumab); Benlysta (Belimumab); Yervoy (Ipilimumab); Adcetris (Brentuximab Vedotin); Perjeta (Pertuzumab); Kadcyla (Ado-trastuzumab emtansine); and Gazyva (Obinutuzumab). Also included are antibody-drug conjugates.

    [0183] The second agent may be a therapeutic agent which is a non-drug treatment. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia and/or surgical excision of tumor tissue.

    [0184] The second agent may be a checkpoint inhibitor. In one embodiment, the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In some embodiments, the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody such as ipilimumab/Yervoy or tremelimumab). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab/Opdivo®; pembrolizumab/Keytruda®; pidilizumab/CT-011). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2/lg fusion protein such as AMP 224). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or a combination thereof.

    [0185] In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent.

    Pharmaceutical Compositions

    [0186] The compounds of the invention are preferably formulated into pharmaceutical compositions for administration to a mammal, preferably, a human, in a biologically compatible form suitable for administration in vivo. Accordingly, in an aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a suitable diluent, carrier, or excipient.

    [0187] The compounds of the invention may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the scope of the invention. In accordance with the methods of the invention, the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

    [0188] A compound of the invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard- or soft-shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, a compound of the invention may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. A compound of the invention may also be administered parenterally. Solutions of a compound of the invention can be prepared in water suitably mixed with a surfactant. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003, 20th ed.) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe. Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant. The aerosol dosage forms can also take the form of a pump-atomizer. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base. A compound described herein may be administered intratumorally, for example, as an intratumoral injection. Intratumoral injection is injection directly into the tumor vasculature and is specifically contemplated for discrete, solid, accessible tumors. Local, regional, or systemic administration also may be appropriate. A compound described herein may advantageously be contacted by administering an injection or multiple injections to the tumor, spaced for example, at approximately, 1 cm intervals. In the case of surgical intervention, the present invention may be used preoperatively, such as to render an inoperable tumor subject to resection. Continuous administration also may be applied where appropriate, for example, by implanting a catheter into a tumor or into tumor vasculature.

    [0189] The compounds of the invention may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.

    Dosages

    [0190] The dosage of the compounds of the invention, and/or compositions comprising a compound of the invention, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds of the invention may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds of the invention are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg. Dose ranges include, for example, between 10-1000 mg.

    [0191] Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1-100 mg/kg.

    EXAMPLES

    Definitions Used in the Following Schemes and Elsewhere Herein are:

    [0192] MeCN or ACN acetonitrile [0193] AIBN azobisisobutyronitrile [0194] Boc tert-butoxycarbonyl [0195] n-BuLi n-butyllithium [0196] t-BuOK potassium tert-butoxide [0197] t-BuONa sodium tert-butoxide [0198] t-BuXPhos Pd G3 [(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate [0199] tBuphos Pd G3 [(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate [0200] DAST diethylaminosulfur trifluoride [0201] DCE dichloroethane [0202] DCM dichloromethane [0203] DCPP-2HBF.sub.4 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) [0204] DEA N,N-diethylamine [0205] DMP Dess-Martin periodinane, 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2- [0206] DIAD diisopropyl azodicarboxylate [0207] DIBAL-H diisobutylaluminum hydride [0208] DIEA or DIPEA N,N-diisopropylethylamine [0209] DMA dimethylacetamide [0210] DMAP 4-(dimethylamino)pyridine [0211] DME 1,2-dimethoxyethane [0212] DMF N,N-dimethylformamide [0213] DMSO dimethylsulfoxide [0214] dppf bis(diphenylphosphino)ferrocene [0215] dtbpf 1,1′-bis(di-tert-butylphosphino)ferrocene [0216] EDCI 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride [0217] ESI electrospray ionization [0218] Et.sub.3N or TEA triethylamine [0219] EA ethyl acetate [0220] EtOH ethyl alcohol [0221] FA formic acid [0222] FCC flash column chromatography [0223] g grams [0224] HATU 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-l, 1,3,3-tetramethylisouronium [0225] HCl hydrochloric acid [0226] HOAc acetic acid [0227] HOBt hydroxybenzotriazole [0228] HPLC high performance liquid chromatography [0229] IPA isopropyl alcohol [0230] L liter [0231] LCMS liquid chromatography/mass spectrometry [0232] LiHMDS lithium bis(trimethylsilyl)amide [0233] m-CPBA 3-chloroperoxybenzoic acid [0234] MeCN acetonitrile [0235] MeI methyl iodide [0236] MeOH methyl alcohol [0237] mL milliliter [0238] mmol millimole [0239] mg milligrams [0240] MHz megahertz [0241] MS mass spectrometry [0242] MTBE methyl tert-butyl ether [0243] m/z mass/charge ratio [0244] NBS N-bromosuccinimide [0245] NIS N-iodosuccinimide [0246] nm nanometer [0247] NMR nuclear magnetic resonance [0248] PdCl2(dtbpf) [1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) [0249] PE petroleum ether [0250] PhMe toluene [0251] ppm parts per million [0252] rt room temperature [0253] RT retention time [0254] SFC supercritical fluid chromatography SPhos Pd G3 (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) [2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate [0255] TBS tert-butyldimethylsilyl [0256] TBSCI tert-butyldimethylsilyl chloride [0257] TBDMS tert-butyldimethylsilyl chloride [0258] TCCA or TClCA trichloroisocyanuric acid [0259] TFA trifluoroacetic acid [0260] TFAA trifluoroacetic anhydride [0261] THF tetrahydrofuran [0262] TMSCN trimethylsilyl cyanide [0263] TosMIC toluenesulfonylmethyl isocyanide [0264] Ziram zinc dimethyldithiocarbamate

    Materials

    [0265] Unless otherwise noted, all materials were obtained from commercial suppliers and were used without further purification. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere.

    Example 1. Preparation of Intermediates

    Intermediates 1 and 2: (4S)-4-Cyano-4-methyl-isochromane-6-carboxylic acid and (4R)-4-Cyano-4-methyl-isochromane-6-carboxylic acid

    [0266] ##STR00564##

    Step 1. Methyl 5-bromo-2-(bromomethyl)benzoate and methyl 5-bromo-2-(dibromomethyl)benzoate

    [0267] N-Bromosuccinimide (130.5 g, 733 mmol) and AIBN (11.47 g, 69.8 mmol) was added to a mixture of methyl 5-bromo-2-methyl-benzoate (160 g, 698 mmol) in CCl.sub.4 (1.6 L). The mixture was stirred at 80° C. for 8 hrs. The mixture was cooled to 25° C. and filtered. The filtrate was concentrated in vacuo affording a mixture of the title compounds (215 g, crude) as a yellow oil, which was used to next step directly.

    Step 2. Methyl 5-bromo-2-(bromomethyl)benzoate

    [0268] Diisopropylethyl amine (48.6 mL, 279 mmol) and 1-ethoxyphosphonoyloxyethane (36.0 mL, 279 mmol) were added to a mixture of methyl 5-bromo-2-(bromomethyl)benzoate and methyl 5-bromo-2-(dibromomethyl)benzoate (215 g, crude) in THE (1 L) at 0° C. The mixture was stirred at 25° C. for 8 hrs. The mixture was diluted with water (1 L) and extracted with EA (1 L×3). The combined organic phase was washed with brine (1 L), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude product was dissolved with PE:EA=10:1 (1 L). The mixture was filtered through a short silica gel column and washed with PE:EA=10:1 (2 L). The filtrate was concentrated under vacuum affording the title compound (210 g, 682 mmol) as yellow oil.

    [0269] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.99 (d, J=2.0 Hz, 1H), 7.82-7.79 (m, 1H), 7.56 (d, J=8.4 Hz, 1H), 4.97 (s, 2H), 3.88 (s, 3H) ppm.

    Step 3. Methyl 6-bromo-4-oxo-isochromane-3-carboxylate

    [0270] Sodium hydride (39 g, 974 mmol, 60% purity) was added to a mixture of methyl 5-bromo-2-(bromomethyl)benzoate (150 g, 487 mmol) and methyl 2-hydroxyacetate (75 mL, 974 mmol) in DMF (1.5 L) at 0° C. The mixture was stirred at 25° C. for 1 hr. The mixture was poured into saturated NH.sub.4Cl (aq., 6 L), and then extracted with MTBE (3 L×2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure affording the title compound (140 g, crude) as a brown oil, which was used to next step directly.

    Step 4. 6-Bromoisochroman-4-one

    [0271] A mixture of methyl 6-bromo-4-oxo-isochromane-3-carboxylate (140 g, 487 mmol) in EtOH (500 mL) and HCl (12 M, I L) was stirred at 120° C. for 1 hr. The reaction mixture was cooled to 25° C. and filtered. The filter cake was saved. The filtrate was diluted with water (2 L) and extracted with MTBE (1.5 L×2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give brown oil. The brown oil was combined with the filter cake and then triturated with EtOH (200 mL) at 0° C. for 0.5 hrs. The solid was collected by filtration, washed with EtOH (50 mL×2) and dried in vacuo affording the title compound (50 g, 242 mmol) as a yellow solid.

    [0272] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.17 (d, J=20 Hz, 1H), 7.69-7.67 (m, 1H), 7.13 (d, J=8.4 Hz, 1H), 4.85 (s, 2H), 4.37 (s, 2H) ppm.

    Step 5. 6-Bromo-4-methyl-isochroman-4-ol

    [0273] Methylmagnesium bromide (3 M in THF, 440 mL) was added dropwise to a mixture of 6-bromoisochroman-4-one (100 g, 440 mmol) and CeCl.sub.3 (54.3 g, 220 mmol, dried in a muffle furnace at 300° C. for 3 hrs.) in THE (2 L) at −50° C. The mixture was warmed to 20° C. and stirred for 1 hr. The reaction mixture was poured into water (2 L) and then filtered through diatomite. The diatomite was then washed with EA (2 L). The filtrate was separated and the aqueous layer was extracted with EA (1 L×2). The combined organic layers were washed with brine (2 L), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The crude residue was purified by FCC (Eluent: PE:EA=50:1 to 3:1) affording the title compound (105 g, 432 mmol) as light yellow oil.

    [0274] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.67 (d, J=2.0 Hz, 1H), 7.38-7.35 (m, 1H), 6.99 (d, J=8.4 Hz, 1H), 5.35 (s, 1H), 4.71-4.58 (m, 2H), 3.68-3.59 (m, 1H), 3.58-3.50 (m, 1H), 1.38 (s, 3H) ppm.

    Step 6. 6-Bromo-4-methyl-isochromane-4-carbonitrile

    [0275] TMSCN (102.9 mL, 823 mmol) was added to a solution of 6-bromo-4-methyl-isochroman-4-ol (100 g, 411 mmol) in DCM (2 L) at 0° C. InBr.sub.3 (29.2 g, 82.3 mmol) was then added, and the mixture was warmed and stirred at 25° C. for 1 hr. The mixture was poured into water (2 L) and extracted with DCM (1 L×2). The combined organic layers were washed with brine (1 L), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue was purified by FCC (Eluent: PE:EA=20:1 to 5:1) affording the title compound (55 g, 218 mmol) as a white solid.

    [0276] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.82 (d, J=2.0 Hz, 1H), 7.55-7.52 (m, 1H), 7.13 (d, J=8.3 Hz, 1H), 4.83-4.68 (m, 2H), 4.17 (d, J=11.5 Hz, 1H), 3.79 (d, J=11.5 Hz, 1H), 1.65 (s, 3H) ppm.

    Step 7. (4S)-4-Cyano-4-methyl-isochromane-6-carboxylic acid and (4R)-4-Cyano-4-methyl-isochromane-6-carboxylic acid

    [0277] Palladium acetate (490 mg, 2.18 mmol) and K.sub.2CO.sub.3 (9.05 g, 65.4 mmol) were added to a mixture 6-bromo-4-methyl-isochromane-4-carbonitrile (11 g, 43.6 mmol) and DCPP-2HBF.sub.4 (2.67 g, 4.36 mmol) in DMSO (110 mL) and H.sub.2O (5.5 mL). The mixture was degassed and purged with CO (g) three times, and then the mixture was stirred at 100° C. for 4 hrs under an atmosphere of CO (15 psi). The aqueous layer was then extracted with EA (1 L×2). The aqueous phase was acidified with HCl (2N) until a pH=3 was achieved. The aqueous layer was then extracted with EA (1 L×3). The combined organic phase was washed with brine (1 L), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The crude product was triturated with EA (100 mL) at 20° C. for 15 min, then the solid was collected by filtration, washed with EA (50 mL), and dried affording the title compounds (30 g, 138 mmol) as a white solid. The mixture of stereoisomers was purified by SFC separation (column: DAICEL CHIRALPAK AD-H (250 mm×30 mm, 5 μm); mobile phase: [0.1% NH.sub.3.H.sub.2O MEOH]; B %: 20%-20%, 3.52 min; 514 minmin). Peak 1 was concentrated under reduced pressure to give an oil. The oil was dissolved in water (200 mL). The mixture was acidified with HCl (2N) to pH=3 and extracted with EA (100 mL×3). The combined organic phase washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum affording Intermediate 1 (4.15 g, 19.1 mmol) as an off-white solid. Peak 2 was concentrated under reduced pressure to give an oil. The oil was dissolved in water (200 mL). The mixture was acidified with HCl (2N) to pH=3 and extracted with EA (100 mL×3). The combined organic phase washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under vacuum affording Intermediate 2 (4.1 g, 18.9 mmol) as an off-white solid.

    [0278] Intermediate 1: Chiral SFC: AD-3_5CM_MEOH(DEA)_5_40_3ML_AT35.M; RT=0.89 min LCMS (ESI) m/z: [M+H]+=218.3.

    [0279] .sup.1HNMR (400 MHz, DMSO-d6) δ=13.17 (br s, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.89-7.87 (m, 1H), 7.29 (d, J=8.0 Hz, 1H), 4.95-4.79 (m, 2H), 4.19 (d, J=11.6 Hz, 1H), 3.88 (d, J=11.6 Hz, 1H), 1.67 (s, 3H) ppm.

    [0280] Intermediate 2: Chiral SFC: AD-3_5CM_MEOH(DEA)_5_40_3ML_AT35.M; RT=1.03 min LCMS (ESI) m/z: [M+H]+=218.3.

    [0281] .sup.1H NMR (400 MHz, DMSO-d6) δ=13.17 (br s, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.89-7.87 (m, 1H), 7.29 (d, J=8.0 Hz, 1H), 4.95-4.79 (m, 2H), 4.19 (d, J=11.6 Hz, 1H), 3.88 (d, J=11.6 Hz, 1H), 1.67 (s, 3H) ppm.

    Intermediates 3 and 4: (4R)-4-Hydroxy-4-methylisochromane-6-carboxylic acid and (4S)-4-Hydroxy-4-methylisochromane-6-carboxylic acid

    [0282] ##STR00565##

    (4R)-4-Hydroxy-4-methylisochromane-6-carboxylic acid and (4S)-4-Hydroxy-4-methylisochromane-6-carboxylic acid

    [0283] A mixture of 6-bromo-4-methyl-isochroman-4-ol (1.00 g, 4.11 mmol), dccp.2BF.sub.4 (252 mg, 0.41 mmol), K.sub.2CO.sub.3 (853 mg, 6.17 mmol), Pd(OAC).sub.2 (92.4 mg, 0.41 mmol) and H.sub.2O (1.48 mL, 82.3 mmol) in DMSO (10 mL) was degassed and purged with CO (g) three times. The mixture was stirred at 100° C. for 14 hrs under a CO atmosphere. The reaction mixture was filtered to remove the black solid and then diluted with water (60 mL) and extracted with EA (60 mL×2). The organic layer was discarded and the aqueous phase was adjusted to pH=6 with aqueous HCl. The aqueous solution was then extracted with EA (100 mL×3). The combined organic layer was washed with brine (200 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure affording a mixture of the title compounds (550 mg, 2.43 mmol) as a light yellow solid. The stereoisomers were separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 m); mobile phase: [0.1% NH.sub.3.H.sub.2O IPA]; B %: 40%-40%, 4.0 min; 60 minmin). The desired fractions were collected and concentrated under reduced pressure. The product was diluted with water, adjusted to pH=4 with aq. HCl, then extracted with EA (80 mL×3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure affording Intermediate 3 (260 mg, 1.18 mmol) as a yellow solid and Intermediate 4 (240 mg, 1.04 mmol) as a yellow solid.

    [0284] Intermediate 3: Chiral SFC: AD-3_5CM_IPA (DEA)_5_40_3ML_AT35.M; RT=1.537 min. LCMS (ESI) m/z: [M−18+H]+=191.1.

    [0285] .sup.1H NMR (400 MHz, DMSO-d6) δ=13.19-12.40 (m, 1H), 8.15 (d, J=1.6 Hz, 1H), 7.75-7.73 (m, 1H), 7.13 (d, J=8.0 Hz, 1H), 5.34 (s, 1H), 4.82-4.68 (m, 2H), 3.71-3.65 (m, 1H), 3.61-3.54 (m, 1H), 1.40 (s, 3H) ppm.

    [0286] Intermediate 4: Chiral SFC: AD-3_5CM_IPA (DEA)_5_40_3ML_AT35.M; RT=1.926 min. LCMS (ESI) m/z: [M−17+H]+=191.1.

    [0287] .sup.1H NMR (400 MHz, DMSO-d6) δ=12.86 (br s, 1H), 8.15 (d, J=1.6 Hz, 1H), 7.75-7.73 (m, 1H), 7.13 (d, J=8.0 Hz, 1H), 5.34 (s, 1H), 4.84-4.67 (m, 2H), 3.73-3.62 (m, 1H), 3.62-3.53 (m, 1H), 1.40 (s, 3H) ppm.

    Intermediates 5 and 6: (S)-4-Cyano-4-methylchroman-6-carboxylic acid and (R)-4-Cyano-4-methylchroman-6-carboxylic acid

    [0288] ##STR00566##

    Step 1. 6-Bromochromane-4-carbonitrile

    [0289] Potassium tert-butoxide (54.4 g, 484 mmol) was added to a solution of 6-bromochroman-4-one (50 g, 220 mmol) and 1-(isocyanomethylsulfonyl)-4-methyl-benzene (64.5 g, 330 mmol) in DME (2.5 L) and EtOH (100 mL) at 0° C. The reaction mixture was warmed and stirred at 25° C. for 16 hrs. The reaction mixture was poured into water (2 L) and adjusted to pH=6˜7 with NH.sub.4Cl (56.9 g). The organic solvents were removed in vacuo. The aqueous phase was extracted with EA (1.5 L×2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated in vacuum. The residue was purified by FCC (Eluent: PE:EA=20:1). The purified residue was combined with another batch that was run under the same conditions and triturated with MTBE (150 mL). The solid was filtered and concentrated in vacuo affording the title compound (40 g, 151 mmol) as a white solid.

    [0290] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.43-7.42 (m, 1H), 7.33-7.31 (m, 1H), 6.76 (d, J=8.8 Hz, 1H), 4.36-4.30 (m, 1H), 4.26-4.21 (m, 1H), 4.01-3.98 (m, 1H), 2.35-2.31 (m, 2H) ppm.

    Step 2. 6-Bromo-4-methyl-chromane-4-carbonitrile

    [0291] Sodium hydride (8.40 g, 210 mmol, 60% purity) was added to a solution of 6-bromochromane-4-carbonitrile (25 g, 105 mmol) in THE (250 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hr, then MeI (32.7 mL, 525 mmol) was added. The reaction mixture was stirred at 25° C. for 2 hrs. The reaction mixture was diluted with saturated NH.sub.4Cl (aq., 800 mL) and extracted with EA (800 mL×3). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude residue was purified by FCC (Eluent: PE/EA=1:0 to 5:1) affording the title compound (18 g, 69.2 mmol) as a light yellow solid.

    [0292] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.69 (d, J=2.4 Hz, 1H), 7.41-7.38 (m, 1H), 6.83 (d, J=8.8 Hz, 1H), 4.33-4.25 (m, 1H), 4.24-4.15 (m, 1H), 2.41-2.35 (m, 1H), 2.17-2.11 (m, 1H), 1.75 (s, 3H) ppm.

    Step 3. (S)-4-Cyano-4-methylchroman-6-carboxylic acid and (R)-4-Cyano-4-methylchroman-6-carboxylic acid

    [0293] A mixture of 6-bromo-4-methyl-chromane-4-carbonitrile (8.5 g, 33.7 mmol), dccp-2HBF.sub.4 (2.06 g, 3.37 mmol), K.sub.2CO.sub.3 (6.99 g, 50.6 mmol), Pd(OAc).sub.2 (757 mg, 3.37 mmol), and H.sub.2O (1.22 mL, 67.4 mmol) in DMSO (85 mL) was degassed and purged with CO (g) three times. The mixture was then stirred at 100° C. for 14 hrs under a CO (15 psi) atmosphere. The reaction mixture combined with a 2.sup.nd batch and filtered to remove the black solid. The filtrate was diluted with water (60 mL) and extracted with EA (60 mL×2). The organic layer was discarded and the pH of aqueous phase was adjusted to pH=4 with aq. HCl resulting in a precipitate. The mixture was filtered and the white solid was washed with water (40 mL×2), filtered, and dried in vacuo affording a mixture of the title compounds (12 g, 51.2 mmol) as a white solid. Intermediates 5 and 6 were separated by chiral SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% NH.sub.3—H.sub.2O MEOH]; B %: 30%-30%, 4.7 min; 600 min.). The fraction was concentrated under reduced pressure to get Intermediate 5 (5.3 g, 24.3 mmol) as an off-white solid and Intermediate 6 (5.2 g, 23.6 mmol) as an off-white solid.

    [0294] Intermediate 5: Chiral SFC: AD-3_5CM_MEOH (DEA)_5_40_3ML_AT35.M, RT=0.958 min LCMS (ESI) m/z: [M+H]+=218.2.

    [0295] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.00 (d, J=2.0 Hz, 1H), 7.79-7.76 (m, 1H), 6.88 (d, J=8.4 Hz, 1H), 4.37-4.22 (m, 2H), 2.45-2.39 (m, 1H), 2.22-1.75 (m, 1H), 1.76 (s, 3H) ppm.

    [0296] Intermediate 6: Chiral SFC: AD-3_5CM_MEOH (DEA)_5_40_3ML_AT35.M, RT=1.294 LCMS (ESI) m/z: [M+H]+=218.2.

    [0297] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.00 (d, J=2.0 Hz, 1H), 7.79-7.76 (m, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.37-4.23 (m, 2H), 2.50-2.41 (m, 1H), 2.22-2.18 (m, 1H), 1.76 (s, 3H) ppm.

    Intermediates 7 and 8: (4R)-4-Fluoro-4-methyl-isochromane-6-carboxylic acid and (4S)-4-Fluoro-4-methyl-isochromane-6-carboxylic acid

    [0298] ##STR00567##

    Step 1. 6-Bromo-4-fluoro-4-methyl-isochromane

    [0299] DAST (52.2 mL, 395 mmol,) was added dropwise to a mixture of Intermediate 8 (32 g, 132 mmol) in DCM (320 mL) at 0° C. The mixture was warmed and stirred at 25° C. for 20 min. The mixture was poured into ice water (600 mL) and extracted with DCM (250 mL×3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=30:1) affording the title compound (24.5 g, 99.96 mmol) as a yellow oil.

    [0300] LCMS (ESI) m/z: [M−18+H]+=226.9.

    [0301] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.72 (s, 1H), 7.45-7.42 (m, 1H), 6.93 (d, J=8.0 Hz, 1H), 4.84-4.74 (m, 1H), 4.73-4.64 (m, 1H), 4.06-4.00 (m, 1H), 3.86-3.78 (m, 1H), 1.76-1.64 (m, 3H) ppm.

    Step 2. (4R)-4-Fluoro-4-methyl-isochromane-6-carboxylic acid and (4S)-4-Fluoro-4-methyl-isochromane-6-carboxylic acid

    [0302] Palladium acetate (687 mg, 3.06 mmol), dccp-2HBF.sub.4 (1.87 g, 3.06 mmol), K.sub.2CO.sub.3 (6.34 g, 45.9 mmol), and H.sub.2O (7.50 mL) were added to a solution of 6-bromo-4-fluoro-4-methyl-isochromane (7.5 g, 30.6 mmol) in DMSO (75 mL) at 25° C. The mixture was purged with CO (g) three times. The mixture was heated and stirred at 100° C. for 4 hrs under an atmosphere of CO (15 psi). The reaction mixture was poured into H.sub.2O (1.2 L) and extracted with EA (400 mL×2). The aqueous phase was acidified with 1 N HCl to pH=5 and extracted with EA (300 mL×3). The combined organic layers were washed with brine (300 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo affording a mixture of the title compounds (2.6 g, 12.2 mmol) as a white solid.

    [0303] .sup.1H NMR (400 MHz, DMSO-d6) δ=13.42-12.67 (m, 1H), 8.13 (s, 1H), 7.92-7.88 (m, 1H), 7.29 (d, J=8.0 Hz, 1H), 4.91-4.82 (m, 1H), 4.77-4.68 (m, 1H), 4.10-4.01 (m, 1H), 3.89-3.76 (m, 1H), 1.70-1.58 (m, 3H) ppm.

    [0304] Intermediates 7 and 8 were separated by SFC (Column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 m); mobile phase: [0.1% NH.sub.3—H.sub.2O MeOH]; B %: 20%-20%, 3.4 min; 2300 minmin) to give two peaks. Peak 1 was concentrated under reduced pressure to remove 95% MeOH and poured into H.sub.2O (500 mL). The mixture was acidified with HCl (1 N) to pH=5 and extracted with EA (150 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford Intermediate 7 (1.06 g, 5.04 mmol) as a white solid. Peak 2 was concentrated under reduced pressure and poured into H.sub.2O (500 mL). The mixture was acidified with HCl (1N) to pH=5 and extracted with EA (150 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford Intermediate 8 (1.07 g, 5.09 mmol) as a white solid.

    [0305] Intermediate 7: Chiral SFC: AD-3_5CM_MEOH (DEA)_5_40_3ML_AT35.M, RT=0.819 min.

    [0306] .sup.1H NMR (400 MHz, DMSO-d6) δ=13.08 (br s, 1H), 8.13 (s, 1H), 7.92-7.88 (m, 1H), 7.29 (d, J=8.0 Hz, 1H), 4.90-4.81 (m, 1H), 4.78-4.68 (m, 1H), 4.05-4.01 (m, 1H), 3.87-3.78 (m, 1H), 1.72-1.58 (m, 3H) ppm.

    [0307] Intermediate 8: Chiral SFC: AD-3_5CM_MEOH (DEA)_5_40_3ML_AT35.M, RT=0.903 min.

    [0308] .sup.1H NMR (400 MHz, DMSO-d6) δ=13.31-12.88 (m, 1H), 8.13 (s, 1H), 7.92-7.88 (m, 1H), 7.29 (d, J=8.0 Hz, 1H), 4.90-4.81 (m, 1H), 4.78-4.68 (m, 1H), 4.08-4.01 (m, 1H), 3.89-3.77 (m, 1H), 1.72-1.58 (m, 3H) ppm.

    Intermediates 9 and 10: (R)-1-(tert-Butoxycarbonyl)-4-cyano-4-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid and (S)-1-(tert-Butoxycarbonyl)-4-cyano-4-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid

    [0309] ##STR00568##

    Step 1. tert-Butyl 6-bromo-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate

    [0310] A mixture of 6-bromo-2,3-dihydro-1H-quinolin-4-one (2 g, 8.85 mmol), Boc.sub.2O (3.86 g, 17.7 mmol), DMAP (108 mg, 0.88 mmol), and DIEA (3.1 mL, 17.7 mmol) in DCM (20 mL) was stirred at 60° C. for 12 hrs. The mixture was concentrated under reduced pressure and then poured into water (5 mL). The aqueous solution was then extracted with EA (5 mL×3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (Eluent: 0 to 12% EA in PE) affording the title compound (1.75 g, 5.37 mmol) as a yellow oil.

    [0311] LCMS (ESI) m/z: [M+H]+=326.0.

    [0312] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.89-7.88 (m, 1H), 7.75 (d, J=1.2 Hz, 2H), 4.11-4.07 (m, 2H), 2.79-2.75 (m, 2H), 1.51 (s, 9H) ppm.

    Step 2. tert-Butyl 6-bromo-4-cyano-3,4-dihydroquinoline-1(2H)-carboxylate

    [0313] Potassium tert-butoxide (1.38 g, 12.26 mmol) was added to a mixture of tert-Butyl 6-bromo-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2 g, 6.13 mmol) and 1-(isocyanomethylsulfonyl)-4-methyl-benzene (1.80 g, 9.20 mmol) in DME (100 mL) and EtOH (4 mL) at 0° C. The mixture was stirred at 25° C. for 12 hrs. The reaction mixture was poured into water (5 mL) and extracted with EA (5 mL×3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by FCC (Eluent: 0 to 20% EA in PE) affording the title compound (900 mg, 2.67 mmol) as a yellow oil.

    [0314] LCMS (ESI) m/z: [M−55]+=281.0.

    [0315] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.67 (d, J=8.8 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.51-7.47 (m, 1H), 4.48-4.44 (m, 1H), 3.74-3.69 (m, 2H), 2.21-2.15 (m, 2H), 1.48 (s, 9H) ppm.

    Step 3. tert-Butyl 6-bromo-4-cyano-4-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

    [0316] Sodium hydride (89 mg, 2.22 mmol, 60% purity) was added slowly to a mixture of tert-butyl 6-bromo-4-cyano-3,4-dihydroquinoline-1(2H)-carboxylate (500 mg, 1.48 mmol) in THE (5 mL) at 0° C. The mixture was stirred at 0° C. for 0.5 hr, then MeI (0.14 mL, 2.22 mmol) was added. The reaction mixture was warmed to 25° C. and stirred for 2 hrs. The reaction mixture was quenched with saturated NH.sub.4Cl (20 mL) and extracted with EA (10 mL×3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting oil was purified by FCC (Eluent: 0 to 50% EA in PE) affording the title compound (370 mg, 1.01 mmol) as yellow oil.

    [0317] LCMS (ESI) m/z: [M−55]+=295.0

    [0318] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.66 (d, J=8.8 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.38-7.36 (m, 1H), 3.89-3.80 (m, 2H), 2.40-2.34 (m, 1H), 2.04-2.00 (m, 1H), 1.73 (s, 3H), 1.53 (s, 9H) ppm.

    Step 4. (R)-1-(tert-Butoxycarbonyl)-4-cyano-4-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid & (S)-1-(tert-Butoxycarbonyl)-4-cyano-4-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid

    [0319] Palladium acetate (11.8 mg, 0.053 mmol) and dccp.2HBF.sub.4 (64.5 mg, 0.11 mmol) were added to a mixture of tert-butyl 6-bromo-4-cyano-4-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (370 mg, 1.05 mmol) and K.sub.2CO.sub.3 (218 mg, 1.58 mmol) in DMSO (3 mL) and H.sub.2O (1 mL) at 25° C. The mixture was degassed and purged with CO (g, 15 psi) three times, and then the mixture was warmed stirred at 100° C. under CO (g) for 12 hrs. The reaction mixture was filtered and the filtrate was purified by reversed-phase HPLC affording a mixture of the title compounds (190 mg, 0.60 mmol) as a white solid. The stereoisomers were separated via chiral SFC (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 m); mobile phase: [0.1% NH.sub.3—H.sub.2O MEOH]; B %: 20%-20%, 1.75 min; 75 minmin) to afford Intermediate 9 (80 mg, 0.25 mmol) as light yellow solid and Intermediate 10 (90 mg, 0.28 mmol) as light yellow solid.

    [0320] Intermediate 9: LCMS (ESI) m/a: [M−55]+=261.1

    [0321] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.96 (d, J=1.6 Hz, 1H), 7.80-7.78 (m, 1H), 7.69 (d, J=8.8 Hz, 1H), 3.79-3.74 (m, 2H), 2.36-2.32 (m, 1H), 2.07-2.05 (m, 1H), 1.71 (s, 3H), 1.47 (s, 9H) ppm. Chiral SFC: AD-3_5CM_MEOH(DEA)_5_40_3ML_AT35.M, Rt=0.766 min, ee value=98.82%.

    [0322] Intermediate 10: LCMS (ESI) m/a: [M−55]+=261.1

    [0323] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.96 (br s, 1H), 7.81-7.78 (m, 1H), 7.71 (br d, J=8.8 Hz, 1H), 3.80-3.74 (m, 2H), 2.36-2.31 (m, 1H), 2.07-2.04 (m, 1H), 1.71 (s, 3H), 1.48 (s, 9H) ppm.

    [0324] Chiral SFC: AD-3_5CM_MEOH(DEA)_5_40_3ML_AT35.M. Rt=0.916 min, ee value=93.82%.

    Intermediate 11: tert-Butyl N-[1-(4-bromo-2-pyridyl)-2-methoxy-ethyl]carbamate

    [0325] ##STR00569##

    Step 1. 1-(4-Bromo-2-pyridyl)-2-methoxy-ethanone

    [0326] n-Butyl lithium (2.5 M, 16.9 mL) was added to a solution of 2,4-dibromopyridine (10.0 g, 42.2 mmol) in toluene (400 mL) at −60° C. The mixture was stirred at −60° C. for 1 hr, and then methyl 2-methoxyacetate (7.53 mL, 76.0 mmol) was added to the mixture and the mixture was stirred at −60° C. for 1 hr. The reaction mixture was quenched by addition water (1 L), and then extracted with EA (1 L×2). The combined organic layers were washed with brine (1 L), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by FCC (Eluent: PE:EA=3:1) affording the title compound (5 g, 21.7 mmol) as a brown solid.

    [0327] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.45 (d, J=5.2 Hz, 1H), 8.23 (d, J=2.0 Hz, 1H), 7.68-7.66 (m, 1H), 5.01 (s, 2H), 3.54 (s, 3H) ppm.

    Step 2. tert-Butyl N-[1-(4-bromo-2-pyridyl)-2-methoxy-ethyl]carbamate

    [0328] Ammonium acetate (13.4 g, 174 mmol) and NaBH.sub.3CN (10.93 g, 174 mmol) were added to a solution of 1-(4-bromo-2-pyridyl)-2-methoxy-ethanone (4 g, 17.4 mmol) in THF (120 mL) at 20° C. The mixture was stirred at 20° C. for 2 hr. Boc.sub.2O (22.8 g, 104 mmol) and saturated NaHCO.sub.3 (60 mL) were added to the reaction mixture and the mixture was stirred at 20° C. for 2 hrs. The reaction mixture was diluted with water (300 mL) and extracted with EA (300 mL×2). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by FCC (Eluent: PE:EA=3:1) and concentrated under reduced pressure to give a white solid. The white solid was then re-purified by RPC. The fractions containing the title compound were collected and concentrated to remove the MeCN. The aqueous layer was basified with sodium carbonate (solid) until pH=9.0 was achieved. The aqueous solution was extracted with EA (100 mL×2). The combined organic layers were dried with anhydrous Na.sub.2SO.sub.4 and concentrated in vacuo affording the title compound (1.5 g, 4.19 mmol) as brown oil.

    [0329] LCMS (ESI) m/z: [Br81M+H]+=333.1.

    [0330] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.41 (d, J=5.2 Hz, 1H), 7.62 (d, J=1.2 Hz, 1H), 7.58-7.56 (m, 1H), 7.37 (br d, J=8.8 Hz, 1H), 4.81-4.76 (m, 1H), 3.56-3.54 (m, 2H), 3.23 (s, 3H), 1.40-1.37 (m, 9H) ppm.

    Intermediates 12 and 13: (S)-4-(Difluoromethyl)-4-fluoroisochroman-6-carboxylic acid and (R)-4-(Difluoromethyl)-4-fluoroisochroman-6-carboxylic acid

    [0331] ##STR00570##

    Step 1. 6-Bromo-4-(difluoro(phenylsulfonyl)methyl)isochroman-4-ol

    [0332] LiHMDS (1 M, 26.4 mL) was added to a solution of 6-bromoisochroman-4-one (3 g, 13.2 mmol), difluoromethylsulfonylbenzene (2.8 mL, 19.8 mmol) in THE (30 mL) at −78° C. The mixture was stirred at −78° C. for 2 hr. The reaction mixture was poured into saturated aq. NH.sub.4Cl (50 mL) and extracted with EA (50 mL×2). The organic layer was washed with brine (50 mL) and dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=10:1 to 3:1) affording the title compound (3 g, 6.70 mmol) as yellow solid.

    [0333] LCMS (ESI) m/z: [M+H.sub.2O]+=435.8, 437.8.

    [0334] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.04 (d, J=7.6 Hz, 2H), 7.90-7.89 (m, 1H), 7.85-7.76 (m, 1H), 7.71-7.62 (m, 2H), 7.49-7.47 (m, 1H), 6.97 (d, J=8.4 Hz, 1H), 5.00 (d, J=12.4 Hz, 1H), 4.93-4.73 (m, 2H), 3.93-3.88 (m, 1H), 3.83 (s, 1H).

    Step 2. 6-Bromo-4-(difluoromethyl)isochroman-4-ol

    [0335] Magnesium (2.61 g, 107 mmol) was added to a solution of 6-bromo-4-(difluoro(phenylsulfonyl)methyl)isochroman-4-ol (3 g, 7.16 mmol) and NaOAc/HOAc (aq., 8 M, 44.7 mL) in DMF (100 mL). The mixture was stirred at 25° C. for 2 hrs. The reaction mixture was poured into water (50 mL), and then extracted with EA (50 mL×3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=10:1 to 3:1) affording the title compound (1.5 g, 5.37 mmol) as colorless oil.

    [0336] LCMS (ESI) m/z: [79BrM−H.sub.2O]+=260.9.

    [0337] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.83-7.60 (m, 1H), 7.51-7.33 (m, 1H), 7.11-6.93 (m, 1H), 6.25-5.88 (m, 1H), 4.92-4.70 (m, 2H), 4.26-4.17 (m, 1H), 3.87-3.66 (m, 1H), 2.75-2.58 (m, 1H).

    Step 3. 6-Bromo-4-(difluoromethyl)-4-fluoroisochroman

    [0338] DAST (1.33 mL, 10.0 mmol) was added to a solution of 6-bromo-4-(difluoromethyl)isochroman-4-ol (1.4 g, 5.02 mmol) in DCM (20 mL) at 0° C. The mixture was stirred at 0° C. for 2 hr. The reaction mixture was poured into water (50 mL) and extracted with DCM (20 mL×2). The organic layer was washed with brine (20 mL) and dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=10:1 to 5:1) affording the title compound (900 mg, 2.88 mmol) as colorless oil.

    [0339] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.73-7.51 (m, 1H), 7.48-7.28 (m, 1H), 7.08-6.89 (m, 1H), 6.20-5.80 (m, 1H), 4.82-4.61 (m, 2H), 4.33-4.18 (m, 1H), 4.01-3.82 (m, 1H).

    Step 4. (S)-4-(Difluoromethyl)-4-fluoroisochroman-6-carboxylic acid and (R)-4-(Difluoromethyl)-4-fluoroisochroman-6-carboxylic acid

    [0340] Palladium acetate (34.0 mg, 0.15 mmol), K.sub.2CO.sub.3 (627 mg, 4.54 mmol) and dccp-.2HBF.sub.4 (185 mg, 0.30 mmol) were added to a solution of 6-bromo-4-(difluoromethyl)-4-fluoroisochroman (850 mg, 3.02 mmol), in H.sub.2O (0.11 mL) and DMSO (10 mL). The mixture was stirred at 100° C. for 16 hrs under CO (g, 15 psi). The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL×2). The organic layer was washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was purified by reverse phase column chromatography affording a mixture of the title compounds (450 mg, 1.64 mmol) as colorless oil. The mixture of stereoisomers was purified by SFC separation (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 m); mobile phase: [0.1% NH.sub.3—H.sub.2O MEOH]; B %: 20%-20%, 3 min; 36 minmin) to give intermediate 12 (220 mg, 0.89 mmol) as a colorless oil and intermediate 13 (220 mg, 0.89 mmol) as a colorless oil.

    [0341] Intermediate 12: Chiral SFC: Chiralpak IG-3 50×4.6 mm I.D., RT=0.928 min.

    [0342] LCMS (ESI) m/z: [M+H.sub.2O]+=247.2.

    [0343] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.36 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 6.38-5.96 (m, 1H), 5.01-4.76 (m, 2H), 4.40-4.35 (m, 1H), 4.18-4.01 (m, 1H).

    [0344] Intermediate 13: Chiral SFC: Chiralpak IG-3 50×4.6 mm I.D., RT=1.115 min.

    [0345] LCMS (ESI) m/z: [M+H.sub.2O]+=247.2.

    [0346] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.36 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 6.38-5.96 (m, 1H), 5.01-4.76 (m, 2H), 4.40-4.35 (m, 1H), 4.18-4.01 (m, 1H).

    Intermediates 14 and 15: (R)-3-Cyano-3-methyl-2,3-dihydrobenzofuran-5-carboxylic acid & (S)-3-Cyano-3-methyl-2,3-dihydrobenzofuran-5-carboxylic acid

    [0347] ##STR00571##

    Step 1. Methyl 5-bromo-2,3-dihydrobenzofuran-3-carboxylate

    [0348] Magnesium (9.53 g, 392 mmol) was added to a solution of methyl 5-bromobenzofuran-3-carboxylate (10 g, 39.2 mmol) in MeOH (400 mL). The reaction solution was stirred at 25° C. for 6 hrs. 4N HCl (200 mL) was carefully added to the solution. After complete dissolution of the magnesium metal, the solution was concentrated under reduced pressure to remove MeOH. The resulting mixture was partitioned between EA (200 mL×3) and water (100 mL). The organic phase was separated, dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by reversed phase chromatography and concentrated under reduced pressure to remove MeCN. The aqueous layer was then extracted with EA (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure affording the title compound (6 g, 23.3 mmol) as a red oil.

    [0349] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.41-7.40 (m, 1H), 7.25-7.16 (m, 1H), 6.62 (d, J=8.8 Hz, 1H), 4.89-4.85 (m, 1H), 4.61-4.60 (m, 1H), 4.28-4.24 (m, 1H), 3.73 (s, 3H) ppm.

    Step 2. Methyl 5-bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxylate

    [0350] Sodium hydride (350 mg, 8.75 mmol, 60% purity) was slowly added to a mixture of methyl 5-bromo-2,3-dihydrobenzofuran-3-carboxylate (1.5 g, 5.83 mmol) in THE (15 mL) at 0° C. The mixture was stirred at 0° C. for 0.5 hr, then MeI (0.54 mL, 8.75 mmol) was added drop-wise at 0° C. The reaction mixture was warmed up to 25° C. and stirred for 2 hrs. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl (30 mL) and extracted with EA (10 mL×3). The combined organic phase was concentrated to afford yellow oil. The oil was purified by FCC (Eluent: 0 to 40% EA/PE) affording the title compound (670 mg, 2.43 mmol) as yellow oil.

    [0351] LCMS (ESI) m/z: [79BrM+H]+=271.0.

    [0352] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.43 (d, J=2.0 Hz, 1H), 7.29-7.27 (m, 1H), 6.71 (d, J=8.4 Hz, 1H), 5.08 (d, J=9.2 Hz, 1H), 4.28 (d, J=9.2 Hz, 1H), 3.76 (s, 3H), 1.61 (s, 3H) ppm.

    Step 3. 5-Bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxylic acid

    [0353] A mixture of methyl 5-bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxylate (650 mg, 2.40 mmol) and NaOH (240 mg, 5.99 mmol) in MeOH (5 mL) and H.sub.2O (2 mL) was stirred at 25° C. for 1 hour. The reaction mixture was diluted with water (10 mL). HCl (1 M) was added to adjust pH to 4, and then the solution was extracted with EA (10 mL×3). The combined organic layer was concentrated affording the title compound (600 mg) as a white solid.

    [0354] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.44 (d, J=2.0 Hz, 1H), 7.34-7.31 (m, 1H), 6.80 (d, J=8.4 Hz, 1H), 4.94 (d, J=9.2 Hz, 1H), 4.30 (d, J=9.2 Hz, 1H), 1.53 (s, 3H) ppm.

    Step 4. 5-Bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxamide

    [0355] Ammonium chloride (1.25 g, 23.3 mmol) was added to a mixture of 5-bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxylic acid (600 mg, 2.33 mmol), DIPEA (2.0 mL, 11.7 mmol), and HATU (1.33 g, 3.50 mmol) in DMF (6 mL) at 25° C. The mixture was stirred for 12 hrs. The reaction mixture was diluted with water (20 mL) and extracted with EA (10 mL×3). The combined organic layer was washed with brine (10 mL×3), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo affording the title compound (580 mg) as a yellow solid.

    [0356] LCMS (ESI) m/z: [79BrM+H]+=257.0.

    [0357] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.60 (d, J=2.0 Hz, 1H), 7.38-7.24 (m, 3H), 6.76 (d, J=8.4 Hz, 1H), 5.03 (d, J=8.8 Hz, 1H), 4.20 (d, J=9.2 Hz, 1H), 1.52 (s, 3H) ppm.

    Step 5. 5-Bromo-3-methyl-2,3-dihydrobenzofuran-3-carbonitrile

    [0358] Triethylamine (0.95 mL, 6.79 mmol) was added to a mixture of 5-bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxamide (580 mg, 2.26 mmol) in DCM (6 mL) at 0° C. TFAA (0.79 mL, 5.66 mmol) was then added at 0° C. The mixture was stirred for 10 minutes. The reaction mixture was diluted with water (20 mL) and extracted with DCM (10 mL×2). The combined organic phase was concentrated to afford yellow oil. The oil was purified by FCC (Eluent: 0 to 20% EA in PE) affording the title compound (500 mg, 1.89 mmol) as yellow oil.

    [0359] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.80 (d, J=2.0 Hz, 1H), 7.47-7.44 (m, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.96 (d, J=9.4 Hz, 1H), 4.46 (d, J=9.6 Hz, 1H), 1.74 (s, 3H) ppm.

    Step 6. (R)-3-Cyano-3-methyl-2,3-dihydrobenzofuran-5-carboxylic acid and (S)-3-Cyano-3-methyl-2,3-dihydrobenzofuran-5-carboxylic acid

    [0360] Palladium acetate (18.9 mg, 0.084 mmol) and dccp.2HBF.sub.4 (103 mg, 0.17 mmol) were added to a mixture of 5-bromo-3-methyl-2,3-dihydrobenzofuran-3-carbonitrile (400 mg, 1.68 mmol) and K.sub.2CO.sub.3 (348 mg, 2.52 mmol) in DMSO (3.2 mL) and H.sub.2O (0.8 mL) at 25° C. The mixture was degassed and purged with CO (g) three times. The mixture was stirred at 100° C. under a CO atmosphere (15 psi) for 12 hrs. The reaction mixture was filtered and the filtrate was purified by reversed-phase HPLC. The desired fractions were concentrated to remove MeCN and lyophilized affording the mixture of the title compounds (210 mg, 1.02 mmol) as a white solid. The stereoisomers were separated by chiral SFC (DAICEL CHIRALPAK IG (250 mm*30 mm, 10 m); mobile phase: [0.1% NH.sub.3—H.sub.2O MEOH]; B %: 20%-20%, 3.9 min).

    [0361] The eluent was concentrated to afford Intermediate 14 (90 mg, 0.44 mmol) as a red solid and Intermediate 15 (100 mg, 0.49 mol) as a light yellow solid.

    [0362] Intermediate 14: Chiral SFC: AD-3_5CM_ETOH(DEA)_5_40_3ML_AT35.M, RT=0.924 min.

    [0363] LCMS (ESI) m/z: [M+H]+=204.1.

    [0364] .sup.1HNMR (400 MHz, DMSO-d6) δ=8.02 (s, 1H), 7.90-7.88 (m, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.99 (d, J=9.6 Hz, 1H), 4.52 (d, J=9.6 Hz, 1H), 1.75 (s, 3H) ppm.

    [0365] Intermediate 15: Chiral SFC: AD-3_5CM_ETOH(DEA)_5_40_3ML_AT35.M, RT=1.078 min.

    [0366] LCMS (ESI) m/z: [M+H]+=204.

    [0367] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.02 (d, J=1.6 Hz, 1H), 7.89-7.87 (m, 1H), 6.97 (d, J=8.4 Hz, 1H), 4.99 (d, J=9.6 Hz, 1H), 4.52 (d, J=9.2 Hz, 1H), 1.75 (s, 3H) ppm.

    Intermediate 16: 3-[3-(difluoromethyl)oxetan-3-yl]benzoic acid

    [0368] ##STR00572##

    Step 1. 3-(3-Bromophenyl)oxetane-3-carbaldehyde

    [0369] DMP (1.66 mL, 5.35 mmol) was added to a solution of [3-(3-bromophenyl)oxetan-3-yl]methanol (1 g, 4.11 mmol) in DCM (10 mL) at 0° C. The mixture was stirred for 1 hr at 25° C. The mixture was filtered and concentrated. The residue was purified by FCC (Eluent: PE:EA=100:1 to 1:100) affording the title compound (850 mg, 3.53 mmol) as colorless oil.

    [0370] LCMS (ESI) m/z: [79BrM+H]+=259.0.

    [0371] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=9.71 (s, 1H), 7.46-7.40 (m, 1H), 7.24 (t, J=8.0 Hz, 1H), 7.18 (t, J=2.0 Hz, 1H), 6.99-6.92 (m, 1H), 5.08 (d, J=6.4 Hz, 2H), 4.91 (d, J=6.4 Hz, 2H) ppm.

    Step 2. 3-(3-Bromophenyl)-3-(difluoromethyl)oxetane

    [0372] DAST (1.15 mL, 8.71 mmol) was added to a solution of 3-(3-bromophenyl)oxetane-3-carbaldehyde (700 mg, 2.90 mmol) in DCM (7 mL) at −78° C. The mixture was warmed and stirred for 1 hr at 0° C. The mixture was poured into saturated aqueous solution of NaHCO.sub.3 (5 mL). The organic layer was collected and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=100:1 to 1:1) affording the title compound (500 mg, 1.90 mmol) as brown oil.

    [0373] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.59-7.45 (m, 1H), 7.34-7.29 (m, 1H), 7.26 (s, 1H), 7.11-6.94 (m, 1H), 6.43-5.96 (m, 1H), 4.99 (s, 4H) ppm.

    Step 3. 3-[3-(Difluoromethyl)oxetan-3-yl]benzoic acid

    [0374] Palladium acetate (6.40 mg, 0.029 mmol), dccp.2HBF.sub.4 (34.9 mg, 0.057 mmol), and K.sub.2CO.sub.3 (118 mg, 0.86 mmol was added to a solution of 3-(3-bromophenyl)-3-(difluoromethyl)oxetane (150 mg, 0.57 mmol) in DMSO (5 mL) and H.sub.2O (2.5 mL) at 25° C. The mixture was degassed and purged with CO (g) three times, and then the mixture was stirred at 100° C. for 16 hrs under a CO atmosphere (15 psi). The mixture was extracted with EA (5 ml). The aqueous layer was adjusted pH to 5-6 with aqueous HCl (1 M) and extracted with EA (5 ml×3). The organic layers were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo affording the title compound (120 mg, 0.53 mmol) as colorless oil.

    [0375] LCMS (ESI) m/z: [M+H]+=229.1.

    Intermediate 17: 4-(3-Oxocyclobutyl)picolinonitrile

    [0376] ##STR00573##

    Step 1: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile

    [0377] To a solution of 4-bromopyridine-2-carbonitrile (25 g, 136.61 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (41.63 g, 163.93 mmol) in dioxane (250 mL) was added KOAc (40.22 g, 409.82 mmol) and Pd(dppf)Cl.sub.2.CH.sub.2C.sub.12 (3 g, 3.67 mmol). The mixture was stirred at 80° C. for 3 hrs. The reaction mixture was poured into water (1000 mL), the solution was extracted with EA (1000 mL*2), the combined organic layer was washed with brine (2000 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10:1-1:1) to give the title compound (24 g, 104.32 mmol, 76.36% yield) as a white solid.

    [0378] LCMS (ESI) m/z: [M+H].sup.+=231.1

    [0379] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.79 (d, J=4.4 Hz, 1H), 8.04 (s, 1H), 7.87 (d, J=4.8 Hz, 1H), 1.31 (s, 12H) ppm

    Step 2: N′-(3-(Benzyloxy)cyclobutylidene)-4-methylbenzenesulfonohydrazide

    [0380] To a solution of 3-benzyloxycyclobutanone (15 g, 85.13 mmol) in MeOH (150 mL) was added 4-methylbenzenesulfonohydrazide (15.85 g, 85.13 mmol). The mixture was stirred at 20° C. for 5 min. The reaction mixture was filtered, the filter cake was washed MeOH (30 mL) and the filtrate dried in vacuo to give the title compound (23 g, 66.78 mmol, 78.45% yield) as a white solid.

    Step 3: 4-(3-(Benzyloxy)cyclobutyl)picolinonitrile

    [0381] To a solution of N′-(3-(benzyloxy)cyclobutylidene)-4-methylbenzenesulfonohydrazide (23 g, 66.78 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (23.05 g, 100.17 mmol) in dioxane (450 mL) was added Cs.sub.2CO.sub.3 (65.27 g, 200.33 mmol). The mixture was refluxed at 130° C. for 48 hr. The reaction mixture was diluted with water (800 mL) and extracted with EA (300 mL*3). The combined organic layers were washed with dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.

    [0382] The residue was purified by column chromatography (SiO.sub.2, DCM/EA=1/0 to 10/1) to give the title compound (3.7 g, 13.29 mmol, 19.90% yield) as yellow oil.

    [0383] LCMS (ESI) m/z: [M+H].sup.+=265.1

    Step 4: 4-(3-Hydroxycyclobutyl)picolinonitrile

    [0384] To a solution of 4-(3-(benzyloxy)cyclobutyl)picolinonitrile (3.7 g, 14.00 mmol) in DCM (120 mL) and H.sub.2O (12 mL) was added DDQ (17.48 g, 76.99 mmol). The mixture was stirred at 30° C. for 16 hrs under N.sub.2. The reaction mixture was poured into sat. NaSO.sub.3 solution (500 mL) and extracted with DCM 10 (500 mL*3). The combined organic layer was washed with brine (500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=5:1-0:1) to give the title compound (1.4 g, 8.04 mmol, 57.41% yield) as a yellow oil.

    Step 5: 4-(3-Oxocyclobutyl)picolinonitrile

    [0385] To a solution of 4-(3-hydroxycyclobutyl)picolinonitrile (1.4 g, 5.44 mmol) in DCM (15 mL) was added Dess-Martin (6.92 g, 16.31 mmol). The mixture was stirred at 30° C. for 2 hrs. The reaction mixture was poured into Na.sub.2SO.sub.3 solution (100 mL) and extracted with EA (100 mL). The combined organic layer was washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=5:1-0:1) to give the title compound (900 mg, 4.98 mmol, 91.62% yield) as an off-white solid.

    [0386] LCMS (ESI) m/z: [M+H].sup.+=173.1

    Intermediate 18: 2-Methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one

    [0387] ##STR00574##

    Step 1: 2-Methyl-2,6-naphthyridin-1(2H)-one

    [0388] To a mixture of 2,6-naphthyridin-1(2H)-one (200 mg, 1.37 mmol) in DMF (10 mL) was added Cs.sub.2CO.sub.3 (668.82 mg, 2.05 mmol) and MeI (291.36 mg, 2.05 mmol, 127.79 uL) at 30° C. The mixture was stirred at 30° C. for 16 hrs. The mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL*3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=20/1, Rf=0.4) to afford the title compound (160 mg, 946.72 umol, 69.18% yield) as a yellow solid.

    [0389] LCMS (ESI) m/z: [M+H].sup.+=161.1.

    [0390] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.98 (s, 1H), 8.69 (d, J=5.2 Hz, 1H), 8.19 (d, J=5.2 Hz, 1H), 7.20 (d, J=7.2 Hz, 1H), 6.58 (d, J=7.2 Hz, 1H), 3.65 (s, 3H) ppm.

    Step 2: 2-Benzyl-6-methyl-5-oxo-5,6-dihydro-2,6-naphthyridin-2-ium bromide

    [0391] A mixture of 2-methyl-2,6-naphthyridin-1(2H)-one (50 mg, 312.16 umol) in EtOH (0.5 mL) was stirred at 70° C. for 10 min. Then benzyl bromide (720.00 mg, 4.21 mmol, 0.5 mL) was added. The mixture was stirred at 80° C. for 16 hrs. The mixture was treated with MTBE (10 mL) and filtered. The filter cake was dried under reduced pressure to afford the title compound (130 mg, crude) as a yellow solid.

    [0392] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.87 (s, 1H), 8.98-8.97 (m, 1H), 8.68 (d, J=6.4 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.59-7.42 (m, 5H), 6.96 (d, J=7.6 Hz, 1H), 5.96 (s, 2H), 3.60 (s, 3H) ppm.

    Step 3: 6-Benzyl-2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one

    [0393] To a mixture of 2-benzyl-6-methyl-5-oxo-5,6-dihydro-2,6-naphthyridin-2-ium bromide (70 mg, 211.35 umol) in MeOH (1 mL) was added NaBH.sub.4 (39.98 mg, 1.06 mmol) in several portions at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was poured into 1 M HCl aqueous solution (5 mL) and basified with sat. NaHCO.sub.3 to pH=8. The mixture was extracted with EA (10 mL*3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (35 mg, 137.62 umol, 65.1% yield) as a yellow solid.

    [0394] LCMS (ESI) m/z: [M+H].sup.+=255.3.

    [0395] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.40-7.28 (m, 5H), 7.07 (d, J=7.2 Hz, 1H), 5.84 (d, J=6.8 Hz, 1H), 3.69 (s, 2H), 3.52 (s, 3H), 3.39 (s, 2H), 2.79-2.64 (m, 4H) ppm.

    Step 4: 2-Methyl-2,6-naphthyridin-1(2H)-one

    [0396] To a mixture of 6-benzyl-2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one (35 mg, 137.62 umol) in MeOH (1 mL) was added TFA (31.38 mg, 275.24 umol, 20.38 uL) and Pd/C (20 mg, 10% purity). The mixture was purged with H.sub.2 3 times and stirred at 30° C. for 16 hrs under H.sub.2 (15 psi). The mixture was filtered and the mother liquor was concentrated under reduced pressure to afford the title compound (30 mg, 107.83 umol, 78.4% yield, TFA salt) as a yellow oil.

    [0397] LCMS (ESI) m/z: [M+H].sup.+=165.1.

    Intermediate 19: 7-Fluoro-5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride

    [0398] ##STR00575##

    Step 1: (E)-N-(2,2-Dimethoxyethyl)-1-(3-fluoro-5-methoxyphenyl)methanimine

    [0399] To a solution of 3-fluoro-5-methoxy-benzaldehyde (2 g, 12.98 mmol) in toluene (20 mL) was added 2,2-dimethoxyethanamine (1.50 g, 14.27 mmol, 1.56 mL). The mixture was stirred at 120° C. for 16 hrs. The reaction mixture was concentrated to give the title compound (3 g, crude) as a yellow oil.

    Step 2: N-(3-Fluoro-5-methoxybenzyl)-2,2-dimethoxyethan-1-amine

    [0400] To a solution of (E)-N-(2,2-dimethoxyethyl)-1-(3-fluoro-5-methoxyphenyl)methanimine (3 g, 12.43 mmol) in MeOH (30 mL) was added NaBH.sub.4 (564.53 mg, 14.92 mmol) at 0° C. The mixture was stirred at 30° C. for 30 min. The reaction mixture was poured into water (100 mL) and the mixture was extracted with EA (100 mL*3). The combined organic layer was washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (2.2 g, 9.04 mmol, 72.73% yield) as a yellow oil.

    [0401] .sup.1H NMR (400 MHz, DMSO-d6) δ=6.66-6.63 (m, 2H), 6.51-6.48 (m, 1H), 4.49-4.46 (m, 1H), 3.79 (s, 3H), 3.76 (s, 2H), 3.47-3.37 (m, 6H), 2.73 (d, J=5.4 Hz, 2H) ppm.

    Step 3: 7-Fluoro-5-methoxy-1,2,3,4-tetrahydroisoquinolin-4-ol

    [0402] A mixture of N-(3-fluoro-5-methoxybenzyl)-2,2-dimethoxyethan-1-amine (1 g, 4.11 mmol) in HCl (10 mL) was stirred at 40° C. for 12 hrs. The reaction mixture was concentrated to give the title compound (810 mg, crude) as a yellow oil.

    Step 4: 7-Fluoro-5-methoxy-1,2,3,4-tetrahydroisoquinoline

    [0403] To a solution of 7-fluoro-5-methoxy-1,2,3,4-tetrahydroisoquinolin-4-ol (810 mg, 4.11 mmol) in 25 DCM (8 mL) was added Et.sub.3SiH (1.43 g, 12.32 mmol, 1.97 mL) and TFA (5.39 g, 47.27 mmol, 3.5 mL). The mixture was stirred at 30° C. for 16 hrs. The reaction mixture was concentrated to give the title compound (744 mg, crude) as a yellow oil.

    [0404] LCMS (ESI) m/z: [M+H].sup.+=182.3

    Step 5: tert-Butyl 7-fluoro-5-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

    [0405] To a solution of 7-fluoro-5-methoxy-1,2,3,4-tetrahydroisoquinoline (744 mg, 4.11 mmol) in DCM (10 mL) was added Et.sub.3N (2.08 g, 20.53 mmol, 2.86 mL) and Boc.sub.2O (1.08 g, 4.93 mmol, 1.13 mL). The mixture was stirred at 30° C. for 2 hrs. The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL*3). The combined organic layer was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=5:1-1:1) to give the title compound (150 mg, 494.22 umol, 12.04% yield) as a white solid.

    [0406] LCMS (ESI) m/z: [M+H].sup.+=226.2

    [0407] .sup.1H NMR (400 MHz, DMSO-d6) δ=6.45-6.42 (m, 2H), 4.54-4.51 (m, 2H), 3.80 (s, 3H), 3.63-3.60 (m, 2H), 2.69-2.66 (m, 2H), 1.49 (s, 9H) ppm.

    Step 6: 7-Fluoro-5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride

    [0408] A mixture of tert-butyl 7-fluoro-5-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (150 mg, 533.20 umol) in HCl/dioxane (2 mL) was stirred at 30° C. for 1 hr. The reaction mixture was concentrated and the residue was triturated with MTBE (10 mL) to give the title compound (60 mg, 263.71 umol, 49.46% yield) as a white solid.

    [0409] LCMS (ESI) m/z: [M+H].sup.+=182.1

    [0410] .sup.1H NMR (400 MHz, DMSO-d6) δ=6.53-6.43 (m, 2H), 4.28 (s, 2H), 3.81 (s, 3H), 3.43 (s, 2H), 3.00 (s, 2H) ppm

    Intermediate 20: 3-Methoxy-3-phenylpyrrolidine hydrochloride

    [0411] ##STR00576##

    Step 1: tert-Butyl 3-methoxy-3-phenylpyrrolidine-1-carboxylate

    [0412] To a solution of tert-butyl 3-hydroxy-3-phenylpyrrolidine-1-carboxylate (200 mg, 759.50 umol) in DMF (3 mL) was added NaH (42.53 mg, 1.06 mmol, 60% purity) at 0° C. The mixture was stirred at 0° C. for 1 hr. MeI (161.70 mg, 1.14 mmol, 70.92 uL) was added to the mixture and stirring at 25° C. continued for 16 hrs. The mixture was poured into water (50 mL) and extracted with EA (30 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-60% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to give the title compound (180 mg, 648.98 umol, 85.45% yield) as a colorless oil.

    [0413] .sup.1HNMR (400 MHz, CDCl.sub.3) δ=7.43-7.29 (m, 5H), 3.97-3.78 (m, 1H), 3.64-3.45 (m, 3H), 3.02 (d, J=5.6 Hz, 3H), 2.48-2.36 (m, 1H), 2.24-2.09 (m, 1H), 1.48 (d, J=4.8 Hz, 9H) ppm.

    Step 2: 3-Methoxy-3-phenylpyrrolidine hydrochloride

    [0414] To a solution of tert-butyl 3-methoxy-3-phenylpyrrolidine-1-carboxylate (170 mg, 612.93 umol) in MeOH (2 mL) was added HCl/dioxane (4 M, 2 mL). The mixture was stirred at 25° C. for 2 hrs. The reaction was concentrated under reduced pressure to give the title compound (120 mg, crude, HCl) as a white solid.

    [0415] .sup.1HNMR (400 MHz, DMSO-d6) δ=9.89 (br s, 1H), 9.48 (br s, 1H), 7.47-7.34 (m, 4H), 3.80-3.67 (m, 1H), 3.40-3.14 (m, 3H), 2.92 (s, 3H), 2.63-2.53 (m, 1H), 2.24-2.10 (m, 1H) ppm.

    Intermediate 21: 1-(Azetidin-3-yl)-1H-indole

    [0416] ##STR00577##

    Step 1: tert-Butyl 3-(1H-indol-1-yl)azetidine-1-carboxylate

    [0417] To a solution of indole (500 mg, 4.27 mmol) in DMF (5 mL) was added NaH (256.06 mg, 6.40 mmol, 60% purity) in portions at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hr. tert-Butyl 3-iodoazetidine-1-carboxylate (1.33 g, 4.69 mmol) was then added dropwise. The reaction solution was stirred at 25° C. for 12.5 hrs. The reaction mixture was quenched by saturated aqueous NH.sub.4Cl (10 mL), diluted with H.sub.2O (10 mL) and extracted with EA (10 mL*3). The combined organic layers were washed with brine (10 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reversed phase chromatography (FA condition). The fraction was concentrated under reduced pressure to remove MeCN and extracted with EA (25 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (520 mg, 1.77 mmol, 41.41% yield) as a red oil.

    [0418] LCMS (ESI) m/z: [M+H].sup.+=273.1

    [0419] .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ=7.66 (d, J=7.6 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.32 (d, J=3.2 Hz, 1H), 7.26-7.22 (m, 1H), 7.19-7.11 (m, 1H), 6.60 (d, J=2.8 Hz, 1H), 5.22-5.18 (m, 1H), 4.52-4.48 (m, 2H), 4.36-4.32 (m, 2H), 1.50 (s, 9H)

    Step 2: 1-(Azetidin-3-yl)-1H-indole

    [0420] To a solution of tert-butyl 3-(1H-indol-1-yl)azetidine-1-carboxylate (220 mg, 807.81 umol) in DCM (3 mL) was added TFA (92.11 mg, 807.81 umol, 59.81 uL). The reaction mixture was stirred at 25° C. for 10 hrs. The reaction mixture was then concentrated under reduced pressure and the residue purified by reversed phase chromatography (FA condition). The fraction was concentrated under reduced pressure to remove MeCN and lyophilized to give the title compound (110 mg, 504.01 umol, 62.39% yield, FA) as a red solid.

    [0421] LCMS (ESI) m/z: [M+H].sup.+=173.1

    Intermediate 22: 7-(Difluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride

    [0422] ##STR00578##

    Step 1: tert-Butyl 7-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

    [0423] To a solution of tert-butyl 7-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (1 g, 3.20 mmol) in THE (40 mL) at −78° C. under N.sub.2 was added n-BuLi (2.5 M, 2.56 mL) dropwise. The reaction was stirred at −78° C. for 0.5 hr. DMF (468.25 mg, 6.41 mmol, 492.89 uL) was then added dropwise at −78° C. and stirred at −78° C. for 2.5 hrs. The reaction mixture was quenched with aq. NH.sub.4Cl (60 mL) and extracted with EA (50 mL*3). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue purified by flash silica gel chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0˜1/1) to give the title compound (280 mg, 1.01 mmol, 31.46% yield) as a colorless oil.

    [0424] LCMS (ESI) m/z: [M+H−56].sup.+=206.1

    [0425] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.95 (s, 1H), 7.76-7.68 (m, 2H), 7.39 (d, J=8.0 Hz, 1H), 4.59 (s, 2H), 3.58-3.55 (m, 2H), 2.88-2.85 (m, 2H), 1.46-1.41 (m, 9H) ppm.

    Step 2: tert-Butyl 7-(difluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

    [0426] To a solution of tert-butyl 7-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (150 mg, 574.02 umol) in DCM (1.5 mL) was added DAST (157.29 mg, 975.83 umol, 128.93 uL) and EtOH (5.29 mg, 114.80 umol, 6.71 uL). The mixture was stirred at 25° C. for 14 hrs. Additional DAST (92.53 mg, 574.02 umol, 75.84 uL) was added at 0° C. and the mixture stirred at 25° C. for 2 hrs. The reaction mixture was diluted with H.sub.2O (20 mL) and extracted with EA (20 mL*3). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 1/1) to give the title compound (120 mg, 388.11 umol, 67.61% yield) as a colorless oil.

    [0427] LCMS (ESI) m/z: [M+H−56].sup.+=228.1

    [0428] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.40-7.34 (m, 2H), 7.32-7.28 (m, 1H), 7.12-6.82 (m, 1H), 4.54 (s, 2H), 3.57-3.52 (m, 2H), 2.83-2.80 (m, 2H), 1.43 (s, 9H) ppm.

    Step 3: 7-(Difluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride

    [0429] To a solution of tert-butyl 7-(difluoromethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (120 mg, 423.56 umol) in dioxane (1 mL) was added HCl/dioxane (4 M, 756.34 uL). The reaction mixture was stirred at 25° C. for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (90 mg, 378.26 umol, 89.30% yield) as white solid.

    [0430] LCMS (ESI) m/z: [M+H].sup.+=184.0.

    Intermediate 23: 7-Bromo-1,5-naphthyridin-2(1H)-one

    [0431] ##STR00579##

    Step 1. 3-Bromo-1,5-naphthyridine

    [0432] Boric acid (5.72 g, 92.5 mmol), FeSO.sub.4.7H.sub.2O (2.09 g, 7.51 mmol), and sodium 3-nitrobenzenesulfonate hydrate (28.1 g, 116 mmol) were added to a solution of concentrated H.sub.2SO.sub.4 (50 mL) and the mixture was stirred at 30° C. for 0.5 hr. Glycerol (20.3 mL, 272 mmol), 5-bromopyridin-3-amine (10.0 g, 57.8 mmol), and H.sub.2O (50 mL) were added to the reaction solution, and the mixture was stirred at 135° C. for 18 hrs. The mixture was cooled to 30° C., and the pH was adjusted to pH=14 with NaOH. The aqueous layer was extracted with EA (300 mL×3), and the combined organic layer was washed with brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=10:1 to 2:1) affording the title compound (4.50 g, 19.9 mmol) as a yellow solid.

    [0433] LCMS (ESI) m/z: [Br79M+H]+=209.0

    [0434] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.98-8.97 (m, 2H), 8.58 (d, J 1.6 Hz, 1H), 8.40-8.37 (m, 1H), 7.67-7.64 (m, 1H).

    Step 2. 7-Bromo-1,5-naphthyridine 1-oxide

    [0435] m-CPBA (5.24 g, 25.8 mmol, 85% purity) was added to a solution of 3-bromo-1,5-naphthyridine 20 (4.50 g, 21.5 mmol) in DCM (45.0 mL). The mixture was stirred at 30° C. for 16 hr. The mixture was poured into saturated Na.sub.2SO.sub.3 (100 mL) and extracted with DCM (100 mL×3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was triturated with MTBE (50 mL), and the solid was filtered. The solid was collected and dried in vacuo affording the title compound (3.3 g, 14.66 mmol) as a yellow solid.

    [0436] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.23-9.22 (m, 1H), 9.03 (d, J=2.0 Hz, 1H), 8.55 (d, J=6.4 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.57-7.53 (m, 1H).

    Step 3. 7-Bromo-1,5-naphthyridin-2(1H)-one

    [0437] Potassium carbonate (6.89 g, 49.86 mmol) in water (25 mL) was added to a solution of 7-bromo-1,5-naphthyridine 1-oxide (3.30 g, 14.7 mmol) and TosCl (3.35 g, 17.6 mmol) in CHCl.sub.3 (60 mL). The mixture was stirred at 30° C. for 16 hrs. The reaction mixture was filtered, and the filter cake was dried in vacuo affording the title compound (2.5 g, 10.0 mmol) as a yellow solid.

    [0438] LCMS (ESI) m/z: [Br79M+H]+=225.1

    [0439] .sup.1H NMR (400 MHz, DMSO-d6) δ=12.21-11.78 (m, 1H), 8.54 (d, J=2.0 Hz, 1H), 7.91 (d, J=10.4 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 6.78-6.74 (m, 1H).

    Intermediate 24: tert-Butyl N-[1-(2-phenyl-1,6-naphthyridin-7-yl)ethyl]carbamate

    [0440] ##STR00580##

    tert-Butyl N-[1-(2-phenyl-1,6-naphthyridin-7-yl)ethyl]carbamate Methylmagnesium bromide (3 M, 1.73 mL) was added to a solution of 2-phenyl-1,6-naphthyridine-7-carbonitrile (300 mg, 1.30 mmol) in THE (6 mL) at 0° C. The mixture was warmed and stirred at 25° C. for 1 hr. The reaction mixture was quenched by addition dry MeOH (3 mL), then NH.sub.4OAc (1 g, 13.0 mmol) and NaBH.sub.3CN (815 mg, 13.0 mmol) were added and the mixture was stirred at 25° C. for 1 hr. Boc.sub.2O (1.70 g, 7.78 mmol) was added and the reaction mixture was stirred at 25° C. for 16 hrs. The reaction mixture was quenched with water (100 mL) and extracted with EA (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under in vacuo. The crude product was purified by FCC (Eluent: PE:EA=1:1) affording the title compound (250 mg, 0.68 mmol) as light yellow oil.

    [0441] LCMS (ESI) m/z: [M+H]+=350.1.

    [0442] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.34 (s, 1H), 8.63 (d, J=8.8 Hz, 1H), 8.33-8.24 (m, 3H), 7.84 (s, 1H), 7.62-7.53 (m, 4H), 4.87 (d, J=7.2 Hz, 1H), 1.47-1.37 (m, 12H) ppm.

    Intermediates 25 and 26: (3S)-3-(Hydroxymethyl)-3-methyl-indane-5-carboxylic acid and (3R)-3-(Hydroxymethyl)-3-methyl-indane-5-carboxylic acid

    [0443] ##STR00581##

    Step 1. 6-Bromoindane-1-carbonitrile

    [0444] Potassium tert-butoxide (53.2 g, 474 mmol) was added to a solution of 6-bromoindan-1-one (50 g, 237 mmol) and 1-(isocyanomethylsulfonyl)-4-methyl-benzene (69.4 g, 356 mmol) in DME (2.5 L) and EtOH (100 mL) at 0° C. The reaction mixture was stirred at 25° C. for 16 hrs. The reaction mixture was poured into water (2 L) and extracted with EA (2 L×2). The combined organic layer was concentrated in vacuo. The crude product was diluted with EA (500 mL), washed with brine (500 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=20:1). The desired fractions were collected and concentrated in vacuo. The solid was then triturated with MTBE (100 mL) affording the title compound (29 g, 130 mmol) as a white solid.

    [0445] .sup.1H NMR (400 MHz, CHLOROFORM-d) 5=7.58 (s, 1H), 7.42-7.40 (m, 1H), 7.16 (d, J=8.4 Hz, 1H), 4.12-4.08 (m, 1H), 3.10-3.00 (m, 1H), 2.97-2.86 (m, 1H), 2.65-2.55 (m, 1H), 2.43-2.37 (m, 1H) ppm.

    Step 2. 6-Bromo-1-methyl-indane-1-carbonitrile

    [0446] Sodium hydride (10.8 g, 270 mmol, 60% purity) was added to a solution of 6-bromoindane-1-carbonitrile (30 g, 135 mmol) in THE (300 mL) at 0° C. The reaction mixture was warmed and stirred at 10° C. for 0.5 hr. CH.sub.3I (42.1 mL, 675.43 mmol) was added at 0° C. The mixture was warmed and stirred at 25° C. for 2 hrs. The reaction was diluted with NH.sub.4Cl (aq., 800 mL) and extracted with EA (500 mL×3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue was purified by FCC (Eluent: PE:EA=1:0 to 5:1) affording the title compound (27 g, 114 mmol) as a yellow solid.

    [0447] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.70 (d, J=2.0 Hz, 1H), 7.50-7.48 (m, 1H), 7.29 (d, J=8.0 Hz, 1H), 2.97-2.93 (m, 2H), 2.60-2.53 (m, 1H), 2.18 (d, J=12.8 Hz, 1H), 1.64 (s, 3H) ppm.

    Step 3. 3-Cyano-3-methyl-indane-5-carboxylic acid

    [0448] A mixture of 6-bromo-1-methyl-indane-1-carbonitrile (6.5 g, 27.5 mmol), dccp.2HBF.sub.4 (1.69 g, 2.75 mmol), potassium carbonate (5.71 g, 41.3 mmol), Pd(OAc).sub.2 (618 mg, 2.75 mmol), and water (0.99 mL) in DMSO (60 mL) was degassed and purged with CO (g) three times. The mixture was stirred at 100° C. for 14 hr under a CO (15 psi) atmosphere. The reaction mixture was filtered to remove the black solid, and then diluted with water (60 mL) and extracted with EA (80 mL×3). The organic layer was discarded and the aqueous phase was adjusted to pH=4 with aq. HCl. The aqueous solution was then extracted with EA (100 mL×3). The combined organic layers were washed with brine (500 mL×2) then dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure affording the title compound (4.5 g, 20.7 mmol) as a brown solid.

    [0449] LCMS (ESI) m/z: [M+H]+=202.1.

    [0450] .sup.1H NMR (400 MHz, DMSO-d6) δ=13.04 (s, 1H), 7.96 (s, 1H), 7.91-7.88 (m, 1H), 7.45 (d, J=8.0 Hz, 1H), 3.07-3.04 (m, 2H), 2.64-2.53 (m, 1H), 2.28-2.19 (m, 1H), 1.65 (s, 3H) ppm.

    Step 4. 3-Formyl-3-methyl-indane-5-carboxylic acid

    [0451] DIBAL-H (1 M, 159.03 mL) was added to a solution of 3-cyano-3-methyl-indane-5-carboxylic acid (16 g, 79.5 mmol) in toluene (160 mL) at −70° C. The mixture was stirred at −70° C. for 2 hrs. The reaction was quenched via the addition of HCl (2 M, 323 mL). The reaction mixture was warmed and stirred at 20° C. for 1 h. The mixture was diluted with water (2 L) and extracted with EA (1.5 L×3). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated affording the title compound (14 g, 58.2 mmol) as a white solid.

    [0452] LCMS (ESI) m/z: [M+H]+=205.1.

    [0453] .sup.1H NMR (400 MHz, DMSO-d6) δ=12.91 (br s, 1H), 9.58 (s, 1H), 7.85-7.83 (m, 1H), 7.73 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 3.06-2.90 (m, 2H), 2.61-2.54 (m, 1H), 1.98-1.87 (m, 1H), 1.39 (s, 3H) ppm.

    Step 5. (3S)-3-(Hydroxymethyl)-3-methyl-indane-5-carboxylic acid and (3R)-3-(Hydroxymethyl)-3-methyl-indane-5-carboxylic acid

    [0454] Sodium borohydride (2.49 g, 65.8 mmol) was added to a solution of 3-formyl-3-methyl-indane-5-carboxylic acid (14 g, 58.2 mmol) in THE (150 mL) at 0° C. The mixture was warmed and stirred at 25° C. for 3 hrs. The reaction was diluted with water (200 mL) and extracted with EA (80 mL×2). The organic layer was discarded and the aqueous phase was adjusted to pH=4 with aq. HCl. The aqueous solution was then extracted with EA (300 mL×3). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was washed with DCM (50 mL×3), filtered, and concentrated to get a white solid. The filtrate was concentrated under reduced pressure and the resulting residue was purified by FCC (Eluent: PE:EA=1:0 to 1:5). The desired fractions were collected and concentrated under reduced pressure to get off-white solid. The solid was then washed with MTBE (20 mL×2). This solid was combined with the filtered solid and dried in vacuo affording a mixture of the title compounds (9.5 g, 44.3 mmol) as a white solid. The stereoisomers were separated by chiral SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase: [0.1% NH.sub.3—H.sub.2O MEOH]; B %: 40%-40%, 5 min; 540 min) affording the pure title compounds.

    [0455] Intermediate 25: (4.0 g, 19.40 mmol, white solid)

    [0456] Chiral SFC: AD-3_5CM_MEOH (DEA)_5_40_3ML_AT35.M, Rt=1.575 min, ee %=100%.

    [0457] LCMS (ESI) m/z: [M+H]+=207.2.

    [0458] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.74-7.68 (m, 2H), 7.17 (d, J=8.4 Hz, 1H), 3.39-3.31 (m, 2H), 2.87-2.80 (m, 2H), 2.15-2.12 (m, 1H), 1.73-1.65 (m, 1H), 1.20 (s, 3H) ppm.

    [0459] Intermediate 26: ((4.3 g, 20.44 mmol, light yellow solid)

    [0460] Chiral SFC: AD-3_5CM_MEOH (DEA)_5_40_3ML_AT35.M, Rt=1.799 min, ee %=97.93%.

    [0461] LCMS (ESI) m/z: [M+H]+=207.2.

    [0462] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.73-7.64 (m, 2H), 7.16 (d, J=8.4 Hz, 1H), 3.44-3.25 (m, 2H), 2.88-2.78 (m, 2H), 2.15-2.12 (m, 1H), 1.73-1.65 (m, 1H), 1.20 (s, 3H) ppm.

    Intermediates 27 and 28: (S)-3-cyano-1,3-dimethylindoline-5-carboxylic acid and (R)-3-cyano-1,3-dimethylindoline-5-carboxylic acid

    [0463] ##STR00582## ##STR00583##

    Step 1. Methyl 3-((4-bromophenyl)(methyl)amino)-3-oxopropanoate

    [0464] TCFH (22.6 g, 80.6 mmol) and NMI (12.5 mL, 161.2 mmol) were added to a mixture of 4-bromo-N-methyl-aniline (10 g, 53.8 mmol) and 3-ethoxy-3-oxo-propanoic acid (8.52 g, 64.5 mmol) in MeCN (150 mL) at 20° C. The mixture was stirred at 20° C. for 15 hrs. The mixture was concentrated and diluted with water (10 mL). The aqueous solution was then extracted with DCM (15 mL×3). The combined organic phase was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=5:1 to 3:1) affording the title compound (13 g, 43.3 mmol) as a white solid.

    [0465] LCMS (ESI) m/z: [M+H]+=286.0.

    [0466] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.56 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 4.13 (d, J=7.2 Hz, 2H), 3.29 (s, 3H), 3.21 (s, 2H), 1.29-1.15 (m, 3H) ppm.

    Step 2. Methyl 3-((4-bromophenyl)(methyl)amino)-2-methyl-3-oxopropanoate

    [0467] Potassium carbonate (4.14 g, 30.0 mmol), and MeI (3.7 mL, 59.9 mmol) were added to a mixture of methyl 3-((4-bromophenyl)(methyl)amino)-3-oxopropanoate (6 g, 20.0 mmol) in DMF (60 mL) at 0° C.

    [0468] The reaction mixture was stirred at 20° C. for 15 hrs. The reaction was diluted with water (100 mL) and extracted with EA (60 mL×3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=5:1 to 3:1) affording the title compound (4 g, 12.7 mmol) as a yellow solid.

    [0469] LCMS (ESI) m/z: [M+H]+=300.0.

    [0470] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.57 (d, J=8.4 Hz, 2H), 7.18-7.11 (m, 2H), 4.19-4.03 (m, 2H), 3.40-3.28 (m, 1H), 3.28 (s, 3H), 1.31 (d, J=7.2 Hz, 3H), 1.27-1.21 (m, 3H) ppm.

    Step 3. Ethyl 5-bromo-1,3-dimethyl-2-oxoindoline-3-carboxylate

    [0471] t-BuOK (2.86 g, 25.5 mmol) and copper(II)acetate monohydrate (5.08 g, 25.5 mmol) were added to a mixture of methyl 3-((4-bromophenyl)(methyl)amino)-2-methyl-3-oxopropanoate (4 g, 12.7 mmol) in DMF (120 mL) at 20° C. The mixture was stirred at 100° C. for 1 hr. The mixture was filtered off, the filtrate was diluted with water (150 mL), and then extracted with EA (50 mL×3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=5:1 to 3:1) affording the title compound (2 g, 5.77 mmol) as a yellow solid.

    [0472] LCMS (ESI) m/z: [M+H]+=312.0.

    [0473] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.46-7.44 (m, 1H), 7.38 (d, J=2.0 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 4.23-4.09 (m, 2H), 3.26-3.19 (m, 3H), 1.66 (s, 3H), 1.21-1.16 (m, 3H) ppm.

    Step 4. Ethyl 5-bromo-1,3-dimethylindoline-3-carboxylate

    [0474] BH.sub.3.THF (1 M, 9.61 mL) was added to a solution of ethyl 5-bromo-1,3-dimethyl-2-oxoindoline-3-carboxylate (2 g, 6.41 mmol) in THE (20 mL) at 0° C. The mixture was stirred at 60° C. for 2 hrs. The mixture was slowly quenched with MeOH (30 mL) at 0° C. and then concentrated. The crude product was purified by FCC (Eluent: PE:EA=10:1 to 3:1) affording the title compound (300 mg, 0.86 mmol) as colorless oil.

    [0475] LCMS (ESI) m/z: [M+H]+=298.0.

    [0476] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.34 (d, J=2.0 Hz, 1H), 7.23-7.20 (m, 1H), 6.35 (d, J=8.4 Hz, 1H), 4.26-4.15 (m, 2H), 3.89 (d, J=9.2 Hz, 1H), 3.19-3.12 (m, 1H), 2.78-2.72 (m, 3H), 1.54 (s, 3H), 1.33-1.25 (m, 3H) ppm.

    Step 5. 5-Bromo-1,3-dimethylindoline-3-carboxylic acid

    [0477] LiOH.H.sub.2O (126.66 mg, 3.02 mmol) was added to a mixture of ethyl 5-bromo-1,3-dimethylindoline-3-carboxylate (300 mg, 1.01 mmol) in MeOH (3 mL) and water (1 mL) at 20° C. The mixture was stirred at 20° C. for 15 hrs. MeOH was removed under vacuum and the solution was diluted with water (1 mL). The pH was adjusted to 3 with 1 N HCl and the solution was extracted with EA (5 mL×3). The combined organic phase was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to affording the title compound (220 mg, 0.70 mmol) as a white solid.

    [0478] LCMS (ESI) m/z: [M+H]+=270.0.

    Step 6. 5-Bromo-1,3-dimethylindoline-3-carboxamide

    [0479] Ammonium chloride (436 mg, 8.14 mmol), HATU (465 mg, 1.22 mmol), and DIPEA (0.56 mL, 4.07 mmol) were added to a mixture of 5-bromo-1,3-dimethylindoline-3-carboxylic acid (220 mg, 0.81 mmol) in DMF (4 mL) at 20° C. The mixture was stirred for 15 hrs. Water (5 mL) was added and the mixture was extracted with EA (5 mL×3). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=1:1) affording the title compound (210 mg, 0.47 mmol) as colorless oil.

    [0480] LCMS (ESI) m/z: [M+H]+=269.0.

    [0481] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.29 (br d, J=2.0 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 3.84 (d, J=9.2 Hz, 1H), 3.10 (d, J=9.2 Hz, 1H), 2.76 (s, 3H), 1.57 (s, 3H) ppm.

    Step 7. 5-Bromo-1,3-dimethylindoline-3-carbonitrile

    [0482] Triethylamine (0.33 mL, 2.34 mmol) was added to a mixture of 5-bromo-1,3-dimethylindoline-3-carboxamide (210 mg, 0.78 mmol) in DCM (3 mL) at 0° C. TFAA (0.27 mL, 1.95 mmol) was added slowly and the resulting mixture was stirred at 20° C. for 4 hrs. The mixture was diluted with water (5 mL) and extracted with DCM (5 mL×3). The combined organic phase was washed with saturated NaHCO.sub.3 (aq.), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=10:1 to 5:1) affording the title compound (100 mg, 0.39 mol) as colorless oil.

    [0483] LCMS (ESI) m/z: [M+H]+=251.1.

    [0484] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.33 (d, J=2.0 Hz), 7.31-7.28 (m, 1H), 6.42 (d, J=8.4 Hz, 1H), 3.70 (d, J=9.2 Hz, 1H), 3.32 (d, J=9.2 Hz, 1H), 2.77 (s, 3H), 1.68 (s, 3H) ppm.

    Step 8. 3-Cyano-1,3-dimethylindoline-5-carboxylic acid

    [0485] Palladium acetate (2.2 mg, 0.010 mol), dccp-2HBF.sub.4 (12.2 mg, 0.020 mmol), and potassium carbonate (41.3 mg, 0.30 mmol) were added to a solution of 5-bromo-1,3-dimethylindoline-3-carbonitrile (50 mg, 0.20 mmol) in DMSO (1 mL) and water (0.007 mL). The mixture was degassed and flushed with CO (g) three times. The mixture was then stirred under a CO atmosphere (15 psi) at 100° C. for 15 hrs. Water (3 mL) was added to the mixture and the mixture was extracted with EA (3 mL×3). The combined organic phase was washed with brine (5 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude product was purified by reversed-phase HPLC. The desired fractions were collected and extracted with DCM (5 mL×3). The combined organic layer was washed with brine (5 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated affording a mixture of the title compounds (40 mg) as a white solid. The stereoisomers were separated by SFC condition (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 5 m); mobile phase: [0.1% NH.sub.3.H.sub.2O IPA]; B %: 20%-20%, 5 min; 85 minmin) affording intermediate 27 (20 mg, 0.09 mmol) as a white solid and Intermediate 28 (15 mg, 0.07 mmol) as a white solid.

    [0486] Intermediate 27: Chiral SFC: IC-3-IPA (DEA)-5-40-3 mL-35T.lcm; RT=1.517 min.

    [0487] LCMS (ESI) m/z: [M+H]+=217.1.

    [0488] .sup.1H NMR (400 MHz, DMSO-d6) δ=12.39 (br s, 1H), 7.85-7.76 (m, 2H), 6.66 (d, J=8.4 Hz, 1H), 3.87 (d, J=10.0 Hz, 1H28 3.44 (d, J=10.0 Hz, 1H), 2.83 (s, 3H), 1.68 (s, 3H) ppm.

    [0489] Intermediate 28: Chiral SFC: IC-3-IPA (DEA)-5-40-3 mL-35T.lcm; RT=1.608 min.

    [0490] LCMS (ESI) m/z: [M+H]+=217.1.

    [0491] .sup.1HNMR (400 MHz, DMSO-d6) δ=12.39 (br s, 1H), 7.85-7.76 (m, 2H), 6.66 (d, J=8.4 Hz, 1H), 3.87 (d, J=10.0 Hz, 1H), 3.44 (d, J=10.0 Hz, 1H), 2.83 (s, 3H), 1.68 (s, 3H) ppm.

    Intermediates 29 and 30: (R)-5-Cyano-5-methyl-6,8-dihydro-5H-pyrano[3,4-b]pyridine-3-carboxylic acid and (S)-5-Cyano-5-methyl-6,8-dihydro-5H-pyrano[3,4-b]pyridine-3-carboxylic acid

    [0492] ##STR00584##

    Step 1. 5-Bromo-N-methoxy-N,2-dimethylnicotinamide

    [0493] Oxalyl chloride (12.2 mL, 139 mmol) was added to a solution of 5-bromo-2-methyl-pyridine-3-carboxylic acid (10 g, 46.29 mmol) and DMF (0.036 mL, 0.46 mmol) in DCM (100 mL). The reaction mixture was stirred at 25° C. for 1 hr. The reaction mixture was concentrated in vacuo and the residue was dissolved in DCM (100 mL). The organic solution was added to a solution of N-methoxymethanamine (6.77 g, 69.4 mmol, HCl salt) and DIEA (40.3 mL, 231 mmol) in DCM (50 mL). The reaction mixture was stirred at 25° C. for 14 hrs. The reaction mixture was poured into water (500 mL) and extracted with DCM (500 mL×2). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=1:0 to 1:1) affording the title compound (11.5 g, 44.4 mmol) as yellow solid.

    [0494] LCMS (ESI) m/z: [79BrM+H]+=259.0.

    Step 2. 1-(5-Bromo-2-methylpyridin-3-yl)ethenone

    [0495] Methylmagnesium bromide (3 M, 21.2 mL) was added to a solution of 5-bromo-N-methoxy-N,2-dimethylnicotinamide (11 g, 42.4 mmol) in THE (100 mL) at 0° C. The reaction mixture was stirred at 25° C. for 1 hr. The reaction mixture was poured into saturated aq. NH.sub.4Cl (400 mL) and extracted with EA (400 mL×2). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=1:0 to 5:1) affording the title compound (9 g, 41.5 mmol) as yellow oil.

    [0496] LCMS (ESI) m/z: [79BrM+H]+=214.0.

    [0497] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.66 (d, J=2.4 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 2.70 (s, 3H), 2.60 (s, 3H) ppm.

    Step 3. 2-(5-Bromo-2-methylpyridin-3-yl)propanenitrile

    [0498] tBuOK (9.23 g, 82.2 mmol) was added to a solution of 1-(5-bromo-2-methylpyridin-3-yl)ethenone (8 g, 37.4 mmol) and 1-(isocyanomethylsulfonyl)-4-methylbenzene (11.0 g, 56.1 mmol) in DME (400 mL) and EtOH (16 mL) at 0° C. The reaction mixture was stirred at 25° C. for 14 hrs. The reaction mixture was poured into saturated aq. NH.sub.4Cl (400 mL). The mixture was concentrated in vacuo to remove DME and EtOH. The aqueous phase was extracted with EA (400 mL×2). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=1:0 to 5:1) affording the title compound (7 g, 31.1 mmol) as colorless oil.

    [0499] LCMS (ESI).sub.3 m/z: [79BrM+H]+=225.1.

    [0500] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.55 (d, J=2.4 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 4.03-3.98 (m, 1H), 2.57 (s, 3H), 1.66 (d, J=7.2 Hz, 3H) ppm.

    Step 4. 2-(5-Bromo-2-methylpyridin-3-yl)-3-hydroxy-2-methylpropanenitrile

    [0501] Paraformaldehyde (1.12 g, 37.3 mmol) was added to a solution of 2-(5-bromo-2-methylpyridin-3-yl)propanenitrile (7 g, 31.1 mmol) and NaHCO.sub.3 (261 mg, 3.11 mmol) in DMSO (60 mL). The reaction mixture was stirred at 25° C. for 14 hrs. The reaction mixture was poured into water (400 mL) and extracted with EA (400 mL×2). The combined organic layer was washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=1:0 to 1:1) affording the title compound (7.5 g, 29.4 mmol) as white solid.

    [0502] LCMS (ESI) m/z: [79BrM+H]+=255.1.

    [0503] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.54 (d, J=2.0 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 4.14-4.09 (m, 1H), 3.96-3.92 (m, 1H), 2.80 (s, 3H), 2.69-2.66 (m, 1H), 1.81 (s, 3H) ppm.

    Step 5. 2-(5-Bromo-2-(bromomethyl)pyridin-3-yl)-3-hydroxy-2-methylpropanenitrile

    [0504] NBS (1.40 g, 7.84 mmol) and AIBN (64.4 mg, 0.39 mmol) were added to a solution of 2-(5-bromo-2-methylpyridin-3-yl)-3-hydroxy-2-methylpropanenitrile (1 g, 3.92 mmol) in MeCN (10 mL). The reaction mixture was stirred at 80° C. for 4 hrs. The reaction mixture was concentrated. The residue was purified by FCC (Eluent: PE:EA=1:0 to 1:1) affording the title compound (0.25 g, 0.76 mmol) as brown solid.

    [0505] LCMS (ESI) m/z: [79BrM+H]+=335.0.

    [0506] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.71 (d, J=2.0 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 5.00-4.85 (m, 2H), 4.21-4.06 (m, 2H), 2.24-2.21 (m, 1H), 1.89 (s, 3H) ppm.

    Step 6. 3-Bromo-5-methyl-6,8-dihydro-5H-pyrano[3,4-b]pyridine-5-carbonitrile

    [0507] Potassium carbonate (1.61 g, 11.7 mmol) was added to a solution of 2-(5-bromo-2-(bromomethyl)pyridin-3-yl)-3-hydroxy-2-methylpropanenitrile (1.3 g, 3.89 mmol) in DMF (65 mL). The reaction mixture was stirred at 25° C. for 12 hrs. The reaction mixture was poured into water (300 mL) and extracted with EA (300 mL×2). The combined organic layer was washed with water (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: PE:EA=1:0 to 1:1) affording the title compound (350 mg, 1.27 mmol) as white solid.

    [0508] LCMS (ESI) m/z: [79BrM+H]+=253.0.

    [0509] .sup.1HNMR (400 MHz, CDCl.sub.3) δ=8.59 (d, J=2.4 Hz, 1H), 7.95 (d, J=2.4 Hz, 1H), 4.85-4.76 (m, 2H), 4.12-3.94 (m, 2H), 1.75 (s, 3H) ppm.

    Step 7. (R)-5-Cyano-5-methyl-6,8-dihydro-5H-pyrano[3,4-b]pyridine-3-carboxylic acid and (S)-5-Cyano-5-methyl-6,8-dihydro-5H-pyrano[3,4-b]pyridine-3-carboxylic acid

    [0510] A mixture of 3-bromo-5-methyl-6,8-dihydro-5H-pyrano[3,4-b]pyridine-5-carbonitrile (270 mg, 1.07 mmol), dccp-2HBF.sub.4 (65.3 mg, 0.11 mmol), Pd(OAc).sub.2 (23.9 mg, 0.11 mmol), H.sub.2O (0.038 mL), and K.sub.2CO.sub.3 (221 mg, 1.60 mmol) in DMSO (3 mL) was degassed and purged with CO (g) three times. The mixture was stirred at 100° C. for 16 hrs under a CO atmosphere (15 psi). The reaction mixture was filtered, poured into water (80 mL), and extracted with EA (30 mL×2). The EA phase was discarded. The aqueous phase was adjusted to pH=5 with aq. HCl (1 M). The aqueous phase was extracted with EA 15 (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo affording a mixture of the title compounds (130 mg, 0.57 mmol) as yellow oil. The stereoisomers were separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 m); mobile phase: [0.1% NH.sub.3.H.sub.2O MEOH]; B %: 30%-30%, 4.2 min; 55 minmin) affording Intermediate 29 (55 mg, 0.24 mmol) as a yellow solid and Intermediate 30 (50 mg, 0.22 mmol) as a yellow solid.

    [0511] Intermediate 29: Chiral SFC: AD-3-MeOH(DEA)-5-40-3 mL-35T.lcm; RT=1.055 min.

    [0512] LCMS (ESI) m/z: [M+H]+=219.0.

    [0513] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.99 (d, J=2.0 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 4.96-4.75 (m, 2H), 4.26 (d, J=11.8 Hz, 1H), 3.92 (d, J=11.8 Hz, 1H), 1.70 (s, 3H).

    [0514] Intermediate 30: Chiral SFC: AD-3-MeOH(DEA)-5-40-3 mL-35T.lcm; RT=1.666 min.

    [0515] LCMS (ESI) m/z: [M+H]+=219.0.

    [0516] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.99 (d, J=2.0 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 4.96-4.75 (m, 2H), 4.26 (d, J=11.8 Hz, 1H), 3.92 (d, J=11.8 Hz, 1H), 1.70 (s, 3H).

    Intermediates 31 and 32: (4S)-4-(hydroxymethyl)-4-methyl-isochromane-6-carboxylic acid and (4R)-4-(hydroxymethyl)-4-methyl-isochromane-6-carboxylic acid

    [0517] ##STR00585##

    Step 1. 6-Bromo-4-methyl-isochromane-4-carboxylic acid

    [0518] Potassium hydroxide (aq., 9M, 5.29 mL) was added to a solution of 6-bromo-4-methyl-isochromane-4-carbonitrile (1.2 g, 4.76 mmol) in EtOH (12 mL). The mixture was stirred at 90° C. for 5 hrs. The reaction mixture was diluted with H.sub.2O (20 mL) and extracted with EA (30 mL×3). The combined organic layers were discarded and the aqueous phase was adjusted pH=4 with 1 N HCl. The aqueous layer was extracted with EA (30 mL×3). The combined organic layers were washed with brine 10 (60 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo affording the title compound (800 mg, 2.95 mmol) as yellow oil.

    [0519] .sup.1H NMR (400 MHz, DMSO-d6) δ=13.11-12.45 (m, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.75-4.62 (m, 2H), 4.16 (d, J=11.2 Hz, 1H), 3.59 (d, J=11.2 Hz, 1H), 1.41 (s, 3H).

    Step 2. (6-Bromo-4-methyl-isochroman-4-yl)methanol

    [0520] 6-bromo-4-methyl-isochromane-4-carboxylic acid (800 mg, 2.95 mmol) was dissolved in BH.sub.3THF (1 M, 8.85) at 0° C. and the resulting mixture was stirred at 25° C. for 2 hrs. The reaction mixture was quenched by addition of 1 N HCl (25 mL) at 20° C. and stirred for 30 min. Then the mixture was diluted with water (20 mL) and extracted with EA (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by FCC (Eluent: DCM:MeOH=100:1 to 10:1) affording the title compound (400 mg, 1.56 mmol) as colorless oil.

    [0521] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.47 (d, J=2.0, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.79-4.68 (m, 2H), 4.05 (d, J=11.6 z, 1H), 3.82-3.75 (m, 1H), 3.71-3.63 (m, 1H), 3.53 (d, J=11.6 Hz, 1H), 1.21 (s, 3H).

    Step 3. 4-(Hydroxymethyl)-4-methyl-isochromane-6-carboxylic acid

    [0522] Water (1 mL), K.sub.2CO.sub.3 (185 mg, 1.34 mmol), Pd(OAc).sub.2 (20.1 mg, 0.089 mmol), and dccp.2HBF.sub.4 (110 mg, 0.18 mmol) were added to a solution of (6-bromo-4-methyl-isochroman-4-yl)methanol (230 mg, 0.89 mmol) in DMSO (5 mL). The reaction mixture was purged with CO (g) three times and the resulting mixture was stirred at 100° C. for 16 hrs under a CO atmosphere (15 psi). The reaction mixture was diluted with H.sub.2O (30 mL) and extracted with EA (50 mL×3). The combined organic layers were discarded and the aqueous layer was adjusted to pH=4 with HCl (1 N). The aqueous layer was extracted with EA (30 mL×3). The combined organic layers were washed with brine (60 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo affording a mixture of the title compounds (150 mg, 0.62 mmol) as a yellow solid. The stereoisomers were separated by chiral SFC (column: DAICEL CHIRALPAK IG (250 mm×30 mm, 10 μm); mobile phase: [0.1% NH.sub.3—H.sub.2O IPA]; B %: 25%-25%, 6.65 min; 66 min). The mobile phase was concentrated under reduced pressure to remove most of the MeOH. Water (40 mL) was added and each desired compound mixture was lyophilized affording Intermediate 31 (44 mg, 0.20 mmol) as an off-white solid and Intermediate 32 (48 mg, 0.21 mmol) as an off-white solid.

    Intermediate 31

    [0523] .sup.1H NMR (400 MHz, DMSO-d6) δ=13.02-12.77 (m, 1H), 7.90 (s, 1H), 7.72 (d, J=1.2 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 4.88-4.87 (m, 1H), 4.74 (d, J=4.0 Hz, 2H), 3.90 (d, J=11.2 Hz, 1H), 3.58-3.50 (m, 1H), 3.42-3.35 (m, 2H), 1.14 (s, 3H).

    Intermediate 32

    [0524] .sup.1H NMR (400 MHz, DMSO-d6) δ=13.02-12.77 (m, 1H), 7.90 (s, 1H), 7.72 (d, J=1.2 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 4.88-4.87 (m, 1H), 4.74 (d, J=4.0 Hz, 2H), 3.90 (d, J=11.2 Hz, 1H), 3.58-3.50 (m, 1H), 3.42-3.35 (m, 2H), 1.14 (s, 3H).

    Intermediate 33: 2-Methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one

    [0525] ##STR00586##

    Step 1: 2-Methyl-2,6-naphthyridin-1(2H)-one

    [0526] To a mixture of 2,6-naphthyridin-1(2H)-one (200 mg, 1.37 mmol) in DMF (10 mL) was added Cs.sub.2CO.sub.3 (668.82 mg, 2.05 mmol) and MeI (291.36 mg, 2.05 mmol, 127.79 uL) at 30° C. The mixture was stirred at 30° C. for 16 hrs. The mixture was poured into H.sub.2O (10 mL) and extracted with DCM (10 mL*3).

    [0527] The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=20/1, Rf=0.4) to afford the title compound (160 mg, 946.72 umol, 69.18% yield) as a yellow solid.

    [0528] LCMS (ESI) m/z: [M+H].sup.+=161.1.

    [0529] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.98 (s, 1H), 8.69 (d, J=5.2 Hz, 1H), 8.19 (d, J=5.2 Hz, 1H), 7.20 (d, J=7.2 Hz, 1H), 6.58 (d, J=7.2 Hz, 1H), 3.65 (s, 3H) ppm.

    Step 2: 2-Benzyl-6-methyl-5-oxo-5,6-dihydro-2,6-naphthyridin-2-ium bromide

    [0530] A mixture of 2-methyl-2,6-naphthyridin-1(2H)-one (50 mg, 312.16 umol) in EtOH (0.5 mL) was stirred at 70° C. for 10 min. Then benzyl bromide (720.00 mg, 4.21 mmol, 0.5 mL) was added. The mixture was stirred at 80° C. for 16 hrs. The mixture was treated with MTBE (10 mL) and filtered. The filter cake was dried under reduced pressure to afford the title compound (130 mg, crude) as a yellow solid.

    [0531] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.87 (s, 1H), 8.98-8.97 (m, 1H), 8.68 (d, J=6.4 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.59-7.42 (m, 5H), 6.96 (d, J=7.6 Hz, 1H), 5.96 (s, 2H), 3.60 (s, 3H) ppm.

    Step 3: 6-Benzyl-2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one

    [0532] To a mixture of 2-benzyl-6-methyl-5-oxo-5,6-dihydro-2,6-naphthyridin-2-ium bromide (70 mg, 211.35 umol) in MeOH (1 mL) was added NaBH.sub.4 (39.98 mg, 1.06 mmol) in several portions at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was poured into 1 M HCl aqueous solution (5 mL) and basified with sat. NaHCO.sub.3 to pH=8. The mixture was extracted with EA (10 mL*3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (35 mg, 137.62 umol, 65.1% yield) as a yellow solid.

    [0533] LCMS (ESI) m/z: [M+H].sup.+=255.3.

    [0534] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.40-7.28 (m, 5H), 7.07 (d, J=7.2 Hz, 1H), 5.84 (d, J=6.8 Hz, 1H), 3.69 (s, 2H), 3.52 (s, 3H), 3.39 (s, 2H), 2.79-2.64 (m, 4H) ppm.

    Step 4: 2-Methyl-2,6-naphthyridin-1(2H)-one

    [0535] To a mixture of 6-benzyl-2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one (35 mg, 137.62 umol) in MeOH (1 mL) was added TFA (31.38 mg, 275.24 umol, 20.38 uL) and Pd/C (20 mg, 10% purity). The mixture was purged with H.sub.2 3 times and stirred at 30° C. for 16 hrs under H.sub.2 (15 psi). The mixture was filtered and the mother liquor was concentrated under reduced pressure to afford the title compound (30 mg, 107.83 umol, 78.4% yield, TFA salt) as a yellow oil.

    [0536] LCMS (ESI) m/z: [M+H].sup.+=165.1.

    Intermediate 34: 1-Bromo-4-cyclobutyl-2-methoxybenzene

    [0537] ##STR00587##

    Step 1: 1-(4-Bromo-3-methoxyphenyl)cyclobutan-1-ol

    [0538] To a mixture of 1-bromo-4-iodo-2-methoxy-benzene (2.4 g, 7.67 mmol, 5.41 mL) in THE (25 mL) was added i-PrMgCl—LiCl (1.3 M, 6.19 mL) dropwise at −40° C. The mixture was stirred at −40° C. for 0.5 hr, then cyclobutanone (591.30 mg, 8.44 mmol) was added at −40° C. slowly. The resulting mixture was stirred at 25° C. for 1 hr. The mixture was poured into sat.NH.sub.4Cl (200 mL) and extracted with EA (150 mL*2). The combined organic layers were washed with brine (250 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=20/1 to 1/1) to give the title compound (1.9 g, 6.65 mmol, 86.71% yield) as a colorless oil.

    [0539] LCMS (ESI) m/z: [M+H].sup.+=211.0.

    [0540] 1H NMR (400 MHz, CDCl.sub.3) δ=7.52 (d, J=8.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.98-6.96 (m, 1H), 4.14-4.12 (m, 1H), 3.93 (s, 3H), 2.61-2.48 (m, 2H), 2.43-2.30 (m, 2H), 2.12-1.97 (m, 3H), 1.80-1.68 (m, 1H) ppm

    Step 2: 1-Bromo-4-cyclobutyl-2-methoxybenzene

    [0541] To a mixture of 1-(4-bromo-3-methoxyphenyl)cyclobutan-1-ol (400 mg, 1.56 mmol) in DCM (20 mL) was added Et.sub.3SiH (1.81 g, 15.56 mmol) and TFA (1.77 g, 15.56 mmol) at 0° C., then the mixture was stirred at 25° C. for 8 hrs. The mixture was diluted with DCM (150 mL), then washed with sat. NaHCO.sub.3 (100 mL*2). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether) to give the title compound (150 mg, 622.09 umol, 39.99% yield) as a colorless oil.

    [0542] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.44 (d, J=8.0 Hz, 1H), 6.78-6.68 (m, 2H), 3.91 (s, 3H), 3.55-3.47 (m, 1H), 2.39-2.32 (m, 2H), 2.15-2.07 (m, 2H), 2.06-1.98 (m, 1H), 1.90-1.85 (m, 1H) ppm

    Intermediate 35: 4-Bromo-7-fluoro-1,2-dimethyl-1H-indole

    [0543] ##STR00588##

    Step 1: 4-Bromo-7-fluoro-2-methyl-1H-indole

    [0544] To a mixture of 4-bromo-1-fluoro-2-nitro-benzene (2 g, 9.09 mmol, 1.12 mL) in THF (20 mL) was added bromo(isopropenyl)magnesium (0.5 M, 72.73 mL) dropwisely at −40° C. under N.sub.2. The mixture was stirred at −40° C. for 1 hr. The mixture was poured into sat. NH.sub.4Cl (100 mL) and extracted with ethyl acetate (50 mL*2). The combined organic phase was washed with brine (50 mL*1), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=20/1) to give the title compound (500 mg, 2.19 mmol, 24.12% yield) as a yellow oil.

    Step 2: 4-Bromo-7-fluoro-1,2-dimethyl-1H-indole

    [0545] To a solution of 4-bromo-7-fluoro-2-methyl-1H-indole (80 mg, 350.78 umol) in THF (1 mL) was added NaH (28.06 mg, 701.57 umol, 60% purity) at 0° C. and stirred at 25° C. for 0.5 hr. MeI (149.37 mg, 1.05 mmol) was then added to the mixture at 0° C. The mixture was stirred at 25° C. for 2 hrs. The reaction mixture was diluted with sat. NH.sub.4Cl (10 mL) and extracted with EA (10 mL*2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=3/1) to give the title compound (60 mg, 247.84 umol, 70.65% yield) as a white solid.

    [0546] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.08-7.06 (m 1H), 6.71-6.66 (m, 1H), 6.30-6.29 (m, 1H), 3.87 (d, J=1.2 Hz, 3H), 2.41 (s, 3H) ppm.

    Intermediate 36: 4-Bromo-2-ethyl-1-methyl-1H-indole

    [0547] ##STR00589##

    Step 1: 4-Bromo-1-tosyl-1H-indole

    [0548] To a solution of 4-bromo-1H-indole (1 g, 5.10 mmol, 641.03 uL) in DMF (10 mL) was added NaH (244.82 mg, 6.12 mmol, 60% purity) at 0° C. and the mixture was stirred at 0° C. for 1 hr under N.sub.2 atmosphere. 4-Methylbenzenesulfonyl chloride (1.16 g, 6.08 mmol) was then added and the mixture was stirred at 25° C. for 1 hr. The reaction mixture was poured into NH.sub.4Cl (30 mL) and extracted with EA (40 mL*3). The combined organic layers were washed with brine (30 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=50/1 to 3/1) to give the title compound (1.6 g, 4.02 mmol, 78.73% yield) as an off-white solid.

    [0549] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.99-7.93 (m, 2H), 7.89 (d, J=8.4 Hz, 2H), 7.49 (d, J=7.6 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.29-7.27 (m, 1H), 6.77 (d, J=3.6 Hz, 1H), 2.31 (s, 3H) ppm.

    Step 2: 4-Bromo-2-ethyl-1-tosyl-1H-indole

    [0550] To a solution of 4-bromo-1-tosyl-1H-indole (1.2 g, 3.43 mmol) in THE (12 mL) was added LDA (2 M, 2.06 mL) at −20° C. under N.sub.2, and the mixture was stirred at −20° C. for 30 min under N.sub.2 atmosphere. Iodoethane (801.58 mg, 5.14 mmol) was then added and the mixture was stirred at 25° C. for 2 hrs. The reaction mixture was diluted with H.sub.2O (30 mL) and extracted with EA (40 mL*3). The combined organic layers were washed with brine (30 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 10/1) to give the title compound (220 mg, 581.58 umol, 16.97% yield) as a white solid.

    [0551] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.15 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.38 (d, J=7.6 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 7.15-7.10 (m, 1H), 6.47 (s, 1H), 3.06-3.01 (m, 2H), 2.36 (s, 3H), 1.39-1.35 (m, 3H) ppm.

    Step 3: 4-Bromo-2-ethyl-1H-indole

    [0552] To a solution of 4-bromo-2-ethyl-1-tosyl-1H-indole (220.00 mg, 581.58 umol) in MeOH (60 mL) was added KOH (1.63 g, 29.08 mmol). The mixture was stirred at 70° C. for 16 hrs. The reaction mixture was treated with 2 N HCl (20 mL) and was extracted with EA (30 mL*3). The combined organic layers were washed with brine (30 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 10/1) to give the title compound (100 mg, 446.24 umol, 76.73% yield) as a colorless oil.

    [0553] .sup.1H NMR (400 MHz, CHLOROFORM-d) 5=8.09-7.95 (m, 1H), 7.24 (d, J=8.0 Hz, 2H), 7.03-6.92 (m, 1H), 6.32 (s, 1H), 2.84-2.79 (m, 2H), 1.40-1.36 (m, 3H) ppm.

    Step 4: 4-Bromo-2-ethyl-1-methyl-1H-indole

    [0554] To a solution of 4-bromo-2-ethyl-1H-indole (150 mg, 669.35 umol) in DMF (2 mL) was added NaH (40.16 mg, 1.00 mmol, 60% purity) at 0° C. under N.sub.2. The resulting mixture was stirred at 0° C. for 15 min under N.sub.2 atmosphere. Iodomethane (114.01 mg, 803.22 umol) was then added and the resulting mixture was stirred at 25° C. for 2 hrs. The reaction mixture was poured into NH.sub.4Cl (30 mL) and extracted with EA (40 mL*3). The combined organic layers were washed with brine (30 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 10/1) to give the title compound (150 mg, 629.93 umol, 94.11% yield) as colorless oil.

    Intermediate 37: 4-Chloro-2-cyclopropyl-1-methyl-1H-indole

    [0555] ##STR00590##

    Step 1: 3-Chloro-2-(cyclopropylethynyl)aniline

    [0556] To a mixture of 3-chloro-2-iodo-aniline (2 g, 7.89 mmol) and ethynylcyclopropane (521.57 mg, 7.89 mmol) in MeCN (40 mL) was added TEA (7.98 g, 78.91 mmol), Pd(PPh3).sub.2C.sub.12 (553.84 mg, 789.06 umol) and CuI (150.28 mg, 789.06 umol). The mixture was degassed and purged with N.sub.2 3 times and the mixture was stirred at 25° C. for 2 hrs under N.sub.2 atmosphere. The reaction mixture was diluted with H.sub.2O (20 mL) and extracted with EA (30 mL*3). The combined organic layers were washed with brine (30 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=50/1 to 5/1) to give the title compound (1.3 g, 6.78 mmol, 85.96% yield) as a yellow oil.

    [0557] .sup.1H NMR (400 MHz, DMSO-d6) δ=6.97-6.95 (m, 1H), 6.59 (d, J=8.0 Hz, 2H), 5.50 (s, 2H), 1.63-1.61 (m, 1H), 0.95-0.86 (m, 2H), 0.83-0.76 (m, 2H) ppm.

    Step 2: 4-Chloro-2-cyclopropyl-1H-indole

    [0558] To a solution of 3-chloro-2-(cyclopropylethynyl)aniline (1 g, 5.22 mmol) in DMF (10 mL) was added CuI (2.98 g, 15.65 mmol). The mixture was stirred at 100° C. for 16 hrs. The reaction mixture was diluted with H.sub.2O (20 mL) and extracted with EA (30 mL*3). The combined organic layers were washed with brine (30 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 10/1) to give the title compound (600 mg, 2.71 mmol, 52.01% yield) as a yellow oil.

    [0559] LCMS (ESI) m/z: [M+H]+=191.9.

    [0560] .sup.1H NMR (400 MHz, CHLOROFORM-d) 5=8.37-7.67 (m, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.11-6.98 (m, 2H), 6.25 (s, 1H), 2.03-1.87 (m, 1H), 1.08-0.95 (m, 2H), 0.89-0.72 (m, 2H) ppm.

    Step 3: 4-Chloro-2-cyclopropyl-1-methyl-1H-indole

    [0561] To a solution of 4-chloro-2-cyclopropyl-1H-indole (180 mg, 939.18 umol) in DMF (2 mL) was added NaH (56.35 mg, 1.41 mmol, 60% purity) at 0° C. under N.sub.2 and the mixture was stirred at 0° C. for 15 min under N.sub.2 atmosphere. Iodomethane (199.96 mg, 1.41 mmol) was then added and the mixture was stirred at 25° C. for 2 hrs. The reaction mixture was poured into NH.sub.4Cl (30 mL) and extracted with EA (40 mL*3). The combined organic layers were washed with brine (30 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 10/1) to give the title compound (190 mg, 864.18 umol, 92.01% yield) as a colorless oil.

    [0562] LCMS (ESI) m/z: [M+H]+=206.0.

    Intermediate 38: 4-Bromo-3-(difluoromethyl)-1-(oxetan-3-yl)-1H-pyrazole

    [0563] ##STR00591##

    Step 1: 1-(Oxetan-3-yl)-1H-pyrazole-3-carbaldehyde

    [0564] To a mixture of 1H-pyrazole-3-carbaldehyde (10 g, 104.07 mmol) and Cs.sub.2CO.sub.3 (67.82 g, 208.14 mmol) in DMF (200 mL) was added 3-iodooxetane (28.72 g, 156.11 mmol), then the mixture was stirred at 60° C. for 10 hrs. The reaction mixture was quenched by the addition of water (1000 mL) and the resulting mixture was extracted with EA (400 mL*3). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 0/1) to give the title compound (3.1 g, 20.37 mmol, 19.58% yield) as a yellow solid.

    [0565] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=10.01 (s, 1H), 7.63-7.62 (m, 1H), 6.86 (d, J=2.4 Hz, 1H), 5.57-5.50 (m, 1H), 5.09 (d, J=6.4 Hz, 4H) ppm.

    Step 2: 3-(Difluoromethyl)-1-(oxetan-3-yl)-1H-pyrazole

    [0566] To a mixture of 1-(oxetan-3-yl)-1H-pyrazole-3-carbaldehyde (600 mg, 3.94 mmol) in DCM (12 mL) was added DAST (1.91 g, 11.83 mmol, 1.56 mL) at −50° C., then the mixture was stirred at 5° C. for 1 hr. The mixture was poured into sat. NaHCO.sub.3 (100 mL) and extracted with EA (50 mL*2). The combined organic layers were washed with brine (40 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by reversed phase HPLC (0.1% FA condition). The product fraction was extracted with EA (150 mL*2) and the combined organic layers were washed with brine (150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give the title compound (170 mg, 898.09 umol, 22.77% yield) as a colorless oil.

    [0567] LCMS (ESI) m/z: [M+H].sup.+=175.1

    Step 3: 4-Bromo-3-(difluoromethyl)-1-(oxetan-3-yl)-1H-pyrazole

    [0568] To a mixture of 3-(difluoromethyl)-1-(oxetan-3-yl)-1H-pyrazole (170 mg, 976.18 umol) in MeCN (4 mL) was added NBS (191.12 mg, 1.07 mmol) and the mixture was stirred at 25° C. for 2 hrs. The mixture was concentrated under vacuum and the residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=20/1 to 5/1) to give the title compound (200 mg, 735.05 umol, 75.30% yield) as a colorless oil.

    [0569] LCMS (ESI) m/z: [.sup.81BrM+H].sup.+=255.0

    [0570] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.68 (s, 1H), 6.84-6.58 (m, 1H), 5.46-5.51 (m, 1H), 5.07-4.99 (m, 4H) ppm

    Intermediate 39: 4-Bromo-3-(2,2-difluoroethyl)-1-(oxetan-3-yl)-1H-pyrazole

    [0571] ##STR00592##

    Step 1: 3-(2,2-Difluorovinyl)-1-(oxetan-3-yl)-1H-pyrazole

    [0572] To a mixture of 1-(oxetan-3-yl)-1H-pyrazole-3-carbaldehyde (1 g, 6.57 mmol) and sodium 2-chloro-2,2-difluoroacetate (1.50 g, 9.86 mmol) in DMF (10 mL) was added PPh3 (2.59 g, 9.86 mmol) under N.sub.2, then the mixture was stirred at 100° C. for 2 hrs. The reaction mixture was diluted with water (250 mL) and extracted with EA (150 mL*2). The combined organic layers were washed with brine (150 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=50/1 to 3/1) to give the title compound (700 mg, 3.12 mmol, 47.49% yield) as a colorless oil.

    [0573] LCMS (ESI) m/z: [M+H].sup.+=187.1

    Step 2: 3-(2,2-Difluoroethyl)-1-(oxetan-3-yl)-1H-pyrazole

    [0574] A mixture of 3-(2,2-difluorovinyl)-1-(oxetan-3-yl)-1H-pyrazole (250 mg, 1.34 mmol) in MeOH (10 mL) and EA (10 mL) was added Pd/C (100 mg, 1.34 mmol, 10% purity) under H.sub.2 (15 psi), then the mixture was stirred at 25° C. for 2 hrs. The mixture was filtered and the filtrate concentrated under vacuum to give the title compound (230 mg, crude) as colorless oil, used directly in the next step.

    [0575] LCMS (ESI) m/z: [M+H].sup.+=189.1

    Step 3: 4-Bromo-3-(2,2-difluoroethyl)-1-(oxetan-3-yl)-1H-pyrazole

    [0576] A mixture of 3-(2,2-difluoroethyl)-1-(oxetan-3-yl)-1H-pyrazole (210 mg, 1.12 mmol) and NBS (218.49 mg, 1.23 mmol) in MeCN (4 mL) was stirred at 25° C. for 2 hrs. The mixture was concentrated under vacuum and the residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/1 to 3/1) to give the title compound (150 mg, 544.80 umol, 48.82% yield) as a colorless oil.

    [0577] LCMS (ESI) m/z: [.sup.81BrM+H].sup.+=269.0

    [0578] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.61 (s, 1H), 6.280-5.97 (m, 1H), 5.40-5.36 (m, 1H), 5. 50-4.98 (m, 4H), 3.27-3.17 (m, 2H) ppm

    Intermediate 40: 4-Bromo-3-fluoro-1-methyl-1H-indole

    [0579] ##STR00593##

    Step 1: 4-Bromo-3,3-difluoroindolin-2-one

    [0580] To a solution of 4-bromoindoline-2,3-dione (1 g, 4.42 mmol) in DCM (10 mL) was added DAST (1.78 g, 11.06 mmol) at 0° C. under N.sub.2. The mixture was stirred at 25° C. for 16 hrs. The reaction mixture was poured into sat. NaHCO.sub.3 (30 mL) and extracted with DCM (30 mL*3). The combined organic layers were washed with brine (30 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=50/1 to 3/1) to give the title compound (1 g, 4.03 mmol, 91.13% yield) as a brown solid.

    [0581] .sup.1H NMR (400 MHz, DMSO-d6) δ=11.41 (d, J=0.8 Hz, 1H), 7.50-7.40 (m, 1H), 7.34 (d, J=8.1 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H) ppm.

    Step 2: 4-Bromo-3-fluoro-1H-indole

    [0582] To a mixture of NaBH.sub.4 (91.52 mg, 2.42 mmol) in THE (2 mL) was added BF3-Et.sub.2O (343.34 mg, 2.42 mmol) at 0° C. under N.sub.2 and the mixture was stirred at 0° C. for 1 hr. This mixture was added to a solution of 4-bromo-3,3-difluoroindolin-2-one (200 mg, 806.37 umol) in THE (2 mL) at 0° C. under N.sub.2 and the resulting mixture was stirred at 25° C. for 16 hrs. After 16 hrs, to a solution of NaBH.sub.4 (152.54 mg, 4.03 mmol) in THE (2 mL) was added BF.sub.3-Et.sub.2O (572.23 mg, 4.03 mmol) at 0° C. and the mixture was stirred at 0° C. for 1 hr. This mixture was then added to the former reaction mixture at 0° C. The resulting mixture was stirred at 25° C. for another 4 hrs. The reaction mixture was quenched by addition of 2N HCl, diluted with H.sub.2O (30 mL) and extracted with EA (40 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=50/1 to 5/1) to give the title compound (100 mg, 420.07 umol, 52.09% yield) as a colorless oil.

    [0583] .sup.1H NMR (400 MHz, DMSO-d6) δ=11.18 (s, 1H), 7.46-7.45 (m, 1H), 7.42-7.35 (m, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.10-7.01 (m, 1H) ppm.

    Step 3: 4-Bromo-3-fluoro-1-methyl-1H-indole

    [0584] To a solution of 4-bromo-3-fluoro-1H-indole (100 mg, 467.22 umol) in DMF (1 mL) was added NaH (28.03 mg, 700.82 umol, 60% purity) at 0° C. under N.sub.2, and the mixture was stirred at 0° C. for 15 min. Iodomethane (79.58 mg, 560.66 umol) was then added and the resulting mixture was stirred at 25° C. for 2 hrs. The reaction mixture was poured into NH.sub.4Cl (30 mL) and extracted with EA (40 mL*3). The combined organic layers were washed with brine (30 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 10/1) to give the title compound (60 mg, 263.09 umol, 56.31% yield) as a colorless oil.

    [0585] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.56-7.44 (m, 2H), 7.25 (d, J=7.6 Hz, 1H), 7.16-7.06 (m, 1H), 3.74 (s, 3H) ppm.

    Intermediate 41: 4-Bromo-2-(difluoromethyl)-1-methyl-1H-indole

    [0586] ##STR00594##

    Step 1: (4-Bromo-1H-indol-2-yl)methanol

    [0587] To a solution of 4-bromo-1H-indole-2-carboxylic acid (2 g, 8.33 mmol) in THE (20 mL) was added LiAlH.sub.4 (948.65 mg, 24.99 mmol) at 0° C. under N.sub.2. The mixture was stirred at 25° C. for 4 hrs. The reaction mixture was quenched by addition of H.sub.2O, the mixture was adjusted to pH=2 with HCl (2 N) and extracted with EA (30 mL*3). The combined organic layers were washed with brine (60 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, DCM/MeOH=100:1-10:1) to give the title compound (1 g, 4.24 mmol, 50.86% yield) as a white solid.

    [0588] LCMS (ESI) m/z: [M+H]+=235.0.

    [0589] .sup.1H NMR (400 MHz, DMSO-d6) δ=11.40 (s, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.16-7.15 (m, 1H), 6.98-6.94 (m, 1H), 6.25 (d, J=1.2 Hz, 1H), 5.34-5.31 (m, 1H), 4.61 (d, J=5.6 Hz, 2H) ppm.

    Step 2: 4-Bromo-1H-indole-2-carbaldehyde

    [0590] To a solution of (4-bromo-1H-indol-2-yl)methanol (300 mg, 1.33 mmol) in DCM (3 mL) was added Dess-Martin (675.42 mg, 1.59 mmol) at 0° C. The mixture was stirred at 25° C. for 2 hrs. The reaction mixture was poured into sat. NaHCO.sub.3 (30 mL) and extracted with DCM (30 mL*3). The combined organic layers were washed with brine (30 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (297 mg, crude) as a brown solid, which was used directly in the next step.

    Step 3: 4-Bromo-2-(difluoromethyl)-1H-indole

    [0591] To a solution of 4-bromo-1H-indole-2-carbaldehyde (290 mg, 1.29 mmol) in DCM (3 mL) was added DAST (625.90 mg, 3.88 mmol) at 0° C. The mixture was stirred at 25° C. for 2 hrs. The reaction mixture was poured into sat. NaHCO.sub.3 (30 mL) and extracted with DCM (30 mL*3). The combined organic layers were washed with brine (30 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=50/1 to 3/1) to give the title compound (110 mg, 408.13 umol, 31.53% yield) as a brown solid.

    [0592] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.56 (s, 1H), 7.40-7.35 (m, 2H), 7.20-7.12 (m, 1H), 7.05-6.68 (m, 2H) ppm.

    Step 4: 4-Bromo-2-(difluoromethyl)-1-methyl-1H-indole

    [0593] To a solution of 4-bromo-2-(difluoromethyl)-1H-indole (110 mg, 447.06 umol) in DMF (1 mL) was added NaH (26.82 mg, 670.59 umol, 60% purity) at 0° C. The mixture was degassed and purged with N.sub.2 for 3 times and stirred at 0° C. for 15 min under N.sub.2 atmosphere. Iodomethane (69.80 mg, 491.77 umol) was then added and the resulting mixture was stirred at 25° C. for 2 hrs. The reaction mixture was poured into NH.sub.4Cl (30 mL) and extracted with EA (40 mL*3). The combined organic layers were washed with brine (30 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 10/1) to give the title compound (110 mg, 422.95 umol, 94.61% yield) as a colorless oil.

    [0594] LCMS (ESI) m/z: [M+H]+=261.9.

    [0595] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.63 (d, J=8.4 Hz, 1H), 7.54-7.20 (m, 4H), 6.80 (s, 1H), 3.86 (s, 3H) ppm.

    Intermediate 42: 4-Bromo-1-(2,2-difluorocyclopropyl)-3-methoxy-1H-pyrazole

    [0596] ##STR00595##

    Step 1: 3-Methoxy-1-vinyl-1H-pyrazole

    [0597] A mixture of 3-methoxy-1H-pyrazole (500 mg, 5.10 mmol), potassium trifluoro(vinyl)borate (1.02 g, 7.65 mmol), Cu(OAc).sub.2 (1.02 g, 5.61 mmol), Na.sub.2CO.sub.3 (1.19 g, 11.21 mmol) and 2,2′-bipyridyl (875.60 mg, 5.61 mmol) in DCE (10 mL) was degassed and purged with O.sub.2 for 3 times. The mixture was stirred at 70° C. for 16 hrs under O.sub.2 atmosphere. The mixture was poured into water (100 mL) and extracted with EA (50 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-20% EA/Petroleum ether gradient@50 mL/min) to give the title compound (400 mg, 3.22 mmol, 63.22% yield) as a yellow oil.

    [0598] LCMS (ESI) m/z: [M+H].sup.+=125.0

    [0599] .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ=7.33 (d, J=2.4 Hz, 1H), 6.94-6.72 (m, 1H), 5.78 (d, J=2.4 Hz, 1H), 5.44-5.32 (m, 1H), 4.67 (d, J=8.8 Hz, 1H), 3.93 (s, 3H) ppm.

    Step 2: 1-(2,2-Difluorocyclopropyl)-3-methoxy-1H-pyrazole

    [0600] To a mixture of 3-methoxy-1-vinyl-1H-pyrazole (400 mg, 3.22 mmol) in THE (5 mL) was added NaI (169.04 mg, 1.13 mmol). TMSCF.sub.3 (1.60 g, 11.28 mmol) was then added slowly at 80° C. under N.sub.2.

    [0601] The reaction was stirred at 80° C. for 30 min. The solvent was removed under vacuum and the residue purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-20% EA/Petroleum ether gradient@50 mL/min) to give the title compound (200 mg, 1.15 mmol, 35.64% yield) as a yellow oil.

    [0602] LCMS (ESI) m/z: [M+H].sup.+=175.0

    [0603] .sup.1HNMR (400 MHz, CDCl.sub.3-d) δ=7.32-7.13 (m, 1H), 5.62 (d, J=2.4 Hz, 1H), 3.91-3.83 (m, 1H), 3.81 (s, 3H), 2.08-1.99 (m, 1H), 1.97-1.88 (m, 1H) ppm.

    Step 3: 4-Bromo-1-(2,2-difluorocyclopropyl)-3-methoxy-1H-pyrazole

    [0604] To a mixture of 1-(2,2-difluorocyclopropyl)-3-methoxy-1H-pyrazole (100 mg, 574.22 umol) in MeCN (5 mL) was added NBS (112.42 mg, 631.65 umol). The reaction was stirred at 25° C. for 2 hrs. The solvent was removed under vacuum and the residue purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-20% EA/Petroleum ether gradient @ 50 mL/min) to give the title compound (120 mg, 474.23 umol, 82.59% yield) as a yellow oil.

    [0605] LCMS (ESI) m/z: [.sup.79BrM+H].sup.+=253.0

    [0606] .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ=7.34 (s, 1H), 3.95 (s, 3H), 3.94-3.88 (m, 1H), 2.15-1.97 (m, 2H) ppm.

    Intermediate 43: 1-(4-Bromo-3-methoxyphenyl)azetidine

    [0607] ##STR00596##

    Step 1: 1-(4-Bromo-3-methoxyphenyl)azetidine

    [0608] To a mixture of 1-bromo-4-iodo-2-methoxy-benzene (500 mg, 1.60 mmol) and azetidine (91.35 mg, 1.60 mmol) in toluene (5 mL) was added Pd.sub.2(dba).sub.3 (146.52 mg, 160.00 umol), Xantphos (185.16 mg, 320.00 umol) and Cs.sub.2CO.sub.3 (1.56 g, 4.80 mmol) under N.sub.2. The mixture was stirred at 80° C. for 16 hrs. The reaction mixture was added slowly into water (50 mL) and extracted with EA (50 mL*2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, PE/EA=10:1-1:1) to give the title compound (150 mg, 619.55 umol, 38.72% yield) as a yellow solid.

    [0609] LCMS (ESI) m/z=[M+H].sup.+=242.0.

    [0610] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.25 (d, J=8.4 Hz, 1H), 6.06 (d, J=2.4 Hz, 1H), 5.93-5.90 (m, 1H), 3.81-3.78 (m, 7H), 2.32-2.24 (m, 2H) ppm.

    Intermediate 44: 1-Bromo-4-(tert-butyl)-2-methoxybenzene

    [0611] ##STR00597##

    Step 1: 2-Bromo-5-(tert-butyl)phenol

    [0612] To a solution of 3-tert-butylphenol (5 g, 33.29 mmol) in DCM (50 mL) was added a solution of Br2 (5.59 g, 34.95 mmol, 1.80 mL) in DCM (25 mL) over 30 mins at 0° C. The mixture was poured into sat. Na.sub.2SO.sub.3 (200 mL) and extracted with DCM (100 mL*2). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give the title compound (8 g, crude) as a colorless oil.

    [0613] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.98 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.77-6.74 (m, 1H), 1.22 (s, 9H) ppm.

    Step 2: 1-Bromo-4-(tert-butyl)-2-methoxybenzene

    [0614] To a solution of 2-bromo-5-(tert-butyl)phenol (1 g, 4.36 mmol) in THE (5 mL) was added t-BuOK (494.66 mg, 4.41 mmol) followed by MeI (631.90 mg, 4.45 mmol). The mixture was stirred at 70° C. for 3 hrs. The mixture was poured into water (100 mL) and extracted with EA (100 mL*2). The combined organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 10/1) to give the title compound (750 mg, 3.08 mmol, 70.67% yield) as a white solid.

    [0615] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.45 (d, J=8.4 Hz, 1H), 7.07-7.04 (m, 1H), 6.91-6.88 (m, 1H), 3.85 (s, 3H), 1.28 (s, 9H) ppm

    Intermediate 45: 4-Bromo-3-(difluoromethoxy)-1-(oxetan-3-yl)-1H-pyrazole

    [0616] ##STR00598##

    Step 1: 1-(3-Hydroxy-1H-pyrazol-1-yl)ethan-1-one

    [0617] To a solution of 1H-pyrazol-3-ol (3 g, 35.68 mmol) in pyridine (15 mL) was added a solution of Ac.sub.2O (3.82 g, 37.47 mmol, 3.51 mL) in pyridine (6 mL) at 95° C. over 30 min, then the mixture was stirred at 95° C. for 3.5 hrs. The reaction mixture was concentrated under reduced pressure and the residue was triturated in MeOH (20 mL) to give the title compound (3.8 g, 30.13 mmol, 84.45% yield) as a yellow solid.

    [0618] .sup.1H NMR (400 MHz, DMSO-d6) δ=10.97 (s, 1H), 8.12 (d, J=3.6 Hz, 1H), 6.00 (d, J=2.8 Hz, 1H), 2.47 (s, 3H) ppm.

    Step 2: 3-(Difluoromethoxy)-1H-pyrazole

    [0619] To a mixture of 1-(3-hydroxy-1H-pyrazol-1-yl)ethan-1-one (1000 mg, 7.93 mmol) and sodium 2-chloro-2,2-difluoroacetate (1.45 g, 9.52 mmol) in DMF (10 mL) was added K.sub.2CO.sub.3 (3.29 g, 23.79 mmol). The mixture was stirred at 80° C. for 10 hrs. The mixture was poured into sat. NH.sub.4Cl (150 mL) and extracted with EA (100 mL*3). The combined organic layers were washed with brine (150 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give the title compound (270 mg, 2.01 mmol, 25.39% yield) as a colorless oil.

    [0620] LCMS (ESI) m/z: [M+H].sup.+=135.1

    [0621] .sup.1H NMR (400 MHz, DMSO-d6) δ=12.49 (s, 1H), 7.69 (s, 1H), 7.41-7.04 (m, 1H), 5.97-5.96 (m, 1H) ppm.

    Step 3: 3-(Difluoromethoxy)-1-(oxetan-3-yl)-1H-pyrazole

    [0622] To a mixture of 3-(difluoromethoxy)-1H-pyrazole (270 mg, 2.01 mmol), 3-iodooxetane (555.70 mg, 3.02 mmol) in DMF (5 mL) was added Cs.sub.2CO.sub.3 (1.31 g, 4.03 mmol). The mixture was stirred at 60° C. for 8 hrs. The mixture was poured into water (50 mL) and extracted with EA (50 mL*2). The combined organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=50/1 to 3/1) to give the title compound (270 mg, 1.18 mmol, 58.53% yield) as a colorless oil.

    [0623] LCMS (ESI) m/z: [M+H].sup.+=427.1

    [0624] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.41 (d, J=2.4 Hz, 1H), 7.07-6.70 (m, 1H), 5.93 (d, J=2.4 Hz, 1H), 5.34-5.27 (m, 1H), 5.08-4.97 (m, 4H) ppm.

    Step 4: 4-Bromo-3-(difluoromethoxy)-1-(oxetan-3-yl)-1H-pyrazole

    [0625] To a mixture of 3-(difluoromethoxy)-1-(oxetan-3-yl)-1H-pyrazole (270 mg, 1.42 mmol) in MeCN (5 mL) was added NBS (278.00 mg, 1.56 mmol), then the mixture was stirred at 25° C. for 2 hrs. The mixture was concentrated under vacuum and the residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 1/1) to give the title compound (300 mg, 1.05 mmol, 73.82% yield) as a white solid.

    [0626] LCMS (ESI) m/z: [.sup.79BrM+H].sup.+=269.0

    [0627] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.49 (s, 1H), 7.16-6.80 (m, 1H), 5.29-5.26 (m, 1H), 5.00 (d, J=6.0 Hz, 4H) ppm.

    [0628] Intermediate 46: Pyrazolo[1,5-a]pyridin-2-yl trifluoromethanesulfonate

    ##STR00599##

    Step 1: Pyrazolo[1,5-a]pyridin-2-yl trifluoromethanesulfonate

    [0629] To a solution of pyrazolo[1,5-a]pyridin-2-ol (200 mg, 1.49 mmol) in DMF (1 mL) and THE (1 mL) was added NaH (65.60 mg, 1.64 mmol, 60% purity) at 0° C. under N.sub.2, then 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (639.21 mg, 1.79 mmol) was added to the reaction mixture at 0° C. The resulting mixture was stirred at 0° C. for 1 hr under N.sub.2. The reaction mixture was quenched by addition of water (20 mL) and then extracted with EA (20 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, PE/EA=5:1) to give the title compound (300 mg, 1.06 mmol, 71.05% yield) as a light yellow oil.

    [0630] LCMS (ESI) m/z: [M+H].sup.+=267.1

    Intermediate 47: 3-(4-Bromo-3-methoxyphenyl)oxetane

    [0631] ##STR00600##

    Step 1: 3-(4-Bromo-3-methoxyphenyl)oxetane

    [0632] To a mixture of 1-bromo-4-iodo-2-methoxy-benzene (500 mg, 1.60 mmol) and 3-iodooxetane (352.75 mg, 1.92 mmol) in DMA (4 mL) was added nickel(II) chloride ethylene glycol dimethyl ether complex (35.11 mg, 159.78 umol), pyridine-2-carboxamidine hydrochloride (25.18 mg, 159.78 umol), TFA (18.22 mg, 159.78 umol, 11.83 uL), Zn (208.96 mg, 3.20 mmol) and NaI (119.75 mg, 798.90 umol) in one portion at 25° C. under N.sub.2. The mixture was stirred at 60° C. for 12 hrs. The solids were removed by filtration and the filtrate concentrated under vacuum. The residue was purified by reversed phase column (0.1% FA). The product fraction was concentrated to remove MeCN and the aqueous phase was extracted with ethyl acetate (20 mL*2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give the title compound (200 mg, 668.21 umol, 41.82% yield) as yellow oil.

    [0633] LCMS (ESI) m/z: [M+H].sup.+=242.8, 244.9.

    Intermediate 48: 1-(8-Bromo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one

    [0634] ##STR00601##

    Step 1: N-(3-Bromo-2-hydroxyphenyl)acetamide

    [0635] To a solution of 2-amino-6-bromo-phenol (1 g, 5.32 mmol) in DCM (10 mL) was added Ac.sub.2O (651.56 mg, 6.38 mmol, 597.76 uL) and TEA (1.61 g, 15.96 mmol, 2.22 mL) at 0° C. under N.sub.2. The mixture was heated to 25° C. and stirred for 1 hr. Water was added (10 mL) and the mixture extracted by dichloromethane (50 mL*3). The combined organic phase was washed with brine (50 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 3/1) to give the title compound (300 mg, 1.11 mmol, 20.84% yield) as a light brown solid.

    [0636] LCMS (ESI) m/z: [.sup.79BrM+H].sup.+=229.9.

    [0637] .sup.1HNMR (400 MHz, CDCl.sub.3) δ=7.96 (br s, 1H), 7.90 (s, 1H), 7.59-7.53 (m, 1H), 7.32-7.28 (m, 1H), 6.80-6.72 (m, 1H), 2.24 (s, 3H).

    Step 2: 1-(8-Bromo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)ethan-1-one

    [0638] To a solution of N-(3-bromo-2-hydroxyphenyl)acetamide (100 mg, 434.67 umol) in DMF (2 mL) was added K.sub.2CO.sub.3 (180.22 mg, 1.30 mmol) and 1,2-dibromoethane (163.32 mg, 869.35 umol, 65.59 uL) under N.sub.2. The mixture was heated to 80° C. and stirred for 12 hrs. The mixture was poured into water (5 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, PE/EA=1:1) to give the title compound (100 mg, 351.43 umol, 26.95% yield) as a white solid.

    [0639] LCMS (ESI) m/z: [.sup.79BrM+H].sup.+=255.9

    [0640] .sup.1HNMR (400 MHz, DMSO-d6) δ=7.77-7.67 (m, 1H), 7.33 (d, J=7.9 Hz, 1H), 6.82 (t, J=8.0 Hz, 1H), 4.40-4.33 (m, 2H), 3.89 (t, J=4.5 Hz, 2H), 3.09 (s, 1H), 2.25 (s, 3H)

    Intermediate 49: 7-Bromo-5-fluoro-2-methylisoquinolin-1(2H)-one

    [0641] ##STR00602##

    Step 1: 3-Bromo-N-(2,2-dimethoxyethyl)-5-fluorobenzamide

    [0642] To a solution of 3-bromo-5-fluoro-benzoic acid (5 g, 22.83 mmol), 2,2-dimethoxyethanamine (2.40 g, 22.83 mmol, 2.49 mL) in DCM (50 mL) was added EDCI (8.75 g, 45.66 mmol), HOBt (6.17 g, 45.66 mmol) and DIEA (7.38 g, 57.08 mmol). The mixture was stirred at 25° C. for 1 hr. The mixture was poured into water (100 mL) and extracted with DCM (30 mL*3). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10:1) to give the title compound (6.1 g, 19.93 mmol, 87.28% yield) as a white solid.

    [0643] LCMS (ESI) m/z: [M+H-OMe].sup.+=275.9.

    [0644] .sup.1H NMR (400 MHz, MeOD-d4) δ=7.84 (s, 1H), 7.58-7.53 (m, 2H), 4.57-4.53 (m, 1H), 3.48 (d, J=5.6 Hz, 2H), 3.40 (s, 6H) ppm.

    Step 2: 7-Bromo-5-fluoroisoquinolin-1(2H)-one and 5-bromo-7-fluoroisoquinolin-1(2H)-one

    [0645] A solution of 3-bromo-N-(2,2-dimethoxyethyl)-5-fluorobenzamide (5.6 g, 18.29 mmol) in H.sub.2SO.sub.4 (34 mL) was stirred at 100° C. for 3 hrs. The mixture poured into water and the resulting solid was collected by filtration and dried to give a mixture of the title compounds (3.5 g, 14.46 mmol, 79.05% yield) as a white solid.

    Step 3: 7-Bromo-5-fluoro-2-methylisoquinolin-1(2H)-one and 5-bromo-7-fluoro-2-methylisoquinolin-1(2H)-one

    [0646] To a solution of 7-bromo-5-fluoroisoquinolin-1(2H)-one and 5-bromo-7-fluoroisoquinolin-1(2H)-one (1.5 g, 6.20 mmol) in THE (15 mL) was added KHMDS (1 M, 7.44 mL) at 0° C. The mixture was stirred for 0.5 hr and then iodomethane (3.52 g, 24.79 mmol) was added. The mixture was stirred for 1 hr at 25° C. before pouring into water (5 mL) and extracting with EA (10 mL*3). The organic layer was concentrated, and the residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1:1, Rf=0.3) to give a mixture of the title compounds (750 mg, 2.93 mmol, 47.26% yield) as a yellow solid.

    [0647] LCMS (ESI) m/z: [M+H].sup.+=256.1.

    Step 4: 7-Bromo-5-fluoro-2-methylisoquinolin-1(2H)-one

    [0648] The mixture of 7-bromo-5-fluoro-2-methylisoquinolin-1(2H)-one and 5-bromo-7-fluoro-2-methylisoquinolin-1(2H)-one (750 mg, 2.93 mmol) was purified by SFC separation: {method column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH.sub.3H.sub.2O MEOH]; B %: 40%-40%, 4.25; 105 min.} to give the title compound (270 mg, 1.05 mmol, 35.95% yield) as a white solid.

    [0649] LCMS (ESI) m/z: [M+H].sup.+=256.2.

    [0650] .sup.1H NMR (400 MHz, MeOD-d4) δ=8.22 (s, 1H), 7.67-7.63 (m, 1H), 7.47 (d, J=7.6 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 3.61 (s, 3H) ppm.

    Intermediate 50: 6-Bromo-7-methoxy-1-methyl-1H-indazole

    [0651] ##STR00603##

    Step 1: 2-Bromo-3-(dimethoxymethyl)phenol

    [0652] To a solution of 2-bromo-3-hydroxybenzaldehyde (2 g, 9.95 mmol) and trimethoxymethane (5.28 g, 49.75 mmol, 5.45 mL) in MeOH (30 mL) was added TsOH (171.33 mg, 994.94 umol). The mixture was stirred at 100° C. for 16 hrs. The solvent was removed under vacuum and the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-60% EA/Petroleum ether gradient @100 mL/min) to give the title compound (1.6 g, 6.48 mmol, 65.08% yield) as a yellow oil.

    [0653] LCMS (ESI) m/z: [M+H].sup.+=214.9

    [0654] .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ=7.29-7.24 (m, 1H), 7.23-7.18 (m, 1H), 7.07-7.02 (m, 1H), 5.79 (s, 1H), 5.53 (s, 1H), 3.40 (s, 6H) ppm.

    Step 2: 2,4-Dibromo-3-hydroxybenzaldehyde

    [0655] To a solution of 2-bromo-3-(dimethoxymethyl)phenol (1.4 g, 5.67 mmol) in CHCl.sub.3 (7 mL) was added a solution of Br.sub.2 (1.18 g, 7.37 mmol, 379.72 uL) in CHCl.sub.3 (7 mL) at 0° C. The reaction was stirred at 25° C. for 16 hrs. The reaction was quenched by aq. Na.sub.2S2O.sub.3 (80 mL) and extracted with EA (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-60% EA/Petroleum ether gradient @ 100 mL/min) to give the title compound (1.3 g, 4.64 mmol, 81.97% yield) as a white solid.

    [0656] LCMS (ESI) m/z: [Br M+H].sup.+=280.8.

    [0657] .sup.1H NMR (400 MHz, DMSO-d6) δ=10.44 (s, 1H), 10.17 (d, J=0.8 Hz, 1H), 7.83-7.65 (m, 1H), 7.27 (d, J=8.4 Hz, 1H) ppm.

    Step 3: 2,4-Dibromo-3-methoxybenzaldehyde

    [0658] To a solution of 2,4-dibromo-3-hydroxybenzaldehyde (1.3 g, 4.64 mmol) and K.sub.2CO.sub.3 (1.28 g, 9.29 mmol) in DMF (15 mL) was added MeI (988.80 mg, 6.97 mmol, 433.69 uL). The mixture was stirred at 25° C. for 2 hrs, then poured into water (60 mL) and extracted with EA (30 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-60% EA/Petroleum ether gradient @ 60 mL/min) to give the title compound (1.2 g, crude) as a white solid.

    [0659] .sup.1H NMR (400 MHz, DMSO-d6) δ=10.17 (s, 1H), 7.89-7.82 (m, 1H), 7.53 (d, J=8.4 Hz, 1H), 3.85 (s, 3H) ppm.

    Step 4: (E)-1-(2,4-Dibromo-3-methoxybenzylidene)-2-methylhydrazine

    [0660] To a solution of 2,4-dibromo-3-methoxybenzaldehyde (500 mg, 1.70 mmol) and methylhydrazine (391.84 mg, 3.40 mmol, 447.82 uL) in EtOH (5 mL) was stirred at 25° C. for 16 hrs. The mixture was poured into water (80 mL) and extracted with EA (30 mL*3). The combined organic layer were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% EA/Petroleum ether gradient @ 60 mL/min) to give the title compound (250 mg, 776.41 umol, 45.64% yield) as a yellow oil.

    [0661] LCMS (ESI) m/z: [Br M+H].sup.+=322.8.

    [0662] .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ=7.72 (s, 1H), 7.58-7.51 (m, 1H), 7.48-7.41 (m, 1H), 5.90 (br s, 1H), 3.90 (s, 3H), 3.02 (s, 3H) ppm.

    Step 5: 6-Bromo-7-methoxy-1-methyl-1H-indazole

    [0663] To a solution of (E)-1-(2,4-dibromo-3-methoxybenzylidene)-2-methylhydrazine (230 mg, 714.29 umol) in DMF (4 mL) was added K.sub.2CO.sub.3 (296.16 mg, 2.14 mmol) and CuI (13.60 mg, 71.43 umol). The mixture was stirred at 100° C. for 16 hrs. Water (40 mL) was added and the products extracted into EA (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-60% Ethylacetate/Petroleum ethergradient @ 40 mL/min) to give the title compound (120 mg, 497.75 umol, 69.68% yield) as a yellow oil.

    [0664] LCMS (ESI) m/z: [Br M+H].sup.+=242.9.

    [0665] .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ=7.98 (s, 1H), 7.41-7.35 (m, 1H), 7.30 (d, J=10.0 Hz, 1H), 4.33 (s, 3H), 4.05 (s, 3H) ppm.

    [0666] Intermediate 51: 2-(3-Methyloxetan-3-yl)pyrimidin-4-yl trifluoromethanesulfonate

    ##STR00604##

    Step 1: 4-(Benzyloxy)-2-chloropyrimidine

    [0667] A mixture of phenylmethanol (29.03 g, 268.50 mmol, 27.92 mL) and t-BuOK (15.06 g, 134.25 mmol) in THE (80 mL) was heated to 70° C. and stirred for 0.5 hr. The reaction mixture was cooled to 0° C. and slowly added dropwise to the solution of 2,4-dichloropyrimidine (20 g, 134.25 mmol) in DMF (100 mL), maintaining the temperature below −70° C. After stirring for 0.5 hr, the reaction was allowed to warm to 25° C. and stirred for 12 hrs. The reaction mixture was added dropwise to cold water (150 mL) and white solid was formed. The solid was collected by filtration and dried to give the title compound (22 g, 84.75 mmol, 63.13% yield) as a white solid.

    [0668] LCMS (ESI) m/z: [M+H].sup.+=221.1

    [0669] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=8.49 (d, J=5.6 Hz, 1H), 7.50-7.46 (m, 2H), 7.42-7.35 (m, 3H), 7.06 (d, J=5.6 Hz, 1H), 5.41 (s, 2H) ppm.

    Step 2: 4-(Benzyloxy)-2-(oxetan-3-yl)pyrimidine

    [0670] To a mixture of 4-(benzyloxy)-2-chloropyrimidine (20 g, 90.64 mmol) and 3-iodooxetane (20.01 g, 108.77 mmol) in DMA (400 mL) was added nickel(II) chloride ethylene glycol dimethyl ether complex (1.99 g, 9.06 mmol), pyridine-2-carboxamidine hydrochloride (1.43 g, 9.06 mmol), TFA (1.03 g, 9.06 mmol, 671.08 uL), Zn (11.85 g, 181.28 mmol) and NaI (6.79 g, 45.32 mmol) in one portion at 25° C. The mixture was stirred at 60° C. for 12 hours under N.sub.2. The reaction mixture was filtered, poured into H.sub.2O (800 mL) and extracted with EA (800 mL*3). The combined organic layer was washed with water (800 mL) and brine (800 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 0-20% EA/Petroleum ether gradient) to give the title compound (1 g, 2.48 mmol, 2.73% yield) as a yellow oil.

    [0671] LCMS (ESI) m/z: [M+H]+=243.1.

    [0672] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.61-8.47 (m, 1H), 7.49-7.31 (m, 5H), 7.14-6.84 (m, 1H), 5.49-5.38 (m, 2H), 4.96-4.66 (m, 4H), 4.37 (d, J=8.8 Hz, 1H) ppm.

    Step 3: 4-(Benzyloxy)-2-(3-methyloxetan-3-yl)pyrimidine

    [0673] To a solution of 4-(benzyloxy)-2-(oxetan-3-yl)pyrimidine (1 g, 4.13 mmol) in THE (4 mL) was added KHMDS (1 M, 6.19 mL) at −68° C. The mixture was stirred at −68° C. for 0.5 hr. Iodomethane (2.93 g, 20.64 mmol, 1.28 mL) was then added at −68° C. The mixture was stirred at 25° C. for 2 hrs. The reaction mixture was quenched with aq. NH.sub.4Cl (40 mL) at 0° C. and extracted with EA (40 mL*3). The combined layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 1/1) to give the title compound (220 mg, 858.37 umol, 20.80% yield) as a yellow oil.

    [0674] LCMS (ESI) m/z: [M+H].sup.+=257.0

    [0675] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.53 (d, J=5.6 Hz, 1H), 7.50-7.44 (m, 2H), 7.43-7.32 (m, 3H), 6.86 (d, J=6.0 Hz, 1H), 5.43 (s, 2H), 4.96 (d, J=5.6 Hz, 2H), 4.48 (d, J=5.6 Hz, 2H), 1.66 (s, 3H) ppm.

    Step 4: 2-(3-Methyloxetan-3-yl)pyrimidin-4-ol

    [0676] To a solution of 4-(benzyloxy)-2-(3-methyloxetan-3-yl)pyrimidine (200 mg, 780.34 umol) in MeOH (15 mL) was added Pd/C (40 mg, 10% purity). The mixture was degassed and purged with H.sub.2 balloon 3 times. The mixture was stirred at 25° C. for 0.5 hr under H.sub.2 atmosphere (15 psi). The reaction was filtered to remove Pd/C and concentrated under reduced pressure to give the title compound (110 mg, 661.95 umol, 84.83% yield) as a white solid.

    [0677] LCMS (ESI) m/z: [M+H].sup.+=167.0.

    [0678] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.89 (d, J=6.8 Hz, 1H), 6.19 (d, J=6.8 Hz, 1H), 4.89 (d, J=6.0 Hz, 2H), 4.38 (d, J=6.0 Hz, 2H), 1.61 (s, 3H) ppm.

    Step 5: 2-(3-Methyloxetan-3-yl)pyrimidin-4-yl trifluoromethanesulfonate

    [0679] To a solution of 2-(3-methyloxetan-3-yl)pyrimidin-4-ol (50 mg, 300.88 umol) and DIEA (116.66 mg, 902.65 umol, 157.22 uL) in DCM (1 mL) was added Tf.sub.2O (101.87 mg, 361.06 umol, 59.57 uL) at 0° C. The mixture was stirred at 0° C. for 0.5 hr. The reaction mixture was quenched with aq. NaHCO.sub.3 (20 mL) and extracted with DCM (20 mL*3). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (88 mg, 295.07 umol, 98.07% yield) as a yellow oil.

    [0680] LCMS (ESI) m/z: [M+H].sup.+=299.0.

    Intermediate 52: 4-Chloro-2-(1-fluorocyclopropyl)pyrimidine

    [0681] ##STR00605##

    Step 1: Methyl 1-fluorocyclopropane-1-carboxylate

    [0682] To a mixture of 1-fluorocyclopropanecarboxylic acid (4 g, 38.43 mmol) in DCM (20 mL) was added oxalyl dichloride (7.32 g, 57.65 mmol, 5.05 mL) at 0° C. The reaction was stirred at 25° C. for 16 hrs. The mixture was concentrated and then dissolved in DCM (20 mL). MeOH (3.69 g, 115.30 mmol, 4.67 mL) was then added at 0° C. and the mixture was stirred at 25° C. for 30 mins. The reaction was quenched with the addition of aq. NaHCO.sub.3 (50 mL) and the products were extracted with DCM (30 mL*3). The combined organic layers were concentrated at 25° C. to give the title product (2 g, crude) as a yellow oil.

    [0683] .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ=3.76 (s, 3H), 1.39-1.29 (m, 4H) ppm.

    Step 2: 1-Fluorocyclopropane-1-carboximidamide

    [0684] To a mixture of NH.sub.4Cl (4.53 g, 84.67 mmol) in toluene (30 mL) was added AlMe.sub.3 (2 M, 42.33 mL) at 0° C. The mixture was stirred at 25° C. for 1 hr. Methyl 1-fluorocyclopropane-1-carboxylate (2 g, 16.93 mmol) was added into the mixture at 0° C. The reaction was stirred at 80° C. for 16 hrs. The reaction mixture was cooled to 0° C., MeOH (50 mL) was added and the mixture stirred for 10 min. The mixture was filtered and the filtrate was concentrated under vacuum to give the title product (2.1 g, crude) as a white solid.

    Step 3: 2-(1-Fluorocyclopropyl)pyrimidin-4-ol

    [0685] To a mixture of 1-fluorocyclopropane-1-carboximidamide (2.02 g, 19.77 mmol) and K.sub.2CO.sub.3 (5.46 g, 39.54 mmol) in EtOH (30 mL) was added ethyl (E)-3-ethoxyprop-2-enoate (0.95 g, 6.59 mmol, 951.90 uL) at 25° C. The reaction was stirred at 75° C. for 16 hrs. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-20% DCM/MeOH gradient @ 100 mL/min) to give the title compound (140 mg, 908.26 umol, 13.78% yield) as a yellow solid.

    [0686] LCMS (ESI) m/z: [M+H].sup.+=155.1

    [0687] .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ=11.80-10.90 (m, 1H), 7.85 (d, J=6.8 Hz, 1H), 6.33 (d, J=6.8 Hz, 1H), 1.68-1.52 (m, 4H) ppm.

    Step 4: 4-Chloro-2-(1-fluorocyclopropyl)pyrimidine

    [0688] To a mixture of 2-(1-fluorocyclopropyl)pyrimidin-4-ol (70 mg, 454.13 umol) and DMF (3.32 mg, 45.41 umol, 3.49 uL) in DCM (1 mL) was added oxalyl chloride (63.41 mg, 499.54 umol, 43.73 uL) at 0° C. The reaction was stirred at 25° C. for 2 hrs. The mixture was poured into aq. NaHCO.sub.3 (30 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-50% PE/EA gradient @ 36 mL/min) to give the title compound (35 mg, 202.80 umol, 44.66% yield) as a yellow oil.

    [0689] .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ=8.58 (d, J=5.6 Hz, 1H), 7.22 (d, J=5.2 Hz, 1H), 1.68-1.61 (m, 2H), 1.58-1.52 (m, 2H) ppm.

    Intermediate 53: 3-(Dimethylamino)pyridin-2(1H)-one

    [0690] ##STR00606##

    Step 1: 2-(Benzyloxy)-3-bromopyridine

    [0691] To a mixture of phenylmethanol (3.37 g, 31.18 mmol, 3.24 mL) in THE (50 mL) was added NaH (1.25 g, 31.18 mmol, 60% purity) in portions at 0° C. under N.sub.2. The mixture was stirred at 0° C. for 30 min, then to the mixture was added 3-bromo-2-chloro-pyridine (5 g, 25.98 mmol) at 0° C. The mixture was stirred at 25° C. for 11.5 hrs. The mixture was poured into water (300 mL) and the products extracted with ethyl acetate (100 mL*2). The combined organic phase was washed with brine (100 mL*1), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=20/1) to give the title compound (5.2 g, 19.69 mmol, 75.78% yield) as a light yellow oil.

    Step 2: 2-(Benzyloxy)-N,N-dimethylpyridin-3-amine

    [0692] To a mixture of 2-(benzyloxy)-3-bromopyridine (500 mg, 1.89 mmol) and dimethylamine hydrochloride (255.62 mg, 5.67 mmol, 287.22 uL) in toluene (10 mL) was added Pd.sub.2(dba).sub.3 (86.54 mg, 94.50 umol), BINAP (117.68 mg, 189.00 umol) and t-BuONa (908.15 mg, 9.45 mmol) in one portion at 25° C. under N.sub.2. The mixture was stirred at 100° C. for 12 hrs. The mixture was poured into water (20 mL) and the products extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*1), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=15/1) to give the title compound (200 mg, 876.08 umol, 46.35% yield) as a yellow oil.

    Step 3: 3-(Dimethylamino)pyridin-2(1H)-one

    [0693] To a solution of 2-(benzyloxy)-N,N-dimethylpyridin-3-amine (100 mg, 438.04 umol) and MeOH (2 mL) was added Pd/C (10 mg, 438.04 umol, 10% purity). The mixture was degassed and purged with H.sub.2 3 times, and then the mixture was stirred at 25° C. for 0.5 hr under H.sub.2 (15 psi). The mixture was filtered and the filtrate was concentrated to give the title compound (50 mg, 361.88 umol, 82.61% yield) as a white solid.

    [0694] LCMS (ESI) m/z: [M+H].sup.+=139.0

    Intermediate 54: 1-Cyclopropylimidazolidin-2-one

    [0695] ##STR00607##

    Step 1: 1-(2-Chloroethyl)-3-cyclopropylurea

    [0696] To a mixture of cyclopropanamine (541.06 mg, 9.48 mmol) in THF (10 mL) was added dropwise 1-chloro-2-isocyanato-ethane (1 g, 9.48 mmol), then the mixture was stirred at 30° C. for 2 hrs. The reaction was concentrated under vacuum to give the title compound (1.52 g, 9.35 mmol, 98.63% yield) as white solid, which was used directly in the next step.

    [0697] .sup.1HNMR (400 MHz, CDCl.sub.3) δ=6.30 (s, 1H), 6.13 (s, 1H), 3.61-3.53 (m, 2H), 3.33-3.28 (m, 2H), 2.43-2.35 (m, 1H), 0.61-0.53 (m, 2H), 0.37-0.29 (m, 2H) ppm.

    Step 2: 1-Cyclopropylimidazolidin-2-one

    [0698] To a mixture of 1-(2-chloroethyl)-3-cyclopropylurea (1.5 g, 9.22 mmol) in THF (50 mL) was added portionwise NaH (442.76 mg, 11.07 mmol, 60% purity) at 0° C., and then the mixture was stirred at 30° C. for 2 hrs. The reaction was quenched by adding sat. NH.sub.4Cl (30 mL) and the products were extracted with DCM (30 mL*5). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was triturated with PE (10 mL) at 20 and the solid was collected by filtered and dried to give the title compound (0.8 g, 6.34 mmol, 68.75% yield) as a gray solid.

    [0699] LCMS (ESI) m/z: [M+H].sup.+=127.1.

    [0700] .sup.1H NMR (400 MHz, DMSO-d6) δ=6.28 (s, 1H), 3.30-3.23 (m, 2H), 3.20-3.12 (m, 2H), 2.36-2.27 (m, 1H), 0.58-0.51 (m, 4H) ppm.

    Intermediate 55: 2-Cyclopropyl-1,2,5-thiadiazolidine 1,1-dioxide

    [0701] ##STR00608##

    Step 1: tert-Butyl (N-cyclopropylsulfamoyl)carbamate

    [0702] To a solution of sulfurisocyanatidic chloride (5 g, 35.33 mmol, 3.07 mL) in DCM (60 mL) was added 2-methylpropan-2-ol (2.62 g, 35.33 mmol, 3.38 mL) at 0° C. After stirring for 90 min, the resulting solution and TEA (10.91 g, 107.77 mmol) in DCM (60 mL) were added dropwise to a solution of cyclopropanamine (2.02 g, 35.33 mmol, 2.45 mL) in DCM (75 mL) and TEA (6.54 g, 64.66 mmol). The reaction mixture was stirred at 5° C. for 3 hrs then poured into water 200 mL and extracted with DCM (200 mL*3). The combined organic layer was washed with brine (500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was triturated with PE (100 mL), and the solid was filtered and dried under vacuum to give the title compound (2.5 g, 10.58 mmol, 29.95% yield) as a white solid.

    [0703] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.17 (br s, 1H), 5.47 (s, 1H), 2.46-2.43 (m, 1H), 1.52 (s, 9H), 0.79-0.72 (m, 4H) ppm

    Step 2: tert-Butyl 5-cyclopropyl-1,2,5-thiadiazolidine-2-carboxylate 1,1-dioxide

    [0704] To a solution of tert-butyl (N-cyclopropylsulfamoyl)carbamate (200 mg, 846.42 umol) and 1,2-dibromoethane (182.20 mg, 969.84 umol) in acetone (3 mL) was added K.sub.2CO.sub.3 (346.34 mg, 2.51 mmol). The resulting mixture was stirred at 60° C. for 16 hrs. The reaction mixture was poured into water (20 mL) and the products were extracted with EA (20 mL*3). The combined organic layer was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (120 mg, 457.45 umol, 54.04% yield) as a white solid.

    [0705] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=3.77-3.73 (m, 2H), 3.41-3.38 (m, 2H), 2.37-2.34 (m, 1H), 1.54 (s, 9H), 0.89-0.84 (m, 2H), 0.77-0.77 (m, 2H) ppm.

    Step 3: 2-Cyclopropyl-1,2,5-thiadiazolidine 1,1-dioxide

    [0706] To a solution of tert-butyl 5-cyclopropyl-1,2,5-thiadiazolidine-2-carboxylate 1,1-dioxide (120 mg, 457.45 umol) in DCM (1.5 mL) was added TFA (1.5 mL). The mixture was stirred at 30° C. for 2 hrs then concentrated under vacuum to give the title compound (74 mg, 456.20 umol, 99.73% yield) as a yellow solid

    [0707] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=3.52-3.45 (m, 4H), 2.35-2.28 (m, 1H), 0.82-0.79 (m, 2H), 0.74-0.72 (m, 2H) ppm.

    Intermediate 56: 3-(Difluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine hydrochloride

    [0708] ##STR00609##

    Step 1: tert-Butyl 3-formyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

    [0709] To a solution of tert-butyl 3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (3000 mg, 9.93 mmol) in THE (30 mL) was added n-BuLi (2.5 M, 8.34 mL) under N.sub.2 at −78° C. and stirred at −78° C. for 0.5 hr. DMF (798.27 mg, 10.92 mmol, 840.28 uL) was then added and the resulting mixture was stirred at −78° C. for another 2 hrs. The reaction mixture was quenched with water (200 mL) and the products were extracted with EA (200 mL*2). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, PE/EA=1:1) to give the title compound (400 mg, 1.45 mmol, 14.59% yield) as a light yellow oil.

    [0710] LCMS (ESI) m/z: [M+H].sup.+=252.2.

    [0711] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=9.88 (s, 1H), 7.95 (s, 1H), 4.92 (s, 2H), 4.23 (t, J=5.2 Hz, 2H), 3.93 (t, J=5.2 Hz, 2H), 1.51 (s, 9H) ppm

    Step 2: tert-Butyl 3-(difluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

    [0712] To a solution of tert-butyl 3-formyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (400 mg, 1.59 mmol) in DCM (8 mL) was added DAST (1.28 g, 7.96 mmol, 1.05 mL) at 0° C., and the mixture was stirred at 30° C. for 4 hrs. Additional DAST (2.57 g, 15.92 mmol, 2.10 mL) was added to the mixture and stirring continued at 30° C. for 12 hr. The mixture was quenched with sat. NaHCO.sub.3 (200 mL) and extracted with EA (200 mL*2). The combined organic layers were washed with brine 200 (mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, PE/EA=2:1) to give the title compound (250 mg, 850.78 umol, 53.45% yield) as a light yellow oil.

    [0713] LCMS (ESI) m/z: [M+H].sup.+=274.0.

    [0714] .sup.1H NMR (400 MHz, CHLOROFORM-d) 5=7.60 (s, 1H), 6.88-6.51 (m, 1H), 4.76 (br s, 2H), 4.21 (br t, J=5.2 Hz, 2H), 3.91 (br t, J=5.2 Hz, 2H), 1.51 (s, 9H) ppm.

    Step 3: 3-(Difluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine hydrochloride

    [0715] A solution of tert-butyl 3-(difluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (100 mg, 365.93 umol) in 4M HCl/dioxane (2 mL) was stirred at 30° C. for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (120 mg, crude) as a white solid.

    Intermediates 57 and 58: (R)-5-Fluoro-5-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine-3-carboxylic acid and (S)-5-fluoro-5-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine-3-carboxylic acid

    [0716] ##STR00610## ##STR00611##

    Step 1: Methyl 5-bromo-2-methylnicotinate

    [0717] To a solution of 5-bromo-2-methylnicotinic acid (10 g, 46.29 mmol, 1 eq) in MeOH (100 mL) was added SOCl.sub.2 (8.26 g, 69.43 mmol, 5.04 mL). The mixture was stirred at 80° C. for 16 hrs. Room temperature was attained and the solvent removed under vacuum. The residue was taken up in aq.NaHCO.sub.3 (200 mL) and extracted with EA (100 mL*3). The combined organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (8.8 g, 38.25 mmol, 82.63% yield) as a brown solid.

    [0718] LCMS (ESI) m/z: [Br M+H].sup.+=229.9

    [0719] .sup.1H NMR (400 MHz, CDCl.sub.3-d) δ=8.66 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 3.93 (s, 3H), 2.78 (s, 3H) ppm.

    Step 2: Methyl 5-bromo-2-(dibromomethyl)nicotinate

    [0720] To a solution of methyl 5-bromo-2-methylnicotinate (5.6 g, 24.34 mmol) in CCl.sub.4 (60 mL) was added NBS (4.77 g, 26.78 mmol) and AIBN (399.71 mg, 2.43 mmol). The mixture was stirred at 80° C. for 16 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (10 g, crude) as yellow oil.

    Step 3: Methyl 5-bromo-2-(bromomethyl)nicotinate

    [0721] To a solution of methyl 5-bromo-2-(dibromomethyl)nicotinate (11 g, 28.36 mmol) and DIEA (1.47 g, 11.34 mmol, 1.98 mL) in THE (100 mL) was added diethyl phosphonate (1.57 g, 11.34 mmol, 1.46 mL) at 0° C. The mixture was stirred at 15° C. for 16 hrs. The mixture was filtered, poured into water (300 mL) and extracted with EA (150 mL*3). The combined organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-50% EA/Petroleum ether gradient @ 120 mL/min) to give the title compound (7.4 g, 23.95 mmol, 84.46% yield) as a yellow oil.

    [0722] LCMS (ESI) m/z: [Br M+H].sup.+=309.7

    Step 4: Methyl 3-bromo-5-hydroxy-8H-pyrano[3,4-b]pyridine-6-carboxylate

    [0723] To a solution of methyl 5-bromo-2-(bromomethyl)nicotinate (9.9 g, 32.04 mmol) and methyl 2-hydroxyacetate (5.77 g, 64.09 mmol, 4.93 mL) in DMF (100 mL) was added NaH (2.56 g, 64.09 mmol, 60% purity) at 0° C. The mixture was stirred at 15° C. for 16 hrs. The mixture was poured into aq. NaHCO.sub.3 (600 mL) and extracted with EA (200 mL*3). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (7.6 g, crude) as a white solid.

    Step 5: 3-Bromo-6H-pyrano[3,4-b]pyridin-5(8H)-one

    [0724] To a solution of methyl 3-bromo-5-hydroxy-8H-pyrano[3,4-b]pyridine-6-carboxylate (7.6 g, 26.57 mmol) in EtOH (80 mL) was added HCl (12 M, 152.00 mL). The mixture was stirred at 130° C. for 2 hrs.

    [0725] The mixture was adjusted to PH=8 with aq. NaHCO.sub.3 and the products were extracted with EA (300 mL*3). The combined organic layers were washed with brine (300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0-60% EA/Petroleum ether gradient @60 mL/min) to give the title compound (3.3 g, 14.47 mmol, 54.47% yield) as a yellow solid.

    Step 6: 3-Bromo-5-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-ol

    [0726] To a solution of 3-bromo-6H-pyrano[3,4-b]pyridin-5(8H)-one (3.3 g, 14.47 mmol) and CeCl.sub.3 (1.78 g, 7.24 mmol) in THE (60 mL) was added MeMgBr (3 M, 14.47 mL) at −50° C. under N.sub.2. The mixture was stirred at 15° C. for 1 hr. Water (150 mL) was added, the mixture was filtered and the products were extracted with EA (80 mL*3). The combined organic layers were washed with brine (80 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-60% EA/Petroleum ether gradient @80 mL/min) to give the title compound (2.9 g, 11.88 mmol, 82.10% yield) as a white solid.

    Step 7: 3-Bromo-5-fluoro-5-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine

    [0727] To a solution of 3-bromo-5-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridin-5-ol (2.9 g, 11.88 mmol in DCM (30 mL) was added DAST (2.11 g, 13.07 mmol, 1.73 mL) at 0° C. The reaction was stirred at 0° C. for 1 hr. The mixture was poured into aq. NaHCO.sub.3 (100 mL) and extracted with DCM (50 mL*3). The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-60% EA/Petroleum ether gradient @100 mL/min) to give the title compound (2.4 g, 9.75 mmol, 82.09% yield) as a yellow oil.

    Step 8: 5-Fluoro-5-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine-3-carboxylic acid

    [0728] A mixture of 3-bromo-5-fluoro-5-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine (2.4 g, 9.75 mmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (597.14 mg, 975.31 umol), Pd(OAc).sub.2 (218.97 mg, 975.31 umol), H2O (351.50 mg, 19.51 mmol, 351.50 uL) and K.sub.2CO.sub.3 (2.02 g, 14.63 mmol) in DMSO (40 mL) was degassed and purged with CO 3 times. The mixture was stirred at 100° C. for 4 hrs under CO atmosphere (15 Psi). The mixture was filtered, poured into water (100 mL) and extracted with EA (60 mL*2). The EA layer was discarded. The aqueous phase was adjusted to PH=5 by aq. HCl (1 M) and extracted with EA (60 mL*5). The combined organic layers were washed with brined (60 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give the title compound (1.6 g, 7.27 mmol, 74.57% yield) as a yellow solid.

    [0729] LCMS (ESI) m/z: [M+H].sup.+=212.0

    [0730] .sup.1H NMR (400 MHz, DMSO-d6) δ=14.29-12.75 (m, 1H), 9.01 (s, 1H), 8.45 (s, 1H), 4.93-4.69 (m, 2H), 4.24-4.03 (m, 1H), 3.97-3.79 (m, 1H), 1.76-1.57 (m, 3H) ppm.

    Step 9: (R)-5-Fluoro-5-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine-3-carboxylic acid and (S)-5-fluoro-5-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine-3-carboxylic acid

    [0731] 5-Fluoro-5-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine-3-carboxylic acid (1.6 g, 7.58 mmol) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [0.1% NH.sub.3H.sub.2O MeOH]; B %: 30%-30%, 4 min; 150 minmin) and SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [0.1% NH.sub.3H.sub.2O EtOH]; B %: 20%-20%, 3.8 min; 80 minmin). The product fractions were concentrated under vacuum, adjusted to PH=5 by aq. HCl (1 M) and extracted with EA (50 mL*6). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated to give Intermediate 50 (610 mg, 2.88 mmol, 37.96% yield) as a white solid and Intermediate 51 (400 mg, 1.83 mmol, 62.21% yield) as a white solid. Stereochemistry was assigned arbitrarily.

    (R)-5-Fluoro-5-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine-3-carboxylic acid LCMS (ESI) m/z: [M+H].SUP.+.=212.0

    [0732] .sup.1H NMR (400 MHz, DMSO-d6) δ=14.20-12.71 (m, 1H), 9.01 (s, 1H), 8.45 (s, 1H), 4.87-4.71 (m, 2H), 4.16-4.05 (m, 1H), 3.97-3.82 (m, 1H), 1.75-1.63 (m, 3H) ppm.

    [0733] Chiral SFC: IG-3_5CM_MEOH(DEA)_5_40_3ML_T35.M; Rt=1.251 mins, ee %=100%.

    (S)-5-Fluoro-5-methyl-5,8-dihydro-6H-pyrano[3,4-b]pyridine-3-carboxylic acid

    [0734] LCMS (ESI) m/z: [M+H].sup.+=212.0

    [0735] .sup.1H NMR (400 MHz, DMSO-d6) δ=13.97-13.03 (m, 1H), 9.04-8.98 (m, 1H), 8.51-8.38 (m, 1H), 4.87-4.71 (m, 2H), 4.16-4.04 (m, 1H), 3.98-3.81 (m, 1H), 1.74-1.61 (m, 3H) ppm.

    [0736] Chiral SFC: IG-3_5CM_MEOH(DEA)_5_40_3ML_T35.M, Rt=1.597 mins, ee %=100%.

    Intermediates 59 and 60: (R)-4-Cyano-8-fluoro-4-methylisochromane-6-carboxylic acid and (S)-4-cyano-8-fluoro-4-methylisochromane-6-carboxylic acid

    [0737] ##STR00612## ##STR00613##

    Step 1: Methyl 5-bromo-3-fluoro-2-methylbenzoate

    [0738] To a mixture of methyl 3-amino-5-bromo-2-methyl-benzoate (50 g, 204.85 mmol) in DCM (500 mL) was added nitrosonium tetrafluoroborate (31.11 g, 266.30 mmol) portionwise at 0° C. under N.sub.2. The mixture was stirred at 0° C. for 1 hr. o-Xylene (869.90 g, 8.19 mol, 990.78 mL) was then added and the mixture slowly heated to 130° C. before stirring at 130° C. for 2 hrs. The reaction mixture was poured into water (200 mL) and extracted with EA (100 mL*3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, PE/EA=50/1 to 10/1) to give the title compound (49 g, 198.33 mmol, 96.82% yield) as a yellow oil.

    [0739] .sup.1H NMR (400 MHz, CHLOROFORM-d) 5=7.75 (s, 1H), 7.29-7.26 (m, 1H), 3.83 (s, 3H), 2.37 (d, J=2.4 Hz, 3H) ppm.

    Step 2: 5-Bromo-3-fluoro-2-methylbenzoic acid

    [0740] To a mixture of methyl 5-bromo-3-fluoro-2-methylbenzoate (10 g, 40.48 mmol) in MeOH (10 mL), THF (10 mL) and H2O (5 mL) was added LiOH.H.sub.2O (5.10 g, 121.43 mmol). The mixture was stirred at 25° C. for 1 hr. The mixture was poured into water (80 mL) and adjusted to pH=4 by 1 N HCl. The mixture was then extracted with EA (30.0 mL*3). The combined organics were washed with brine (80 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (8.5 g, 36.48 mmol, 90.12% yield) as a white solid.

    [0741] .sup.1H NMR (400 MHz, DMSO-d6) δ=13.54-13.49 (m, 1H), 7.76-7.73 (m, 2H), 2.36 (d, J=2.4 Hz, 3H) ppm.

    Step 3: 5-Bromo-3-fluoro-N-methoxy-N,2-dimethylbenzamide

    [0742] To a mixture of 5-bromo-3-fluoro-2-methylbenzoic acid (14.7 g, 63.08 mmol) and DMF (46.11 mg, 630.81 umol) in DCM (150 mL) was added (COCl).sub.2 (24.02 g, 189.24 mmol). The mixture was stirred at 25° C. for 1 hr and then concentrated under vacuum. The residue was dissolved in DCM (150 mL) and the resulting solution was added to a mixture of N-methoxymethanamine (9.23 g, 94.62 mmol, 1.5 eq) and DIEA (32.61 g, 252.32 mmol, 43.95 mL) in DCM (50 mL). The reaction was stirred at 25° C. for 16 hrs. The reaction mixture was poured into water (400 mL) and extracted with DCM (300 mL*2). The combined organic layer was washed with brine (400 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=100:1-8:1) to give the title compound (11.5 g, 41.65 mmol, 66.03% yield) as a white solid.

    [0743] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.58-7.55 (m, 1H), 7.40 (s, 1H), 3.43 (br s, 3H), 3.29 (br d, J=8.8 Hz, 3H), 2.09 (d, J=2.0 Hz, 3H) ppm.

    Step 4: 1-(5-Bromo-3-fluoro-2-methylphenyl)ethan-1-one

    [0744] To a solution of 5-bromo-3-fluoro-N-methoxy-N,2-dimethylbenzamide (11 g, 39.84 mmol) in THE (100 mL) was added MeMgBr (3 M, 19.92 mL) at 0° C. The reaction mixture was stirred at 25° C. for 1 hr. The reaction mixture was poured into sat. NH.sub.4Cl (300 mL) and extracted with EA (80 mL*3). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=100:1-5:1) to give the title compound (9.1 g, 39.38 mmol, 98.85% yield) as a white solid.

    [0745] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.81 (s, 1H), 7.71-7.68 (m, 1H), 2.57 (s, 3H), 2.23 (d, J=2.0 Hz, 3H) ppm.

    Step 5: 2-(5-Bromo-3-fluoro-2-methylphenyl)propanenitrile

    [0746] To a mixture of 1-(5-bromo-3-fluoro-2-methylphenyl)ethan-1-one (10 g, 43.28 mmol) and p-toluenesulfonylmethyl isocyanide (12.67 g, 64.92 mmol) in DME (500 mL) and EtOH (15.95 g, 346.23 mmol) was added t-BuOK (10.68 g, 95.21 mmol) at 0° C. The resulting mixture was stirred at 25° C. for 12 hrs. The reaction mixture was poured into sat. NH.sub.4Cl (400 mL) and extracted with EtOAc (200 mL*2). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=30:1-5:1) to give the title compound (7.7 g, 31.81 mmol, 73.49% yield) as a white solid.

    [0747] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.54-7.51 (m, 1H), 7.45 (s, 1H), 4.53-4.47 (m, 1H), 2.20 (d, J=2.4 Hz, 3H), 1.54 (d, J=7.2 Hz, 3H) ppm.

    Step 6: 2-(5-Bromo-3-fluoro-2-methylphenyl)-3-hydroxy-2-methylpropanenitrile

    [0748] To a mixture of 2-(5-bromo-3-fluoro-2-methylphenyl)propanenitrile (7.7 g, 31.81 mmol) and NaHCO.sub.3 (267.20 mg, 3.18 mmol) in DMSO (60 mL) was added paraformaldehyde (1.15 g, 38.17 mmol). The mixture was stirred at 25° C. for 16 hrs. Water (400 mL) was added and the mixture was extracted with EtOAc (200 mL*2). The combined organic phase was washed with brine (400 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, PE; EtOAc=10:1-3:1) to give the title compound (8.0 g, 29.40 mmol, 92.43% yield) as a white solid.

    [0749] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.58-7.56 (m, 1H), 7.36 (s, 1H), 5.84-5.81 m, 1H), 3.95-3.91 (m, 1H), 3.69-3.66 (m, 1H), 2.40 (d, J=4.0 Hz, 3H), 1.70 (s, 3H) ppm.

    Step 7: 2-(5-Bromo-2-(bromomethyl)-3-fluorophenyl)-3-hydroxy-2-methylpropanenitrile

    [0750] To a mixture of 2-(5-bromo-3-fluoro-2-methylphenyl)-3-hydroxy-2-methylpropanenitrile (8 g, 29.40 mmol) in MeCN (80 mL) was added NBS (10.99 g, 61.74 mmol) and AIBN (1.45 g, 8.82 mmol). The mixture was stirred at 80° C. for 2 hrs. The solvent was removed under reduced pressure and the residue purified by column chromatography (SiO.sub.2, PE:EtOAc=10:1-3:1) to give the title compound (8.5 g, 24.22 mmol, 82.37% yield) as a colorless oil.

    [0751] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.74-7.71 (m, 1H), 7.44 (s, 1H), 5.93 (br s, 1H), 4.97-4.86 (m, 2H), 3.95-3.91 (m, 1H), 3.77-3.73 (m, 1H), 1.76 (s, 3H) ppm.

    Step 8: 6-Bromo-8-fluoro-4-methylisochromane-4-carbonitrile

    [0752] To a mixture of 2-(5-bromo-2-(bromomethyl)-3-fluorophenyl)-3-hydroxy-2-methylpropanenitrile (6.3 g, 17.95 mmol) in DMF (320 mL) was added K.sub.2CO.sub.3 (7.44 g, 53.84 mmol). The mixture was stirred at 25° C. for 16 hrs. Water (3000 mL) was added and the mixture was extracted with EtOAc (500 mL*2). The combined organic phase was washed with brine (1000 mL*2), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, PE; EtOAc=10:1-3:1) to give the title compound (2.5 g, 9.26 mmol, 51.57% yield) as a white solid.

    [0753] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.75 (s, 1H), 7.61-7.59 (m, 1H), 4.87-4.71 (m, 2H), 4.20 (d, J=11.2 Hz, 1H), 3.81 (d, J=11.6 Hz, 1H), 1.67 (s, 3H) ppm.

    Step 9: (R)-4-Cyano-8-fluoro-4-methylisochromane-6-carboxylic acid and (S)-4-cyano-8-fluoro-4-methylisochromane-6-carboxylic acid

    [0754] A mixture of 6-bromo-8-fluoro-4-methylisochromane-4-carbonitrile (2.1 g, 7.77 mmol), K.sub.2CO.sub.3 (1.61 g, 11.66 mmol), Pd(OAc).sub.2 (174.55 mg, 777.50 umol) and 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (952.06 mg, 1.55 mmol) in DMSO (40 mL) and H.sub.2O (4 mL) was degassed and purged with CO 3 times. The mixture was stirred under CO (15 psi) atmosphere at 100° C. for 4 hrs. The mixture was poured into water (300 mL) and extracted with EA (50.0 mL*2). The combined organics were discarded, the aqueous was adjusted to pH=5 by aq. HCl (1 M), and the products were extracted with EA (50.0 mL*3). The combined organics were washed with brine (100.0 mL*2), dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness to give racemic 4-cyano-8-fluoro-4-methylisochromane-6-carboxylic acid. The racemate was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 5 um); mobile phase: [0.1% NH.sub.3H.sub.2O EtOH]; B %: 20%-20%, 3.1 min; 600 minmin). The eluent of peak 1 (Rt=1.120 min) was concentrated under vacuum. The residue was diluted with H.sub.2O (50 mL) and adjusted to pH=5 with 1 N HCl, then the mixture was extracted with EA (50 mL*2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (570 mg, 2.30 mmol, 29.58% yield) as a yellow solid. The eluent of peak 2 (Rt=1.258 min) was concentrated under vacuum. The residue was diluted with H.sub.2O (50 mL) and adjusted to pH=5 with 1 N HCl, then the mixture was extracted with EA (50 mL*2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give a yellow solid. This product was further purified by SFC separation (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 5 um); mobile phase: [0.1% NH.sub.3H.sub.2O EtOH]; B %: 20%-20%, 3.2 min; 73 min) to give the title compound (590 mg, 2.48 mmol, 31.84% yield) as a yellow solid. Stereochemistry was assigned arbitrarily.

    (R)-4-Cyano-8-fluoro-4-methylisochromane-6-carboxylic acid

    [0755] .sup.1H NMR (400 MHz, DMSO-d6) δ=13.84-13.85 (m, 1H), 7.95 (s, 1H), 7.66-7.64 (m, 1H), 4.97-4.84 (m, 2H), 4.21 (d, J=11.6 Hz, 1H), 3.90 (d, J=11.6 Hz, 1H), 1.69 (s, 3H) ppm.

    [0756] Chiral SFC: IC-3-EtOH(DEA)-5-40-3 mL-35T.lcm, Rt=1.120 min, ee %=95.99%.

    (S)-4-Cyano-8-fluoro-4-methylisochromane-6-carboxylic acid

    [0757] .sup.1H NMR (400 MHz, DMSO-d6) δ=13.58-13.50 (m, 1H), 7.96 (s, 1H), 7.67-7.64 (m, 1H), 4.97-4.84 (m, 2H), 4.21 (d, J=11.6 Hz, 1H), 3.90 (d, J=11.6 Hz, 1H), 1.69 (s, 3H) ppm.

    [0758] Chiral SFC: IC-3-EtOH(DEA)-5-40-3 mL-35T.lcm, Rt=1.159 min, ee %=99.13%.

    Intermediate 61: 3-Bromo-6H-pyrano[3,4-b]pyridin-5(8H)-one-6,6-d.SUB.2

    [0759] ##STR00614##

    Step 1: 3-Bromo-6H-pyrano[3,4-b]pyridin-5(8H)-one-6,6-d.SUB.2

    [0760] To a solution of 3-bromo-6H-pyrano[3,4-b]pyridin-5(8H)-one (3.00 g, 13.155 mmol, 1.00 equiv) in THE (250.00 mL) was added NaHDMS (52 mL, 1 M, 52.620 mmol, 4.00 equiv) under nitrogen at 0° C. The resulting mixture was stirred at 0° C. for 2 hours. D.sub.2O (100.00 mL) was then added to the reaction mixture and stirring at room temperature continued for 16 hours. The aqueous layer was extracted with EtOAc (50 mL×3). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford the title compound (1.1 g, 36.35%) as a yellow solid.

    [0761] LCMS (ESI) m/z: [M+H].sup.+=230.

    Intermediate 62:_3-Chloro-6H-pyrano[3,4-b]pyridin-5(8H)-one-8,8-d.SUB.2

    [0762] ##STR00615##

    Step 1: (3-Bromo-5-chloropyridin-2-yl)methan-d.SUB.2.-ol

    [0763] To a stirred solution of methyl 3-bromo-5-chloropyridine-2-carboxylate (1.00 g, 3.992 mmol, 1.00 equiv) in CD.sub.3OD (10.00 mL) was added NaBD.sub.4 (670.71 mg, 15.969 mmol, 4.00 equiv) at 0° C. under N.sub.2 atmosphere. The resulting mixture was stirred for 2 h at room temperature under N.sub.2 atmosphere. The reaction was quenched with water at room temperature. The aqueous mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (12:1) to give the title compound (644 mg, 71.86%) as a light yellow solid.

    [0764] (LCMS (ESI) m/z [M+H].sup.+=224.

    Step 2: tert-Butyl 2-((3-bromo-5-chloropyridin-2-yl)methoxy-d.SUB.2.)acetate

    [0765] To a stirred solution of (3-bromo-5-chloropyridin-2-yl)methan-d.sub.2-ol (5.10 g, 22.719 mmol, 1.00 equiv) and tert-butyl 2-bromoacetate (8.86 g, 45.438 mmol, 2.00 equiv) in toluene (30.00 mL) were added Bu.sub.4NHSO.sub.4 (0.77 g, 2.272 mmol, 0.10 equiv) and 10 M NaOH (30 mL) at 0° C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched by the addition of sat. NH.sub.4Cl (10 mL) at room temperature. The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (12:1) to give the title compound (6.5 g, crude) as a light yellow oil.

    [0766] (LCMS (ESI) m/z [M+H].sup.+=338.

    Step 3: 2-((3-Bromo-5-chloropyridin-2-yl)methoxy-d.SUB.2.)acetic acid

    [0767] To a stirred solution of tert-butyl 2-((3-bromo-5-chloropyridin-2-yl)methoxy-d.sub.2)acetate (6.50 g, 19.196 mmol, 1.00 equiv) in DCM (40.00 mL) was added TFA (10.00 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to give the title compound (6.4 g, crude) as a white solid.

    [0768] (LCMS (ESI) m/z [M+H].sup.+=282.

    Step 4: 2-((3-Bromo-5-chloropyridin-2-yl)methoxy-d.SUB.2.)-N-methoxy-N-methylacetamide

    [0769] To a stirred solution of 2-((3-bromo-5-chloropyridin-2-yl)methoxy-d.sub.2)acetic acid (6.40 g, 22.654 mmol, 1.00 equiv) and N,O-dimethylhydroxylamine (1.66 g, 27.185 mmol, 1.20 equiv) in DMF (60.00 mL) were added HATU (10.34 g, 27.185 mmol, 1.20 equiv) and DIEA (8.78 g, 67.962 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. Water was added and the aqueous mixture was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (4.45 g, 60.33%) as a light yellow oil.

    [0770] (LCMS (ESI) m/z [M+H].sup.+=325.

    Step 5: 3-Chloro-6H-pyrano[3,4-b]pyridin-5(8H)-one-8,8-d.SUB.2

    [0771] To a stirred solution of 2-((3-bromo-5-chloropyridin-2-yl)methoxy-d.sub.2)-N-methoxy-N-methylacetamide (3 g, 9.214 mmol, 1.00 equiv) in THE (40.00 mL) was added nBuLi (4.42 mL, 11.057 mmol, 1.20 equiv) at −78° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 h at −78° C. under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH.sub.4Cl (10 mL) at room temperature. The aqueous mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (380 mg, 22.22%) as a light yellow oil.

    [0772] (LCMS (ESI) m/z [M+H].sup.+=187.

    Intermediate 63: Ethyl 2-azabicyclo[2.2.2]octane-4-carboxylate

    [0773] ##STR00616##

    Step 1. 2-tert-Butyl 4-ethyl 2-azabicyclo[2.2.2]octane-2,4-dicarboxylate

    [0774] 2-[(tert-Butoxy)carbonyl]-2-azabicyclo[2.2.2]octane-4-carboxylic acid (0.2 g, 0.783 mmol) was dissolved in EtOH (2.6 mL). Catalytic sulfuric acid (0.26 mL) was added and the reaction mixture stirred overnight. The excess solvent was then removed under vacuum. The crude residue was dissolved in EtOAc, the organic layer washed with saturated NaHCO.sub.3, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil (0.14 g).

    [0775] LCMS (ESI) m/z: [M+H-Boc]+=184.2.

    Step 2. Ethyl 2-azabicyclo[2.2.2]octane-4-carboxylate

    [0776] 2-Azabicyclo[2.2.2]octane-2,4-dicarboxylate (0.065 g, 0.24 mmol) was dissolved in DCM in (1.2 mL) and cooled to 0° C. Trifluoroacetic acid (0.19 mL, 2.4 mmol) was added dropwise and the reaction mixture stirred for 1 h at 0° C. The solvent was then removed under vacuum. The crude residue was dissolved in DCM, the organic layer washed with saturated NaHCO.sub.3, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil (0.04 g).

    [0777] LCMS (ESI) m/z: [M+H]+=184.2.

    Intermediate 64: 2-Chloro-8-fluoro-1,6-naphthyridine-7-carbonitrile

    [0778] ##STR00617##

    Step 1: 2-Chloro-3-fluoro-5-iodopyridin-4-amine

    [0779] To a stirred solution of 2-chloro-3-fluoropyridin-4-amine (6.00 g, 40.942 mmol, 1.00 equiv) and Ag.sub.2SO.sub.4 (12.77 g, 40.956 mmol, 1.00 equiv) in ethanol (150 mL) was added 12 (10.39 g, 40.942 mmol, 1 equiv). The resulting mixture was stirred at 55° C. for 2 h. The solid was filtered out and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (300 mL), washed with water (50 mL×2) and saturated brine (30 mL×1), dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (8.8 g, 78.89%) as a light yellow solid.

    [0780] LCMS (ESI) m/z: [M+H].sup.+=273.

    Step 2: Ethyl (E)-3-(4-amino-6-chloro-5-fluoropyridin-3-yl)acrylate

    [0781] To a stirred solution of 2-chloro-3-fluoro-5-iodopyridin-4-amine (6.00 g, 22.022 mmol, 1.00 equiv) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (6.47 g, 28.629 mmol, 1.3 equiv) in DME (90 mL) and H.sub.2O (30 mL) were added Pd(PPh.sub.3).sub.4 (2.54 g, 2.202 mmol, 0.1 equiv) and Na.sub.2CO.sub.3 (4.67 g, 44.045 mmol, 2 equiv). The resulting mixture was stirred at 100° C. for 3 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (5:1) to give the title compound (5.0 g, 92.80%) as a light yellow oil.

    [0782] LCMS (ESI) m/z: [M+H].sup.+=245.

    Step 3: 7-Chloro-8-fluoro-1,6-naphthyridin-2(1H)-one

    [0783] A solution of ethyl (E)-3-(4-amino-6-chloro-5-fluoropyridin-3-yl)acrylate (5.00 g, 20.437 mmol, 1.00 equiv) and NaSMe (17.88 g, 51.093 mmol, 2.5 equiv, 20% in H.sub.2O) in ethanol (60 mL) was stirred for 4 h at 60° C. The mixture was acidified to pH 7 with 1 N. HCl. The resulting mixture was extracted with EtOAc (200 mL×2). The combined organic layers were washed with water (100 mL) and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (5:1) to give the title compound (2.23 g, 54.95%) as a light yellow solid.

    [0784] LCMS (ESI) m/z: [M+H].sup.+=199.

    Step 4: 8-Fluoro-2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile

    [0785] To a stirred solution of 7-chloro-8-fluoro-1,6-naphthyridin-2(1H)-one (1.00 g, 5.036 mmol, 1.00 equiv) and Zn(CN).sub.2 (1.18 g, 10.072 mmol, 2 equiv) in DMF (5 mL) were added Pd.sub.2(dba).sub.3 (0.92 g, 1.007 mmol, 0.2 equiv) and XPhos (0.96 g, 2.014 mmol, 0.4 equiv). The resulting mixture was stirred at 100° C. for 4 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (561 mg, 58.90%) as a light yellow solid.

    [0786] LCMS (ESI) m/z: [M+H].sup.+=190.

    Step 5: 2-Chloro-8-fluoro-1,6-naphthyridine-7-carbonitrile

    [0787] A solution of trichloroisocyanuric acid (568.01 mg, 2.444 mmol, 0.67 equiv) and PPh.sub.3 (1913.59 mg, 7.296 mmol, 2 equiv) in toluene (1 mL) was stirred overnight at room temperature under nitrogen atmosphere. To the above mixture was added 8-fluoro-2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile (690.00 mg, 3.648 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for an additional 4 h at 110° C. under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:1) to give the title compound (346 mg, 45.69%) as a white solid.

    [0788] LCMS (ESI) m/z: [M+H].sup.+=208.

    Intermediate 65: tert-Butyl ((6-bromoisoquinolin-3-yl)methyl)carbamate

    [0789] ##STR00618##

    Step 1: 6-Bromo-3-methylisoquinoline

    [0790] To a solution of (4-bromophenyl)methanamine (30 g, 161.25 mmol) in DCM (500 mL) was added 1,1-dimethoxypropan-2-one (20.95 g, 177.37 mmol) and MgSO.sub.4 (60.00 g, 498.47 mmol). The resulting mixture was stirred at 40° C. for 16 hrs. NaBH.sub.3CN (12.16 g, 193.50 mmol) was then added and the mixture stirred at 30° C. for 5 hrs before filtering. The filtrate was concentrated to give a yellow oil. Chlorosulfonic acid (157.50 g, 1.35 mol) was cooled to −10° C. and the above crude product was added dropwise for 3 hrs under N.sub.2. The reaction mixture was heated to 120° C. for 10 mins. The reaction mixture was cooled to 25° C. and poured into ice water (2 L). The solution was neutralized with 2 M NaOH and extracted with EA (1000 mL*3). The combined organic layer was washed with brine (2000 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10:1-5:1) to give the title compound (8.5 g, 38.27 mmol, 23.74% yield) as a yellow solid.

    [0791] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.06 (s, 1H), 7.8 (d, J=1.2 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.52-7.50 (m, 1H), 7.30 (s, 1H), 2.62 (s, 3H) ppm.

    Step 2: 6-Bromo-3-(bromomethyl)isoquinoline

    [0792] To a solution of 6-bromo-3-methylisoquinoline (8.3 g, 37.37 mmol) in trifluoromethylbenzene (200 mL) was added NBS (7.97 g, 44.77 mmol) and AIBN (919.64 mg, 5.60 mmol). The mixture was stirred at 80° C. for 16 hrs. The reaction mixture was concentrated and the residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=40:1-20:1) to give the title compound (3 g, 9.22 mmol, 24.68% yield) as a yellow solid.

    [0793] LCMS (ESI) m/z: [.sup.79BrM+H].sup.+=301.9

    [0794] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.22 (s, 1H), 8.02-8.00 (m, 2H), 7.86 (d, J=8.8 Hz, 1H), 7.72-7.68 (m, 2H), 4.72 (s, 2H) ppm.

    Step 3: 2-((6-Bromoisoquinolin-3-yl)methyl)isoindoline-1,3-dione

    [0795] A mixture of 6-bromo-3-(bromomethyl)isoquinoline (3 g, 9.97 mmol) and (1,3-dioxoisoindolin-2-yl)potassium (2.03 g, 10.96 mmol) in DMF (65 mL) was stirred at 30° C. for 16 hrs. The reaction mixture was poured into NaHCO.sub.3 solution (200 mL) and the products were extracted with DCM (200 mL*3). The combined organic layer was washed with brine (500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (3.6 g, 9.80 mmol, 98.36% yield) as a yellow solid.

    [0796] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.15 (s, 1H), 7.95-7.89 (m, 3H), 7.76-7.74 (m, 3H), 7.65 (s, 1H), 7.54 (s, 1H), 5.30 (s, 2H) ppm.

    Step 4: (6-Bromoisoquinolin-3-yl)methanamine

    [0797] To a solution of 2-((6-bromoisoquinolin-3-yl)methyl)isoindoline-1,3-dione (3.6 g, 9.80 mmol) in EtOH (60 mL) was added NH.sub.2NH.sub.2.H.sub.2O (1.72 g, 34.31 mmol). The mixture was stirred at 30° C. for 16 hrs. The reaction mixture was concentrated under vacuum to give the title compound (2.32 g, 9.79 mmol, 100.00% yield) as a yellow solid.

    [0798] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.25-9.23 (m, 1H), 8.22-8.20 (m, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.78-7.71 (m, 2H), 3.95 (s, 2H) ppm.

    Step 5: tert-Butyl ((6-bromoisoquinolin-3-yl)methyl)carbamate

    [0799] To a solution of (6-bromoisoquinolin-3-yl)methanamine (2.32 g, 9.79 mmol) in THE (25 mL) was added NaHCO.sub.3 (1.64 g, 19.57 mmol) and Boc.sub.2O (2.56 g, 11.74 mmol). The mixture was stirred at 30° C. for 2 hrs. The reaction mixture was poured into water (100 mL) and the products were extracted with EA (50 mL*3). The combined organic layer was washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=20:1-2:1) to give the title compound (2.2 g, 6.25 mmol, 63.87% yield) as a yellow solid.

    [0800] LCMS (ESI) m/z: [.sup.79BrM+H].sup.+=339.1

    [0801] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.17 (s, 1H), 7.97-7.95 (m, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.67-7.64 (m, 1H), 7.53 (s, 1H), 4.58 (br d, J=6.0 Hz, 2H), 1.48 (s, 9H) ppm.

    Intermediate 66: 2-((6-Bromocinnolin-3-yl)methyl)isoindoline-1,3-dione

    [0802] ##STR00619##

    Step 1: Diethyl hydrazineylphosphonate

    [0803] Hydrazine hydrate (21.32 g, 362.05 mmol, 20.70 mL) was added dropwise with efficient stirring to a mixture of CCl.sub.4 (180 mL), DCM (300 mL), anhydrous K.sub.2CO.sub.3 (75.06 g, 543.08 mmol) and benzyl(triethyl)ammonium chloride (824.66 mg, 3.62 mmol) at 25° C. Stirring was continued for 15 min at 25° C. and a solution of diethyl phosphonate (50 g, 362.05 mmol, 46.73 mL) in DCM (60 mL) was then added at 25° C. with occasional external cooling. After the addition had been completed, stirring was continued for 4 hrs at 25° C. Potassium carbonate was then filtered off and the filter cake washed with DCM. The filtrate was concentrated under reduced pressure to provide the title compound (56 g, 333.07 mmol, 92.00% yield) as a light yellow oil that was used directly in the next step.

    Step 2: Diethyl (Z)-(2-(1-(3-bromophenyl)propan-2-ylidene)hydrazineyl)phosphonate

    [0804] A mixture of 1-(3-bromophenyl)propan-2-one (20.9 g, 98.09 mmol), diethyl hydrazineylphosphonate (17.32 g, 102.99 mmol) and HCl (0.6 mL) in EtOH (400 mL) was stirred at 80° C. for 2 hrs. The reaction mixture was concentrated to afford a yellow oil. The oil was dissolved in water (100 mL) and sat. NaHCO.sub.3 was added to adjust pH to 9. The products were extracted with DCM (50 mL*3). The combined organic phase was dried over anhydrous Na.sub.2SO.sub.4 and concentrated to afford a brown residue. The residue was purified by column chromatography (SiO.sub.2, Dichloromethane/Methanol=1/0 to 10/1) to give the title compound (26.65 g, 66.04 mmol, 67.33% yield) as a light yellow solid.

    [0805] LCMS (ESI) m/z: [M+H]+=362.9/364.9

    Step 3: (6-Bromocinnolin-3-yl)methyl acetate

    [0806] To a solution of diethyl (Z)-(2-(1-(3-bromophenyl)propan-2-ylidene)hydrazineyl)phosphonate (3.65 g, 10.05 mmol) in toluene (92 mL) was added Cu(OAc).sub.2.H.sub.2O (2.01 g, 10.05 mmol, 2.01 mL) at 25° C. The mixture was stirred at 130° C. for 12 hrs under O.sub.2 (15 psi). The mixture was diluted with H.sub.2O (500 mL) and extracted with EA (500 mL*2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, DCM/EA=1/0 to 0/1) to give the title compound (1 g, 3.56 mmol, 17.70% yield) as a brown solid.

    [0807] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.45 (d, J=9.2 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.94-7.91 (m, 1H), 7.83 (s, 1H), 5.70 (s, 2H), 2.20 (s, 3H) ppm.

    Step 4: (6-Bromocinnolin-3-yl)methanol

    [0808] To a solution of (6-bromocinnolin-3-yl)methyl acetate (1 g, 3.56 mmol) in MeOH/THE/H.sub.2O=2/2/1 (10 mL) was added NaOH (213.44 mg, 5.34 mmol). The mixture was stirred at 40° C. for 3 hrs. The reaction mixture was diluted with H.sub.2O (30 mL) and extracted with DCM (30 mL*2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was triturated with MTBE (20 mL) and the yellow solid was collected by filtration to give the title compound (580 mg, 2.43 mmol, 68.20% yield) as a yellow solid.

    [0809] LCMS (ESI) m/z: [M+H]+=238.8/240.8.

    [0810] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.47 (d, J=1.6 Hz, 1H), 8.41 (d, J=9.2 Hz, 1H), 8.16 (s, 1H), 8.03-8.01 (m, 1H), 5.82-5.79 (m, 1H), 5.07 (d, J=5.6 Hz, 2H) ppm.

    Step 5: 2-((6-Bromocinnolin-3-yl)methyl)isoindoline-1,3-dione

    [0811] To a solution of (6-bromocinnolin-3-yl)methanol (580 mg, 2.43 mmol), isoindoline-1,3-dione (392.65 mg, 2.67 mmol) and PPh.sub.3 (954.51 mg, 3.64 mmol) in THF (20 mL) was added a solution of DEAD (633.79 mg, 3.64 mmol, 661.58 uL) in THE (10 mL) at 0° C. The mixture was stirred at 25° C. for 2 hrs under N.sub.2. The reaction mixture was diluted with H.sub.2O (100 mL) and extracted with DCM (100 mL*2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was triturated with MeOH (20 mL) and the off-white solid collected by filtration to give the title compound (550 mg, 1.49 mmol, 61.57% yield).

    [0812] LCMS (ESI) m/z: [M+H]+=369.9.

    [0813] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.39-8.37 (m, 2H), 8.21 (s, 1H), 8.04-8.02 (m, 1H), 7.96-7.93 (m, 2H), 7.90-7.89 (m, 2H), 5.34 (s, 2H) ppm.

    Intermediate 67: tert-Butyl ((3-bromo-1,7-naphthyridin-6-yl)methyl)carbamate

    [0814] ##STR00620##

    Step 1: 5-Bromo-3-iodopicolinic acid

    [0815] To a solution of 3-amino-5-bromo-pyridine-2-carboxylic acid (4 g, 18.43 mmol) in 10% H.sub.2SO.sub.4 (30 mL) was added NaNO.sub.2 (1.91 g, 27.65 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min. KI (9.18 g, 55.29 mmol) was added and the reaction was stirred at 0° C. for 30 min and then heated to 80° C. for 1 hr. The reaction mixture was cooled to 20° C. and slowly poured into ice water (80 mL). The resulting yellow solid was collected by filtration and dried to give the title compound (4.5 g, 13.72 mmol, 74.46% yield).

    [0816] LCMS (ESI) m/z: [.sup.79BrM+H].sup.+=327.8.

    [0817] .sup.1HNMR (400 MHz, DMSO-d6) δ=8.73 (d, J=2.0 Hz, 1H), 8.70 (d, J=2.0 Hz, 1H) ppm.

    Step 2: 5-Bromo-3-iodo-N-methoxy-N-methylpicolinamide

    [0818] To a solution of 5-bromo-3-iodopicolinic acid (2 g, 6.10 mmol) in DCM (15 mL) was added HATU (3.48 g, 9.15 mmol), DIPEA (3.94 g, 30.50 mmol) and N,O-dimethylhydroxylamine (713.95 mg, 7.32 mmol). The mixture was stirred at 30° C. for 2 hrs. Water (30 mL) was added and the products extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/1) to give the title compound (2.2 g, 5.93 mmol, 97.23% yield) as a yellow oil.

    [0819] LCMS (ESI) m/z: [.sup.81BrM+H].sup.+=372.8.

    Step 3: 5-Bromo-3-iodopicolinaldehyde

    [0820] To a solution of 5-bromo-3-iodo-N-methoxy-N-methylpicolinamide (1 g, 2.70 mmol) in THE (10 mL) was added drop wise DIBAL-H (1 M, 5.39 mL, 5.39 mmol) at −70° C. under N.sub.2. The mixture was stirred at −70° C. for 1 hr. The reaction was quenched by adding water (50 mL) and the products were 5 extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=3/1) to give the title compound (0.6 g, 1.92 mmol, 71.36% yield) as a yellow oil.

    [0821] LCMS (ESI) m/z: [.sup.79BrM+H].sup.+=311.8.

    [0822] .sup.1HNMR (400 MHz, CDCl.sub.3) δ=9.98 (s, 1H), 8.83 (d, J=2.0 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H) ppm.

    Step 4: tert-Butyl (3-(5-bromo-2-formylpyridin-3-yl)prop-2-yn-1-yl)carbamate

    [0823] 5-Bromo-3-iodopicolinaldehyde (150 mg, 480.92 umol), tert-butyl N-prop-2-ynylcarbamate (74.64 mg, 480.92 umol), Et.sub.3N (486.64 mg, 4.81 mmol, 669.39 uL), CuI (9.16 mg, 48.09 umol) and Pd(PPh.sub.3).sub.2Cl.sub.2 (33.76 mg, 48.09 umol) in CH.sub.3CN (6 mL) was de-gassed and purged with N.sub.2 before stirring at 20° C. for 2 hrs under N.sub.2. The reaction was quenched by adding water (30 mL) and the products were extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (0.2 g, crude) as a yellow oil that was used in the next step without further purification.

    [0824] LCMS (ESI) m/z: [.sup.79BrM+H].sup.+=339.0.

    Step 5: tert-Butyl ((3-bromo-1,7-naphthyridin-6-yl)methyl)carbamate

    [0825] To a solution of tert-butyl (3-(5-bromo-2-formylpyridin-3-yl)prop-2-yn-1-yl)carbamate (0.2 g, 589.65 umol) in tBuOH (5 mL) was added NH.sub.4OAc (68.18 mg, 884.48 umol) and AgOTf (30.30 mg, 117.93 umol). The mixture was stirred at 20° C. for 16 hrs. The reaction mixture was quenched by adding water (30 mL) and the products were extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/1) to give the title compound (110 mg, 315.49 umol, 53.51% yield) as a yellow oil.

    [0826] LCMS (ESI) m/z: [.sup.79BrM+H].sup.+=338.1.

    Intermediate 68: 2-((2-Chlorothiazolo[5,4-c]pyridin-6-yl)methyl)isoindoline-1,3-dione

    [0827] ##STR00621##

    Step 1: 6-Methylthiazolo[5,4-c]pyridine-2(1H)-thione

    [0828] A solution of 5-bromo-2-methylpyridin-4-amine (7.50 g, 40.098 mmol, 1.00 equiv) and potassium ethyl xanthate (25.71 g, 160.393 mmol, 4 equiv) in DMF (75 mL) was stirred for 15 h at 130° C. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (300 mL). The organic layer was discarded, and the aqueous layer was concentrated under reduced pressure. The residue was slurried with EtOAc (500 mL) and stirred at 25° C. for 1 h. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (3.5 g, 47.89%) as a light yellow solid.

    [0829] LCMS (ESI) m/z: [M+H].sup.+=183.

    Step 2: 2-Chloro-6-methylthiazolo[5,4-c]pyridine

    [0830] A solution of 6-methylthiazolo[5,4-c]pyridine-2(1H)-thione (2.10 g, 11.522 mmol, 1.00 equiv) in sulfonyl chloride (20.00 mL) was stirred at room temperature for 2 hours. The mixture was poured into ice-water (200 mL). The aqueous mixture was basified to pH 9 with Na.sub.2CO.sub.3. And extracted with EtOAc (200 mL×3). The combined organic layers were washed with water (50 mL×1), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (0.726 g, 34.13%) as a light yellow solid.

    [0831] LCMS (ESI) m/z: [M+H].sup.+=185.

    Step 3: 6-(Bromomethyl)-2-chlorothiazolo[5,4-c]pyridine and 2-chloro-6-(dibromomethyl)thiazolo[5,4-c]pyridine

    [0832] To a stirred solution of 2-chloro-6-methylthiazolo[5,4-c]pyridine (1.83 g, 9.911 mmol, 1.00 equiv) and NBS (1.76 g, 9.911 mmol, 1 equiv) in CCl.sub.4 (30 mL) was added AIBN (0.16 g, 0.991 mmol, 0.1 equiv). The resulting mixture was stirred at 80° C. for 15 hours under nitrogen atmosphere. The reaction mixture was poured into water (30 mL) and extracted with DCM (60 mL). The combined organic layers were washed with brine (30 mL×1), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (10:1) to give a mixture of the title compounds (1.57 g, 60.11%) as a light yellow solid.

    [0833] LCMS (ESI) m/z: [M+H].sup.+=265.

    Step 4: 6-(Bromomethyl)-2-chlorothiazolo[5,4-c]pyridine

    [0834] To a stirred solution of a mixture of 6-(bromomethyl)-2-chlorothiazolo[5,4-c]pyridine and 2-chloro-6-(dibromomethyl)thiazolo[5,4-c]pyridine (1.87 g, 5.461 mmol, 1.00 equiv) and diethyl phosphonate (4.53 g, 32.766 mmol, 6 equiv) in THE (25 mL) was added DIEA (4.23 g, 32.766 mmol, 6 equiv). The mixture was stirred at room temperature for 15 hours. The mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography, eluting with PE/EtOAc (12:1) to give the title compound (1.42 g, 98.67%) as a light yellow solid.

    [0835] LCMS (ESI) m/z: [M+H].sup.+=265.

    Step 5: 2-((2-Chlorothiazolo[5,4-c]pyridin-6-yl)methyl)isoindoline-1,3-dione

    [0836] A solution of 6-(bromomethyl)-2-chlorothiazolo[5,4-c]pyridine (100.00 mg, 0.379 mmol, 1.00 equiv) and potassium phthalimide (84.34 mg, 0.455 mmol, 1.2 equiv) in DMF (1 mL) was stirred for 1 hour at room temperature. The mixture was poured into water (2 mL) and stirred for 10 min. The resulting mixture was filtered, the filter cake was washed with water (5 mL×2). The solid was dried under vacuum to give the title compound (114 mg, 91.11%) as a white solid.

    [0837] LCMS (ESI) m/z: [M+H].sup.+=330.

    Intermediate 69: tert-Butyl ((6-chloropyrido[3,2-c]pyridazin-3-yl)methyl)carbamate

    [0838] ##STR00622##

    Step 1: Ethyl (E)-3-(4-amino-6-chloropyridazin-3-yl)acrylate

    [0839] To a stirred solution of 3,6-dichloropyridazin-4-amine (24.00 g, 146.350 mmol, 1.00 equiv), ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (39.70 g, 175.620 mmol, 1.20 equiv) in DME (270.00 mL) and H.sub.2O (90.00 mL) was added Pd(PPh.sub.3).sub.4 (16.91 g, 14.635 mmol, 0.10 equiv) and Na.sub.2CO.sub.3 (31.02 g, 292.701 mmol, 2.00 equiv). The mixture was stirred at 100° C. for overnight. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (300 mL) and extracted with EtOAc (300 mL×5). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude product was purified by silica gel column chromatography, elution gradient 0 to 100% EtOAc in petroleum ether to give a mixture of 3,6-dichloropyridazin-4-amine and the title compound (15 g, crude) as a yellow solid. The mixture was re-crystallized from EtOAc (260 mL) to give the title compound (10 g, 30.02%) as a yellow solid.

    [0840] LCMS (ESI) m/z: [M+H].sup.+=228.

    Step 2: 3-Chloropyrido[3,2-c]pyridazin-6-ol

    [0841] To a stirred solution of ethyl (E)-3-(4-amino-6-chloropyridazin-3-yl)acrylate (11.80 g, 51.834 mmol, 1.00 equiv) in EtOH (150 mL) was added NaSMe (9.08 g, 129.548 mmol, 2.50 equiv) dropwise at room temperature. The resulting mixture was stirred for 2 h at 60° C. The mixture was diluted with water (100 mL) and neutralized to pH 7 with 1M HCl (aq.). The resulting mixture was filtered and the filter cake was washed with tert-butyl methyl ether (10 mL×3). The filter cake was dried under vacuum to give the title compound (6.3 g, 63.59%) as a grey solid.

    [0842] LCMS (ESI) m/z: [M+H].sup.+=182.

    Step 3: 6-Hydroxypyrido[3,2-c]pyridazine-3-carbonitrile

    [0843] To a stirred solution of 3-chloropyrido[3,2-c]pyridazin-6-ol (3500.00 mg, 19.275 mmol, 1.00 equiv) in DMF (40 mL) was added Zn(CN).sub.2 (4527.53 mg, 38.551 mmol, 2 equiv), Pd.sub.2(dba).sub.3 (3530.15 mg, 3.855 mmol, 0.2 equiv) and XPhos (3675.53 mg, 7.710 mmol, 0.40 equiv). The mixture was stirred at 100° C. overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC to give the title compound (900 mg, 31.64%) as a yellow solid.

    [0844] LCMS (ESI) m/z: [M+H].sup.+=173.

    Step 4: 6-Chloropyrido[3,2-c]pyridazine-3-carbonitrile

    [0845] To a stirred solution of PPh.sub.3 (3047.23 mg, 11.618 mmol, 2 equiv) in 1,4-dioxane (100 mL) was added trichloroisocyanuric acid (904.51 mg, 3.892 mmol, 0.67 equiv) in portions. The resulting mixture was stirred for 23 h at room temperature. To the above mixture was added 6-hydroxypyrido[3,2-c]pyridazine-3-carbonitrile (1000.00 mg, 5.809 mmol, 1.00 equiv) in portions. The resulting mixture was stirred for additional 4 h at 108° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 100% PE in EtOAc to give the title compound (581 mg, 52.48%) as a yellow solid.

    [0846] LCMS (ESI) m/z: [M+H].sup.+=191.

    Step 5: tert-Butyl ((6-chloropyrido[3,2-c]pyridazin-3-yl)methyl)carbamate and tert-butyl ((6-chloro-1,2-dihydropyrido[3,2-c]pyridazin-3-yl)methyl)carbamate

    [0847] To a stirred solution of 6-chloropyrido[3,2-c]pyridazine-3-carbonitrile (300.00 mg, 1.574 mmol, 1.00 equiv) in THE (8 mL) was added a 2.5 M solution of LiAlH.sub.4 (1.9 mL, 4.722 mmol, 3.00 equiv) in THE dropwise at 0° C. The resulting mixture was stirred for 30 min at 0° C. The reaction was quenched by the addition of sat. NaHCO.sub.3 (aq.) (10 mL) at 0° C. To the above mixture was added Boc.sub.2O (1030.60 mg, 4.722 mmol, 3.00 equiv) dropwise at 0° C. The resulting mixture was stirred for additional 1 h at room temperature. The mixture was concentrated under reduced pressure to give a mixture of the title compounds (231 mg, crude) that was used directly without further purification.

    [0848] LCMS (ESI) m/z: [M+H].sup.+=295.

    Step 6: tert-Butyl ((6-chloropyrido[3,2-c]pyridazin-3-yl)methyl)carbamate

    [0849] To a stirred solution of the mixture of tert-butyl ((6-chloropyrido[3,2-c]pyridazin-3-yl)methyl)carbamate and tert-butyl ((6-chloro-1,2-dihydropyrido[3,2-c]pyridazin-3-yl)methyl)carbamate (231 mg, crude) in DCM (8 mL) was added DDQ (714.64 mg, 3.148 mmol, 2.00 equiv) in portions. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was filtered and the filter cake was washed with DCM (5 mL×3). The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (112 mg, 24.14%) as a brown solid.

    [0850] LCMS (ESI) m/z: [M+H].sup.+=295.

    Intermediate 70: tert-Butyl ((5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methyl)carbamate

    [0851] ##STR00623##

    Step 1: 2-Benzyl-7-(((tert-butoxycarbonyl)amino)methyl)-2,6-naphthyridin-2-ium bromide

    [0852] To a solution of tert-butyl ((2,6-naphthyridin-3-yl)methyl)carbamate (3.6 g, 13.88 mmol) in DCM (10 mL) was added (bromomethyl)benzene (3.56 g, 20.83 mmol). The mixture was stirred at 30° C. for 16 hrs. The reaction mixture was concentrated and the residue was triturated in MTBE (50 mL) to give the title compound (4.5 g, crude) as a gray solid.

    [0853] LCMS (ESI) m/z: [M].sup.+=350.3.

    Step 2: tert-Butyl ((6-benzyl-5-methyl-5,6-dihydro-2,6-naphthyridin-3-yl)methyl)carbamate

    [0854] 2-Benzyl-7-(((tert-butoxycarbonyl)amino)methyl)-2,6-naphthyridin-2-ium bromide (2.0 g, 4.65 mmol) was added portionwise to a solution of MeMgBr (3 M, 9.30 mL) in THE (50 mL) at 0° C. under N.sub.2. The mixture was stirred at 20° C. for 1 hr. The reaction was quenched by adding sat. NH.sub.4Cl (50 mL) and the products were extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (2 g, crude) as a yellow oil.

    [0855] LCMS (ESI) m/z: [M+H].sup.+=366.3.

    Step 3: tert-Butyl ((6-benzyl-5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methyl)carbamate

    [0856] To a solution of tert-butyl ((6-benzyl-5-methyl-5,6-dihydro-2,6-naphthyridin-3-yl)methyl)carbamate (2 g, 5.47 mmol) in MeOH (20 mL) and phosphate buffer pH 7.0 (20 mL) was added NaBH.sub.4 (828.09 mg, 21.89 mmol) at 0° C. The mixture was stirred at 20° C. for 1 hr. The reaction was quenched by adding 0.5N HCl (50 mL) and the products were extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 0/1) to give the title compound (1.3 g, crude) as a yellow oil.

    [0857] LCMS (ESI) m/z: [M+H].sup.+=368.2.

    Step 4: tert-Butyl ((5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methyl)carbamate

    [0858] A mixture of tert-butyl ((6-benzyl-5-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methyl)carbamate (0.5 g, 1.36 mmol) and Pd/C (666.67 mg, 634.92 umol, 10% purity) in MeOH (15 mL) was degassed and purged with H.sub.2 3 times. The mixture was stirred at 40° C. for 40 hrs under H.sub.2 atmosphere (15 psi). The reaction mixture was filtered and the filtrate was concentrated under vacuum to give the title compound (0.35 g, crude) as a yellow oil.

    [0859] LCMS (ESI) m/z: [M+H].sup.+=278.3.

    [0860] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.10 (s, 1H), 7.40-7.22 (m, 1H), 7.01 (s, 1H), 4.18-4.12 (m, 2H), 3.93-3.82 (m, 1H), 3.20-3.15 (m, 1H), 3.13-3.04 (m, 1H), 2.82-2.74 (m, 1H), 2.70-2.65 (m, 1H), 2.59 (br s, 1H), 1.44-1.38 (m, 9H), 1.32-1.29 (m, 3H) ppm.

    Intermediate 71: 2-((5,6,7,8-tetrahydropyrido[4,3-c]pyridazin-3-yl)methyl)isoindoline-1,3-dione hydrochloride

    [0861] ##STR00624##

    Step 1: Benzyl 3-oxo-3,5,7,8-tetrahydropyrido[4,3-c]pyridazine-6(2H)-carboxylate

    [0862] A mixture of benzyl 4-oxopiperidine-1-carboxylate (25 g, 107.18 mmol), KOAc (0.4 g, 4.08 mmol) and glyoxylic acid monohydrate (10 g, 135.07 mmol) was stirred at 90° C. for 12 hours. N.sub.2H.sub.4.H.sub.2O (5.67 g, 96.19 mmol, 5.5 mL) was then added dropwise to the mixture at 90° C. before stirring at 90° C. for an additional 0.5 hr. The mixture was diluted with MeOH (100 mL), cooled to 25° C. and filtered. The solid was washed with MeOH and dried to give the title compound (10 g, 35.05 mmol, 32.70% yield) as a white solid.

    [0863] LCMS (ESI) m/z: [M+H].sup.+=286.0.

    [0864] .sup.1H NMR (400 MHz, DMSO-d6) δ=7.48-7.25 (m, 5H), 6.80 (s, 1H), 5.13 (s, 2H), 4.54 (br s, 2H), 3.67 (br s, 2H), 2.75-2.72 (m, 2H).

    Step 2: Benzyl 3-chloro-7,8-dihydropyrido[4,3-c]pyridazine-6(5H)-carboxylate

    [0865] To a mixture of benzyl 3-oxo-3,5,7,8-tetrahydropyrido[4,3-c]pyridazine-6(2H)-carboxylate (9 g, 31.55 mmol) in POCl.sub.3 (38.61 g, 251.81 mmol, 23.40 mL) was added Et.sub.3N (65.43 mg, 646.61 umol) in one portion at 25° C. under N.sub.2. The mixture was stirred at 80° C. 3 hours. The mixture was poured into water (2000 mL, 25° C.) and stirred for 5 min. Sat. NaHCO.sub.3 was added to the mixture to adjust pH=7. The aqueous phase was extracted with EA (1000 mL*2). The combined organic phase was washed with brine (1000 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=3/1) to give the title compound (7.7 g, 25.35 mmol, 80.36% yield) as a yellow oil.

    [0866] LCMS (ESI) m/z: [M+H].sup.+=304.0.

    [0867] .sup.1H NMR (400 MHz, MeOD) δ=7.75-7.63 (m, 1H), 7.46-7.28 (m, 5H), 5.23-5.15 (m, 2H), 4.82-4.74 (m, 2H), 4.63-4.57 (m, 1H), 3.96-3.84 (m, 2H), 3.24-3.12 (m, 2H).

    Step 3: 6-Benzyl 3-methyl 7,8-dihydropyrido[4,3-c]pyridazine-3,6(5H)-dicarboxylate

    [0868] To a solution of benzyl 3-chloro-7,8-dihydropyrido[4,3-c]pyridazine-6(5H)-carboxylate (7.5 g, 24.69 mmol) in DMSO (225 mL) was added Pd(OAc).sub.2 (277.18 mg, 1.23 mmol), K.sub.2CO.sub.3 (5.12 g, 37.04 mmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (1.51 g, 2.47 mmol) and MeOH (11.88 g, 370.69 mmol, 15.00 mL) under N.sub.2 at 25° C. The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (15 psi) at 100° C. for 1.5 hours. The combined mixture was poured into water (1500 mL) and extracted with ethyl acetate (500 mL*2). The combined organic phase was washed with brine (500 mL*2), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=1/2) to give the title compound (3.3 g, 9.92 mmol, 40.16% yield) as a yellow oil.

    [0869] LCMS (ESI) m/z: [M+H].sup.+=327.9.

    [0870] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.21-8.12 (m, 1H), 7.43-7.28 (m, 5H), 5.17-5.10 (m, 2H), 4.89-4.68 (m, 2H), 3.99-3.90 (m, 3H), 3.86-3.75 (m, 2H), 3.26-3.13 (m, 2H).

    Step 4: 6-(tert-Butyl) 3-methyl 7,8-dihydropyrido[4,3-c]pyridazine-3,6(5H)-dicarboxylate

    [0871] To a solution of 6-benzyl 3-methyl 7,8-dihydropyrido[4,3-c]pyridazine-3,6(5H)-dicarboxylate (3.2 g, 9.78 mmol) in MeOH (65 mL) was added Boc.sub.2O (3.20 g, 14.66 mmol, 3.37 mL) and Pd/C (300 mg, 10% purity) under N.sub.2. The suspension was degassed and purged with H.sub.2 several times. The mixture was stirred under H.sub.2 (15 psi) at 25° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (2.9 g, crude) as a light yellow oil, which was used directly in the next step.

    [0872] LCMS (ESI) m/z: [M+H].sup.+=294.0.

    [0873] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.89-7.84 (m, 1H), 4.66-4.60 (m, 2H), 3.79-3.72 (m, 2H), 3.32-3.21 (m, 2H), 1.44-1.42 (m, 9H).

    Step 5: tert-Butyl 3-(hydroxymethyl)-7,8-dihydropyrido[4,3-c]pyridazine-6(5H)-carboxylate

    [0874] To a mixture of 6-(tert-butyl) 3-methyl 7,8-dihydropyrido[4,3-c]pyridazine-3,6(5H)-dicarboxylate (2.8 g, 9.55 mmol) and CaCl.sub.2 (4.24 g, 38.18 mmol) in MeOH (28 mL)/THF (14 mL) was added NaBH.sub.4 (722.29 mg, 19.09 mmol) in one portion at 0° C. under N.sub.2. The mixture was stirred at 25° C. for 1 hour. The mixture was poured into sat. NH.sub.4Cl (100 mL) and extracted with ethyl acetate (100 mL*2). The combined organic phase was washed with brine (100 mL*1), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by reverse phase column (FA). The eluent was concentrated to remove MeCN and the aqueous phase was extracted with ethyl acetate (50 mL*2). The combined organic phase was washed with brine (50 mL*1), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (1.3 g, 4.90 mmol, 51.33% yield) as a light yellow oil.

    [0875] LCMS (ESI) m/z: [M+H].sup.+=266.0.

    [0876] .sup.1H NMR (400 MHz, MeOD) δ=7.68-7.60 (m, 1H), 4.85-4.84 (m, 2H), 4.75-4.66 (m, 2H), 3.85-3.77 (m, 2H), 3.21-3.08 (m, 2H), 2.03-1.99 (m, 2H), 1.51-1.49 (m, 9H).

    Step 6: tert-butyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-7,8-dihydropyrido[4,3-c]pyridazine-6(5H)-carboxylate

    [0877] To a mixture of tert-butyl 3-(hydroxymethyl)-7,8-dihydropyrido[4,3-c]pyridazine-6(5H)-carboxylate (1.15 g, 4.33 mmol), PPh.sub.3 (1.71 g, 6.50 mmol) and isoindoline-1,3-dione (701.53 mg, 4.77 mmol) in THE (12 mL) was added DEAD (1.13 g, 6.50 mmol, 1.18 mL) dropwise at 0° C. under N.sub.2. The mixture was stirred at 25° C. for 2 hours. The combined mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL*2). The combined organic phase was washed with brine (30 mL*1), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=1/1) to give the title compound (1.2 g, 3.04 mmol, 70.19% yield) as a yellow oil.

    [0878] LCMS (ESI) m/z: [M+H].sup.+=395.0.

    [0879] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.85-7.75 (m, 2H), 7.71-7.65 (m, 2H), 7.13-7.08 (m, 1H), 5.14-5.08 (m, 2H), 4.56-4.48 (m, 2H), 3.75-3.64 (m, 2H), 3.17-3.07 (m, 2H), 1.43-1.39 (m, 9H).

    Step 7: 2-((5,6,7,8-Tetrahydropyrido[4,3-c]pyridazin-3-yl)methyl)isoindoline-1,3-dione hydrochloride

    [0880] To a mixture of tert-butyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-7,8-dihydropyrido[4,3-c]pyridazine-6(5H)-carboxylate (950 mg, 2.41 mmol) in dioxane (5 mL) was added HCl/dioxane (4 M, 5 mL) in one portion at 25° C. under N.sub.2. The mixture was stirred at 25° C. for 30 min. The mixture was filtered and the solid was washed with MTBE (5 mL) to give the title compound (360 mg, 1.09 mmol, 45.19% yield) as a yellow solid.

    [0881] LCMS (ESI) m/z: [M+H].sup.+=294.9.

    [0882] .sup.1H NMR (400 MHz, MeOD) δ=8.11-8.04 (m, 1H), 7.96-7.81 (m, 4H), 5.25 (s, 2H), 4.62 (s, 2H), 3.77-3.68 (m, 2H), 3.57-3.49 (m, 2H).

    Intermediate 72: 2-Bromo-6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine

    [0883] ##STR00625##

    Step 1: 2-Bromo-6-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine

    [0884] To a solution of 1-(6-bromo-2-pyridyl)ethanone (5 g, 25.00 mmol), TBSCI (15.07 g, 99.98 mmol, 12.25 mL) and NaI (14.99 g, 99.98 mmol) in MeCN (100 mL) was added TEA (11.38 g, 112.48 mmol, 15.66 mL). The mixture was stirred at 80° C. for 16 hrs. The reaction mixture was poured into water (500 mL) and extracted with EA (500 mL*3). The combined organic layer was washed with brine (800 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate/Petroleum ether gradient) to give the title compound (7.5 g, 23.79 mmol, 95.16% yield) as a yellow oil.

    [0885] LCMS (ESI) m/z: [81 BrM+H]+=316.1.

    [0886] 1H NMR (400 MHz, CDCl.sub.3) δ=7.53 (s, 2H), 7.37-7.35 (m, 1H), 5.69 (d, J=1.2 Hz, 1H), 4.60 (d, J=1.2 Hz, 1H), 1.01 (s, 9H), 0.25 (s, 6H) ppm.

    Step 2: 2-Bromo-6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine

    [0887] To a solution of diethylzinc (1 M, 38.18 mL) in DCM (180 mL) at 0° C. was added a solution of chloro(iodo)methane (13.47 g, 76.36 mmol, 5.54 mL) in DCM (60 mL) dropwise. The reaction mixture was stirred at 0° C. for 30 minutes. Then to the mixture was added a solution of 2-bromo-6-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine (4 g, 12.73 mmol) in DCM (180 mL). The reaction mixture was stirred at 0° C. for 2 hrs. The reaction mixture was poured into aq. NH.sub.4Cl (200 mL) and extracted with DCM (100 mL*3). The combined organic layer was washed with brine (400 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate/Petroleum ether gradient) to give the title compound (700 mg, 2.13 mmol, 16.75% yield) as a colorless solid.

    [0888] LCMS (ESI) m/z: [79BrM+H]+=328.1.

    [0889] 1H NMR (400 MHz, CDCl.sub.3) δ=7.60-7.58 (m, 1H), 7.49-7.45 (m, 1H), 7.23-7.21 (m, 1H), 1.45-1.39 (m, 2H), 1.27-1.23 (m, 2H), 0.95 (s, 9H), 0.10 (s, 6H) ppm.

    Intermediate 73: 6-Phenyl-2,7-naphthyridine-3-carbonitrile

    [0890] ##STR00626##

    Step 1: 2,7-Naphthyridine-1,3,6,8-tetraol

    [0891] To a solution of propanedinitrile (5.39 g, 81.60 mmol, 5.13 mL) in EtOH (70 mL) was added diethyl 3-oxopentanedioate (15 g, 74.18 mmol, 13.51 mL) and ethylamine (167.21 mg, 3.71 mmol, 242.68 uL). The mixture was stirred at 30° C. for 48 hrs. The reaction mixture was concentrated under reduced pressure. The residue was added to H.sub.2SO.sub.4 (70%, 20 mL) and stirred at 100° C. for 10 mins. The mixture was cooled to 20° C. and quenched by pouring slowly into ice water (180 mL), generating a yellow solid. The solid was collected and dried to give the title compound (14 g, 72.11 mmol, 97.21% yield).

    [0892] LCMS (ESI) m/z: [M+H]+=195.0.

    [0893] 1 HNMR (400 MHz, DMSO-d6) δ=11.38 (s, 2H), 5.79 (s, 2H) ppm.

    Step 2: 1,3,6,8-Tetrachloro-2,7-naphthyridine

    [0894] A mixture of 2,7-naphthyridine-1,3,6,8-tetraol (5 g, 25.75 mmol) and POCl.sub.3 (49.50 g, 322.83 mmol, 30.00 mL) was stirred at 160° C. for 48 hrs. The reaction mixture was quenched by addition of sat. NaHCO.sub.3 (1000 mL) and extracted with ethyl acetate (300 mL*3). The combined organic phase was washed with brine (100 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1) to give the title compound (1.6 g, 5.97 mmol, 23.19% yield) as a yellow solid.

    [0895] LCMS (ESI) m/z: [M+H]+=268.9.

    [0896] 1HNMR (400 MHz, CDCl.sub.3) δ=7.58 (s, 2H) ppm.

    Step 3: 3,6-Dichloro-2,7-naphthyridine

    [0897] A mixture of 1,3,6,8-tetrachloro-2,7-naphthyridine (1 g, 3.73 mmol), NaBH.sub.3CN (1.17 g, 18.66 mmol), Pd(dppf)Cl.sub.2 (273.10 mg, 373.24 umol) and TMEDA (1.08 g, 9.33 mmol, 1.41 mL) in THE (10 mL) was degassed and purged with N.sub.2 3 times. The mixture was stirred at 30° C. for 4 hrs under N.sub.2 atmosphere. The reaction mixture was quenched by addition of water (30 mL), and extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (10 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=5/1) to give the title compound (0.6 g, 2.83 mmol, 75.92% yield) as a yellow solid.

    [0898] LCMS (ESI) m/z: [M+H]+=199.0.

    [0899] 1HNMR (400 MHz, CDCl.sub.3) δ=9.30-9.20 (m, 2H), 7.68 (m, 2H) ppm.

    Step 4: 3-Chloro-6-phenyl-2,7-naphthyridine

    [0900] A mixture of 3,6-dichloro-2,7-naphthyridine (150 mg, 753.63 umol), triphenylbismuth (109.50 mg, 248.70 umol), Cs.sub.2CO.sub.3 (982.19 mg, 3.01 mmol) and Pd(PPh.sub.3).sub.4 (87.09 mg, 75.36 umol) in DMA (5 mL) was degassed and purged with N.sub.2 3 times. The mixture was stirred at 90° C. for 4 hrs under N.sub.2 atmosphere. The reaction was quenched by adding water (15 mL) and the mixture was extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine (10 mL*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/1) to give the title compound (160 mg, 664.76 umol, 88.21% yield) as a yellow solid.

    [0901] LCMS (ESI) m/z: [M+H]+=241.1.

    Step 5: 6-Phenyl-2,7-naphthyridine-3-carbonitrile

    [0902] A mixture of 3-chloro-6-phenyl-2,7-naphthyridine (50 mg, 207.74 umol), Pd(dppf)Cl.sub.2 (15.20 mg, 20.77 umol), Zn (2.72 mg, 41.55 umol) and Zn(CN).sub.2 (48.79 mg, 415.48 umol, 26.37 uL) in DMA (3 mL) was degassed and purged with N.sub.2 for 3 times. The mixture was stirred at 100° C. for 2 hrs under N.sub.2 atmosphere. The reaction mixture was quenched by addition of water (10 mL), and extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO.sub.2, Petroleum ether/Ethyl acetate=1/1) to give the title compound (35 mg, 148.32 umol, 71.40% yield) as a yellow oil.

    [0903] LCMS (ESI) m/z: [M+H]+=232.1.

    [0904] 1HNMR (400 MHz, CDCl.sub.3) δ=9.61 (s, 1H), 9.46 (s, 1H), 8.22-8.17 (m, 3H), 8.12 (s, 1H), 7.60-7.49 (m, 3H) ppm.

    Example 2. Methyl (R)-3-((2-((4-cyano-4-methylchromane-6-carboxamido)methyl)pyridin-4-yl)ethynyl)benzoate

    [0905] ##STR00627##

    Step 1. Methyl 3-[2-[2-[(tert-butoxycarbonylamino)methyl]-4-pyridyl]ethynyl]benzoate

    [0906] Pd(PPh.sub.3).sub.2Cl.sub.2 (73.3 mg, 0.10 mmol) and methyl 3-ethynylbenzoate (669 mg, 4.18 mmol) were added to a solution of tert-butyl N-[(4-bromo-2-pyridyl)methyl]carbamate (300 mg, 1.04 mmol), CuI (19.9 mg, 0.10 mmol), and Et.sub.3N (0.44 mL, 3.13 mmol) in DMF (3 mL). The mixture was stirred at 100° C. for 1 hr. The mixture was filtered. The filtered liquid was diluted with water (20 mL) and extracted with EA (20 mL×2). The combined organic layer was dried with anhydrous Na.sub.2SO.sub.4 and concentrated to afford a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 0/1). The eluent was concentrated to give the title compound (300 mg, 0.54 mmol) as colorless oil.

    [0907] LCMS (ESI) m/z: [M+H]+=367.1.

    Step 2. Methyl 3-[2-[2-(aminomethyl)-4-pyridyl]ethynyl]benzoate

    [0908] TFA (0.24 mL, 3.28 mmol) was added to a solution of methyl 3-[2-[2-[(tert-butoxycarbonylamino)methyl]-4-pyridyl]ethynyl]benzoate (120 mg, 0.33 mmol) in DCM (1 mL). The mixture was stirred at 25° C. for 1 hr. The mixture was diluted with water (3 mL) and extracted with DCM (3 mL×2). The combined organic layer was discarded. The aqueous layer was adjusted to pH=10 with saturated NaHCO.sub.3 solution and extracted with DCM (3 mL×2). The combined organic layer was dried with anhydrous Na.sub.2SO.sub.4 and concentrated affording the title compound (40 mg, 0.14 mmol) as a white solid which was used into the next step without further purification.

    [0909] LCMS (ESI) m/z: [M+H]+=267.1.

    Step 3. Methyl 3-[2-[2-[[[(4R)-4-cyano-4-methyl-chromane-6-carbonyl]amino]methyl]-4-pyridyl]ethynyl]benzoate

    [0910] HOBt (30.4 mg, 0.23 mmol), EDCI (43.2 mg, 0.23 mmol), and DIPEA (0.078 mL, 0.45 mmol) were added to a solution of methyl 3-[2-[2-(aminomethyl)-4-pyridyl]ethynyl]benzoate (40 mg, 0.15 mmol) and (4R)-4-cyano-4-methyl-chromane-6-carboxylic acid (35.9 mg, 0.17 mmol) in DCM (0.5 mL). The mixture was stirred at 25° C. for 1 hr. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL×2). The combined organic layers were dried with anhydrous Na.sub.2SO.sub.4 and concentrated to afford a residue. The residue was purified by prep-HPLC (FA condition) (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [water (0.225% FA)-ACN]; B %: 45%-75%, 7 min). The eluent was lyophilized to afford the title compound (23.5 mg, 0.051 mmol) as a white solid.

    [0911] LCMS (ESI) m/z: [M+H]+=466.2.

    [0912] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.15-9.12 (m, 1H), 8.60-8.58 (m, 1H), 8.12 (d, J=2.0 Hz, 2H), 8.03-8.01 (m, 1H), 7.89-7.86 (m, 2H), 7.63-7.59 (m, 1H), 7.47-7.44 (m, 2H), 6.95 (d, J=8.4 Hz, 1H), 4.60 (d, J=4.4 Hz, 2H), 4.35-4.33 (m, 2H), 3.87 (s, 3H), 2.47-2.41 (m, 1H), 2.23-2.21 (m, 1H), 1.79 (s, 3H) ppm.

    [0913] The following examples in Table 4 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 2.

    TABLE-US-00005 TABLE 4 Compounds of the Invention LCMS # (m/z) 1H NMR 1 408.1 1H NMR (400 MHz, DMSO-d6) δ = 9.28-9.24 (m, 1H), 8.59-8.57 (m, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.91-7.88 (m, 1H), 7.65-7.56 (m, 2H), 7.52-7.40 (m, 5H), 7.28 (d, J = 8.0 Hz, 1H), 4.95-4.77 (m, 2H), 4.61 (d, J = 4.4 Hz, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 1.69 (s, 3H) ppm. 2 438.0 1H NMR (400 MHz, DMSO-d6) δ = 9.33-9.21 (m, 1H), 8.58 (d, J = 4.8 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.95-7.85 (m, 1H), 7.47-7.40 (m, 2H), 7.38-7.32 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.20-7.13 (m, 2H), 7.07-7.01 (m, 1H), 4.93-4.79 (m, 2H), 4.66- 4.57 (m, 2H), 4.21 (d, J = 11.2 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.78 (s, 3H), 1.69 (s, 3H) ppm. 3 466.1 1H NMR (400 MHz, DMSO-d6) δ = 9.35-9.21 (m, 1H), 8.60 (d, J = 4.4 Hz, 1H), 8.21- 8.10 (m, 2H), 8.06-7.98 (m, 1H), 7.95-7.81 (m, 2H), 7.66-7.58 (m, 1H), 7.52- 7.45 (m, 2H), 7.29 (d, J = 8.0 Hz, 1H), 4.95-4.78 (m, 2H), 4.62 (d, J = 5.6 Hz, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.90-3.82 (m, 4H), 1.69 (s, 3H). ppm. 5 473.2 1H NMR (400 MHz, DMSO-d6) δ = 9.25-9.23 (m, 1H), 8.51-8.49 (m, 1H), 8.14- 8.13 (m, 1H), 7.90-7.88 (m, 1H), 7.32-7.20 (m, 3H), 4.94-4.77 (m, 2H), 4.58-4.56 (m, 2H), 4.22-4.20 (m, 1H), 3.88-3.84 (m, 1H), 3.75-3.62 (m, 1H), 3.54 (s, 3H), 3.48-3.41 (m, 1H), 3.29 (s, 2H), 2.84-2.74 (m, 1H), 1.98-1.85 (m, 1H), 1.68 (s, 3H), 1.67-1.56 (m, 2H), 1.48-1.34 (m, 1H) ppm 13 412.9 1H NMR (400 MHz, DMSO-d6) δ = 9.22-9.19 (m, 1H), 8.58 (d, J = 4.8 Hz, 1H), 7.93 (m, 1H), 7.77 (s, 1H), 7.61-7.59 (m, 2H), 7.55-7.54 (m, 1H), 7.48-7.42 (m, 6H), 6.67-6.39 (m, 1H), 4.95-4.90 (m, 4H), 4.61 (m, 2H) ppm. 14 401.2 1H NMR (400 MHz, DMSO-d6) δ = 9.26-9.24 (m, 1H), 8.58 (d, J = 4.8 Hz, 1H), 8.22 (s, 1H), 7.93 (m, 1H), 7.60-7.59 (m, 2H), 7.45-7.42 (m, 5H), 7.29 (m, 1H), 4.86- 4.82 (m, 1H), 4.74-4.73 (m, 1H), 4.62-4.59 (m, 2H), 4.06-4.03 (m, 1H), 3.87-3.76 (m, 1H), 1.70-1.65 (m, 3H) ppm. 15 422.3 1H NMR (400 MHz, MeOD-d4) δ = 9.24 (m, 1H), 8.50 (s, 1H), 8.14 (d, J = 1.2 Hz, 1H), 7.89 (m, 1H), 7.64-7.57 (m, 2H), 7.53-7.43 (m, 3H), 7.39 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 4.92-4.79 (m, 2H), 4.57 (m, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.85 (d, J = 11.6 Hz, 1H), 2.43 (s, 3H), 1.77-1.61 (m, 3H) ppm. 16 426.3 1H NMR (400 MHz, MeOD-d4) δ = 8.41-8.25 (m, 1H), 8.16-8.03 (m, 1H), 7.92- 7.79 (m, 1H), 7.65-7.55 (m, 2H), 7.54-7.37 (m, 4H), 7.31-7.18 (m, 1H), 4.96-4.89 (m, 2H), 4.84-4.77 (m, 2H), 4.29-4.12 (m, 1H), 4.03-3.83 (m, 1H), 1.75 (s, 3H) ppm. 17 458.1 1H NMR (400 MHz, DMSO-d6) δ = 9.29-9.27 (m, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.91-7.89 (m, 1H), 7.80-7.78 (m, 2H), 7.65-7.64 (m, 1H), 7.63- 7.56 (m, 1H), 7.47-7.45 (m, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.27-6.91 (m, 1H), 4.91- 4.84 (m, 2H), 4.62 (m, 2H), 4.22 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 1.68 (s, 3H) ppm. 20 426.3 1H NMR (400 MHz, MeOD-d4) δ = 8.48 (d, J = 1.2 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.87 (m, 1H), 7.61-7.53 (m, 3H), 7.49-7.38 (m, 3H), 7.26 (d, J = 8.0 Hz, 1H), 4.90 (d, J = 3.6 Hz, 2H), 4.69 (s, 2H), 4.19 (d, J = 11.6 Hz, 1H), 3.92 (d, J = 11.6 Hz, 1H), 1.75 (s, 3H) ppm. 21 473.3 1H NMR (400 MHz, MeOD-d4) δ = 8.45 (d, J = 5.6 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.90-7.83 (m, 1H), 7.37 (s, 1H), 7.30-7.23 (m, 2H), 4.90 (d, J = 3.6 Hz, 2H), 4.67 (s, 2H), 4.20 (d, J = 11.2 Hz, 1H), 3.92 (d, J = 11.6 Hz, 1H), 3.83-3.76 (m, 2H), 3.68 (s, 3H), 3.30-3.19 (m, 2H), 2.96-2.84 (m, 1H), 1.96-1.83 (m, 2H), 1.75 (s, 3H), 1.69- 1.58 (m, 2H) ppm. 22 459.2 1H NMR (400 MHz, DMSO-d6) δ = 9.23-9.20 (m, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.89-7.87 (m, 1H), .32-7.24 (m, 3H), 4.95-4.78 (m, 2H), 4.57 (d, J = 4.8 Hz, 2H), 4.21 (d, J = 11.2 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.66-3.60 (m, 1H), 3.58 (s, 3H), 3.45-3.40 (m, 1H), 3.35 (s, 1H), 3.30-3.25 (m, 2H), 2.22- 2.17 (m, 1H), 2.06-1.86 (m, 1H), 1.68 s, 3H) ppm. 23 457.2 1H NMR (400 MHz, MeOD-d4) δ = 8.57 (d, J = 5.2 Hz, 1H), 8.19 (d, J = 1.6 Hz, 2H), 8.08-8.05 (m, 1H), 7.83-7.74 (m, 2H), 7.62-7.59 (m, 1H), 7.57-7.50 (m, 2H), 7.17 (d, J = 8.0 Hz, 1H), 4.82 (d, J = 3.2 Hz, 2H), 4.74 (s, 2H), 3.93 (s, 3H), 3.81-3.72 (m, 2H), 1.55 (s, 3H) ppm. 37 452.2 1H NMR (400 MHz, DMSO-d6) δ = 9.11-9.08 (m, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.12 (d, J = 2.0 Hz, 2H), 8.03-8.01 (m, 1H), 7.95-9.92 (m, 1H), 7.89-7.87 (m, 1H), 7.63- 7.59 (m, 1H), 7.48-7.46 (m, 2H), 7.05 (d, J = 8.8 Hz, 1H), 5.01 (d, J = 9.6 Hz, 1H), 4.60 (d, J = 6.0 Hz, 2H), 4.55 (d, J = 9.6 Hz, 1H), 3.87 (s, 3H), 1.76 (s, 3H) ppm 39 465.3 1H NMR (400 MHz, DMSO + D2O) δ = 8.89-8.88 (m, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.06 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.82-7.80 (m, 2H), 7.58-7.55 (m, 2H), 7.423(d, J = 5.2 Hz, 1H), 7.36 (s, 1H), 6.57 (d, J = 8.8 Hz, 1H), 4.51 (brs, 2H), 3.82 (s, 3H), 3.31-3.28 (m, 2H), 2.18-2.12 (m, 1H), 1.95-1.90 (m, 1H), 1.66 (s, 3H) ppm 43 452.2 1H NMR (400 MHz, DMSO-d6) δ = 9.00 (d, J = 8.0 Hz, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.93-7.91 (m, 1H), 7.63-7.60 (m, 3H), 7.49-7.44 (m, 4H), 7.28 (d, J = 8.0 Hz, 1H), 5.44-5.38 (m, 1H), 4.92-4.81 (m, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.88-3.81 (m, 3H), 3.31 (s, 3H), 1.70 (s, 3H) ppm 47 437.2 1H NMR (400 MHz, MeOD-d4) δ = 8.52 (d, J = 5.2 Hz, 1H), 8.21 (s, 1H), 8.02-7.94 (m, 1H), 7.60-7.48 (m, 3H), 7.45-7.33 (m, 5H), 6.54-6.21 (m, 1H), 4.84-4.78 (m, 2H), 4.71 (s, 2H), 4.34-4.26 (m, 1H), 4.15-4.04 (m, 1H) ppm 48 437.2 1H NMR (400 MHz, MeOD-d4) δ = 8.52 (d, J = 5.2 Hz, 1H), 8.21 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.59-7.47 (m, 3H), 7.45-7.33 (m, 5H), 6.54-6.21 (m, 1H), 4.80 (s, 2H), 4.71 (s, 2H), 4.34-4.27 (m, 1H), 4.14-4.04 (m, 1H) ppm

    Example 3. (4R)-4-Cyano-4-methyl-N-[[4-(2-phenyl-2,7-diazaspiro[3.4]octan-7-yl)-2-pyridyl]methyl]isochromane-6-carboxamide

    [0914] ##STR00628##

    Step 1. (4R)—N-[(4-Bromo-2-pyridyl)methyl]-4-cyano-4-methyl-isochromane-6-carboxamide

    [0915] EDCI (1.54 g, 8.02 mmol), HOBt (1.08 g, 8.02 mmol), DIEA (4.66 mL, 26.7 mmol), and (4-bromo-2-pyridyl)methanamine (1 g, 5.35 mmol, HCl) were added to a solution of (4R)-4-cyano-4-methyl-isochromane-6-carboxylic acid (1.28 g, 5.88 mmol) in DCM (10 mL). The reaction mixture was stirred at 25° C. for 2 hrs. The mixture was diluted with H.sub.2O (40 mL), and then extracted with DCM (40 mL×2). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by flash silica gel chromatography SiO.sub.2, Petroleum ether/Ethyl Acetate=1/0 to 1/10) affording the title compound (1.2 g, 3.10 mmol) as white a solid.

    [0916] LCMS (ESI) m/z: [81 BrM+H]+=388.0.

    [0917] .sup.1HNMR (400 MHz, CDCl.sub.3) δ=8.39 (d, J=5.6 Hz, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.78-7.76 (m, 1H), 7.56-7.49 (m, 2H), 7.42-7.40 (m, 1H), 7.13 (d, J=8.0 Hz, 1H), 4.87 (s, 2H), 4.74 (d, J=5.2 Hz, 2H), 4.14-4.11 (m, 1H), 3.94 (d, J=11.2 Hz, 1H), 1.76 (s, 3H) ppm.

    Step 2. tert-Butyl 7-[2-[[[(4R)-4-cyano-4-methyl-isochromane-6-carbonyl]amino]methyl]-4-pyridyl]-2,7-diazaspiro[3.4]octane-2-carboxylate

    [0918] [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (41.1 mg, 51.8 μmol) and tBuONa (149.3 mg, 1.55 mmol) were added to a solution of (4R)—N-[(4-bromo-2-pyridyl)methyl]-4-cyano-4-methyl-isochromane-6-carboxamide (200 mg, 0.52 mmol) and tert-butyl 2,7-diazaspiro[3.4]octane-2-carboxylate (220 mg, 1.04 mmol) in dioxane (4 mL). The mixture was stirred at 70° C. for 2 hrs. The reaction mixture was poured into water (80 mL) and extracted with EA (30 mL×3). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA condition). The fractions containing product were combined and extracted with EA (20 mL×3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated affording the title compound (80 mg, 0.11 mmol) as yellow oil.

    [0919] LCMS (ESI) m/z: [M+H]+=518.2.

    Step 3. (4R)-4-Cyano-N-[[4-(2,6-diazaspiro[3.4]octan-6-yl)-2-pyridyl]methyl]-4-methyl-isochromane-6-carboxamide

    [0920] TFA (0.5 mL) was added to a solution of tert-Butyl 7-[2-[[[(4R)-4-cyano-4-methyl-isochromane-6-carbonyl]amino]methyl]-4-pyridyl]-2,7-diazaspiro[3.4]octane-2-carboxylate (80 mg, 0.11 mmol) in DCM (1 mL). The mixture was stirred at 25° C. for 1 hr. The reaction mixture was concentrated in vacuo. The crude residue was triturated with a mixture of PE (2 mL) and MTBE (1 mL). The residue was filtered and dried in vacuo affording the title compound (70 mg, TFA) as a yellow oil which was used directly for next step.

    [0921] LCMS (ESI) m/z: [M+H]+=418.2.

    Step 4. (4R)-4-Cyano-4-methyl-N-[[4-(2-phenyl-2,7-diazaspiro[3.4]octan-7-yl)-2-pyridyl]methyl]isochromane-6-carboxamide

    [0922] A mixture of (4R)-4-cyano-N-[[4-(2,6-diazaspiro[3.4]octan-6-yl)-2-pyridyl]methyl]-4-methyl-isochromane-6-carboxamide (65 mg, 0.12 mmol, TFA), bromobenzene (57.6 mg, 0.37 mmol, 39 μL), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (9.7 mg, 12 μmol), and t-BuONa (58.8 mg, 0.61 mmol) in dioxane (1.5 mL) was degassed and purged with N.sub.2 three times. The reaction mixture was then stirred at 70° C. for 3 hrs. The reaction mixture was then poured into water (80 mL) and extracted with EA (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50 mm*10 um; mobile phase: [water (10 mM NH.sub.4HCO3)-ACN]; B %: 46%-66%, 10 min) and the fraction was lyophilized to give the title compound (3.62 mg, 7.13 μmol, 5.83% yield) as a white solid.

    [0923] LCMS (ESI) m/z: [M+H]+=494.2.

    [0924] .sup.1HNMR (400 MHz, DMSO-d6) δ=9.17-9.07 (m, 1H), 8.12 (d, J=1.6 Hz, 1H), 8.07 (d, J=6.0 Hz, 1H), 7.91-7.83 (m, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.20-7.12 (m, 2H), 6.72-6.64 (m, 1H), 6.52-6.39 (m, 4H), 4.92-4.78 (m, 2H), 4.52-4.42 (m, 2H), 4.20 (d, J=11.6 Hz, 1H), 3.85 (d, J=11.6 Hz, 1H), 3.77 (s, 4H), 3.54 (s, 2H), 3.40-3.35 (m, 2H), 2.27-2.18 (m, 2H), 1.67 (s, 3H) ppm.

    [0925] The following examples in Table 5 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 3.

    TABLE-US-00006 TABLE 5 Compounds of the Invention LCMS # (m/z) 1H NMR 10 480.2 1H NMR (400 MHz, DMSO-d6) δ = 9.16-9.06 (m, 1H), 8.13-8.05 (m, 2H), 7.89- 7.83 (m, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.20-7.12 (m, 2H), 6.71-6.64 (m, 1H), 6.42 (d, J = 7.8 Hz, 2H), 6.36-6.27 (m, 2H), 4.92-4.77 (m, 2H), 4.51-4.37 (m, 2H), 4.20 (d, J = 11.6 Hz, 1H), 4.09 (s, 4H), 3.96 (s, 4H), 3.84 (d, J = 11.6 Hz, 1H), 1.67 (s, 3H) ppm. 12 494.3 1H NMR (400 MHz, MeOD-d4) δ = 9.11-9.08 (m, 1H), 8.12 (d, J = 1.6 Hz, 1H), 8.08 (d, J = 5.6 Hz, 1H), 7.87-7.85 (m, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.16-7.12 (m, 2H), 6.60-6.57 (m, 1H), 6.51 (d, J = 8.0 Hz, 2H), 6.32 (d, J = 2.0 Hz, 1H), 6.29-6.27 (m, 1H), 4.93-4.77 (m, 2H), 4.52-4.35 (m, 2H), 4.20 (d, J = 11.2 Hz, 1H), 3.94-3.81 (m, 4H), 3.45 (s, 2H), 3.30-3.27 (m, 2H), 2.23-2.20 (m, 2H), 1.67 (s, 3H) ppm. 28 439.3 1H NMR (400 MHz, MeOD-d4) δ = 8.14-8.09 (m, 2H), 7.86-7.84 (m, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.23-7.16 (m, 4H), 6.88 (d, J = 2.4 Hz, 1H), 6.80-6.77 (m, 1H), 4.89 (d, J = 3.2 Hz, 2H), 4.60 (d, J = 2.4 Hz, 2H), 4.53 (s, 2H), 4.19 (d, J = 11.2 Hz, 1H), 3.92 (d, J = 11.2 Hz, 1H), 3.65-3.62 (m, 2H), 2.97-2.94 (m, 2H), 1.75 (s, 3H) ppm. 31 425.2 1H NMR (400 MHz, DMSO-d6) δ = 9.16 (t, J = 5.6 Hz, 1H), 8.18-8.14 (m, 3H), 7.89- 7.88 (m, 1H), 7.40-7.38 (m, 2H), 7.32-7.30 (m, 3H), 6.60 (d, J = 2.4 Hz, 1H), 6.54- 6.53 (m, 1H), 4.91-4.84 (m, 2H), 4.67-4.64 (m, 4H), 4.53-4.48 (m, 2H), 4.22 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 1.69 (s, 3H) ppm 33 439.4 1H NMR (400 MHz, MeOD) δ = 8.11 (d, J = 1.6 Hz, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.87-7.84 (m, 1H), 7.42-7.32 (m, 4H), 7.30-7.22 (m, 2H), 6.59-6.43 (m, 2H), 4.67- 4.55 (m, 4H), 4.54-4.49 (m, 2H), 4.18 (d, J = 11.6 Hz, 1H), 4.15-4.04 (m, 3H), 3.92 (d, J = 11.2 Hz, 1H), 1.74 (s, 3H) ppm 42 468.4 1H NMR (400 MHz, DMSO-d6) δ = 9.12-9.08 (m, 1H), 8.18-8.12 (m, 2H), 7.89-7.86 (m, 1H), 7.30-7.19 (m, 3H), 6.97 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 2.4 Hz, 1H), 6.83- 6.77 (m, 2H), 4.95-4.79 (m, 2H), 4.57-4.40 (m, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.47-3.43 (m, 4H), 3.26-3.23 (m, 4H), 1.69 (s, 3H) ppm 44 453.3 1H NMR (400 MHz, DMSO-d6) δ = 9.10-9.07 (m, 1H), 8.12 (d, J = 1.2 Hz, 1H), 8.06 (d, J = 6.0 Hz, 1H), 7.87-7.84 (m, 1H), 7.33-7.31 (m, 4H), 7.26-7.22 (m, 2H), 6.50 (s, 1H), 6.46-6.44 (m, 1H), 4.90-4.83 (m, 2H), 4.46-4.44 (m, 2H), 4.20 (d, J = 11.6 Hz, 1H), 3.85 (d, J = 11.6 Hz, 1H), 3.74-3.72 (m, 1H), 3.53-3.46 (m, 4H), 2.38- 2.34 (m, 1H), 2.10-2.08 (m, 1H), 1.66 (s, 3H) ppm 46 440.2 1H NMR (400 MHz, MeOD) δ = 8.37 (d, J = 2.8 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.85-7.83 (m, 1H), 7.38-7.32 (m, 4H), 7.25-7.23 (m, 2H), 6.59 (d, J = 2.8 Hz, 1H), 4.87 (br s, 2H), 4.70 (s, 2H), 4.50-7.49 (m, 2H), 4.18 (d, J = 11.6 Hz, 1H), 4.15- 4.06(m, 3H), 3.91 (d, J = 11.2 Hz, 1H), 1.72 (s, 3H) ppm

    Example 4. (4R)-4-Cyano-4-methyl-N-[[4-(1-phenylazetidin-3-yl)-2-pyridyl]methyl]isochromane-6-carboxamide

    [0926] ##STR00629##

    Step 1. tert-Butyl 3-(2-cyano-4-pyridyl)azetidine-1-carboxylate

    [0927] A mixture of 4-bromopyridine-2-carbonitrile (4 g, 21.9 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (7.43 g, 26.2 mmol), dichloronickel;1,2-dimethoxyethane (480 mg, 2.19 mmol), pyridine-2-carboxamidine hydrochloride (344 mg, 2.19 mmol), NaI (1.64 g, 10.9 mmol), Zn (2.86 g, 43.7 mmol), and TFA (249 mg, 2.19 mmol, 162 μL) in DMA (80 mL) was degassed and purged with N.sub.2 three times. The reaction mixture was stirred at 60° C. for 4 hrs. The mixture was filtered. The filtrate was diluted with water (500 mL) and extracted with EA (500 mL×2). The combined organic layers were dried with anhydrous Na.sub.2SO.sub.4 and concentrated to afford a crude residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EA=1/0 to 0/1). The eluent was concentrated affording the title compound (3.8 g, 14.6 mmol) as yellow oil.

    [0928] LCMS (ESI) m/z: [M+H]+=260.0.

    [0929] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.70-7.68 (m, 1H), 8.08-8.07 (m, 1H), 7.72-7.70 (m, 1H), 4.24-4.23 (m, 2H), 3.93-3.90 (m, 3H), 1.40 (s, 9H) ppm.

    Step 2. 4-(Azetidin-3-yl)pyridine-2-carbonitrile

    [0930] A mixture of tert-butyl 3-(2-cyano-4-pyridyl)azetidine-1-carboxylate (2.0 g, 7.71 mmol) in HCl/dioxane (4N, 20 mL) was stirred at 25° C. for 0.5 hrs. The mixture was concentrated affording the title compound (1.6 g, crude, HCl) as a white solid which was used into the next step without further purification.

    [0931] LCMS (ESI) m/z: [M+H]+=160.0.

    Step 3. 4-(1-Phenylazetidin-3-yl)pyridine-2-carbonitrile

    [0932] To a solution of phenylboronic acid (3.0 g, 24.5 mmol) and 4-(azetidin-3-yl)pyridine-2-carbonitrile (1.6 g, 8.18 mmol, HCl) in pyridine (16 mL) was added copper (II) acetate (1.71 g, 9.40 mmol) and 4 A molecular sieves (1.6 g). The mixture was stirred at 80° C. for 12 hrs under oxygen atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL×2), the combined organic layer was dried with anhydrous Na.sub.2SO.sub.4 and concentrated to afford a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/0 to 0/1). The eluent was concentrated affording the title compound (120 mg, 0.45 mmol) as a white solid.

    [0933] LCMS (ESI) m/z: [M+H]+=236.0.

    [0934] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.71 (d, J=4.8 Hz, 1H), 8.12-8.11 (m, 1H), 7.78-7.77 (m, 1H), 7.21-7.17 (m, 2H), 6.74-6.70 (m, 1H), 6.50 (d, J=7.6 Hz, 2H), 4.22-4.19 (m, 2H), 4.04-4.01 (m, 1H), 3.87-3.84 (m, 2H) ppm.

    Step 4. tert-Butyl N-[[4-(1-phenylazetidin-3-yl)-2-pyridyl]methyl]carbamate

    [0935] To a solution of 4-(1-phenylazetidin-3-yl)pyridine-2-carbonitrile (100 mg, 0.43 mmol) and NiCl.sub.2.6H.sub.2O (253 mg, 1.06 mmol) in MeOH (2 mL) was added NaBH.sub.4 (161 mg, 4.25 mmol) at 0° C. The mixture was stirred at 25° C. for 1 hr. Boc.sub.2O (1.39 g, 6.38 mmol) was added. Then the mixture was stirred at 25° C. for 2 hrs. THE (2 mL) and NaHCO.sub.3 (2 mL) was added to the mixture. Then the mixture was stirred at 25° C. for 12 hrs. The mixture was diluted with saturated NH.sub.4Cl solution (30 mL) and extracted with EA (30 mL×2). The combined organic layers were dried with anhydrous Na.sub.2SO.sub.4 and concentrated to afford a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethylacetate/Petroleum ether gradient @40 mL/min). The eluent was concentrated affording the title compound (50 mg, 0.12 mmol) as a white solid.

    [0936] LCMS (ESI) m/z: [M+H]+=340.3.

    Step 5. [4-(1-Phenylazetidin-3-yl)-2-pyridyl]methanamine

    [0937] TFA (168 mg, 1.47 mmol, 109 μL) was added to a solution of tert-Butyl N-[[4-(1-phenylazetidin-3-yl)-2-pyridyl]methyl]carbamate (50 mg, 0.15 mmol) in DCM (1 mL). The mixture was stirred at 25° C. for 1 hr. The reaction mixture was dried by N.sub.2 airflow. The crude product was triturated with PE/MTBE=1:1 (3 mL) affording the title compound (30 mg, 0.085 mmol, TFA) as a yellow solid which was used into the next step without further purification.

    [0938] LCMS (ESI) m/z: [M+H]+=240.0.

    Step 6. (4R)-4-Cyano-4-methyl-N-[[4-(1-phenylazetidin-3-yl)-2-pyridyl]methyl]isochromane-6-carboxamide

    [0939] HOBt (17.2 mg, 0.13 mmol), EDCI (24.4 mg, 0.13 mmol), and DIPEA (32.9 mg, 0.25 mmol, 44 L) were added to a solution of [4-(1-phenylazetidin-3-yl)-2-pyridyl]methanamine (30 mg, 0.085 mmol, TFA salt) and (4R)-4-cyano-4-methylisochromane-6-carboxylic acid (20.3 mg, 0.093 mmol) in DCM (0.5 mL). The mixture was stirred at 25° C. for 1 hr. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL×2). The combined organic layers were dried with anhydrous Na.sub.2SO.sub.4 and concentrated to afford a crude residue. The residue was purified by prep-HPLC (neutral condition) (column: Waters Xbridge C18 150*50 mm*10 m; mobile phase: [water (10 mM NH.sub.4HCO.sub.3)-ACN]; B %: 36%-66%, 10 min) affording the title compound (12.8 mg, 0.030 mmol) as a yellow gum.

    [0940] LCMS (ESI) m/z: [M+H]+=439.3.

    [0941] .sup.1HNMR (400 MHz, CD.sub.3OD) δ=8.46 (d, J=5.2 Hz, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.82-7.80 (m, 1H), 7.51 (s, 1H), 7.38-7.37 (m, 1H), 7.21-7.17 (m, 3H), 6.75-6.70 (m, 1H), 6.52-6.50 (m, 2H), 4.88 (s, 2H), 4.70 (s, 2H), 4.26-4.24 (m, 2H), 4.18 (d, J=11.2 Hz, 1H), 3.91-3.83 (m, 4H), 1.71 (s, 3H) ppm.

    [0942] The following examples in Table 6 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 4.

    TABLE-US-00007 TABLE 6 Compounds of the Invention LCMS # (m/z) 1H NMR 18 438.3 1H NMR (400 MHz, DMSO-d6) δ = 9.23 (br s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.16 (s, 1H), 7.90 (m, 1H), 7.39-7.24 (m, 7H), 7.23-7.21 (m, 1H), 4.86 (d, J = 12.0 Hz, 2H), 4.69-4.54 (m, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.63-3.61 (m, 2H), 2.59-2.53 (m, 4H), 1.68 (s, 3H) ppm. 19 438.3 1H NMR (400 MHz, DMSO-d6) δ = 9.23-9.20 (m, 1H), 8.44 (d, J = 5.2 Hz, 1H), 8.14 (d, J = 1.2 Hz, 1H), 7.91-7.89 (m, 1H), 7.31-7.24 (m, 6H), 7.23-7.17 (m, 2H), 4.93- 4.79 (m, 2H), 4.59 (br d, J = 4.4 Hz, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.57-3.45 (m, 2H), 2.77-2.67 (m, 2H), 2.20-2.08 (m, 2H), 1.67 (s, 3H) ppm.

    Example 5. (R,E)-4-Cyano-N-((4-(1,2-difluoro-2-phenylvinyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide

    [0943] ##STR00630##

    Step 1. tert-Butyl N-[[4-[(E)-1,2-difluoro-2-phenyl-vinyl]-2-pyridyl]methyl]carbamate

    [0944] Pd(PPh.sub.3).sub.4 (53 mg, 0.046 mmol) and K.sub.3PO.sub.4 (292 mg, 1.37 mmol) were added to a mixture of (Z)-(2-chloro-1,2-difluorovinyl)benzene (80 mg, 0.46 mmol) and (2-(((tert-butoxycarbonyl)amino)methyl) pyridin-4-yl)boronic acid (173 mg, 0.69 mmol) in dioxane (3 mL) at 25° C. under N.sub.2. The mixture was stirred at 100° C. for 2 hrs. The reaction mixture was poured into water (30 mL) and extracted with EA (30 mL×2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether/EA=3/1) affording the title compound (60 mg, 0.14 mmol) as a light yellow solid.

    [0945] LCMS (ESI) m/z: [M+H]+=347.2.

    Step 2. [4-[(E)-1,2-difluoro-2-phenyl-vinyl]-2-pyridyl]methanamine

    [0946] 4N HCl/dioxane (0.22 mL) was added to a mixture of tert-butyl N-[[4-[(E)-1,2-difluoro-2-phenyl-vinyl]-2-pyridyl]methyl]carbamate (60 mg, 0.17 mmol) in dioxane (1 mL) at 25° C. The mixture was stirred for 30 minutes. The mixture was concentrated under reduced pressure affording the title compound (40 mg, 0.14 mmol, HCl salt) as a light yellow solid.

    [0947] LCMS (ESI) m/z: [M+H]+=247.2.

    Step 3. (4R)-4-Cyano-N-[[4-[(E)-1,2-difluoro-2-phenyl-vinyl]-2-pyridyl]methyl]-4-methyl-isochromane-carboxamide

    [0948] HOBt (28.7 mg, 0.21 mmol), EDCI (40.7 mg, 0.21 mmol), and DIEA (0.12 mL, 0.71 mmol) were added to a mixture of [4-[(E)-1,2-difluoro-2-phenyl-vinyl]-2-pyridyl]methanamine (40 mg, 0.14 mmol, HCl salt) and (4R)-4-cyano-4-methyl-isochromane-6-carboxylic acid (36.9 mg, 0.17 mmol) in DCM (2 mL) at 25° C. The mixture was stirred for 2 hrs. The mixture was poured into water (20 mL) and extracted with DCM (10 mL×2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuum. The residue was purified by reverse phase column chromatography. The eluent was lyophilized affording the title compound (22.3 mg, 0.050 mmol, FA salt) as a white solid.

    [0949] LCMS (ESI) m/z: [M+H]+=446.3.

    [0950] .sup.1H NMR (400 MHz, CD.sub.3OD) δ=8.68-8.56 (m, 1H), 8.17-8.08 (m, 1H), 7.90-7.84 (m, 1H), 7.82-7.73 (m, 3H), 7.68-7.60 (m, 1H), 7.56-7.42 (m, 3H), 7.33-7.19 (m, 1H), 4.92-4.88 (m, 2H), 4.76 (s, 2H), 4.20-3.90 (m, 2H), 1.75 (s, 3H) ppm.

    [0951] The following examples in Table 7 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 5.

    TABLE-US-00008 TABLE 7 Compounds of the Invention LCMS # (m/z) 1H NMR 27 428.1 1H NMR (400 MHz, DMSO-d6) δ = 9.28 (m, 1H), 8.62 (d, J = 5.2 Hz, 1H), 8.16 (d, J = 1.2 Hz, 1H), 7.91 (m, 1H), 7.70 (d, J = 7.5 Hz, 2H), 7.66-7.60 (m, 2H), 7.48-7.41 (m, 2H), 7.40-7.33 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.19-6.99 (m, 1H), 4.95-4.79 (m, 2H), 4.65 (m, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 1.69 (s, 3H) ppm. 29 428.3 1H NMR (400 MHz, MeOD-d4) δ = 8.48 (d, J = 5.2 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.89-7.87 (m, 1H), 7.75-7.73 (m, 2H), 7.67 (s, 1H), 7.56-7.55 (m, 1H), 7.45-7.44 (m, 3H), 7.27 (d, J = 8.0 Hz, 1H), 6.66-6.55 (m, 1H), 4.90 (d, J = 4.0 Hz, 2H), 4.73 (s, 2H), 4.20 (d, J = 11.6 Hz, 1H), 3.92 (d, J = 11.2 Hz, 1H), 1.76 (s, 3H) ppm.

    Example 6. (4R)—N-[(4-Benzyloxy-2-pyridyl)methyl]-4-cyano-4-methyl-isochromane-6-carboxamide

    [0952] ##STR00631##

    Step 1. 4-Benzyloxypyridine-2-carbonitrile

    [0953] t-BuOK (2.43 g, 21.65 mmol) was added to a solution of 4-chloropyridine-2-carbonitrile (1 g, 7.2 mmol) and phenylmethanol (0.90 mL, 8.7 mmol) in THE (10 mL) at 0° C. The mixture was warmed to 25° C. and stirred for 1 hr. The reaction mixture was poured into saturated NH.sub.4Cl (aq., 20 mL) and extracted with EA (7 mL×2). The organic layer was washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated. The crude product was purified by column chromatography (SiO.sub.2, Petroleum ether/EA=10/1 to 1/1) affording the title compound (1.1 g, 4.24 mmol) as a yellow solid.

    [0954] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.63 (d, J=5.2 Hz, 1H), 8.45 (d, J=5.6 Hz, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.78-7.76 (m, 1H), 7.64 (d, J=2.8 Hz, 1H), 7.45-7.39 (m, 2H), 7.23-7.21 (m, 1H), 5.29 (s, 2H) ppm.

    Step 2. (4-Benzyloxy-2-pyridyl)methanamine

    [0955] BH.sub.3-THE (1 M, 4.76 mL) was added dropwise to a solution of 4-benzyloxypyridine-2-carbonitrile (200 mg, 0.95 mmol) in THE (2 mL) at 0° C. The reaction mixture was warmed 25° C. and stirred for 4 hrs. The reaction mixture was cooled to 0° C. and 2N HCl (5 mL) was added. The reaction mixture was heated to reflux for 30 minutes and then cooled to 25° C. 2N NaOH was added until pH=12 was achieved. The reaction mixture was then extracted with EA (5 mL×2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated affording the title compound (170 mg, 0.56 mmol) as yellow oil.

    [0956] LCMS (ESI) m/z: [M+H]+=215.1.

    [0957] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.48-8.43 (m, 1H), 8.30 (d, J=5.6 Hz, 2H), 7.64 (d, J=2.8 Hz, 1H), 7.44-7.39 (m, 5H), 7.25-7.21 (m, 1H), 5.19 (s, 2H), 4.50 (d, J=2.8 Hz, 2H) ppm.

    Step 3. (4R)—N-[(4-Benzyloxy-2-pyridyl)methyl]-4-cyano-4-methyl-isochromane-6-carboxamide

    [0958] DIEA (0.41 mL, 2.3 mmol) was added to a solution of (4-benzyloxy-2-pyridyl)methanamine (100 mg, 0.47 mmol), (4R)-4-cyano-4-methyl-isochromane-6- carboxylic acid (101 mg, 0.47 mmol), EDCI (179 mg, 0.93 mmol), and HOBt (126 mg, 0.93 mmol) in DMF (2 mL). The mixture was stirred at 2500 for 1 hr. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (column: Phenomenex Synergi 018 150*25*7-m; mobile phase: [water (0.225% FA)-ACN]; B %: 20%-50%, 9 μm) affording the title compound (51.8 mg, 0.11 mmol, FA salt) as a yellow gum.

    [0959] LCMS (ESI) m/z: [M+H]+=414.2.

    [0960] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.21-9.18 (i, 1H), 8.40-8.30 (m, 1H), 8.14 (d, J=1.6 Hz, 1H), 7.89-7.88 (m, 1H), 7.48-7.39 (m, 2H), 7.38-7.32 (m, 3H), 7.28 (d, J=8.0 Hz, 1H), 6.99-6.91 (m, 2H), 5.17 (s, 2H), 4.95-4.80 (m, 2H), 4.58-4.49 (m, 2H), 4.22 (d, J=11.6 Hz, 1H), 3.86 (d, J=11.6 Hz, 1H), 1.69 (s, 3H) ppm.

    [0961] The following examples in Table 8 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 6.

    TABLE-US-00009 TABLE 8 Compounds of the Invention LCMS # (m/z) 1H NMR 34 470.3 1H NMR (400 MHz, MeOD) δ = 8.31 (d, J = 6.0 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.86- 7.81 (m, 1H), 7.50-7.40 (m, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.97-6.93 (m, 1H), 6.69 (d, J = 7.2 Hz, 1H), 6.26 (d, J = 8.4 Hz, 1H), 5.09 (s, 2H), 4.90 (d, J = 4.0 Hz, 2H), 4.64 (s, 2H), 4.20 (d, J = 11.6 Hz, 1H), 4.00-3.95 (m, 4H), 3.91 (d, J = 11.6 Hz, 1H), 2.40-2.33 (m, 2H), 1.75 (s, 3H) ppm 36 415.2 1H NMR (400 MHz, DMSO-d6) δ = 9.19-9.16 (m, 1H), 8.51-8.50 (m, 1H), 8.38- 8.37 (m, 1H), 8.35-8.33 (m, 1H), 8.12 (d, J = 1.2 Hz, 1H), 7.90-7.88 (m, 1H), 7.81- 7.77 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.33-7.30 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 2.8 Hz, 2H), 5.23 (s, 2H), 4.91-4.80 (m, 2H), 4.53-4.50 (m, 2H), 4.24-4.14 (m, 1H), 3.85 (d, J = 11.6 Hz, 1H), 1.68 (s, 3H) ppm 40 469.1 1H NMR (400 MHz, MeOD) δ = 8.30 (d, J = 5.6 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.89- 7.79 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.15-7.06 (m, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.98-6.93 (m, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.48 (s, 1H), 6.43-6.34 (m, 1H), 5.13 (s, 2H), 4.93 (br d, J = 9.6 Hz, 2H), 4.64 (s, 2H), 4.20 (d, J = 11.6 Hz, 1H), 3.92 (d, J = 11.2 Hz, 1H), 3.85-3.76 (m, 4H), 2.40-2.26 (m, 2H), 1.75 (s, 3H) ppm 45 474.2 1H NMR (400 MHz, MeOD) δ = 8.30 (d, J = 6.0 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.88- 7.80 (m, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 7.01-6.91 (m, 3H), 5.09 (s, 2H), 4.90 (br d, J = 3.6 Hz, 2H), 4.65-4.57 (m, 4H), 4.19 (d, J = 11.6 Hz, 1H), 3.92 (d, J = 11.2 Hz, 1H), 3.23-3.14 (m, 2H), 1.75 (s, 3H) ppm 61 422.2 1H NMR (400 MHz, DMSO-d6) δ = 9.21-9.18 (m, 1H), 8.33 (d, J = 5.6 Hz, 1H), 8.14 (s, 1H), 7.90-7.88 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.95-6.82 (m, 2H), 4.97-4.78 (m, 2H), 4.60-4.47 (m, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.97-3.78 (m, 5H), 3.31- 3.25 (m, 2H), 2.06-1.92 (m, 1H), 1.74-1.57 (m, 5H), 1.34-1.28 (m, 2H) ppm

    Example 7. (4R)-4-Cyano-4-methyl-N-[[4-[(1S,2S)-2-phenylcyclopropyl]-2-pyridyl]methyl]isochromane-6-carboxamide and (4R)-4-Cyano-4-methyl-N-[[4-[(1R,2R)-2-phenylcyclopropyl]-2-pyridyl]methyl]isochromane-6-carboxamide

    [0962] ##STR00632##

    Step 1. (4R)-4-Cyano-4-methyl-N-[[4-[(1S,2S)-2-phenylcyclopropyl]-2-pyridyl]methyl]isochromane-6-carboxamide and (4R)-4-cyano-4-methyl-N-[[4-[(1R,2R)-2-phenylcyclopropyl]-2-pyridyl]methyl]isochromane-6-carboxamide

    [0963] PdCl.sub.2 (dtbpf) (33.7 mg, 0.052 mmol) and K.sub.3PO.sub.4 (165 mg, 0.78 mmol) were added to a solution of (4R)—N-[(4-bromo-2-pyridyl)methyl]-4-cyano-4-methyl-isochromane-6-carboxamide (100 mg, 0.26 mmol), and (2-phenylcyclopropyl)boronic acid (83.9 mg, 0.52 mmol) in dioxane (1 mL) and H.sub.2O (0.1 mL). The mixture was stirred at 80° C. for 12 hrs. The reaction mixture was washed with water (50 mL) and extracted with EA (50 mL×2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.1% TFA)-ACN]; B %: 32%-52%, 10 min) affording a mixture of the title compounds (60 mg, 132.24 μmol, 51.08% yield) as a brown solid. The mixture was separated by chiral SFC (column: DAICEL CHIRALCEL OJ-H (250 mm×30 mm, 5 μm); mobile phase: [0.1% NH.sub.3.H.sub.2O MeOH]; B %: 40%-40%, 3.9 min; 70 min), the solution was concentrated under reduced pressure affording the title compounds. 1.sup.st eluting compound (12.9 mg, 0.029 mmol, off-white solid):

    [0964] LCMS (ESI) m/z: [M+H]+=424.1.

    [0965] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.18-9.14 (m, 1H), 8.37 (d, J=5.2 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H), 7.90-7.86 (m, 1H), 7.29-7.25 (m, 3H), 7.19-7.15 (m, 4H), 7.07-7.04 (m, 1H), 4.91-4.79 (m, 2H), 4.57-4.53 (m, 2H), 4.21 (d, J=11.2 Hz, 1H), 3.85 (d, J=11.6 Hz, 1H), 2.29-2.21 (m, 2H), 1.68 (s, 3H), 1.57-1.52 (m, 2H) ppm.

    [0966] 2.sup.nd eluting compound (11.3 mg, 0.027 mmol, yellow solid):

    [0967] LCMS (ESI) m/z: [M+H]+=424.1.

    [0968] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.25-9.21 (m, 1H), 8.43 (d, J=5.2 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 7.90-7.87 (m, 1H), 7.30-7.25 (m, 3H), 7.20-7.16 (m, 4H), 7.07-7.03 (m, 1H), 4.91-4.79 (m, 2H), 4.60 (d, J=5.2 Hz, 2H), 4.21 (d, J=11.6 Hz, 1H), 3.85 (d, J=11.2 Hz, 1H), 2.36-2.30 (m, 2H), 1.67 (s, 3H), 1.64-1.59 (m, 2H) ppm.

    [0969] The following examples in Table 9 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Examples 7.

    TABLE-US-00010 TABLE 9 Compounds of the Invention LCMS # (m/z) 1H NMR 4 410.2 1H NMR (400 MHz, DMSO-d6) δ = 9.36 (m, 1H), 8.65 (d, J = 5.6 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.91 (m, 1H), 7.88-7.88 (m, 1H), 7.88-7.79 (m, 2H), 7.77 (s, 3H), 7.50- 7.35 (m, 4H), 7.30 (d, J = 8.0 Hz, 1H), 4.94-4.80 (m, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.88-3.85 (m, 1H), 1.69 (s, 3H) ppm. 38 440.3 1H NMR (400 MHz, DMSO-d6) δ = 9.26-9.23 (m, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.93-7.92 (m, 1H), 7.55-7.44 (m, 3H), 7.37-7.27 (m, 3H), 7.26- 7.21 (m, 2H), 6.91-6.89 (m, 1H), 4.99-4.77 (m, 2H), 4.62-4.60 (m, 2H), 4.23 (d, J = 11.2 Hz) ppm

    Example 8. (4R)-4-Cyano-4-methyl-N-[[4-(2-phenylethyl)-2-pyridyl]methyl]isochromane-6-carboxamide

    [0970] ##STR00633##

    Step 1. tert-butyl N-[[4-[(E)-styryl]-2-pyridyl]methyl]carbamate

    [0971] Pd(OAc).sub.2 (7.8 mg, 0.0325 mmol) was added to a solution of tert-butyl ((4-bromopyridin-2-yl)methyl)carbamate (200 mg, 0.70 mmol), styrene (363 mg, 3.48 mmol), Et.sub.3N (0.14 mL, 1.04 mmol), and tris-o-tolylphosphane (21.2 mg, 0.070 mmol) in DMF (2 mL). The mixture was stirred at 100° C. for 2 hrs.

    [0972] The reaction mixture was diluted with H.sub.2O (10 mL) and extracted with DCM (10 mL×2), the combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (SiO.sub.2, Petroleum ether/EA=1/0 to 0/1) affording the title compound (200 mg, 0.64 mmol) as a yellow solid.

    [0973] LCMS (ESI) m/z: [M+H]+=311.4

    [0974] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.51 (d, J=5.2 Hz, 1H), 7.55 (d, J=7.2 Hz, 2H), 7.42-7.40 (m, 2H), 7.38-7.28 (m, 4H), 7.04 (d, J=16.4 Hz, 1H), 4.47 (d, J=5.6 Hz, 2H), 1.49 (s, 9H) ppm.

    Step 2. tert-Butyl N-[[4-(2-phenylethyl)-2-pyridyl]methyl]carbamate

    [0975] Pd(OH).sub.2/C (30 mg) was added to a mixture of tert-butyl N-[[4-[(E)-styryl]-2-pyridyl]methyl]carbamate (100 mg, 0.32 mmol) in MeOH (2 mL). The mixture was degassed and purged with H.sub.2 three times, and then the mixture was stirred at 25° C. for 12 hrs under a H.sub.2 atmosphere (15 psi). The reaction mixture was filtered. The filtrate was concentrated affording the title compound (90 mg, 0.29 mmol) as a yellow oil.

    [0976] LCMS (ESI) m/z: [M+H]+=313.0.

    [0977] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.41 (d, J=4.8 Hz, 1H), 7.31-7.27 (m, 2H), 7.21-7.18 (m, 1H), 7.16-7.14 (m, 2H), 7.06 (s, 1H), 6.98-6.97 (m, 1H), 4.41 (br d, J=5.2 Hz, 2H), 2.92 (s, 4H), 1.47 (s, 9H) ppm.

    Step 3. [4-(2-Phenylethyl)-2-pyridyl]methanamine

    [0978] A solution of tert-butyl N-[[4-(2-phenylethyl)-2-pyridyl]methyl]carbamate (90 mg, 0.29 mmol) in 4N HCl/dioxane (5.0 mL) was stirred at 25° C. for 1 hr. The reaction mixture was concentrated affording the title compound (70 mg, 0.28 mmol, HCl salt) as a white solid.

    [0979] LCMS (ESI) m/z: [M+H]+=213.3.

    Step 4. (4R)-4-cyano-4-methyl-N-[[4-(2-phenylethyl)-2-pyridyl]methyl]isochromane-6-carboxamide

    [0980] DIEA (0.14 mL, 0.80 mmol), EDCI (46.2 mg, 0.24 mmol), and HOBt (32.6 mg, 0.24 mmol) were added to a solution of [4-(2-Phenylethyl)-2-pyridyl]methanamine (40 mg, 0.16 mmol, HCl salt) and (4R)-4-cyano-4-methylisochromane-6-carboxylic acid (38.4 mg, 0.18 mmol) in DCM (0.5 mL). The mixture was stirred at 30° C. for 12 hrs. The reaction mixture was diluted with H.sub.2O (3 mL) and extracted with DCM (3 mL×2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiO.sub.2, Petroleum ether/EA=1/0 to 0/1) affording the title compound (23.5 mg, 0.054 mmol) as a yellow solid.

    [0981] LCMS (ESI) m/z: [M+H]+=412.3.

    [0982] .sup.1H NMR (400 MHz, CD.sub.3OD) δ=8.34 (d, J=4.8 Hz, 1H), 8.10 (d, J=0.8 Hz, 1H), 7.85-7.83 (m, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.20-7.16 (m, 3H), 7.14-7.12 (m, 3H), 7.10-7.07 (m, 1H), 4.90 (d, J=3.2 Hz, 2H), 4.64 (s, 2H), 4.20 (d, J=11.6 Hz, 1H), 3.92 (d, J=11.2 Hz, 1H), 2.95-2.92 (m, 4H), 1.74 (s, 3H) ppm.

    Example 9. Methyl 3-[(E)-2-[2-[[[(4R)-4-cyano-4-methyl-isochromane-6-carbonyl]amino]methyl]-4-pyridyl]vinyl]benzoate

    [0983] ##STR00634##

    Step 1. Methyl 3-[(E)-2-[2-[(tert-butoxycarbonylamino)methyl]-4-pyridyl]vinyl]benzoate

    [0984] Pd(OAc).sub.2 (15.6 mg, 0.070 mmol), tris-o-tolylphosphane (42.4 mg, 0.14 mmol) and Et.sub.3N (0.19 mL, 1.39 mmol) were added to a mixture of tert-butyl N-[(4-bromo-2-pyridyl)methyl]carbamate (200 mg, 0.70 mmol) and methyl 3-vinylbenzoate (226 mg, 1.39 mmol) in DMF (2 mL). The reaction mixture was stirred at 100° C. for 1 hr. The reaction mixture was poured into water (30 mL) and extracted with EA (20 mL×2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (Petroleum ether/EA=10/1 to 3/1) affording the title compound (200 mg, 0.54 mmol) as light yellow oil

    [0985] LCMS (ESI) m/z: [M+H]+=369.2.

    [0986] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.52 (d, J=5.2 Hz, 1H), 8.24 (s, 1H), 8.00 (d, J=7.6 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.48-7.46 (m, 1H), 7.39-7.28 (m, 3H), 7.10 (d, J=16.4 Hz, 1H), 4.48 (d, J=5.6 Hz, 2H), 4.12 (s, 3H), 1.55 (s, 9H) ppm.

    Step 2. Methyl 3-[(E)-2-[2-(aminomethyl)-4-pyridyl]vinyl]benzoate

    [0987] TFA (0.50 mL, 6.75 mmol) was added to a mixture of Methyl 3-[(E)-2-[2-[(tert-butoxycarbonylamino)methyl]-4-pyridyl]vinyl]benzoate (100 mg, 0.27 mmol) in DCM (1 mL). The reaction mixture was stirred at 25° C. for 1 hrs. The mixture was poured into saturated NaHCO.sub.3 (30 mL) and extracted with DCM (20 mL×2). The combined organic phase was washed with brine (20 mL×2), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo affording the title compound (60 mg, 0.22 mmol) as yellow oil.

    [0988] LCMS (ESI) m/z: [M+H]+=269.1.

    Step 3. Methyl 3-[(E)-2-[2-[[[(4R)-4-cyano-4-methyl-isochromane-6-carbonyl]amino]methyl]-4-pyridyl]vinyl]benzoate

    [0989] HOBt (22.7 mg, 0.17 mmol), EDCI (32.1 mg, 0.17 mmol, and DIEA (0.058 mL, 0.33 mmol) were added to a mixture of Methyl 3-[(E)-2-[2-(aminomethyl)-4-pyridyl]vinyl]benzoate (30 mg, 0.11 mmol) and (4R)-4-cyano-4-methyl-isochromane-6-carboxylic acid (29.1 mg, 0.13 mmol) in DCM (1 mL). The mixture was stirred at 25° C. for 12 hrs. The mixture was poured into water (20 mL) and extracted with DCM (20 mL×2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude residue was purified by prep-TLC (DCM/MeOH=10/1) affording the title compound (25.2 mg, 0.052 mmol) as a blue solid.

    [0990] LCMS (ESI) m/z: [M+H]+=468.3.

    [0991] .sup.1H NMR (400 MHz, CD.sub.3OD) δ=8.52-8.46 (m, 1H), 8.30-8.24 (m, 1H), 8.18-8.14 (m, 1H), 8.01-7.95 (m, 1H), 7.93-7.85 (m, 2H), 7.64-7.60 (m, 1H), 7.59-7.49 (m, 3H), 7.34-7.26 (m, 2H), 4.94-4.91 (m, 2H), 4.74 (s, 2H), 4.25-3.90 (m, 5H), 1.77 (s, 3H) ppm.

    [0992] The following examples in Table 10 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 9.

    TABLE-US-00011 TABLE 10 Compounds of the Invention LCMS # (m/z) 1H NMR 33 428.2 1H NMR (400 MHz, DMSO-d6) δ = 9.16-9.13 (m, 1H), 8.35 (d, J = 5.0 Hz, 1H), 8.14 (d, J = 1.4 Hz, 1H), 7.88-7.85 (dm, 1H), 7.76-7.70 (m, 2H), 7.67-7.56 (m, 1H), 7.51- 7.17 (m, 5H), 4.94-4.79 (m, 2H), 4.78-4.62 (m, 2H), 4.27-4.16 (m, 1H), 3.93-3.80 (m, 1H), 1.68(s, 3H)ppm 41 454.2 1H NMR (400 MHz, DMSO-d6) δ = 8.97 (d, J = 8.0, 1H), 8.53 (d, J = 5.2, 1H), 8.18 (d, J = 1.2, 1H), 7.93-7.90 (m, 1H), 7.67-7.61 (m, 3H), 7.55-7.49 (m, 2H), 7.42-7.38 (m, 2H), 7.35-7.31 (m, 1H), 7.29-7.25 (m, 2H), 5.43-5.38 (m, 1H), 4.91-4.80 (m, 2H), 4.21 (d, J = 11.6, 1H), 3.87-3.81 (m, 3H), 3.30 (s, 3H), 1.69 (s, 3H) ppm

    Example 10. (4R)-4-Cyano-4-methyl-N-[[4-(phenoxymethyl)-2-pyridyl]methyl]isochromane-6-carboxamide

    [0993] ##STR00635##

    Step 1. 2-[(tert-Butoxycarbonylamino)methyl]pyridine-4-carboxylic acid

    [0994] Pd(OAc).sub.2 (62.6 mg, 0.28 mmol), DCPP (171 mg, 0.28 mmol), H.sub.2O (2 mL), and K.sub.2CO.sub.3 (578 mg, 4.18 mmol) were added to a solution of 2 tert-butyl N-[(4-bromo-2-pyridyl)methyl]carbamate (800 mg, 2.79 mmol) in DMSO (8 mL). The reaction mixture was purged with CO(g) three times. The resulting mixture was stirred at 100° C. for 16 hr under a CO atmosphere (15 psi). The reaction mixture was diluted with H.sub.2O (30 mL) and extracted with EA (30 mL×3). The combined organic layers were discarded, and the aqueous layers were combined and 1 N HCl was added until a pH=4 was achieved. The reaction mixture was extracted with EA (30 mL×3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure affording the title compound (436 mg, 1.68 mmol) as a yellow solid.

    [0995] LCMS (ESI) m/z: [M+H]+=253.2.

    [0996] .sup.1H NMR (400 MHz, DMSO-d6) δ=13.63-13.56 (m, 1H), 8.67-8.66 (m, 1H), 7.71 (s, 1H), 7.68-7.66 (m, 1H), 7.55-7.53 (m, 1H), 4.29 (br d, J=5.6 Hz, 2H), 1.40 (s, 9H) ppm.

    Step 2. tert-Butyl N-[[4-(hydroxymethyl)-2-pyridyl]methyl]carbamate

    [0997] BH.sub.3.Me.sub.2S (10 M, 0.18 mL) was added dropwise to a solution of 2-[(tert-Butoxycarbonylamino)methyl]pyridine-4-carboxylic acid (150 mg, 0.59 mmol) in THE (2 mL) at 0° C. The mixture was warmed to 25° C. and stirred for 12 hrs. MeOH (5 mL) was added to the reaction mixture at 0° C. and then warmed and stirred at 70° C. for 1 hr. The mixture was then diluted with H.sub.2O (40 mL) and extracted with EA (40 mL×2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (SiO.sub.2, Petroleum ether/EA=1/0 to 0/1) affording the title compound (100 mg, 0.42 mmol) as yellow oil.

    [0998] LCMS (ESI) m/z: [M+H]+=239.2.

    [0999] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.50 (d, J=5.2 Hz, 1H), 7.29-7.27 (m, 1H), 7.19 (d, J=4.8 Hz, 1H), 5.56 (br s, 1H), 4.74 (s, 2H), 4.44 (br d, J=5.6 Hz, 2H), 1.46 (s, 9H) ppm.

    Step 3. tert-Butyl N-[[4-(phenoxymethyl)-2-pyridyl]methyl]carbamate

    [1000] DIAD (0.098 mL, 0.50 mmol) was added to a solution of tert-Butyl N-[[4-(hydroxymethyl)-2-pyridyl]methyl]carbamate (80 mg, 0.34 mmol), PPh.sub.3 (132 mg, 0.50 mmol), and phenol (0.060 mL, 0.67 mmol) in THE (1 mL) at 0° C. The mixture was warmed and stirred at 25° C. for 16 hr. The mixture was diluted with H.sub.2O (10 mL) and extracted with EA (10 mL×2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (SiO.sub.2, Petroleum ether/EA=1/0 to 1/1) affording the title compound (75 mg, 0.24 mmol) as a yellow solid.

    [1001] LCMS (ESI) m/z: [M+H]+=315.2.

    [1002] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.54 (d, J=5.2 Hz, 1H), 7.34-7.29 (m, 3H), 7.25 (br s, 1H), 7.00-6.94 (m, 3H), 5.54 (br s, 1H), 5.09 (s, 2H), 4.47 (br d, J=4.8 Hz, 2H), 1.47 (s, 9H) ppm.

    Step 4. [4-(Phenoxymethyl)-2-pyridyl]methanamine

    [1003] A solution of tert-butyl N-[[4-(phenoxymethyl)-2-pyridyl]methyl]carbamate (40 mg, 0.13 mmol) in HCl/dioxane (4N, 1 mL) was stirred at 25° C. for 1 hr. The reaction mixture was concentrated affording the title compound (30 mg, 0.12 mmol, HCl salt) as a white solid.

    [1004] LCMS (ESI) m/z: [M+H]+=215.3.

    Step 5. (4R)-4-Cyano-4-methyl-N-[[4-(phenoxymethyl)-2-pyridyl]methyl]isochromane-6-carboxamide

    [1005] DIEA (0.10 mL, 0.60 mmol), EDCI (34.4 mg, 0.18 mmol), and HOBt (24.2 mg, 0.18 mmol) were added to a solution of (4R)-4-cyano-4-methyl-isochromane-6-carboxylic acid (26 mg, 0.12 mmol) and [4-(phenoxymethyl)-2-pyridyl]methanamine (30 mg, 0.12 mmol, HCl salt) in DCM (0.5 mL). The mixture was stirred at 30° C. for 12 hrs. The reaction mixture was diluted with H.sub.2O (3 mL) and extracted with DCM (3 mL×2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiO.sub.2, Petroleum ether/EA=1/0 to 0/1) affording the title compound (18.8 mg, 0.045 mmol) as a white solid.

    [1006] LCMS (ESI) m/z: [M+H]+=414.4.

    [1007] .sup.1H NMR (400 MHz, CD.sub.3OD) δ=8.49 (d, J=5.12 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 7.84-7.82 (m, 1H), 7.51-7.40 (m, 1H), 7.26-7.21 (m, 3H), 6.95-6.91 (m, 3H) 5.17 (s, 2H), 4.90 (d, J=4.0 Hz, 2H), 4.71 (s, 2H), 4.20 (d, J=11.6 Hz, 1H), 3.92 (d, J=11.6 Hz, 1H), 1.74 (s, 3H) ppm.

    Examples 11 and 12: (R)-4-Cyano-4-methyl-N-((4-((1r,3R)-3-(6-morpholinopyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)isochromane-6-carboxamide and (R)-4-cyano-4-methyl-N-((4-((1s,3S)-3-(6-morpholinopyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)isochromane-6-carboxamide

    [1008] ##STR00636## ##STR00637##

    Step 1: 4-(6-Bromopyridin-2-yl)morpholine

    [1009] To a mixture of 2,6-dibromopyridine (2 g, 8.44 mmol) and morpholine (2.94 g, 33.77 mmol, 2.97 mL) in DMSO (20 mL) was added DIEA (3.27 g, 25.33 mmol). The mixture was stirred at 120° C. for 10 hrs. The mixture was poured into water (150 mL), then extracted with EA (100 mL*3). The combined organic layers were washed with brine (250 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, DCM/Ethyl acetate=50/1 to 1/1) to give the title compound (1.6 g, 6.58 mmol, 77.96% yield) as a white solid.

    [1010] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.34-7.30 (m, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.52 (d, J=8.4 Hz, 1H), 3.87-3.75 (m, 4H), 3.52-3.49 (m, 4H) ppm.

    Step 2: 4-(3-Hydroxy-3-(6-morpholinopyridin-2-yl)cyclobutyl)picolinonitrile

    [1011] To a mixture of 4-(6-bromopyridin-2-yl)morpholine (1.41 g, 5.81 mmol) in THF (10 mL) was added n-BuLi (2.5 M, 2.32 mL) at −70° C. under N.sub.2. The mixture was stirred at −70° C. for 0.5 hr, then the resulting solution was added to a solution of 4-(3-oxocyclobutyl)picolinonitrile (500 mg, 2.90 mmol) in THF (10 mL) at −70° C. under N.sub.2. The mixture was stirred at −70° C. for 2 hrs. The mixture was poured into sat. NH.sub.4Cl (100 mL), and extracted with EA (100 mL*2). The combined organic layers were washed with brine (150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=20/1 to 0/1) to give the title compound (430 mg, 1.25 mmol, 43.14% yield) as a white solid.

    [1012] LCMS (ESI) m/z: [M+H].sup.+=337.1

    [1013] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.68 (d, J=5.2 Hz, 1H), 8.08-8.07 (m, 1H), 7.73-7.71 (m, 1H), 7.58-7.54 (m, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.84 (s, 1H), 5.75 (s, 1H), 3.74-3.72 (m, 4H), 3.49-3.47 (m, 4H), 2.95-2.90 (m, 2H), 2.42-2.37 (m, 2H) ppm.

    Step 3: O-(3-(2-Cyanopyridin-4-yl)-1-(6-morpholinopyridin-2-yl)cyclobutyl)S-methyl carbonodithioate

    [1014] To a mixture of NaH (59.45 mg, 1.49 mmol, 60% purity) in THE (2 mL) was added 4-(3-hydroxy-3-(6-morpholinopyridin-2-yl)cyclobutyl)picolinonitrile (200 mg, 594.55 umol) in THE (2 mL) at 0° C. under N.sub.2. The mixture was stirred at 10° C. for 0.5 hr, then CS.sub.2 (242.19 mg, 3.18 mmol, 192.22 uL) was added drop wise at 0° C. The resulting mixture was stirred at 10° C. for 1 hr, then MeI (219.41 mg, 1.55 mmol, 96.23 uL) was added to the mixture drop wise at 0° C. The resulting mixture was stirred at 10° C. for 1 hr. The reaction mixture was diluted with H.sub.2O (40 mL) and extracted with EA (30 mL*3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10:1-1:1) to give the title compound (250 mg, 533.34 umol, 89.70% yield) as a yellow oil.

    [1015] LCMS (ESI) m/z: [M+H].sup.+=427.1

    Step 4: 4-(3-(6-Morpholinopyridin-2-yl)cyclobutyl)picolinonitrile

    [1016] To a mixture of O-(3-(2-cyanopyridin-4-yl)-1-(6-morpholinopyridin-2-yl)cyclobutyl)S-methyl carbonodithioate (125 mg, 293.05 umol) in toluene (3 mL) was added Bu.sub.3SnH (255.88 mg, 879.14 umol, 232.62 uL) and AIBN (9.62 mg, 58.61 umol). The mixture was stirred at 110° C. for 2 hrs. The mixture was 25 poured into sat. KF solution (50 mL) and stirred for 15 min. The mixture was extracted with EA (50 mL*2). The combined organic layers was washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 0/1) to give the title compound (80 mg, 187.27 umol, 63.91% yield) as a yellow oil.

    [1017] LCMS (ESI) m/z: [M+H].sup.+=321.2

    Step 5: tert-Butyl ((4-(3-(6-morpholinopyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)carbamate

    [1018] To a mixture of 4-(3-(6-morpholinopyridin-2-yl)cyclobutyl)picolinonitrile (80 mg, 249.70 umol) in MeOH (2 mL) and EA (2 mL) was added TEA (75.80 mg, 749.09 umol), (Boc).sub.20 (108.99 mg, 499.40 umol) and Raney-Ni (50 mg, 583.60 umol). The mixture was stirred at 25° C. for 2 hrs. The mixture was diluted with EA then filtered carefully with EA (15 mL*3). The filtrate was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 0/1) to give the title compound (90 mg, 188.68 umol, 75.56% yield) as a white solid.

    [1019] LCMS (ESI) m/z: [M+H].sup.+=425.3.

    Step 6: (4-(3-(6-Morpholinopyridin-2-yl)cyclobutyl)pyridin-2-yl)methanamine hydrochloride

    [1020] A mixture of tert-butyl ((4-(3-(6-morpholinopyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)carbamate (90 mg, 212.00 umol) in HCl/dioxane (4 M, 4 mL) was stirred at 25° C. for 1 hr. The mixture was concentrated under vacuum to give the title compound (76 mg, crude, HCl salt) as a white solid, used directly in the next step.

    [1021] LCMS (ESI) m/z: [M+H].sup.+=325.2

    Step 7: (R)-4-Cyano-4-methyl-N-((4-((1r,3R)-3-(6-morpholinopyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)isochromane-6-carboxamide and (R)-4-cyano-4-methyl-N-((4-((1s,3S)-3-(6-morpholinopyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)isochromane-6-carboxamide

    [1022] To a mixture of (4-(3-(6-morpholinopyridin-2-yl)cyclobutyl)pyridin-2-yl)methanamine hydrochloride (76 mg, 210.60 umol), (4R)-4-cyano-4-methyl-isochromane-6-carboxylic acid (54.89 mg, 252.72 umol) and DIEA (81.65 mg, 631.79 umol, 110.05 uL) in DCM (3 mL) was added EDCI (60.56 mg, 315.89 umol) and HOBt (42.68 mg, 315.89 umol). The mixture was stirred at 25° C. for 2 hrs. The mixture concentrated under vacuum to remove DCM. The residue was purified by prep-TLC (DCM:MeOH=10:1) to give crude racemic product (34 mg). The racemic product was further separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH.sub.3H.sub.2O IPA]; B %: 50%-50%, 4.5 min; 25 minmin) to give peak 1 (Rf=0.743 min) and peak 2 (Rf=1.102 min). The fraction of peak 1 (Rf=0.743 min) was concentrated under vacuum to give a residue, then purified by reversed phase HPLC (0.1% FA condition) and lyophilized to give (R)-4-cyano-4-methyl-N-((4-((1r,3R)-3-(6-morpholinopyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)isochromane-6-carboxamide (3.10 mg, 5.92 umol, 2.81% yield) as an off-white solid. The fraction of peak 2 (Rf=1.102 mins) was concentrated under vacuum to give a residue, then purified by reversed phase HPLC (0.1% FA condition) and lyophilized to give (R)-4-cyano-4-methyl-N-((4-((1 s,3S)-3-(6-morpholinopyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)isochromane-6-carboxamide (7.55 mg, 14.42 umol, 6.85% yield) as an off-white solid.

    (R)-4-Cyano-4-methyl-N-((4-((1r,3R)-3-(6-morpholinopyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)isochromane-6-carboxamide

    [1023] LCMS (ESI) m/z: [M+H].sup.+=524.2

    [1024] .sup.1H NMR (400 MHz, MeOD) δ=8.43 (d, J=4.8 Hz, 1H), 8.12 (d, J=1.6 Hz, 1H), 7.88-7.85 (m, 1H), 7.49-7.45 (m, 1H), 7.39 (s, 1H), 7.32-7.30 (m, 1H), 7.26 (d, J=8.0 Hz, 1H), 6.62-6.58 (m, 2H), 4.90 (s, 2H), 4.70 (s, 2H), 4.19 (d, J=11.2 Hz, 1H), 3.91 (d, J=11.2 Hz, 1H), 3.92-3.78 (m, 5H), 3.55-3.51 (m, 5H), 2.79-2.72 (m, 2H), 2.56-2.49 (m, 2H), 1.74 (s, 3H) ppm.

    [1025] Chiral SFC: AD-3_5CM_IPA(DEA)_40_3ML_T35.M, Rt=0.743 min, ee %=100%.

    (R)-4-Cyano-4-methyl-N-((4-((1s,3S)-3-(6-morpholinopyridin-2-yl)cyclobutyl)pyridin-2-yl)methyl)isochromane-6-carboxamide

    [1026] LCMS (ESI) m/z: [M+H].sup.+=524.2

    [1027] .sup.1H NMR (400 MHz, MeOD) δ=8.40 (d, J=4.8 Hz, 1H), 8.10 (d, J=1.2 Hz, 1H), 7.86-7.83 (m, 1H), 7.44-7.41 (m, 1H), 7.36 (s, 1H), 7.27-7.24 (m, 2H), 6.58-6.53 (m, 2H), 4.90 (s, 1H), 4.66 (m, 2H), 4.18 (d, J=11.2 Hz, 1H), 3.91 (d, J=11.2 Hz, 1H), 3.76-3.73 (m, 4H), 3.56-3.42 (m, 6H), 2.72-2.64 (m, 2H), 2.50-2.42 (m, 2H), 1.72 (s, 3H) ppm.

    [1028] Chiral SFC: AD-3_5CM_IPA(DEA)_40_3ML_T35.M, Rt=1.100 mins, ee %=100%.

    [1029] The following examples in Table 11 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Examples 11 and 12.

    TABLE-US-00012 TABLE 11 Compounds of the Invention LCMS # (m/z) 1H NMR 76 482.4 1H NMR (400 MHz, DMSO-d6) δ = 8.48-8.39 (m, 1H), 8.27-8.19 (m, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.87-7.85 (m, 1H), 7.52-7.49 (m, 1H), 7.42 (s, 1H), 7.33-7.32 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.60-6.56 (m, 2H), 4.93 (br s, 2H), 4.71 (s, 2H), 4.20- 4.17 (m, 1H), 3.91 (d, J = 11.6 Hz, 1H), 3.84-3.80 (m, 1H), 3.65-3.59 (m, 1H), 3.13 (s, 6H), 2.77-2.75 (m, 2H), 2.60-2.55 (m, 2H), 1.74 (s, 3H) ppm 77 479.3 1H NMR (400 MHz, DMSO-d6) δ = 8.44 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.87-7.85 (m, 1H), 7.55-7.51 (m, 1H), 7.41 (s, 1H), 7.32 (d, J = 5.4 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.05-6.97 (m, 2H), 4.89 (s, 2H), 4.71 (s, 2H), 4.19 (d, J = 11.6 Hz, 1H), 3.91 (d, J = 11.6 Hz, 1H), 3.79-3.75 (m, 1H), 3.66-3.64 (m, 1H), 2.74- 2.72 (m, 2H), 2.58-2.55 (m, 2H), 2.06-2.01 (m, 1H), 1.74 (s, 3H), 1.00-0.95 (m, 4H) ppm 78 479.3 1H NMR (400 MHz, DMSO-d6) δ = 8.42 (d, J = 4.8 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.87-7.85 (m, 1H), 7.55-7.50 (m, 1H), 7.38 (s, 1H), 7.31-7.30 (m, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.99-6.95 (m, 2H), 4.90 (br s, 2H), 4.70 (s, 2H), 4.19 (d, J = 11.6 Hz, 1H), 3.91 (d, J = 11.6 Hz, 1H), 3.62-3.55 (m, 2H), 2.75-2.70 (m, 2H), 2.47-2.42 (m, 2H), 2.05-2.02 (m, 1H), 1.73 (s, 3H), 0.95-0.93 (m, 4H) ppm 81 552.3 1H NMR (400 MHz, DMSO-d6) δ = 9.22-9.20 (m, 1H), 8.52-8.43 (m, 1H), 8.39 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.89-7.87 (m, 1H), 7.48-7.44 (m, 1H), 7.28-7.26 (m, 3H), 6.66-6.57 (m, 2H), 4.91-4.79 (m, 2H), 4.64-4.55 (m, 2H), 4.22-4.16 (m, 3H), 3.85 (d, J = 11.2 Hz, 1H), 3.68-3.48 (m, 5H), 2.68-2.62 (m, 2H), 2.46-2.34 (m, 4H), 1.68 (s, 3H), 1.14 (d, J = 6.4 Hz, 6H) ppm 82 552.3 1H NMR (400 MHz, DMSO-d6) δ = 9.20-9.17 (m, 1H), 8.44 (d, J = 4.8 Hz, 1H), 8.36 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.89-7.87 (m, 1H), 7.45-7.41 (m, 1H), 7.28-7.24 (m, 3H), 6.65 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 7.2 Hz, 1H), 4.91-4.80 (m, 2H), 4.61- 4.56 (m, 2H), 4.23-4.14 (m, 3H), 3.86 (d, J = 11.6 Hz, 1H), 3.64-3.58 (m, 2H), 3.47 (br d, J = 7.6 Hz, 2H), 2.64-2.59 (m, 2H), 2.39-2.31 (m, 4H), 1.68 (s, 3H), 1.15 (d, J = 6.0 Hz, 6H) ppm

    Examples 13 and 14: (R)-4-Cyano-N-((4-((1r,3R)-3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide and (R)-4-cyano-N-((4-((1s,3S)-3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide

    [1030] ##STR00638## ##STR00639##

    Step 1: 4-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyridine

    [1031] To a mixture of (4-bromo-2-pyridyl)methanol (3 g, 15.96 mmol) and imidazole (1.63 g, 23.93 mmol) in DCM (75 mL) was added TBSCI (2.89 g, 19.15 mmol, 2.35 mL) at 15° C. The mixture was stirred at 15° C. for 16 hrs. The mixture was filtered and the mother liquor was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=20/1-5/1) and to afford the title compound (5.4 g, crude) as a yellow oil.

    [1032] LCMS (ESI) m/z: [.sup.79BrM+H].sup.+=302.2.

    [1033] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.32 (d, J=5.2 Hz, 1H), 7.69 (d, J=0.8 Hz, 1H), 7.35-7.27 (m, 1H), 4.82 (s, 2H), 0.98 (s, 9H), 0.14 (s, 6H) ppm.

    Step 2: 1-Methoxy-3-vinylbenzene

    [1034] To a mixture of methyltriphenylphosphonium bromide (25.19 g, 70.51 mmol) in THE (100 mL) was added t-BuOK (8.57 g, 76.39 mmol) in several portions at 0° C. under N.sub.2. The mixture was stirred at 0° C. for 1 hr under N.sub.2. Then 3-methoxybenzaldehyde (8 g, 58.76 mmol, 7.14 mL) was added dropwise at 0° C. under N.sub.2. The mixture was stirred at 25° C. for 16 hr. The mixture was diluted with PE (100 mL) and filtered. The mother liquor was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE−PE/EA=100/1) to afford the title compound (4 g, 29.81 mmol, 50.7% yield) as a yellow oil.

    [1035] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.27-7.22 (m, 1H), 7.02 (d, J=7.6 Hz, 1H), 6.98-6.94 (m, 1H), 6.84-6.81 (m, 1H), 6.73-6.66 (m, 1H), 5.78-5.73 (m, 1H), 5.26 (d, J=10.8 Hz, 1H), 3.83 (s, 3H) ppm.

    Step 3: 3-(3-Methoxyphenyl)cyclobutan-1-one

    [1036] Trifluoromethanesulfonic anhydride (14.72 g, 52.17 mmol, 8.61 mL) was added dropwise at 0° C. under N.sub.2 to a mixture of DMA (3.90 g, 44.72 mmol, 4.16 mL) and DCE (50 mL). The mixture was stirred at 0° C. for 30 min. A mixture of 1-methoxy-3-vinylbenzene (5 g, 37.26 mmol, 5.17 mL) and 2,4,6-trimethylpyridine (6.32 g, 52.17 mmol, 6.89 mL) in DCE (25 mL) was then added dropwise under N.sub.2. The mixture was stirred at 90° C. for 16 hrs. Then the mixture was concentrated to afford a residue which was dissolved in CCl.sub.4 (50 mL) and H.sub.2O (50 mL). The mixture was stirred at 90° C. for 4 hrs. The reaction mixture was diluted with H.sub.2O (100 mL) and extracted with DCM (100 mL*2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE−PE/EA=20/1) to afford the title compound (3.2 g, 18.16 mmol, 48.7% yield) as a yellow oil.

    [1037] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.32-7.28 (m, 1H), 6.91 (d, J=7.6 Hz, 1H), 6.88-6.78 (m, 2H), 3.83 (s, 3H), 3.71-3.65 (m, 1H), 3.56-3.44 (m, 2H), 3.33-3.22 (m, 2H) ppm.

    Step 4: 1-(2-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-3-(3-methoxyphenyl)cyclobutan-1-ol

    [1038] To a mixture of 4-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (3.29 g, 10.90 mmol) in THE (30 mL) was added n-BuLi (2.5 M, 5.45 mL) dropwise at −70° C. The mixture was stirred at −70° C. for 1 hr. A solution of 3-(3-methoxyphenyl)cyclobutan-1-one (1.6 g, 9.08 mmol) in THE (10 mL) was then added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hr. The reaction mixture was added dropwise to H.sub.2O (150 mL) and extracted with EA (100 mL*2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=10/1-2/1) to afford the title compound (1.6 g, 4.00 mmol, 44.1% yield) as a yellow solid.

    [1039] LCMS (ESI) m/z: [M+H].sup.+=400.1.

    [1040] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.56 (d, J=5.2 Hz, 1H), 7.79 (d, J=1.2 Hz, 1H), 7.43-7.40 (m, 1H), 7.30-7.27 (m, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.86-6.83 (m, 1H), 6.80-6.77 (m, 1H), 4.90 (s, 2H), 3.83 (s, 3H), 3.27-3.16 (m, 1H), 3.06-2.94 (m, 2H), 2.66-2.55 (m, 2H), 2.19 (s, 1H), 0.99 (s, 9H), 0.16 (s, 6H) ppm.

    Step 5: O-(1-(2-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-3-(3-methoxyphenyl)cyclobutyl)S-methyl carbonodithioate

    [1041] To a mixture of NaH (250.23 mg, 6.26 mmol, 60% purity) in THE (8 mL) was added a solution of 1-(2-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-3-(3-methoxyphenyl)cyclobutan-1-ol (1 g, 2.50 mmol) in THE (12 mL) dropwise at 0° C. under N.sub.2. The mixture was stirred at 10° C. for 30 min under N.sub.2. Then CS.sub.2 (1.02 g, 13.39 mmol, 809.05 uL) was added dropwise to the mixture at 0° C. The mixture was stirred at 10° C. for 1 hr. Then MeI (923.53 mg, 6.51 mmol, 405.06 uL) was added to the mixture dropwise at 0° C. The mixture was stirred at 10° C. for 1 hr. The reaction mixture was quenched with MeOH (2 mL), diluted with H.sub.2O (40 mL) and extracted with EA (30 mL*3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel chromatography (PE/EA=10/1-3/1) to afford the title compound (1.08 g, 2.21 mmol, 88.1% yield) as a yellow solid.

    [1042] LCMS (ESI) m/z: [M+H].sup.+=490.5.

    [1043] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.52 (d, J=5.2 Hz, 1H), 7.65 (d, J=0.8 Hz, 1H), 7.26-7.23 (m, 2H), 6.87 (d, J=7.6 Hz, 1H), 6.82-6.78 (m, 2H), 4.88 (s, 2H), 3.83 (s, 3H), 3.44-3.34 (m, 1H), 3.23-3.18 (m, 2H), 2.93-2.86 (m, 2H), 2.50 (s, 3H), 0.99 (s, 9H), 0.14 (s, 6H) ppm.

    Step 6: 2-(((tert-Butyldimethylsilyl)oxy)methyl)-4-(3-(3-methoxyphenyl)cyclobutyl)pyridine

    [1044] To a mixture of O-(1-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-4-yl)-3-(3-methoxyphenyl)cyclobutyl)S-methyl carbonodithioate (1.08 g, 2.21 mmol) in toluene (11 mL) was added Bu.sub.3SnH (1.93 g, 6.62 mmol, 1.75 mL) and triethylborane (1 M, 6.62 mL) at 25° C. The mixture was stirred at 25° C. for 16 hrs. The mixture was poured into saturated KF aqueous solution (30 mL) and stirred at 15° C. for 30 min. The mixture was then extracted with EA (30 mL*3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=20/1-5/1) to afford the title compound (740 mg, 1.88 mmol, 85.0% yield) as a yellow oil.

    [1045] LCMS (ESI) m/z: [M+H].sup.+=384.2.

    Step 7: (4-(3-(3-Methoxyphenyl)cyclobutyl)pyridin-2-yl)methanol

    [1046] A mixture of 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(3-(3-methoxyphenyl)cyclobutyl)pyridine (740 mg, 1.93 mmol) in DCM (4 mL) and TFA (12.32 g, 108.05 mmol, 8 mL) was stirred at 25° C. for 72 hrs. The mixture was poured into H.sub.2O (50 mL) and the pH adjusted to 9 with NaHCO.sub.3. The mixture was extracted with DCM (30 mL*2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=5/1−EA) to afford the title compound (470 mg, 1.75 mmol, 90.5% yield) as a yellow oil.

    [1047] LCMS (ESI) m/z: [M+H].sup.+=270.0.

    Step 8: 2-((4-(3-(3-Methoxyphenyl)cyclobutyl)pyridin-2-yl)methyl)isoindoline-1,3-dione

    [1048] To a mixture of (4-(3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methanol (200 mg, 742.56 umol), isoindoline-1,3-dione (163.88 mg, 1.11 mmol) and PPh.sub.3 (292.15 mg, 1.11 mmol) in THE (4 mL) was added DIAD (225.23 mg, 1.11 mmol, 216.57 uL) dropwise at 0° C. under N.sub.2. The mixture was stirred at 25° C. for 15 hrs. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel chromatography (PE/EA=10/1-1/1) to afford the title compound (245 mg, 582.96 umol, 78.5% yield) as a yellow oil.

    [1049] LCMS (ESI) m/z: [M+H].sup.+=399.3.

    [1050] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.50-8.39 (m, 1H), 7.94-7.86 (m, 2H), 7.80-7.69 (m, 2H), 7.26-6.70 (m, 6H), 5.04-4.98 (m, 2H), 3.87-3.77 (m, 3H), 3.69-3.41 (m, 2H), 2.86-2.15 (m, 4H) ppm.

    Step 9: (4-(3-(3-Methoxyphenyl)cyclobutyl)pyridin-2-yl)methanamine

    [1051] To a mixture of 2-((4-(3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methyl)isoindoline-1,3-dione (245 mg, 614.88 umol) in MeOH (3 mL) was added NH.sub.2NH.sub.2.H.sub.2O (307.81 mg, 6.15 mmol, 298.84 uL). The mixture was stirred at 25° C. for 30 min. The mixture was poured into H.sub.2O (20 mL) and extracted with EA (20 mL*3). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the title compound (170 mg, crude) as a yellow oil.

    [1052] LCMS (ESI) m/z: [M+H].sup.+=269.2.

    Step 10: (R)-4-Cyano-N-((4-(3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide

    [1053] To a mixture of (4-(3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methanamine (80 mg, 298.12 umol) (4R)-4-cyano-4-methyl-isochromane-6-carboxylic acid (64.76 mg, 298.12 umol), EDCI (85.72 mg, 447.17 umol) and HOBt (60.42 mg, 447.17 umol) in DMF (1.5 mL) was added DIEA (115.59 mg, 894.35 umol, 155.78 uL). The mixture was stirred at 25° C. for 1 hr. The mixture was poured into H.sub.2O (15 mL) and extracted with EA (10 mL*2). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=5/1−EA) to afford the title compound (85 mg, 175.04 umol, 58.7% yield) as a yellow solid.

    [1054] LCMS (ESI) m/z: [M+H].sup.+=468.4.

    Step 11: (R)-4-Cyano-N-((4-((1r,3R)-3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide and (R)-4-cyano-N-((4-((1s,3S)-3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide

    [1055] (R)-4-Cyano-N-((4-(3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide (85 mg, 181.80 umol) was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH.sub.3H2OIPA]; B %: 50%-50%, 5.0 min; 30 min). The mobile phase (Peak 1, Rt=0.487 min) was concentrated under reduced pressure to afford a yellow solid. The yellow solid was purified by reverse phase column (0.1% FA condition). The eluent was concentrated under reduced pressure to remove MeCN and lyophilized to afford (R)-4-cyano-N-((4-((1s,3S)-3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide (34.42 mg, 73.62 umol, 40.5% yield, 100% purity) as a white solid. The mobile phase (Peak 2, Rt=0.679 min) was concentrated under reduced pressure to afford a yellow solid. The yellow solid was purified by reverse phase column (0.1% FA condition). The eluent was concentrated under reduced pressure to remove MeCN and lyophilized to afford: (R)-4-cyano-N-((4-((1r,3R)-3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide (14.46 mg, 30.93 umol, 17.01% yield) as a white solid.

    (R)-4-Cyano-N-((4-((1s,3S)-3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide

    [1056] LCMS (ESI) m/z: [M+H]+=468.3.

    [1057] .sup.1H NMR (400 MHz, MeOD-d4) δ=8.40 (d, J=5.2 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.86-7.83 (m, 1H), 7.34 (s, 1H), 7.28-7.21 (m, 2H), 7.18-7.14 (m, 1H), 6.81-6.80 (m, 1H), 6.77-6.70 (m, 2H), 4.90 (d, J=3.6 Hz, 2H), 4.69 (s, 2H), 4.19 (d, J=11.2 Hz, 1H), 3.91 (d, J=11.2 Hz, 1H), 3.75 (s, 3H), 3.61-3.48 (m, 2H), 2.86-2.74 (m, 2H), 2.26-2.15 (m, 2H), 1.73 (s, 3H) ppm.

    [1058] Chiral SFC: AD-3_5CM_MEOH(DEA)_5_40_3ML_AT35.M, Rt=0.493 min, ee %=100%.

    (R)-4-Cyano-N-((4-((1r,3R)-3-(3-methoxyphenyl)cyclobutyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide

    [1059] LCMS (ESI) m/z: [M+H].sup.+=468.3.

    [1060] .sup.1H NMR (400 MHz, MeOD-d4) δ=8.46 (d, J=5.2 Hz, 1H), 8.14 (d, J=1.2 Hz, 1H), 7.90-7.87 (m, 1H), 7.46 (s, 1H), 7.37 (d, J=5.2 Hz, 1H), 7.32-7.21 (m, 2H), 6.92 (d, J=7.6 Hz, 1H), 6.87 (s, 1H), 6.78-6.75 (m, 1H), 4.92-4.91 (m, 2H), 4.74 (s, 2H), 4.20 (d, J=11.2 Hz, 1H), 3.93 (d, J=11.6 Hz, 1H), 3.81 (s, 3H), 3.73-3.61 (m, 2H), 2.72-2.58 (m, 4H), 1.76 (s, 3H) ppm.

    [1061] Chiral SFC: Cellucoat-IPA+ACN(DEA)-50-3 mL-35T, Rt=0.639 min, ee %=100%.

    [1062] The following examples in Table 12 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Examples 13 and 14.

    TABLE-US-00013 TABLE 12 Compounds of the Invention LCMS # (m/z) 1H NMR 70 468.4 .sup.1H NMR (400 MHz, MeOD) δ = 8.30 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.77- 7.74 (m, 1H), 7.24 (s, 1H), 7.16-7.12 (m, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 4.81-4.79 (m, 2H), 4.58 (s, 2H), 4.09 (d, J = 11.6 Hz, 1H), 3.81 (d, J = 11.6 Hz, 1H), 3.64 (s, 3H), 3.41-3.35 (m, 2H), 2.68-2.62 (m, 2H), 2.10-2.05 (m, 2H), 1.61 (s, 3H) ppm 72 468.4 1H NMR (400 MHz, MeOD) δ = 8.44 (d, J = 4.8 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.87-7.85 (m, 1H), 7.43 (s, 1H), 7.34 (d, J = 4.8 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.91-4.90 (m, 2H), 4.71 (s, 2H), 4.19 (d, J = 11.2 Hz, 1H), 3.92 (d, J = 11.2 Hz, 1H), 3.76 (s, 3H), 3.66-3.57 (m, 2H), 2.60-2.57 (m, 4H), 1.73 (s, 3H) ppm

    Example 15: (R)-4-Cyano-4-methyl-N-((4-(6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridin-2(1H)-yl)pyridin-2-yl)methyl)isochromane-6-carboxamide

    [1063] ##STR00640##

    Step 1: (R)-4-cyano-4-methyl-N-((4-(6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridin-2(1H)-yl)pyridin-2-yl)methyl)isochromane-6-carboxamide

    [1064] To a mixture of (4R)—N-[(4-bromo-2-pyridyl)methyl]-4-cyano-4-methyl-isochroman e-6-carboxamide (30 mg, 77.67 umol) in DMSO (1 mL) was added 2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one (43.22 mg, 155.34 umol, TEA salt) and DIEA (50.19 mg, 388.36 umol, 67.64 uL) at 30° C. The mixture was stirred at 120° C. for 40 hrs. The mixture was poured into H.sub.2O (10 mL) and extracted with EA (10 mL*2). The aqueous phase was purified by reverse phase column (0.1% FA condition). The eluent was concentrated under reduced pressure to remove MeCN and lyophilized to afford the title compound (10.33 mg, 20.04 umol, 25.8% yield, FA salt) as a yellow solid.

    [1065] LCMS (ESI) m/z: [M+H]+=470.2.

    [1066] .sup.1H NMR (400 MHz, MeOD) δ=8.65-8.41 (9, 1H), 8.18-8.09 (m, 2H), 7.87-7.84 (m, 1H), 7.50 (d, J=6.8 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.98 (brd, J=6.4 Hz, 1H), 6.28 (d, J=7.2 Hz, 1H), 4.89 (d, J 2.6 Hz, 2H), 4.64 (m, 2H), 4.48 (m, 2H), 4.19 (d, J 11.6 Hz, 1H), 3.92 (d, J=11.6 Hz, 1H), 3.78-3.75 (m, 2H), 3.55 (s, 3H), 2.74-2.71 (m, 2H), 1.75 (s, 3H) ppm.

    [1067] Chiral SFC: AD-3-MeOH+ACN(DEA)-50-3 mL-35T, Rt=0.893 m, ee %=100%.

    [1068] The following examples in Table 13 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 15.

    TABLE-US-00014 TABLE 13 Compounds of the Invention LCMS # (m/z) 1H NMR 49 487.3 1H NMR (400 MHz, DMSO-d6) δ = 9.09-9.06 (m, 1H), 8.27 (s, 1H), 8.13-8.17 (m, 2H), 7.87-7.85 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.80- 6.78 (m, 1H), 6.75-6.71 (m, 1H), 6.67-6.64 (m, 1H), 4.91-4.80 (m, 2H), 4.50- 4.41 (m, 4H), 4.21 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.77 (s, 3H), 3.63- 3.60 (m, 2H), 2.68-2.65 (m, 2H), 1.68 (s, 3H) ppm 50 453.2 1HNMR (400 MHz, MeOD-d4) δ = 9.18-9.05 (m, 1H), 8.15 (s, 0.5H), 8.14 (d, J = 1.6 Hz, 1H), 8.10 (d, J = 6.0 Hz, 1H), 7.89-7.85 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.15-7.07 (m, 4H), 6.80-6.72 (m, 2H), 4.93-4.78 (m, 2H), 4.54-4.41 (m, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.68-3.61 (m, 4H), 2.93-2.85 (m, 4H), 1.69 (s, 3H) ppm 51 487.3 1H NMR (400 MHz, DMSO-d6) δ = 9.09-9.06 (m, 1H), 8.27 (s, 1H), 8.13-8.17 (m, 2H), 7.87-7.85 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 6.80- 6.78 (m, 1H), 6.75-6.71 (m, 1H), 6.67-6.64 (m, 1H), 4.91-4.80 (m, 2H), 4.50- 4.41 (m, 4H), 4.21 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.77 (s, 3H), 3.63- 3.60 (m, 2H), 2.68-2.65 (m, 2H), 1.68 (s, 3H) ppm 53 426.4 1H NMR (400 MHz, DMSO-d6) δ = 9.17-9.14 (m, 1H), 8.64 (s, 1H), 8.52 (d, J = 4.8 Hz, 1H), 8.18-8.16 (m, 2H), 7.91-7.88 (m, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 6.56-6.54 (m, 1H), 4.92-4.81 (m, 2H), 4.70 (d, J = 4.8 Hz, 4H), 4.58-4.45 (m, 2H), 4.22 (d, J = 11.2 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm 54 469.1 1HNMR (400 MHz, DMSO-d6) δ = 9.13-9.04 (m, 1H), 8.12 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.91-7.83 (m, 1H), 7.54 (d, J = 7.2 Hz, 2H), 7.40-7.32 (m, 2H), 7.31- 7.21 (m, 2H), 6.47-6.36 (m, 2H), 5.64-5.35 (m, 1H), 4.93-4.76 (m, 2H), 4.49- 4.40 (m, 2H), 4.20 (d, J = 11.6 Hz, 1H), 3.84 (d, J = 11.6 Hz, 1H), 3.56-3.45 (m, 4H), 2.43-2.34 (m, 1H), 2.24-2.11 (m, 1H), 1.66 (s, 3H) ppm 55 467.3 1H NMR (400 MHz, MeOD) δ = 8.10 (s, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.87-7.85 (m, 1H), 7.32-7.22 (m, 6H), 7.11-7.04 (m, 2H), 4.89 (d, J = 2.0 Hz, 2H), 4.65 (s, 2H), 4.33-4.25 (m, 1H), 4.24-4.13 (m, 2H), 3.93-3.91 (m, 1H), 3.30-3.23 (m, 2H), 2.89-2.72 (m, 1H), 2.09-2.06 (m, 1H), 2.02-1.86 (m, 2H), 1.71 (d, J = 5.2 Hz, 4H) ppm 56 469.1 1HNMR (400 MHz, DMSO-d6) δ = 13.34-13.30 (m, 1H), 9.27-9.25 (m, 1H), 8.23- 8.18 (m, 1H), 8.12 (d, J = 1.2 Hz, 1H), 7.88-7.86 (m, 1H), 7.31-7.20 (m, 4H), 6.91- 6.85 (m, 2H), 4.92-4.78 (m, 4H), 4.64-4.62 (m, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.87- 3.85(m, 3H), 3.80 (s, 3H), 2.87-2.84 (m, 2H), 1.68 (s, 3H) ppm 57 445.3 1H NMR (400 MHz, DMSO-d6) δ = 9.27-9.24 (m, 1H), 8.24-8.06 (m, 2H), 7.90- 7.88 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.13 (br s, 1H), 7.08-6.99 (m, 1H), 5.00- 4.76 (m, 2H), 4.57 (br d, J = 5.6 Hz, 2H), 4.30-4.15 (m, 2H), 4.02 (br d, J = 13.2 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.07-3.05 (m, 1H), 2.74-2.70 (m, 1H), 1.78-1.54 (m, 7H), 1.31-1.19 (m, 3H), 1.18-1.05 (m, 2H), 1.04-0.88 (m, 2H) ppm 58 483.1 1HNMR (400 MHz, DMSO-d6) δ = 9.29 (s, 1H), 8.21-8.06 (m, 2H), 7.89 (d, J = 8.0 Hz, 1H), 7.50-7.36 (m, 5H), 7.29 (d, J = 8.0 Hz, 1H), 6.92-6.70 (m, 2H), 4.96- 4.78 (m, 2H), 4.59 (d, J = 5.6 Hz, 2H), 4.22 (d, J = 11.2 Hz, 1H), 4.07 (d, J = 12.8 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.65 (d, J = 12.0 Hz, 2H), 3.59-3.51 (m, 1H), 2.92 (s, 3H), 2.72-2.65 (m, 1H), 2.42-2.31 (m, 1H), 1.68 (s, 3H) ppm 59 478.1 1H NMR (400 MHz, DMSO-d6) δ = 9.16-9.12 (m, 1H), 8.18-8.10 (m, 2H), 7.89- 7.86 (m, 1H), 7.67 (d, J = 3.2 Hz, 1H), 7.59-7.53 (m, 2H), 7.26 (d, J = 8.0 Hz, 1H), 7.19-7.12 (m, 1H), 7.10-7.01 (m, 1H), 6.53 (d, J = 3.2 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.42-6.40 (m, 1H), 5.68-5.54 (m, 1H), 4.93-4.75 (m, 2H), 4.56-4.40 (m, 4H), 4.28-4.18 (m, 3H), 3.85 (d, J = 11.6 Hz, 1H), 1.68 (s, 3H) ppm 63 489.2 1H NMR (400 MHz, DMSO-d6) δ = 9.09-9.06 (m, 1H), 8.21-8.08 (m, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.41-7.32 (m, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.14- 6.84 (m, 2H), 6.83-6.77 (m, 1H), 4.98-4.76 (m, 2H), 4.57 (s, 2H), 4.54-4.42 (m, 2H), 4.21 (d, J = 11.2 Hz, 1H), 3.86 (d, J = 11.2 Hz, 1H), 3.63-3.60 (m, 2H), 2.95 (s, 2H), 1.68 (s, 3H) ppm. 66 457.1 1H NMR (400 MHz, MeOD) δ = 8.10 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 5.6 Hz, 1H), 7.84-7.82 (m, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.18-7.17(m, 4H), 6.98-6.95 (m, 1H), 4.87 (s, 2H), 4.72 (d, J = 2.4 Hz, 2H), 4.54 (s, 2H), 4.19 (d, J = 11.6 Hz, 1H), 3.91 (d, J = 11.2 Hz, 1H), 3.73-3.70 (m, 2H), 3.00-2.97 (m, 2H), 1.73 (s, 3H) ppm. 67 489.2 1H NMR (400 MHz, DMSO-d6) δ = 9.11-9.08 (m, 1H), 8.25 (s, 1H), 8.18-8.10 (m, 2H), 7.88-7.86 (m, 1H), 7.39 (d, J = 9.6 Hz, 3H), 7.27 (d, J = 8.0 Hz, 1H), 7.14- 6.84 (m, 2H), 6.81-6.78 (m, 1H), 4.94-4.78 (m, 2H), 4.58-4.41 (m, 4H), 4.21 (d, J = 11.2 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.63-3.60 (m, 2H), 2.96-2.94 (m, 2H), 1.68 (s, 3H) ppm. 68 443.3 1H NMR (400 MHz, MeOD) δ = 8.29 (br s, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 6.0 Hz, 1H), 7.86-7.84 (m, 1H), 7.38-7.36 (m, 2H), 7.33-7.31 (m, 2H), 7.25 (d, J = 8.0 Hz, 1H), 6.79-6.75 (m, 1H), 4.98 (d, J = 3.2 Hz, 4H), 4.88 (s, 2H), 4.73 (d, J = 2.0 Hz, 2H), 4.19 (d, J = 11.6 Hz, 1H), 3.91 (d, J = 11.6 Hz, 1H), 1.73 (s, 3H) ppm. 75 440.3 1H NMR (400 MHz, MeOD) δ = 8.85 (d, J = 3.2 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.87-7.84 (m, 1H), 7.29-7.18 (m, 5H), 6.99 (d, J = 2.8 Hz, 1H), 4.89 (d, J = 2.8 Hz, 2H), 4.73 (s, 2H), 4.61 (s, 2H), 4.18 (d, J = 11.2 Hz, 1H), 3.91 (d, J = 11.6 Hz, 1H), 3.73-3.69 (m, 2H), 3.02-2.98 (m, 2H), 1.74 (s, 3H) ppm

    Example 16: (4R)-4-Cyano-N-((4-(3-fluoro-3-phenylpyrrolidin-1-yl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide

    [1069] ##STR00641##

    Step 1: (4R)-4-Cyano-N-((4-(3-fluoro-3-phenylpyrrolidin-1-yl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide

    [1070] To a solution of (4R)-4-cyano-N-((4-(3-hydroxy-3-phenylpyrrolidin-1-yl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide (20 mg, 42.69 umol) in DCM (0.5 mL) was added DAST (34.40 mg, 213.43 umol, 28.20 uL) at −78° C. The mixture was stirred at −78° C. for 1 hr then poured into water (30 mL) and extracted with EA (10 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex Gemini NX-C18 (75*30 mm*3 um); mobile phase: [water (10 mM NH.sub.4HCO.sub.3)-ACN]; B %: 38%-58%, 8 min). The product fraction was concentrated under vacuum to remove MeCN and lyophilized to give the title compound (3.55 mg, 7.27 umol, 17.04% yield) as a white solid.

    [1071] LCMS (ESI) m/z: [M+H].sup.+=471.1.

    [1072] .sup.1HNMR (400 MHz, MeOD-d4) δ=8.15-8.03 (m, 2H), 7.89-7.77 (m, 1H), 7.54 (d, J=7.6 Hz, 2H), 7.48-7.34 (m, 3H), 7.25 (d, J=8.4 Hz, 1H), 6.59 (s, 1H), 6.56-6.44 (m, 1H), 4.88 (br d, J=3.2 Hz, 3H), 4.17 (d, J=11.2 Hz, 1H), 3.96-3.79 (m, 3H), 3.78-3.58 (m, 3H), 2.74-2.47 (m, 2H), 1.72 (s, 3H) ppm.

    [1073] Chiral SFC: IC-3-EtOH (DEA)-60-3 mL-35T.lcm; Rt=1.386 mins, Rt=1.826 mins.

    Example 17: (R)-4-Cyano-N-((4-((3-cyanobenzyl)oxy)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide

    [1074] ##STR00642##

    Step 1: (R)-4-Cyano-N-((4-((3-cyanobenzyl)oxy)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide

    [1075] To a mixture of (R)—N-((4-bromopyridin-2-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide (100 mg, 258.91 umol) in DMSO (1 mL) was added Cs.sub.2CO.sub.3 (168.71 mg, 517.81 umol) and 3-(hydroxymethyl) benzonitrile (68.94 mg, 517.81 umol). The mixture was stirred at 100° C. for 16 hrs. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL*2). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by prep. HPLC (FA condition) and the product fraction was concentrated under vacuum to remove MeCN followed by lyophilization to give the title compound (15.18 mg, 31.74 umol, 12.26% yield) as a white solid.

    [1076] LCMS (ESI) m/z: [M+H].sup.+=439.1

    [1077] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.18-9.15 (m, 1H), 8.36 (d, J=5.6 Hz, 1H), 8.12 (d, J=1.2 Hz, 1H), 7.90-7.86 (m, 2H), 7.81-7.76 (m, 2H), 7.59-7.55 (m, 1H), 7.27 (d, J=8.4 Hz, 1H), 6.97-6.95 (m, 2H), 5.23 (s, 2H), 4.91-4.80 (m, 2H), 4.54-4.52 (m, 2H), 4.21 (d, J=11.2 Hz, 1H), 3.85 (d, J=11.6 Hz, 1H), 1.68 (s, 3H) ppm.

    [1078] Chiral SFC: Cellucoat-MeOH(DEA)-40-3 mL-35T.lcm, Rt=0.680 min, ee value=100%.

    [1079] The following examples in Table 14 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 17.

    TABLE-US-00015 TABLE 14 Compounds of the Invention LCMS # (m/z) 1H NMR 64 439.1 1H NMR (400 MHz, MeOD) δ = 8.38-8.32 (m, 1 H), 8.12-8.08 (m, 1 H), 7.84- 7.80 (m, 1 H), 7.69-7.63 (m, 2 H), 7.60-7.55 (m, 2 H), 7.30-7.25 (m, 1 H), 7.04- 7.00 (m, 2 H), 5.35-5.29 (m, 2 H), 4.93-4.90 (m, 2 H), 4.66-4.63 (m, 2 H), 4.26- 3.90 (m, 2 H), 1.75 (s, 3 H) ppm

    Example 18: (R)—N-((4-(Benzylthio)pyridin-2-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide

    [1080] ##STR00643##

    Step 1: (R)—N-((4-(Benzylthio)pyridin-2-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide

    [1081] To a solution of phenylmethanethiol (28.94 mg, 233.01 umol, 27.30 uL) in DMF (0.5 mL) was added NaH (8.70 mg, 217.48 umol, 60% purity) at 0° C. The reaction mixture stirred at 0° C. for 0.5 hr. (R)—N-((4-bromopyridin-2-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide (30 mg, 77.67 umol) was then added into the mixture. The reaction was stirred at 25° C. for 2 hrs. The mixture was poured into water (60 mL) and extracted with EA (30 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by prep-TLC (PE/EA=0/1) and lyophilized to give the title compound (23.19 mg, 53.16 umol, 68.45% yield) as a white solid.

    [1082] LCMS (ESI) m/z: [M+H].sup.+=430.0

    [1083] .sup.1HNMR (400 MHz, MeOD-d4) δ=8.23 (d, J=5.6 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.90-7.79 (m, 1H), 7.39-7.31 (m, 2H), 7.29-7.24 (m, 2H), 7.23-7.12 (m, 4H), 4.90 (d, J=4.0 Hz, 2H), 4.61 (s, 2H), 4.28 (s, 2H), 4.19 (d, J=11.6 Hz, 1H), 3.91 (d, J=11.2 Hz, 1H), 1.74 (s, 3H) ppm.

    [1084] Chiral SFC: AD-3-MeOH+ACN (DEA)-60-3 mL-35T.lcm; Rt=0.585 mins, ee %=100%.

    Example 19: (4R)-4-Cyano-N-((4-(1-(6-(difluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide

    [1085] ##STR00644## ##STR00645##

    Step 1: 2-((4-Bromopyridin-2-yl)methyl)isoindoline-1,3-dione

    [1086] To a solution of (4-bromopyridin-2-yl)methanol (20 g, 106.37 mmol), isoindoline-1,3-dione (23.48 g, 159.56 mmol) and PPh.sub.3 (41.85 g, 159.56 mmol) in THE (400 mL) was added DIAD (32.26 g, 159.56 mmol) at 0° C. The resulting mixture was stirred at 30° C. for 2 hrs. The reaction mixture was poured into water (1000 mL) and EA (1000 mL), the solution was filtered and the filter cake was dried under vacuum to give the title compound (32 g, 100.90 mmol, 94.86% yield) as a white solid.

    Step 2: tert-Butyl 3-(2-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

    [1087] To a solution of 2-((4-bromopyridin-2-yl)methyl)isoindoline-1,3-dione (700 mg, 2.21 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (977.31 mg, 3.31 mmol) in dioxane (8 mL) and H.sub.2O (2 mL) was added [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (143.86 mg, 220.72 umol) and K.sub.3PO.sub.4 (937.06 mg, 4.41 mmol) at 25° C. under N.sub.2 atmosphere. The mixture was stirred for 2 hr at 60° C. Water (10 mL) was added and the mixture extracted with EA (20 mL*3). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=100/1 to 1/100) to give the title compound (890 mg, 2.20 mmol, 99.45% yield) as a yellow oil.

    [1088] LCMS (ESI) m/z: [M+H].sup.+=406.0.

    [1089] .sup.1HNMR (400 MHz, MeOD-d4) δ=8.43-8.37 (m, 1H), 7.93-7.88 (m, 2H), 7.86-7.81 (m, 2H), 7.46 (d, J=4.4 Hz, 1H), 7.36-7.33 (m, 1H), 6.66-6.58 (m, 1H), 4.99 (s, 2H), 4.55-4.43 (m, 2H), 4.36-4.27 (m, 2H), 1.51 (d, J=5.6 Hz, 9H) ppm.

    Step 3: tert-Butyl 3-(2-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-4-yl)pyrrolidine-1-carboxylate

    [1090] To a solution of tert-butyl 3-(2-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (890 mg, 2.20 mmol) in MeOH (150 mL) was added Pd/C (100 mg, 220.35 umol, 10% purity) under H.sub.2 atmosphere, then the mixture was stirred under hydrogen atmosphere (20 Psi) for 2 hrs at 25° C. The mixture was filtered and the filtrate was concentrated to give the title compound (890 mg, 2.18 mmol, 99.51% yield) as a yellow oil which was used directly in the next step.

    [1091] LCMS (ESI) m/z: [M+H].sup.+=408.0.

    Step 4: 2-((4-(Pyrrolidin-3-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione hydrochloride

    [1092] To a solution of tert-butyl 3-(2-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-4-yl)pyrrolidine-1-carboxylate (300 mg, 515.39 umol) in dioxane (3 mL) was added HCl/dioxane (4 M, 3.00 mL). The mixture was stirred at 25° C. for 0.5 hr and then concentrated to give the title compound (160 mg, 465.38 umol, 90.30% yield) as yellow oil which was used directly in the next step.

    [1093] LCMS (ESI) m/z: [M+H].sup.+=308.0.

    Step 5: 2-((4-(1-(6-(Difluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione

    [1094] To a solution of 2-((4-(pyrrolidin-3-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione hydrochloride (160 mg, 465.38 umol) and 2-bromo-6-(difluoromethyl) pyridine (387.20 mg, 1.86 mmol) in DMSO (2 mL) was added DIEA (601.45 mg, 4.65 mmol, 810.59 uL) at 25° C., then the mixture was stirred for 12 hrs at 140° C. Water (3 mL) was added and the mixture extracted with EA (5 mL*3). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, PE: EA=1:1, Rf=0.3) to give the title compound (200 mg, 460.37 umol, 98.92% yield) as a yellow solid.

    [1095] LCMS (ESI) m/z: [M+H].sup.+=435.0.

    Step 6: (4-(1-(6-(Difluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)pyridin-2-yl)methanamine

    [1096] To a solution of 2-((4-(1-(6-(difluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)pyridin-2-yl)methyl)isoindoline-1,3-dione (50 mg, 115.09 umol) in EtOH (0.5 mL) was added N.sub.2H4.H.sub.2O (8.82 mg, 172.64 umol, 8.56 uL, 98% purity) at 25° C., then the mixture was stirred at 75° C. for 2 hrs. The mixture was filtered and the filtrate was concentrated to give the title compound (30 mg, 98.57 umol, 85.65% yield) as a yellow solid which was used directly in the next step.

    [1097] LCMS (ESI) m/z: [M+H].sup.+=305.0.

    Step 7: (4R)-4-Cyano-N-((4-(1-(6-(difluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide

    [1098] To a solution of (4-(1-(6-(difluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)pyridin-2-yl)methanamine (20 mg, 65.72 umol), (R)-4-cyano-4-methylisochromane-6-carboxylic acid (14.27 mg, 65.72 umol) in DMF (0.2 mL) was added EDCI (25.20 mg, 131.43 umo), HOBt (17.76 mg, 131.43 umol) and DIEA (21.23 mg, 164.29 umol, 28.62 uL). The mixture was stirred at 25° C. for 1 hr. Water (3 mL) was added and the mixture extracted with EA (5 mL*3). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 33%-63%, 8.5 min) and lyophilized to give the title compound (8 mg, 15.77 umol, 24.00% yield) as a yellow solid.

    [1099] LCMS (ESI) m/z: [M+H].sup.+=504.3.

    [1100] .sup.1HNMR (400 MHz, MeOD-d4) δ=8.46 (d, J=5.2 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.84-7.80 (m, 1H), 7.61-7.55 (m, 1H), 7.39 (d, J=5.6 Hz, 1H), 7.32 (d, J=5.2 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.84-6.81 (m, 1H), 6.60-6.30 (m, 2H), 4.91 (d, J=4.0 Hz, 2H), 4.71 (s, 2H), 4.23-4.19 (m, 1H), 3.98-3.90 (m, 2H), 3.70-3.54 (m, 4H), 2.55-2.44 (m, 1H), 2.21-2.08 (m, 1H), 1.75 (d, J=1.6 Hz, 3H) ppm.

    [1101] Chiral SFC: AD-3-MeOH+ACN (DEA)-40-3ML-35T.lcm; Rt=0.974 min/Rt=1.137 min.

    [1102] The following examples in Table 15 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 19.

    TABLE-US-00016 TABLE 15 Compounds of the Invention LCMS # (m/z) 1H NMR 62 453.2 1HNMR (400 MHz, CDCl3) δ = 8.51 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.80- 7.76 (m, 1H), 7.61-7.53 (m, 1H), 7.26 (d, J = 4.0 Hz, 2H), 7.17-7.12 (m, 2H), 6.76- 6.71 (m, 1H), 6.62 (d, J = 8.0 Hz, 2H), 4.88 (s, 2H), 4.76 (d, J = 4.8 Hz, 2H), 4.14 (d, J = 11.2 Hz, 1H), 3.94 (d, J = 11.6 Hz, 1H), 3.77-3.72 (m, 1H), 3.58-3.51 (m, 2H), 3.50- 3.39 (m, 2H), 2.53-2.42 (m, 1H), 2.18-2.11 (m, 1H), 1.77 (s, 3H) ppm

    Example 20: (R)-4-Cyano-N-((4-((3-((2-methoxyethyl)carbamoyl)phenyl)ethynyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide

    [1103] ##STR00646##

    Step 1: (R)-3-((2-((4-Cyano-4-methylisochromane-6-carboxamido)methyl)pyridin-4-yl)ethynyl)benzoic acid

    [1104] A solution of methyl (R)-3-((2-((4-cyano-4-methylisochromane-6-carboxamido)methyl)pyridin-4-yl)ethynyl)benzoate (226.00 mg, 0.485 mmol, 1.00 equiv), LiOH.H.sub.2O (61.12 mg, 1.456 mmol, 3.00 equiv) and H.sub.2O (1.00 mL) in THE (5.00 mL) was stirred overnight at room temperature. The mixture was acidified to pH 5 with 2M HCl (aq.). The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (208 mg, 94.89%) as a light yellow solid.

    [1105] LCMS (ESI) m/z: [M+H].sup.+=452.

    [1106] .sup.1H NMR (300 MHz, DMSO-d6) δ 13.23 (s, 1H), 9.28 (t, J=5.9 Hz, 1H), 8.60 (dd, J=5.0, 0.9 Hz, 1H), 8.19-8.07 (m, 2H), 8.01 (dt, J=7.8, 1.5 Hz, 1H), 7.92 (dd, J=8.0, 1.7 Hz, 1H), 7.85 (dt, J=7.7, 1.5 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.54-7.44 (m, 2H), 7.29 (d, J=8.1 Hz, 1H), 4.98-4.75 (m, 2H), 4.63 (d, J=5.8 Hz, 2H), 4.22 (d, J=11.5 Hz, 1H), 3.86 (d, J=11.5 Hz, 1H), 1.70 (s, 3H).

    Step 2: (R)-4-Cyano-N-((4-((3-((2-methoxyethyl)carbamoyl)phenyl)ethynyl)pyridin-2-yl)methyl)-4-methylisochromane-6-carboxamide

    [1107] To a solution of (R)-3-((2-((4-cyano-4-methylisochromane-6-carboxamido)methyl)pyridin-4-yl)ethynyl)benzoic acid (20.00 mg, 0.044 mmol, 1.00 equiv) and 2-methoxyethan-1-amine (3.99 mg, 0.053 mmol, 1.2 equiv) in DMF (1.00 mL) was added HATU (25.27 mg, 0.066 mmol, 1.5 equiv) and DIEA (17.18 mg, 0.133 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction solution was purified by reverse flash chromatography to afford the title compound (10 mg, 44.39%) as a white solid.

    [1108] LCMS (ESI) m/z [M+H].sup.+=509.10.

    [1109] .sup.1H NMR (400 MHz, DMSO-d6) δ 9.30 (t, J=5.9 Hz, 1H), 8.63 (dd, J=22.5, 5.2 Hz, 2H), 8.16 (d, J=1.7 Hz, 1H), 8.07 (d, J=1.8 Hz, 1H), 7.92 (dq, J=8.0, 1.7 Hz, 2H), 7.75 (dt, J=7.7, 1.4 Hz, 1H), 7.55 (t, J=7.7 Hz, 1H), 7.46 (dd, J=6.9, 1.7 Hz, 2H), 7.29 (d, J=8.1 Hz, 1H), 4.96-4.78 (m, 2H), 4.63 (d, J=5.9 Hz, 2H), 4.22 (d, J=11.5 Hz, 1H), 3.86 (d, J=11.5 Hz, 1H), 3.45 (tt, J=9.6, 4.2 Hz, 4H), 3.26 (s, 3H), 1.69 (s, 3H).

    [1110] The following examples in Table 16 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 20.

    TABLE-US-00017 TABLE 16 Compounds of the Invention LCMS # (m/z) 1H NMR 84 479.25 1H NMR (300 MHz, DMSO-d6) δ 9.29 (t, J = 5.9 Hz, 1H), 8.60 (dd, J = 5.0, 0.9 Hz, 1H), 8.15 (d, J = 1.8 Hz, 1H), 7.91 (dd, J = 8.1, 1.8 Hz, 1H), 7.72-7.58 (m, 2H), 7.57- 7.42 (m, 4H), 7.29 (d, J = 8.0 Hz, 1H), 4.96-4.77 (m, 2H), 4.62 (d, J = 5.7 Hz, 2H), 4.22 (d, J = 11.5 Hz, 1H), 3.86 (d, J = 11.5 Hz, 1H), 2.94 (d, J = 26.3 Hz, 6H), 1.69 (s, 3H).

    Example 21. (R)-4-Cyano-4-methyl-N-((2-phenyl-1,6-naphthyridin-7-yl)methyl)chromane-6-carboxamide

    [1111] ##STR00647## ##STR00648##

    Step 1. 2-Bromo-5-iodo-pyridin-4-amine

    [1112] NIS (93.6 g, 416 mmol) was added to a solution of 2-bromopyridin-4-amine (60 g, 347 mmol) in MeCN (1.5 L) at 80° C. The reaction mixture was stirred at 80° C. for 36 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with saturated Na.sub.2SO.sub.3 (1.5 L) and extracted with EA (1.5 L×2). The combined organic layers were washed with brine (1 L), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, PE/EA=20:3) and concentrated under reduced pressure affording the title compound (65 g, 217 mmol) as a light yellow solid.

    [1113] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.31 (s, 1H), 6.79 (s, 1H), 4.75 (br s, 2H) ppm.

    Step 2. Ethyl-3-(4-amino-6-bromo-3-pyridyl)prop-2-enoate

    [1114] Ethyl prop-2-enoate (45.1 mL, 415 mmol), Et.sub.3N (43.3 mL, 311 mmol), Pd(OAc).sub.2 (2.3 g, 10.4 mmol), and tris-o-tolylphosphane (6.3 g, 20.7 mmol) was added to a solution of 2-bromo-5-iodo-pyridin-4-amine (62 g, 207 mmol) in DMF (620 mL). The mixture was stirred at 100° C. for 3 hrs. The reaction mixture was diluted with water (4 L) and extracted with EA (2 L×2). The combined organic layers were washed with brine (2 L), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, PE/EA=20:3) and concentrated under reduced pressure affording the title compound (50 g, 170 mmol) as a light yellow solid.

    [1115] LCMS (ESI) m/z: [79BrM+H]+=271.1.

    [1116] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.23 (s, 1H), 7.73 (d, J=16.0 Hz, 1H), 6.90-6.67 (m, 3H), 6.52 (d, J=16.0 Hz, 1H), 4.18 (d, J=7.2 Hz, 2H), 1.25 (d, J=7.2 Hz, 3H) ppm.

    Step 3. 7-Bromo-1H-1,6-naphthyridin-2-one

    [1117] NaSMe (24.2 mL, 380 mmol) was added to a solution of ethyl-3-(4-amino-6-bromo-3-pyridyl)prop-2-enoate (40 g, 148 mmol) in EtOH (200 mL). The reaction mixture was stirred at 60° C. for 2 hrs. The reaction mixture was diluted with water (400 mL) and then neutralized with 1 N HCl to pH=7.0. The solid was filtered and the filter cake was washed with water (50 mL). The filter cake was concentrated under reduced pressure affording the title compound (22 g, 96.8 mmol) as an off-white solid.

    [1118] LCMS (ESI) m/z: [79BrM+H]+=224.9.

    [1119] .sup.1H NMR (400 MHz, DMSO-d6) δ=12.08 (br s, 1H), 8.65 (s, 1H), 7.99 (d, J=9.6 Hz, 1H), 7.36 (s, 1H), 6.62 (d, J=9.6 Hz, 1H) ppm.

    Step 4. 2-Oxo-1H-1,6-naphthyridine-7-carbonitrile

    [1120] Zn (406.80 mg, 6.22 mmol) was added to a solution of 7-bromo-1H-1,6-naphthyridin-2-one (7 g, 31.1 mmol), Zn(CN).sub.2 (3.95 mL, 62.2 mmol), and Pd(dppf)Cl.sub.2—CH.sub.2C.sub.12 (5.08 g, 6.22 mmol) in DMA (140 mL). The reaction mixture was degassed and purged with N.sub.2 three times then the mixture was stirred at 120° C. for 2 hrs. The reaction mixture was diluted with water (200 mL) and extracted with DCM/isopropanol (v/v=3:1) (150 mL×2). The combined organic layers were filtered, washed with brine 20 (200 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, PE/EA=1:1) and concentrated under reduced pressure affording the title compound (3 g, 17.5 mmol) as an off-white solid.

    [1121] .sup.1H NMR (400 MHz, DMSO-d6) δ=12.37 (br s, 1H), 8.97 (s, 1H), 8.09 (d, J=9.6 Hz, 1H), 7.67 (s, 1H), 6.77 (d, J=9.6 Hz, 1H) ppm.

    Step 5. 2-Chloro-1,6-naphthyridine-7-carbonitrile

    [1122] A mixture of 2-oxo-1H-1,6-naphthyridine-7-carbonitrile (3.0 g, 17.5 mmol) and POCl.sub.3 (30 mL, 323 mmol) was stirred at 80° C. for 2 hrs. The reaction mixture was poured into H.sub.2O (2 L) and adjusted to pH=7 with NaHCO.sub.3. The solution was extracted with EA (1.5 L×2), the combined organic layers were washed with brine (2 L), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford the title compound (1.1 g, 5.76 mmol) as a brown solid.

    [1123] LCMS (ESI) m/z: [M+H]+=190.1.

    [1124] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.58 (d, J=0.8 Hz, 1H), 8.79 (d, J=0.8 Hz, 1H), 8.69 (s, 1H), 8.00 (d, J=8.8 Hz, 1H) ppm.

    Step 6. 2-Phenyl-1,6-naphthyridine-7-carbonitrile

    [1125] A mixture of 2-chloro-1,6-naphthyridine-7-carbonitrile (270 mg, 1.42 mmol), phenylboronic acid (208.4 mg, 1.71 mmol), K.sub.3PO.sub.4 (907 mg, 4.27 mmol), ditert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (92.8 mg, 142 μmol), and H.sub.2O (0.3 mL) in dioxane (3 mL) was degassed and purged with N.sub.2 three times. The mixture was stirred at 80° C. for 2 hrs. The reaction mixture was diluted with H.sub.2O (30 mL) and extracted with EA (30 mL×3). The combined organic layers were washed with brine (60 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=30/1 to 3/1) to afford the title compound (248 mg, 1.07 mmol) as a white solid.

    [1126] LCMS (ESI) m/z: [M+H]+=232.1

    [1127] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.52 (s, 1H), 8.80 (d, J=8.8 Hz, 1H), 8.69 (s, 1H), 8.53 (d, J=8.8 Hz, 1H), 8.37-8.30 (m, 2H), 7.65-7.60 (m, 3H) ppm.

    Step 7. tert-Butyl N-[(2-phenyl-1,6-naphthyridin-7-yl)methyl]carbamate

    [1128] Boc.sub.2O (340 mg, 1.56 mmol) and Et.sub.3N (0.29 mL, 2.08 mmol) were added to a solution of 2-phenyl-1,6-naphthyridine-7-carbonitrile (240 mg, 1.04 mmol) in MeOH (10 mL). Ni (305 mg, 5.19 mmol) was added and the reaction mixture was degassed and purged with H.sub.2 three times. The reaction mixture was stirred at 25° C. for 16 hrs under H.sub.2 atmosphere (15 psi). The suspension was filtered and the filter cake was washed with MeOH (2 mL×3), filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 1/1) affording the title compound (110 mg, 0.33 mmol) as a colorless oil.

    [1129] LCMS (ESI) m/z: [M+H]+=336.2.

    Step 8. (2-Phenyl-1,6-naphthyridin-7-yl)methanamine

    [1130] A mixture of tert-butyl N-[(2-phenyl-1,6-naphthyridin-7-yl)methyl]carbamate (110 mg, 328 μmol) in HCl/dioxane (4N, 5 mL) was stirred at 25° C. for 1 hr. The reaction mixture was concentrated under vacuum affording the title compound (118 mg, crude, HCl) as an off-white solid.

    [1131] LCMS (ESI) m/z: [M+H]+=236.2.

    Step 9. (4R)-4-Cyano-4-methyl-N-[(2-phenyl-1,6-naphthyridin-7-yl)methyl]chromane-6-carboxamide

    [1132] EDCI (27.5 mg, 0.14 mmol), HOBt (19.4 mg, 0.14 mmol), and DIEA (0.058 mL, 0.33 mmol) were added to a solution of (4R)-4-cyano-4-methyl-chromane-6-carboxylic acid (28.8 mg, 0.13 mmol) in DCM (1 mL). (2-phenyl-1,6-naphthyridin-7-yl)methanamine (30 mg, 0.11 mmol, HCl salt) was added to the reaction mixture and stirred at 25° C. for 2 hrs. The reaction mixture was diluted with H.sub.2O (20 mL) and extracted with EA (15 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase flash chromatography. The eluent was concentrated under reduced pressure to remove MeCN and the residue was lyophilized affording the title compound (13.6 mg, 0.030 mmol) as an off-white solid.

    [1133] LCMS (ESI) m/z: [M+H]+=435.1.

    [1134] .sup.1H NMR (400 MHz, CD.sub.3OD) δ=9.34-9.25 (m, 1H), 8.60 (d, J=9.6 Hz, 1H), 8.22-8.14 (m, 4H), 7.95 (s, 1H), 7.88 (d, J=2.4, 1H), 7.59-7.52 (m, 3H), 6.97 (d, J=8.4 Hz, 1H), 4.91 (s, 3H), 4.41-4.36 (m, 2H), 2.52-2.44 (m, 1H), 2.27-2.18 (m, 1H), 1.85 (s, 3H) ppm.

    [1135] The following examples in Table 17 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 21.

    TABLE-US-00018 TABLE 17 Compounds of the Invention LCMS # (m/z) 1H NMR 1 435.1 1H NMR (400 MHz, MeOD-d4) δ = 9.31 (s, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.22-8.14 (m, 4H), 7.99-7.90 (m, 2H), 7.59-7.52 (m, 3H), 7.29 (d, J = 8.0 Hz, 1H), 4.94-4.90 (m, 4H), 4.21 (d, J = 11.6 Hz, 1H), 3.92 (d, J = 11.6 Hz, 1H), 1.77 (s, 3H) ppm. 2 428.2 1H NMR (400 MHz, DMSO-d6) δ = 9.47-9.34 (m, 2H), 8.66 (d, J = 8.8 Hz, 1H), 8.34- 8.25 (m, 4H), 7.98 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.64-7.51 (m, 3H), 7.35-7.25 (m, 1H), 4.96-4.69 (m, 4H), 4.08 (m, 1H), 3.92-3.78 (m, 1H), 1.80-1.64 (m, 3H) ppm. 41 490.2 1H NMR (400 MHz, DMSO-d6) δ = 9.41-9.37 (m, 1H), 9.28 (s, 1H), 8.50 (br d, J = 8.4 Hz, 1H), 8.20-8.16 (m, 4H), 7.95 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.51 (d, J = 8.8 Hz, 2H), 4.94-4.77 (m, 6H), 4.23 (br d, J = 11.2 Hz, 2H), 3.96- 3.91 (m, 4H), 1.70 (s, 3H) ppm. 42 490.3 1H NMR (400 MHz, DMSO-d6) δ = 9.39-9.38 (m, 2H), 8.62 (d, J = 8.4 Hz, 1H), 8.23- 8.19 (m, 2H), 7.93-7.92 (m, 1H), 7.80 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.35-7.27 (m, 3H), 6.59-6.57 (m, 1H), 4.93-4.80 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.90-3.85 (m, 6H), 2.33 (br s, 1H), 1.70 (s, 3H) ppm. 5 426.1 1H NMR (400 MHz, MeOD-d4) δ = 9.31 (s, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.26-8.13 (m, 4H), 7.95 (s, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.59-7.52 (m, 3H), 7.19 (d, J = 8.0 Hz, 1H), 4.92 (s, 2H), 4.84 (d, J = 3.6 Hz, 2H), 3.82-3.73 (m, 2H), 1.56 (s, 3H) ppm. 6 424.3 1H NMR (400 MHz, MeOD-d4) δ = 9.30 (s, 1H), 8.59 (d, J = 0.8 Hz, 1H), 8.21-8.14 (m, 3H), 7.95 (s, 1H), 7.82-7.77 (m, 2H), 7.58-7.51 (m, 3H), 7.33 (d J = 7.6 Hz, 1H), 4.90 (s, 2H), 3.60-3.53 (m, 2H), 3.02-2.91 (m, 2H), 2.29-2.27 (m, 1H), 1.90-1.86 (m, 1H), 1.33 (s, 3H) ppm. 7 465.1 1H NMR (400 MHz, MeOD-d4) δ = 9.30 (s, 1H), 8.59-8.57 (m, 1H), 8.17-8.14 (m, 2H), 7.96 (s, 1H), 7.94-7.91 (m, 1H), 7.77-7.72 (m, 2H), 7.48-7.44 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.11-7.09 (m, 1H), 4.92-4.90 (m, 4H), 4.20 (d, J = 11.6 Hz, 1H), 3.93- 3.89 (m, 4H), 1.76 (s, 3H) ppm. 3 449.2 1H NMR (400 MHz, DMSO-d6) δ = 9.39 (s, 1H), 9.10 (d, J = 8.0 Hz, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.30-8.27 (m, 3H), 8.18 (d, J = 1.6 Hz, 1H), 7.96-7.88 (m, 2H), 7.58- 7.54 (m, 3H), 7.29 (d, J = 8.0 Hz, 1H), 5.44-5.39 (m, 1H), 4.92-4.81 (m, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 11.2 Hz, 1H), 1.72-1.63 (m, 6H) ppm. 4 449.2 1H NMR (400 MHz, DMSO-d6) δ = 9.39 (s, 1H), 9.09 (d, J = 7.6 Hz, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.31-8.21 (m, 4H), 7.97-7.90 (m, 2H), 7.58-7.55 (m, 3H), 7.29 (d, J = 8.4 Hz, 1H), 5.45-5.41 (m, 1H), 4.92-4.81 (m, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.85 (d, J = 11.6 Hz, 1H), 1.69-1.65 (m, 6H) ppm. 9 493.2 1H NMR (400 MHz, DMSO-d6) δ = 9.41-9.38 (m, 2H), 8.86-8.84 (m, 1H), 8.70 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 8.13-8.11 (m, 1H), 7.96-7.94 (m, 1H), 7.86 (s, 1H), 7.74-7.71 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.93-4.81 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 3.91-3.85 (m, 4H), 1.70 (s, 3H) ppm. 10 399.2 1H NMR (400 MHz, MeOD-d4) δ = 9.17 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 7.96-7.88 (m, 1H), 7.76 (s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 4.91 (d, J = 3.6 Hz, 2H), 4.87-4.86 (m, 2H), 4.20 (d, J = 11.6 Hz, 1H), 3.92 (d, J = 11.6 Hz, 1H), 2.35-2.26 (m, 1H), 1.76 (s, 3H), 1.21-1.17 (m, 4H) ppm. 11 508.2 1H NMR (400 MHz, MeOD-d4) δ = 9.31 (s, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.97-7.90 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 7.23- 7.17 (m, 1H), 7.06-7.02 (m, 1H), 6.35-6.28 (m, 1H), 4.93-4.90 (m, 4H), 4.21 (d, J = 11.4 Hz, 1H), 4.01-3.89 (m, 5H), 2.46-2.36 (m, 2H), 1.77 (s, 3H) ppm. 12 434.2 1H NMR (400 MHz, DMSO-d6) δ = 9.43 (s, 1H), 9.12-9.10 (m, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.41-8.29 (m, 3H), 8.06-7.93 (m, 2H), 7.82 (s, 1H), 7.62-7.60 (m, 3H), 6.80 (d, J = 8.4 Hz, 1H), 4.83 (d, J = 5.6 Hz, 2H), 3.92 (d, J = 9.6 Hz, 1H), 3.48 (d, J = 9.6 Hz, 1H), 2.90 (s, 3H), 1.77 (s, 3H) ppm. 14 485.1 1H NMR (400 MHz, DMSO-d6) δ = 9.42 (s, 2H), 8.71 (d, J = 8.4 Hz, 1H), 8.52 (s, 1H), 8.47 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.98-7.95 (m, 1H), 7.85 (s, 1H), 7.80- 7.67 (m, 2H), 7.35-7.01 (m, 2H), 5.03-4.73 (m, 4H), 4.24 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H), 1.71 (s, 3H) ppm. 15 421 1H NMR (400 MHz, DMSO-d6) δ = 9.37 (s, 1H), 9.24 (t, J = 6.0 Hz, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.30-8.27 (m, 3H), 8.17 (d, J = 1.6 Hz, 1H), 8.00-7.97 (m, 1H), 7.79 (s, 1H), 7.59-7.54 (m, 3H), 7.08 (d, J = 8.4 Hz, 1H), 5.02 (d, J = 9.6 Hz, 1H), 4.79 (d, J = 6.0 Hz, 2H), 4.56 (d, J = 9.6 Hz, 1H), 1.78 (s, 3H) ppm. 16 446.2 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.33 (m, 2H), 8.66 (d, J = 8.8 Hz, 1H), 8.33- 8.27 (m, 3H), 7.99 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.6 Hz, 2H), 7.60-7.54 (m, 4H), 7.44 (d, J = 6.8 Hz, 1H), 6.76-6.37 (m, 1H), 4.96 (s, 4H), 4.81 (d, J = 6.0 Hz, 2H) ppm 17 483.2 1H NMR (400 MHz, DMSO-d6) δ = 9.31 (s, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.20-8.07 (m, 2H), 7.99-7.85 (m, 2H), 7.61 (d, J = 1.6 Hz, 1H), 7.55-7.51 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.89-6.85 (m, 1H), 4.96-4.89 (m, 4H), 4.20 (d, J = 11.6 Hz, 1H), 3.94 (s, 1H), 3.91-3.90 (m, 3H), 1.76 (s, 3H) ppm 18 436.2 1H NMR (400 MHz, MeOD-d4) δ = 9.34 (s, 1H), 8.76-8.71 (m, 1H), 8.68-8.60 (m, 3H), 8.18 (d, J = 1.6 Hz, 1H), 8.03-7.96 (m, 2H), 7.95-7.92 (m, 1H), 7.55-7.50 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.95-4.90 (m, 4H), 4.21 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 1.77 (s, 3H) ppm 20 439.1 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.37 (m, 1H), 9.25 (s, 1H), 8.55 (s, 1H), 8.50 (d, J = 8.4 Hz, 1H), 8.21 (s, 2H), 7.98-7.93 (m, 2H), 7.65 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 4.94-4.84 (m, 2H), 4.78-4.77 (m, 2H), 4.25-4.22 (m, 1H), 3.92(s, 3H), 3.89-3.86 (m, 1H), 1.71 (s, 3H) ppm 21 489.2 1H NMR (400 MHz, MeOD) δ = 9.29 (s, 1H), 8.64 (s, 1H), 8.57 (d, J = 8.8 Hz, 1H), 8.39- 8.33 (m, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.20-8.14 (m, 2H), 7.98-7.92 (m, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 4.93-4.91 (m, 4H), 4.21 (d, J = 11.4 Hz, 1H), 4.12 (s, 3H), 3.93 (d, J = 11.6 Hz, 1H), 1.77 (s, 3H) ppm 22 435.2 1H NMR (400 MHz, DMSO-d6) δ = 9.38-9.35 (m, 1H), 9.01 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.33-8.27 (m, 3H), 8.14 (d, J = 1.6 Hz, 1H), 7.92-7.90 (m, 1H), 7.61-7.50 (m, 3H), 7.29 (d, J = 8.0 Hz, 1H), 4.92-4.78(m, 4H), 4.21 (d, J = 11.6 Hz, 1H), 3.87-3.84 (m, 1H), 1.68 (s, 3H) ppm 23 443.3 1H NMR (400 MHz, MeOD) δ = 9.37 (s, 1H), 8.57 (d, J = 8.6 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.98 (s, 1H), 7.94-7.92 (m, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 4.96-4.91 (m, 4H), 4.22 (d, J = 11.4 Hz, 1H), 4.11-4.09(m, 2H), 3.95 (d, J = 11.4 Hz, 1H), 3.64-3.63 (m, 2H), 3.31-3.23 (m, 1H), 2.11-1.87 (m, 4H), 1.78 (s, 3H)ppm 24 465.1 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.35 (m, 2H), 8.59 (d, J = 8.4 Hz, 1H), 8.30- 8.19 (m, 4H), 7.96-7.93 (m, 1H), 7.7 (s, 1H), 7.31 (d, J = 8.4, 1H), 7.11-7.09 (m, 2H), 4.93-4.79 (m, 4H), 4.23 (m, J = 11.6, 1H), 3.86(d, J = 11.2, 4H), 1.70 (s, 3H) ppm 25 440.1 1H NMR (400 MHz, DMSO-d6) δ = 9.38 (s, 1H), 9.27-9.26(m, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.34-8.25 (m, 3H), 7.98(s, 1H), 7.81-7.76 (m, 2H), 7.56-7.54(m, 3H), 7.16 (d, J = 8.0 Hz, 1H), 4.88-4.86 (m, 1H), 4.80-4.74(m, 4H), 3.96-3.93 (m, 1H), 3.59-3.57 (m, 1H), 3.42 (s, 2H), 1.19 (s, 3H) ppm 26 489.3 1H NMR (400 MHz, DMSO-d6) δ = 9.43-9.40 (m, 2H), 8.70 (d, J = 8.4 Hz, 1H), 8.58 (s, 1H), 8.45 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 8.13-8.11 (m, 2H), 7.97-7.95 (m, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.93-4.81 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 4.16 (s, 3H), 3.87 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm 27 465.4 1H NMR (400 MHz, MeOD) δ = 9.30 (s, 1H), 8.50 (br d, J = 8.8 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.93-7.90 (m, 2H), 7.71-7.69 (m, 1H), 7.50-7.48 (m, 1H), 7.28(br d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.11-7.09 (m, 1H), 4.91 (s, 2H), 4.90 (br d, J = 3.6 Hz, 2H), 4.20 (d, J = 11.6 Hz, 1H), 3.92 (d, J = 11.6 Hz, 1H), 3.88 (s, 3H), 1.75 (s, 3H)ppm 29 439.2 1H NMR (400 MHz, DMSO-d6) δ = 9.39-9.36 (m, 1H), 9.31 (s, 1H), 8.54 (d, J = 8.8 Hz, 1H), 8.23-8.17 (m, 2H), 7.96-7.93(m, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.75-7.71 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 4.94-4.83 (m, 2H), 4.82- 4.77 (m, 2H), 4.23 (d, J = 11.6 Hz, 1H), 3.97 (s, 3H), 3.87 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm 30 436.2 1H NMR (400 MHz, MeOD-d4) δ = 9.41-9.34 (m, 2H), 8.71-8.63 (m, 3H), 8.24 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.99 (s, 1H), 7.95-7.91 (m, 1H), 7.67-7.59 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.93 (s, 2H), 4.91 (d, J = 3.6 Hz, 2H), 4.20 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 1.77 (s, 3H) ppm 32 434.2 1H NMR (400 MHz, DMSO-d6) δ = 9.31 (s, 1H), 9.00-8.98 (m, 1H), 8.62 (d, J = 8.8 Hz, 1H), 8.21-8.19 (m, 3H), 7.88 (br s, 1H), 7.71 (s, 1H), 7.65 (br d, J = 8.4 Hz, 1H), 7.54-7.53 (m, 3H), 6.60 (d, J = 8.4 Hz, 1H), 4.72 (br d, J = 5.2 Hz, 2H), 3.33-3.30 (m, 2H), 2.19-2.14 (m, 1H), 1.97-1.93 (m, 1H), 1.68 (s, 3H) ppm 37 500.3 1H NMR (400 MHz, DMSO-d6) δ = 9.38-9.35 (m, 1H), 9.32 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.95-7.92 (m, 1H), 7.69 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.92-4.81 (m, 2H), 4.78 (d, J = 5.6 Hz, 2H), 4.23-4.14 (m, 2H), 4.03-3.96 (m, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.58 (s, 3H), 3.21-2.99 (m, 2H), 2.91-2.81 (m, 1H), 2.07-2.02 (m, 1H), 1.84-1.72 (m, 2H), 1.69 (s, 3H), 1.57-1.46 (m, 1H) ppm 38 436.1 1H NMR (400 MHz, DMSO-d6) δ = 9.65-9.49 (m, 1H), 9.39 (s, 1H), 9.08 (d, J = 2.0 Hz, 1H), 8.69-8.62 (m, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.36-8.24 (m, 3H), 7.87 (s, 1H), 7.61- 7.52 (m, 3H), 4.94-4.80 (m, 4H), 4.29 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 1.72 (s, 3H) ppm 28 460.3 1H NMR (400 MHz, CDCl.sub.3): δ = 9.33 (s, 1H), 8.53 (s, 1H), 8.47 (d, J = 8.1 Hz, 2H), 8.04 (d, J = 6.8 Hz, 2H), 7.84 (t, J = 7.8 Hz, 2H), 7.69 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 5.04 (s, 1H), 4.88 (s, 2H), 4.14 (d, J = 11.3 Hz, 1H), 3.94 (d, J = 11.4 Hz, 1H), 1.26 (s, 3H) ppm

    Example 22. (4R)-4-cyano-4-methyl-N-[[2-(1-piperidyl)-1,6-naphthyridin-7-yl]methyl]isochromane-6-carboxamide

    [1136] ##STR00649##

    Step 1. 2-(1-Piperidyl)-1,6-naphthyridine-7-carbonitrile

    [1137] DIEA (0.37 mL, 2.11 mmol) and piperidine (0.31 mL, 3.16 mmol) were added to a mixture of 2-chloro-1,6-naphthyridine-7-carbonitrile (200 mg, 1.05 mmol) in DMSO (2 mL) at 20° C. The mixture was heated and stirred at 100° C. for 2 hr. The mixture was poured into H.sub.2O (20 mL) and filtered. The filter cake was washed with MTBE (20 mL). The filter cake was dried under reduced pressure affording the title compound (170 mg, 0.62 mmol) as a yellow solid.

    [1138] LCMS (ESI) m/z: [M+H]+=239.7.

    Step 2. tert-Butyl N-[[2-(1-piperidyl)-1,6-naphthyridin-7-yl]methyl]carbamate

    [1139] A mixture of 2-(1-piperidyl)-1,6-naphthyridine-7-carbonitrile (170 mg, 0.71 mmol), Et.sub.3N (0.20 mL, 1.43 mmol), Boc.sub.2O (234 mg, 1.07 mmol), and Raney-Ni (61.1 mg) in MeOH (20 mL) and EA (20 mL) was stirred at 20° C. for 16 hr under a H.sub.2 atmosphere (15 psi). The reaction mixture was vented to nitrogen and then filtered. The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (Petroleum Ether/EA=5/1) affording the title compound (165 mg, 0.48 mmol) as a white solid.

    [1140] LCMS (ESI) m/z: [M+H]+=343.4.

    [1141] .sup.1H NMR (400 MHz, CD.sub.3OD) δ=8.72 (s, 1H), 8.02 (d, J=9.6 Hz, 1H), 7.36 (s, 1H), 7.21 (d, J=9.6 Hz, 1H), 4.40 (s, 2H), 3.87-3.79 (m, 4H), 1.81-1.73 (m, 2H), 1.72-1.63 (m, 4H), 1.49 (s, 9H) ppm.

    Step 3. [2-(1-Piperidyl)-1,6-naphthyridin-7-yl]methanamine

    [1142] A mixture of tert-butyl N-[[2-(1-piperidyl)-1,6-naphthyridin-7-yl]methyl]carbamate (165 mg, 0.48 mmol) in HCl/dioxane (4N, 2 mL) was stirred at 20° C. for 2 hrs. The mixture was concentrated under reduced pressure affording the title compound (135 mg, 0.56 mmol, HCl salt) as a white solid.

    [1143] LCMS (ESI) m/z: [M+H]+=243.0.

    Step 4. (4R)-4-Cyano-4-methyl-N-[[2-(1-piperidyl)-1,6-naphthyridin-7-yl]methyl]isochromane-6-carboxamide

    [1144] DIEA (0.047 mL, 0.27 mmol) was added to a mixture of [2-(1-Piperidyl)-1,6-naphthyridin-7-yl]methanamine (25 mg, 0.090 mmol, HCl salt), (4R)-4-cyano-4-methylisochromane-6-carboxylic acid (21.4 mg, 0.099 mmol), EDCI (25.8 mg, 0.3 mmol), and HOBt (18.2 mg, 0.13 mmol) in DMF (0.5 mL). The mixture was stirred at 20° C. for 16 hrs. The mixture was poured into H.sub.2O (10 mL) and filtered. The filter cake was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5 m; mobile phase: [water (10 mM NH.sub.4—HCO.sub.3)-ACN]; B %: 28%-58%, 9 min) affording the title compound (20.2 mg, 0.046 mmol) as a white solid.

    [1145] LCMS (ESI) m/z: [M+H]+=442.4.

    [1146] .sup.1H NMR (400 MHz, CD.sub.3OD) δ=8.77 (s, 1H), 8.15 (d, J=1.6 Hz, 1H), 8.04 (d, J=9.2 Hz, 1H), 7.92-7.88 (m, 1H), 7.41 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.22 (d, J=9.6 Hz, 1H), 4.90 (d, J=4.0 Hz, 2H), 4.76 (s, 2H), 4.20 (d, J=11.2 Hz, 1H), 3.91 (d, J=11.2 Hz, 1H), 3.86-3.77 (m, 4H), 1.79-1.70 (m, 5H), 1.69-1.60 (m, 4H) ppm.

    Example 23. (R)-4-cyano-4-methyl-N-((2-phenyl-1,6-naphthyridin-7-yl)methyl)chromane-6-carboxamide

    [1147] ##STR00650##

    Step 1. 3-chloro-6-phenylisoquinoline

    [1148] 6-bromo-3-chloroisoquinoline (0.500 g, 2.06 mmol), Pd(PPh.sub.3).sub.4 (0.476 g, 0.412 mmol), phenylboronic acid (0.500 g, 2.06 mmol), and zinc (6.3 mg, 0.096 mmol) were added to a 40 mL vial and it was purged with nitrogen. 10 mL of a 1:1 mixture of DME/water was added to the vial and the reaction mixture was heated to 80° C. and stirred under nitrogen atmosphere for 3 h at 80° C. After cooling down to rt, the reaction mixture was extracted with DCM (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, 0-60% EtOAc in heptane) and concentrated under reduced pressure affording the title compound (310 mg, 1.29 mmol) as a light yellow solid.

    [1149] LCMS (ESI) m/z: [M+H]+=240.1.

    [1150] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=9.09 (d, J=1.1 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.93 (s, 1H), 7.86 (dd, J=8.5, 1.7 Hz, 1H), 7.77 (s, 1H), 7.74-7.67 (m, 2H), 7.57-7.49 (m, 2H), 7.49-7.41 (m, 1H) ppm.

    Step 2. 6-phenylisoquinoline-3-carbonitrile

    [1151] 3-chloro-6-phenylisoquinoline (0.23 g, 0.9595 mmol), potassium carbonate (0.263 g, 1.91 mmol), Pd(PPh.sub.3).sub.4 (0.221 g, 0.1919 mmol), and Zn(CN).sub.2 (0.167 g, 1.43 mmol) were added to a 20 mL vial and it was purged with nitrogen. DMF (4.8 mL) was added and the mixture was heated to 100° C. and stirred at for 3 hrs. After cooling down to rt, the reaction was quenched by the addition of water and the crude mixture was extracted with DCM (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, 0-70% EtOAc in heptane) and concentrated under reduced pressure affording the title compound (140 mg, 0.608 mmol, 64% yield) as a light yellow solid.

    [1152] LCMS (ESI) m/z: [M+H]+=231.2.

    [1153] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=9.30 (t, J=0.9 Hz, 1H), 8.20 (d, J=1.0 Hz, 1H), 8.17-8.11 (m, 1H), 8.10-8.03 (m, 2H), 7.75-7.69 (m, 2H), 7.58-7.51 (m, 2H), 7.51-7.45 (m, 1H) ppm.

    Step 3. (6-phenylisoquinolin-3-yl)methanamine

    [1154] A solution LiAlH.sub.4 in THE (1.0 M, 0.22 mL, 0.22 mmol) was added dropwise to a solution of 6-phenylisoquinoline-3-carbonitrile (0.050 g, 0.217 mmol) in THE (1 mL) at 0° C. The reaction mixture was allowed to stir for 2 h at which point it had warmed to rt. The reaction was quenched by addition of 1 mL of water followed by 0.5 mL of a 6N NaOH aqueous solution. The reaction mixture was extracted with 10% MeOH in DCM solution (3×5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude amine (51.2 mg) as a brown solid.

    [1155] LCMS (ESI) m/z: [79BrM+H]+=224.9.

    [1156] .sup.1H NMR (500 MHz, CDCl.sub.3) δ=9.25 (s, 1H), 8.09-7.91 (m, 1H), 7.88-7.79 (m, 1H), 7.72 (d, J=7.8 Hz, 2H), 7.56-7.39 (m, 4H), 3.75 (s, 2H) ppm.

    Step 4. (R)-4-cyano-4-methyl-N-((6-phenylisoquinolin-3-yl)methyl)isochromane-6-carboxamide

    [1157] EDCI (49.0 mg, 0.256 mmol), HOBt (34.5 mg, 0.256 mmol), and DIEA (66.1 mg, 0.512 mmol, 89 L) were added to a solution of (4R)-4-cyano-4-methyl-chromane-6-carboxylic acid (46.3 mg, 0.2133 mmol) in DCM (1 mL). 1-(6-phenylisoquinolin-3-yl)methanamine (50.0 mg, 0.2133 mmol) was added to the reaction mixture and stirred at 25° C. for 2 hrs. The reaction mixture was diluted with H.sub.2O (5 mL) and extracted with EA (5 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase flash (0.1% FA condition). The eluent was concentrated under reduced pressure to remove MeCN and the residue was lyophilized affording the title compound (39.4 mg, 0.0909 mmol) as an off-white solid.

    [1158] LCMS (ESI) m/z: [M+H]+=434.3.

    [1159] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.56 (d, J=4.0 Hz, 2H), 7.51 (d, J=1.6 Hz, 1H), 7.47-7.41 (m, 2H), 7.21 (ddd, J=13.1, 8.3, 1.8 Hz, 2H), 7.10 (dd, J=8.3, 1.3 Hz, 2H), 7.04 (s, 1H), 6.77 (dd, J=8.3, 6.8 Hz, 2H), 6.71-6.65 (m, 1H), 6.54 (d, J=8.1 Hz, 1H), 4.01 (d, J=5.8 Hz, 2H), 3.46 (d, J=11.4 Hz, 1H), 3.11 (d, J=11.5 Hz, 1H), 2.75 (s, 1H), 0.94 (s, 3H) ppm.

    Example 24. (R)-4-cyano-4-methyl-N-((6-phenyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methyl)isochromane-6-carboxamide

    [1160] ##STR00651##

    Step 1. 7-chloro-2-phenyl-1,2,3,4-tetrahydro-2,6-naphthyridine

    [1161] 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine hydrochloride (0.300 g, 1.46 mmol), iodobenzene (0.455 g, 2.19 mmol), Pd-RuPhos G3 (0.183 g, 0.219 mmol), and cesium carbonate (0.951 g, 2.92 mmol) were added to a 20 mL vial. The vial was purged with nitrogen before a 5:1 mixture of dioxane/water (7.3 mL) was added and the reaction mixture heated to 80° C. and stirred at this temperature for 3 h. After cooling to rt, 5 mL of water was added. The reaction mixture was extracted with 10% MeOH in DCM solution (3×5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, 0-100% EtOAc in heptane) and concentrated under reduced pressure affording the title compound (80.0 mg, 0.327 mmol) as a white solid.

    [1162] LCMS (ESI) m/z: [M+H]+=245.1.

    [1163] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.20 (s, 1H), 7.35-7.28 (m, 1H), 7.28 (d, J=0.8 Hz, 1H), 7.26 (s, 2H), 7.14 (s, 1H), 7.00-6.93 (m, 2H), 6.89 (td, J=7.3, 1.1 Hz, 1H), 4.36 (s, 2H), 3.58 (t, J=5.8 Hz, 2H), 2.95 (t, J=5.8 Hz, 2H) ppm.

    Step 2. 6-phenyl-5,6,7,8-tetrahydro-2,6-naphthyridine-3-carbonitrile

    [1164] 7-chloro-2-phenyl-1,2,3,4-tetrahydro-2,6-naphthyridine (0.026 g, 0.106 mmol), Pd(PPh.sub.3).sub.4 (0.0245 g, 0.0212 mmol), zinc (1.0 mg, 0.0159 mmol), and Zn(CN).sub.2 (18.7 mg, 0.159 mmol) were added to a 1 mL vial and it was purged with nitrogen. DMF (4.8 mL) was added and the mixture was heated to 100° C. and stirred at for 3 hrs. After cooling down to rt, the reaction was quenched by the addition of water and the crude mixture was extracted with DCM (3×5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO.sub.2, 0-70% EtOAc in heptane) and concentrated under reduced pressure affording the title compound (15.1 mg, 0.0642 mmol) as a light yellow solid.

    [1165] LCMS (ESI) m/z: [M+H]+=236.1.

    [1166] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.54 (s, 1H), 7.50 (s, 1H), 7.37 (dd, J=8.7, 7.3 Hz, 2H), 7.13 (d, J=8.1 Hz, 2H), 7.03 (t, J=7.4 Hz, 1H), 4.45 (s, 2H), 3.65 (t, J=5.8 Hz, 2H), 3.15 (t, J=5.8 Hz, 2H) ppm.

    Step 3. (6-phenyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methanamine

    [1167] To 6-phenyl-5,6,7,8-tetrahydro-2,6-naphthyridine-3-carbonitrile (0.015 g, 0.0642 mmol) in THE (0.5 mL) at 0° C. was added a solution LiAlH.sub.4 in THE (1.0 M, 0.22 mL, 0.22 mmol) dropwise. The reaction mixture was allowed to stir for 2 h at which point it had warmed to rt. The reaction was quenched by addition of 1 mL of water followed by 0.5 mL of a 6N NaOH aqueous solution. The reaction mixture was 5 extracted with 10% MeOH in DCM solution (3×5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude amine (15.0 mg) as a brown solid.

    [1168] LCMS (ESI) m/z: [M+H]+=240.1.

    [1169] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.55-8.28 (m, 1H), 7.26 (s, 2H), 7.07-6.76 (m, 4H) ppm, 4.40 (dd, J=23.8, 6.7 Hz, 2H), 4.03-3.34 (m, 4H), 3.08-2.88 (m, 2H).

    Step 4. (R)-4-cyano-4-methyl-N-((6-phenyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methyl)isochromane-6-carboxamide

    [1170] DIEA (19.4 mg, 0.150 mmol, 26 μL) was added to a vial containing 1-(6-phenyl-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methanamine (15.0 mg, 0.0627 mmol), EDCI (14.5 mg, 0.0752 mmol), HOBt (10.4 mg, 0.0752 mmol), and (4R)-4-cyano-4-methyl-chromane-6-carboxylic acid (13.6 mg, 0.0627 mmol) in DCM (0.5 mL). The reaction mixture stirred at 25° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase flash chromatography affording the title compound (6.2 mg, 0.0141 mmol) as an off-white solid.

    [1171] LCMS (ESI) m/z: [M+H]+=439.2.

    [1172] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.38 (s, 1H), 8.28 (s, 1H), 8.09-8.00 (m, 2H), 7.81 (dd, J=8.0, 1.7 Hz, 1H), 7.35-7.27 (m, 3H), 7.13 (dd, J=15.5, 8.1 Hz, 2H), 7.02-6.95 (m, 2H), 6.89 (t, J=7.3 Hz, 1H), 4.87 (d, J=15.6 Hz, 4H), 4.75 (dd, J=5.5, 3.1 Hz, 2H), 4.42 (s, 2H), 4.14 (dd, J=11.3, 6.4 Hz, 2H), 3.93 (dd, J=14.3, 11.3 Hz, 2H), 3.59 (t, J=5.7 Hz, 2H), 3.50 (s, 2H), 3.00 (t, J=5.7 Hz, 2H), 1.78 (s, 3H) ppm.

    Example 25. (4R)-4-cyano-4-methyl-N-[(2-phenylthiazolo[5,4-c]pyridin-6-yl)methyl]isochromane-6-carboxamide

    [1173] ##STR00652##

    Step 1. 2,5-Dichloro-4-isothiocyanato-pyridine

    [1174] Thiocarbonyl dichloride (0.94 mL, 12.3 mmol) was added to a solution of 2,5-dichloropyridin-4-amine (1 g, 6.13 mmol) and Na.sub.2CO.sub.3 (2.60 g, 24.5 mmol) in DCM (15 mL) at 25° C. The mixture was stirred for 15 hrs. The mixture was filtered and concentrated in vacuo. The crude residue was purified by column chromatography (SiO.sub.2, Petroleum Ether/EA=10/1 to 5/1) affording the title compound (750 mg, 3.66 mmol) as a brown solid.

    [1175] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.63 (s, 1H), 7.85-7.76 (m, 1H) ppm.

    Step 2. N-(2,5-Dichloro-4-pyridyl)benzenecarbothioamide

    [1176] Phenylmagnesium bromide (3 M, 1.6 mL) was added slowly to a mixture of 2,5-Dichloro-4-isothiocyanato-pyridine (650 mg, 3.17 mmol) in THE (8 mL) at −40° C. After the addition, the mixture was stirred at −40° C. for 30 min. The reaction mixture was then warmed to 25° C. and stirred for 2 hrs. The mixture was quenched via the addition of water (5 mL) and extracted with EA (5 mL). The organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (SiO.sub.2, Petroleum Ether/EA=10/1 to 5/1) affording the title compound (650 mg, 2.30 mmol) as a white solid.

    [1177] .sup.1H NMR (400 MHz, CD.sub.3OD) δ=8.55-8.51 (m, 1H), 8.08-8.03 (m, 1H), 7.97-7.90 (m, 2H), 7.60-7.53 (m, 1H), 7.50-7.43 (m, 2H) ppm.

    Step 3. 6-Chloro-2-phenyl-thiazolo[5,4-c]pyridine

    [1178] Na.sub.2CO.sub.3 (412 mg, 3.88 mmol) was added to a mixture of N-(2,5-Dichloro-4-pyridyl)benzenecarbothioamide (550 mg, 1.94 mmol) in DMA (8 mL) at 25° C. The mixture was warmed and stirred at 120° C. for 3 hrs. The mixture was quenched with water (20 mL) and extracted with EA (15 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (SiO.sub.2, Petroleum Ether/EA=10/1 to 5/1) affording the title compound (250 mg, 1.01 mmol) as a yellow solid.

    [1179] LCMS (ESI) m/z: [M+H]+=247.0.

    [1180] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.25 (d, J=0.4 Hz, 1H), 8.21-8.16 (m, 3H), 7.70-7.59 (m, 3H) ppm.

    Step 4. tert-Butyl N-[(2-phenylthiazolo[5,4-c]pyridin-6-yl)methyl]carbamate

    [1181] SPhos Pd G3 (25.3 mg, 0.032 mmol) and Cs.sub.2CO.sub.3 (211 mg, 0.65 mmol) were added to a mixture of 6-chloro-2-phenyl-thiazolo[5,4-c]pyridine (80 mg, 0.32 mmol) and potassium;2-(tertbutoxycarbonylamino) ethyl-trifluoro-boranuide (122 mg, 0.49 mmol) in dioxane (3 mL) and H.sub.2O (0.5 mL) at 20° C. The mixture was warmed and stirred at 100° C. for 15 hrs. The mixture was filtered and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (SiO.sub.2, Petroleum Ether/EA=5/1 to 3/1) affording the title compound (60 mg, 0.18 mmol) as a white solid.

    [1182] LCMS (ESI) m/z: [M+H]+=342.1.

    [1183] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=9.13 (s, 1H), 8.15-8.13 (m, 2H), 7.94 (s, 1H), 7.62-7.49 (m, 4H), 5.50 (s, 1H), 4.62 (d, J=5.2 Hz, 2H), 1.49 (s, 9H) ppm.

    Step 5. (2-Phenylthiazolo[5,4-c]pyridin-6-yl)methanamine

    [1184] A mixture of tert-Butyl N-[(2-phenylthiazolo[5,4-c]pyridin-6-yl)methyl]carbamate (60 mg, 0.18 mmol) in HCl/dioxane (4N, 2 mL) was stirred at 25° C. for 2 hrs. The mixture was concentrated in vacuo affording the title compound (30 mg, 0.11 mmol, HCl salt) as a white solid.

    [1185] LCMS (ESI) m/z: [M+H]+=242.1

    Step 6. (4R)-4-Cyano-4-methyl-N-[(2-phenylthiazolo[5,4-c]pyridin-6-yl)methyl]isochromane-6-carboxamide

    [1186] EDCI (20.7 mg, 0.11 mmol), HOBt (14.6 mg, 0.11 mmol), and DIPEA (0.047 mL, 0.27 mmol) were added to a mixture of (2-phenylthiazolo[5,4-c]pyridin-6-yl)methanamine (15 mg, 0.054 mmol, HCl salt), and (4R)-4-cyano-4-methylisochromane-6-carboxylic acid (11.7 mg, 0.054 mmol) in DMF (1 mL) at 20° C. The mixture was stirred for 15 hrs. The mixture was quenched via the addition of water (5 mL) and then extracted with EA (3 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude product was purified by pre-HPLC (column: Phenomenex Synergi C18 150*25*10 m; mobile phase: [water (0.225% FA)-ACN]; B %: 39%-69%, 10 min) affording the title compound (20.8 mg, 0.047 mmol) as gray oil.

    [1187] LCMS (ESI) m/z: [M+H]+=441.1.

    [1188] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.41-9.30 (m, 2H), 8.21-8.13 (m, 3H), 7.96-7.90 (m, 2H), 7.68-7.57 (m, 3H), 7.29 (d, J=8.0 Hz, 1H), 4.94-4.80 (m, 2H), 4.75 (d, J=5.6 Hz, 2H), 4.22 (d, J=11.6 Hz, 1H), 3.86 (d, J=11.6 Hz, 1H), 1.70 (s, 3H) ppm.

    [1189] The following examples in Table 18 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 25.

    TABLE-US-00019 TABLE 18 Compounds of the Invention LCMS # (m/z) 1H NMR 31 446.1 1H NMR (400 MHz, DMSO-d6) δ = 9.35 (s, 1H), 9.20-9.18(m, 1H), 8.20-8.13 (m, 2H), 7.93 (d, J = 20.0 Hz, 2H), 7.76(d, J = 8.0 Hz, 1H), 7.68-7.57 (m, 3H), 7.14 (d, J = 8.0 Hz, 1H), 4.89-4.87 (m, 1H), 4.78-4.70 (m, 4H), 3.94 (d, J = 11.2 Hz, 1H), 3.59-3.54 (m, 1H), 3.41 (s, 2H), 1.18 (s, 3H) ppm 33 427.1 1H NMR (400 MHz, DMSO-d6) δ = 9.35 (d, J = 0.8 Hz, 1H), 9.18-9.15 (m, 1H), 8.22- 8.12 (m, 3H), 8.01-7.89 (m, 2H), 7.69-7.57 (m, 3H), 7.06 (d, J = 8.4 Hz, 1H), 5.01 (d, J = 9.6 Hz, 1H), 4.73 (d, J = 6.0 Hz, 2H), 4.55 (d, J = 9.6 Hz, 1H), 1.78 (s, 3H) ppm 34 441.1 1H NMR (400 MHz, DMSO-d6) δ = 9.35 (s, 1H), 9.21-9.19 (m, 1H), 8.20-8.12 (m, 3H), 7.91 (s, 1H), 7.88-7.86 (m, 1H), 7.67-7.58 (m, 3H), 6.96 (d, J = 8.4 Hz, 1H), 4.73 (br d, J = 6.0 Hz, 2H), 4.40-4.24 (m, 2H), 2.44-2.41 (m, 1H), 2.23-2.18 (m, 1H), 1.80 (s, 3H) ppm 35 432.2 1H NMR (400 MHz, DMSO-d6) δ = 9.35 (d, J = 0.4 Hz, 1H), 9.24-9.21 (m, 1H), 8.18- 8.15 (m, 3H), 7.88 (s, 1H), 7.80-7.77 (m, 1H), 7.67-7.58 (m, 3H), 7.14 (d, J = 8.0 Hz, 1H), 5.29 (s, 1H), 4.79-4.67 (m, 4H), 3.70-3.67 (m, 1H), 3.61-3.58 (m, 1H), 1.43 (s, 3H) ppm 36 440.2 1H NMR (400 MHz, DMSO + D2O) δ = 9.30 (d, J = 3.2 Hz, 1H), 8.92-8.991 (m, 1H), 8.15-8.13 (m, 2H), 7.89-7.83 (m, 1H), 7.84 (s, 1H), 7.64-7.59 (m, 4H), 6.59 (d, J = 8.8 Hz, 1H), 4.74-4.62 (m, 2H), 3.34-3.31 (m, 2H), 2.21-2.15 (m, 1H), 1.99-1.94 (m, 1H), 1.70 (s, 3H) ppm

    Example 26: (R)-4-Cyano-N-((2-(4-cyclobutyl-2-methoxyphenyl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide

    [1190] ##STR00653## ##STR00654##

    Step 1: 2-(4-Cyclobutyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

    [1191] To a mixture 1-bromo-4-cyclobutyl-2-methoxybenzene (88.46 mg, 348.37 umol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (88.46 mg, 348.37 umol) and KOAc (85.47 mg, 870.92 umol) in dioxane (2 mL) was added [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (23.71 mg, 29.03 umol) under N.sub.2. The mixture was stirred at 80° C. for 2 hrs. The mixture was diluted with EA (20 mL) and filtered. The filtrate was concentrated under vacuum to give the title compound (83 mg, crude) as black oil.

    [1192] LCMS (ESI) m/z=[M+H].sup.+=289.1.

    Step 2: (2-Chloro-1,6-naphthyridin-7-yl)methanamine

    [1193] To a solution of 2-chloro-1,6-naphthyridine-7-carbonitrile (25 g, 131.86 mmol) in DCM (1000 mL) was added DIBAL-H (1 M, 329.64 mL, 2.5 eq) dropwise at −70° C. under N.sub.2. The reaction mixture was stirred at −70° C. for 2 h. The reaction mixture was quenched with water (500 mL) and sat. potassium sodium tartrate (1500 mL) and stirred for an additional 30 min. The mixture was extracted with DCM:MeOH=10:1 (6000 mL*3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (51 g, crude) as a brown solid, which was used directly in the next step.

    [1194] LCMS (ESI) m/z: [.sup.35CIM+H].sup.+=194.2

    Step 3: tert-Butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate

    [1195] To a solution of (2-chloro-1,6-naphthyridin-7-yl)methanamine (51 g, 263.39 mmol) in DCM (1500 mL) was added (Boc).sub.2O (172.45 g, 790.16 mmol) and DIEA (102.12 g, 790.16 mmol). The mixture was stirred at 25° C. for 16 hr. The reaction mixture was diluted with water (1500 mL) and then filtered. The filtrate was extracted with DCM (1000 mL*3). The combined organic layers were washed with brine (1500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=10/1 to 2/1 to 1/3) to give the title compound (21 g, 64.34 mmol, 24.43% yield) as a light yellow solid.

    [1196] LCMS (ESI) m/z: [M+H]+=293.9.

    [1197] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.37 (s, 1H), 8.62 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.58-7.53 (m, 2H), 4.39 (d, J=6.4 Hz, 2H), 4.20-4.25 (m, 2H), 1.41 (s, 9H) ppm

    Step 4: tert-Butyl ((2-(4-cyclobutyl-2-methoxyphenyl)-1,6-naphthyridin-7-yl)methyl)carbamate

    [1198] A mixture of tert-butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate (45 mg, 153.19 umol), 2-(4-cyclobutyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (79.47 mg, 275.75 umol), [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (9.98 mg, 15.32 umol) and K.sub.3PO.sub.4 (97.55 mg, 459.58 umol) in H.sub.2O (0.4 mL) and dioxane (2 mL) was degassed and purged with N.sub.2 for 3 times. The mixture was then stirred at 80° C. for 2 hrs under N.sub.2 atmosphere. The mixture was concentrated under vacuum and the residue purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=20/1 to 0/1), to give the title compound (55 mg, 120.62 umol, 78.73% yield) as a yellow solid.

    [1199] LCMS (ESI) m/z=[M+H].sup.+=420.3

    Step 5: (2-(4-Cyclobutyl-2-methoxyphenyl)-1,6-naphthyridin-7-yl)methanamine hydrochloride

    [1200] A mixture of tert-butyl ((2-(4-cyclobutyl-2-methoxyphenyl)-1,6-naphthyridin-7-yl)methyl)carbamate (55 mg, 131.10 umol) in HCl/dioxane (4 M, 4 mL) was stirred at 25° C. for 1 hr under N.sub.2 atmosphere. The mixture was concentrated under vacuum to give the title compound (46 mg, crude) as a yellow solid.

    [1201] LCMS (ESI) m/z=[M+H].sup.+=320.3

    Step 6: (R)-4-Cyano-N-((2-(4-cyclobutyl-2-methoxyphenyl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide

    [1202] To a mixture of (2-(4-cyclobutyl-2-methoxyphenyl)-1,6-naphthyridin-7-yl)methanamine hydrochloride (46 mg, 129.26 umol), EDCI (37.17 mg, 193.90 umol), (R)-4-cyano-4-methylisochromane-6-carboxylic acid (33.69 mg, 155.12 umol) and DIEA (83.53 mg, 646.32 umol) in DCM (1 mL) was added EDCI (37.17 mg, 193.90 umol) and HOBt (26.20 mg, 193.90 umol). The mixture was stirred at 25° C. for 4 hrs under N.sub.2 atmosphere. The mixture was concentrated under vacuum and the residue was purified by reversed phase HPLC (0.1% FA condition). The product fraction was concentrated under vacuum to remove MeCN, then lyophilized to give the title compound (27.13 mg, 52.31 umol, 40.47% yield) as a yellow solid.

    [1203] LCMS (ESI) m/z=[M+H].sup.+=519.3.

    [1204] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.39-9.36 (m, 1H), 9.34 (s, 1H), 8.51 (d, J=8.4 Hz, 1H), 8.19 (d, J=1.6 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.95-7.93 (m, 1H), 7.77-7.75 (m, 2H), 7.30 (d, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.97 (d, J=8.0 Hz, 1H), 4.92-4.79 (m, 4H), 4.22 (d, J=11.2 Hz, 1H), 3.84-3.84 (m, 4H), 3.62-3.57 (m, 1H), 2.34-2.31 (m, 2H), 2.21-2.12 (m, 2H), 2.03-1.964 (m, 1H), 1.87-1.83 (m, 1H), 1.69 (s, 3H) ppm

    Example 27: (R)-4-Cyano-N-((2-(7-fluoro-1,2-dimethyl-1H-indol-4-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide

    [1205] ##STR00655##

    Step 1: 7-Fluoro-1,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

    [1206] To a solution of 4-bromo-7-fluoro-1,2-dimethyl-1H-indole (60 mg, 247.84 umol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (69.23 mg, 272.63 umol) in dioxane (1 mL) was added KOAc (72.97 mg, 743.53 umol) and [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (16.15 mg, 24.78 umol). The mixture was stirred at 80° C. for 2 hrs under N.sub.2. The mixture was diluted with EA (10 mL) and filtered. The filtrate was concentrated to afford the title compound (70 mg, crude) as brown oil which was used directly in the next step.

    Step 2: (R)—N-((2-Chloro-1,6-naphthyridin-7-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide

    [1207] To a dry 4 mL vial containing 1-(2-chloro-1,6-naphthyridin-7-yl)methanamine (0.040 g, 0.207 mmol, 1 equiv.) was added (R)-4-cyano-4-methylisochromane-6-carboxylic acid (0.045 g, 0.207 mmol, 1 equiv.), EDCI (0.048 g, 0.248 mmol, 1.2 equiv.), DIEA (0.087 mL, 0.496 mmol, 2.4 equiv.), HOBt (0.034 g, 0.248 mmol, 1.2 equiv.) and DCM (1.4 mL, 0.15 M). The reaction mixture was stirred at rt overnight and directly loaded onto silica gel for purification (5% MeOH in DCM as the eluent) to give (4R)—N-[(2-chloro-1,6-naphthyridin-7-yl)methyl]-4-cyano-4-methyl-3,4-dihydro-1H-2-benzopyran-6-carboxamide (68.4 mg, 0.207 mmol, 84% yield) as an off-white solid.

    [1208] LCMS (m/z) 393.17 [M+H]

    Step 3: (R)-4-Cyano-N-((2-(7-fluoro-1,2-dimethyl-1H-indol-4-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide

    [1209] To a solution of (R)—N-((2-chloro-1,6-naphthyridin-7-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide (40 mg, 101.82 umol) and 7-fluoro-1,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (58.88 mg, 203.65 umol) in dioxane/H.sub.2O=4/1 (1 mL) was added K.sub.3PO.sub.4 (64.84 mg, 305.47 umol) and [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (6.64 mg, 10.18 umol). The mixture was stirred at 80° C. for 12 hrs under N.sub.2. The mixture was diluted with sat. NaHCO.sub.3 (10 mL) and extracted with DCM (10 mL*2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by reversed phase prep-HPLC (0.1% FA condition). The product fraction was concentrated to remove ACN and lyophilized to afford the title compound (12.07 mg, 22.87 umol, 22.46% yield) as a yellow solid.

    [1210] LCMS (ESI) m/z: [M+H].sup.+=520.2

    [1211] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.40-9.35 (m, 2H), 8.60 (d, J=8.8 Hz, 1H), 8.20-8.16 (m, 2H), 7.95-7.93 (m, 1H), 7.84 (s, 1H), 7.69-7.68 (m, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.08-7.01 (m, 2H), 4.92-4.81 (m, 4H), 4.23 (d, J=11.2 Hz, 1H), 3.89-3.84 (m, 4H), 2.44 (s, 3H), 1.70-1.68 (m, 3H) ppm.

    [1212] Chiral SFC: Cellucoat-MeOH(DEA)-40-3 mL-35T.lcm, Rt=1.380; ee %=100%.

    Example 28: (R)-4-Cyano-N-((2-(imidazo[1,2-b]pyridazin-3-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide

    [1213] ##STR00656##

    Step 1: 3-(Tributylstannyl)imidazo[1,2-b]pyridazine

    [1214] To a solution of 3-bromoimidazo[1,2-b]pyridazine (200 mg, 1.01 mmol) and Bu.sub.3SnH (411.56 mg, 1.41 mmol, 374.14 uL) in THE (2 mL) was added LiCl (64.22 mg, 1.51 mmol, 31.02 uL) and Pd(PPh.sub.3).sub.4 (116.71 mg, 101.00 umol) at 25° C. The mixture was stirred at 80° C. for 2 hr under N.sub.2. Water (5 mL) was added and the products extracted into EA (10 mL*3). The organic layer was concentrated and the residue was purified by column chromatography (SiO.sub.2, PE:EA=5:1, Rf=0.5) and concentrated to give the title compound (100 mg, 245.00 umol, 24.26% yield) as a colorless oil.

    [1215] LCMS (ESI) m/z: [M+H]+=410.0.

    Step 2: (R)-4-Cyano-N-((2-(imidazo[1,2-b]pyridazin-3-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide

    [1216] To a solution of 3-(tributylstannyl)imidazo[1,2-b]pyridazine (37.41 mg, 91.64 umol) in dioxane (0.5 mL) was added (R)—N-((2-chloro-1,6-naphthyridin-7-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide (30 mg, 76.37 umol) and Pd(PPh.sub.3).sub.4 (4.41 mg, 3.82 umol) at 2500 under N.sub.2. The mixture was heated to 10000 and stirred for 2 hrs. The mixture was quenched with saturated aqueous KF (5 mL), then extracted with EA (10 mL*3). The organic layer was concentrated and the residue purified by prep-HPLC (FA method) to give the title compound (12 mg, 20.89 umol, 27.35% yield) as a light yellow solid.

    [1217] LCMS (ESI) m/z: [M+H]+=476.3.

    [1218] .sup.1HNMR (400 MHz, MeOD-d.sub.4) δ=9.34-9.28 (n, 1H), 8.96 (d, J=8.8 Hz, 1H), 8.75-8.62 (m, 3H), 8.54-8.44 (in, H), 8.23-8.17 (m, 2H), 7.97-7.91 (m, 2H), 7.47-7.43 (m, 1H), 7.30 (d, J=8.4 Hz, 1H), 4.93-4.91 (m, 4H), 4.21 (d, J=1.6 Hz, 1H), 3.93 (d, J=11.6 Hz, 1H), 1.77 (s, 3H) ppm.

    [1219] Chiral SFC: Cellucoat-MeOH+ACN(DEA)-40-3 mL-35T.lcm; Rt=1.034 min, ee %=100%.

    [1220] The following examples in Table 19 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Examples 21, 26, 27 and 28.

    TABLE-US-00020 TABLE 19 Compounds of the Invention LCMS # (m/z) 1H NMR 128 577.3 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.37 (m, 2H), 8.72-8.70 (m, 2H), 8.43 (d, J = 8.0 Hz, 1H), 8.21 (s, 2H), 7.99-7.88 (m, 2H), 7.84 (s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.96-4.80 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.49-3.46 (m, 2H), 3.26 (s, 3H), 3.05-3.02 (m, 2H), 2.84-2.74 (m, 1H), 2.56-2.53 (m, 2H), 2.16-2.15 (m, 2H), 1.94-1.84 (m, 4H), 1.71 (s, 3H) ppm 130 495.05 1H NMR (300 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.38-9.22 (m, 2H), 8.82 (d, J = 9.0 Hz, 2H), 8.65 (d, J = 8.7 Hz, 1H), 8.14 (d, J = 1.8 Hz, 1H), 7.88 (dd, J = 8.1, 1.7 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 5.05-4.73 (m, 4H), 4.21 (d, J = 11.5 Hz, 1H), 3.85 (d, J = 11.5 Hz, 1H), 2.45-2.32 (m, 1H), 1.68 (s, 3H), 1.28-1.08 (m, 4H). 131 533.3 1H NMR (400 MHz, MeOD) δ = 9.34 (s, 1H), 8.76 (d, J = 8.4 Hz, 1H), 8.62 (d, J = 8.0 Hz, 1H), 8.55-8.47 (m, 3H), 8.18 (d, J = 1.6 Hz, 1H), 7.98 (s, 1H), 7.96-7.90 (m, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.94-4.91 (m, 4H), 4.21 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 3.49 (d, J = 12.0 Hz, 2H), 3.16-3.06 (m, 1H), 3.02-2.90 (m, 2H), 2.79 (s, 3H), 2.27-2.19 (m, 4H), 1.77 (s, 3H) ppm 132 578.3 1H NMR (400 MHz, DMSO + D2O) δ = 9.44-9.42 (m, 1H), 9.35 (s, 1H), 8.69-8.53 (m, 2H), 8.26 (s, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.92-7.90 (m, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.78 (s, 1H), 7.73-7.69 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 4.95-4.70 (m, 4H), 4.20 (d, J = 11.6 Hz, 1H), 3.84-3.81 (m, 1H), 3.64-3.57 (m, 4H), 3.49-3.46 (m, 2H), 3.23 (s, 3H), 2.59-2.53 (m, 6H), 1.67 (s, 3H) ppm 133 546.2 1H NMR (400 MHz, DMSO-d6) δ = 9.43-9.33 (m, 2H), 8.60 (d, J = 8.4 Hz, 1H), 8.41 (s, 1H), 8.24-8.18 (m, 2H), 7.95-7.93 (m, 1H), 7.85 (s, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.23-7.21 (m, 1H), 6.95 (s, 1H), 4.94-4.78 (m, 4H), 4.38-4.35 (m, 2H), 4.22 (d, J = 11.2 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.63-3.61 (m, 2H), 3.20 (s, 3H), 2.47 (s, 3H), 1.70 (s, 3H) ppm 134 516.3 1H NMR (400 MHz, DMSO-d6) δ = 9.43-9.34 (m, 2H), 8.60 (d, J = 8.8 Hz, 1H), 8.44-8.39 (m, 1H), 8.26-8.17 (m, 2H), 7.94 (d, J = 1.6 Hz, 1H), 7.83 (s, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.36-7.18 (m, 2H), 6.99 (s, 1H), 4.94-4.80 (m, 4H), 4.29-4.17 (m, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.74 (s, 3H), 2.85-2.79 (m, 2H), 1.69 (s, 3H), 1.30-1.27 (m, 3H) ppm 135 528.3 1H NMR (400 MHz, DMSO-d6) δ = 9.47-9.29 (m, 2H), 8.59 (d, J = 8.8 Hz, 1H), 8.26-8.16 (m, 2H), 7.96 (d, J = 1.6 Hz, 1H), 7.84 (s, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.35-7.20 (m, 2H), 6.83 (s, 1H), 4.94-4.80 (m, 4H), 4.22 (d, J = 11.2 Hz, 1H), 3.90-3.84 (m, 4H), 2.13-2.01 (m, 1H), 1.70 (s, 3H), 1.06-0.96 (m, 2H), 0.76-0.66 (m, 2H) ppm 136 545.2 1H NMR (400 MHz, DMSO-d6) δ = 9.37-9.31 (m, 1H), 9.31-9.25 (m, 1H), 8.89 (s, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 7.99-7.90 (m, 2H), 7.69 (s, 1H), 7.35-7.25 (m, 1H), 6.69-6.35 (m, 1H), 5.62-5.59 (m, 1H), 4.98-4.93 (m, 4H), 4.92-4.81 (m, 2H), 4.87 (d, J = 6.0 Hz, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.87-3.85 (m, 1H), 3.80-3.66 (m, 2H), 1.69 (s, 3H) ppm 137 507.3 1H NMR (400 MHz, DMSO-d6) δ = 9.51 (s, 1H), 9.44-9.41 (m, 1H), 9.05 (d, J = 5.2 Hz, 1H), 8.82 (d, J = 8.8 Hz, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.97-7.95 (m, 1H), 7.90 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.13 (d, J = 5.6 Hz, 2H), 4.95-4.81 (m, 4H), 4.61 (d, J = 5.6 Hz, 2H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 1.80 (s, 3H), 1.71 (s, 3H) ppm 138 506.2 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.32 (m, 2H), 8.62 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.96-7.94 (m, 2H), 7.80 (s, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.56-7.45 (m, 2H), 7.41-7.24 (m, 2H), 4.96-4.77 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.81 (s, 3H), 1.69 (s, 3H) ppm 139 538.2 1H NMR (400 MHz, DMSO-d6) δ = 9.45-9.35 (m, 2H), 8.66 (d, J = 8.8 Hz, 1H), 8.47-8.39 (m, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 1.2 Hz, 1H), 7.98-7.85 (m, 3H), 7.79 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.57-7.40 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 4.95-4.79 (m, 4H), 4.22 (d, J = 11.2 Hz, 1H), 3.92 (s, 3H), 3.86 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm 140 531.2 1H NMR (400 MHz, DMSO-d6) δ = 9.49-9.34 (m, 1H), 9.25 (s, 1H), 8.56- 8.46 (m, 2H), 8.42 (br s, 1H), 8.20 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 4.98-4.82 (m, 2H), 4.77 (br d, J = 6.0 Hz, 2H), 4.53-4.39 (m, 1H), 4.23 (d, J = 11.6 Hz, 1H), 4.00 (s, 3H), 3.87 (d, J = 11.2 Hz, 1H), 2.62-2.56 (m, 1H), 2.34- 2.22 (m, 1H), 1.70 (s, 3H) ppm 141 532.2 1H NMR (400 MHz, DMSO-d6) δ = 9.45-9.30 (m, 2H), 8.63 (d, J = 8.8 Hz, 1H), 8.29-8.15 (m, 2H), 7.94 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.39-7.25 (m, 2H), 7.23 (s, 1H), 4.97-4.71 (m, 4H), 4.65 (s, 2H), 4.29-4.16 (m, 1H), 3.86 (d, J = 11.2 Hz, 1H), 3.83- 3.76 (m, 3H), 3.29 (s, 3H), 1.70 (s, 3H) ppm 144 479.20 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.44-9.38 (m, 2H), 8.56 (d, J = 8.7 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.99-7.90 (m, 1H), 7.82 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.06 (d, J = 1.5 Hz, 1H), 6.96-6.90 (m, 1H), 4.95-4.79 (m, 4H), 4.22 (d, J = 11.4 Hz, 1H), 3.91-3.83 (m, 4H), 2.39 (s, 3H), 1.70 (s, 3H). 145 531.2 1H NMR (400 MHz, DMSO-d6) δ = 9.38-9.30 (m, 2H), 8.98 (s, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.00-8.00 (m, 1H), 7.96- 7.69 (m, 3H), 7.30 (d, J = 8.0 Hz, 1H), 5.73-5.66 (m, 1H), 5.01-4.94 (m, 4H), 4.92-4.85 (m, 2H), 4.81-4.78 (m, 2H), 4.22 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 1.69 (s, 3H)ppm 146 520.2 1H NMR (400 MHz, DMSO-d6) δ = 9.37-9.34 (m, 1H), 9.24 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.95- 7.93 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.12-6.07 (m, 2H), 4.92-4.81 (m, 2H), 4.77 (br d, J = 6.0 Hz, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.94-3.90 (m, 4H), 3.87-3.84 (m, 4H), 2.38- 2.33 (m, 2H), 1.69 (s, 3H) ppm 147 538.2 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.39 (m, 2H), 8.64-8.62 (m, 1H), 8.25-8.20 (m, 2H), 7.95 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.81-7.79 (m, 2H), 7.53-7.52 (m, 1H), 7.35-7.27 (m, 3H), 6.53-6.26 (m, 1H), 4.92- 4.74 (m, 6H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 1.70 (s, 3H) ppm 148 521.2 1H NMR (400 MHz, DMSO-d6) δ = 9.39-9.35 (m, 2H), 8.51 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.99-7.93 (m, 1H), 7.76-7.74 (m, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.15-7.11 (m, 2H), 4.92-4.79(m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 3.89-3.84 (m, 4H), 1.69 (s, 3H), 1.34 (s, 9H) ppm 149 504.2 1H NMR (400 MHz, DMSO-d6) δ = 9.45-9.31 (m, 2H), 8.59-8.57 (m, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.93-7.91 (m, 1H), 7.78-7.69 (m, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.14-7.12 (m, 1H), 6.75-6.62 (m, 2H), 4.92- 4.84 (m, 2H), 4.80-4.79 (m, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.24-3.18 (m, 2H), 2.89 (s, 3H), 2.65-2.62 (m, 2H), 1.81- 1.75 (m, 2H), 1.69 (s, 3H) ppm 150 503.2 1H NMR (400 MHz, DMSO-d6) δ = 9.44 (s, 1H), 9.40 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.36-8.31 (m, 2H), 8.20 (d, J = 1.6 Hz, 1H), 7.96-7.91 (m, 2H), 7.76 (d, J = 4.8 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 0.8 Hz, 1H), 4.94-4.81 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 3.80 (s, 3H), 2.52 (s, 3H), 1.70 (s, 3H) ppm 151 489.2 1H NMR (400 MHz, DMSO-d6) δ = 9.50-9.32 (m, 2H), 9.19 (s, 1H), 8.64 (d, J = 8.8 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.07- 7.98 (m, 2H), 7.95-7.93 (m, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.45-7.41 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 4.92-4.78 (m, 4H), 4.25-4.17 (m, 4H), 3.87 (d, J = 11.6 Hz, 1H), 1.71 (s, 3H) ppm 152 519.2 1H NMR (400 MHz, DMSO-d6) δ = 9.45-9.36 (m, 2H), 8.85 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.41-8.36 (m, 1H), 8.20 (d, J = 1.2 Hz, 1H), 8.00- 7.93 (m, 3H), 7.88 (d, J = 8.4 Hz, 1H), 7.58-7.53 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.94-4.81 (m, 5H), 4.53-4.50 (m, 2H), 4.23 (d, J = 11.2 Hz, 1H), 3.89-3.81 (m, 3H), 1.70 (s, 3H) ppm 153 479.25 .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 9.30 (d, J = 0.8 Hz, 1H), 8.48 (dd, J = 8.7, 0.9 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.95- 7.89 (m, 2H), 7.57-7.50 (m, 1H), 7.33-7.23 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 4.93-4.88 (m, 4H), 4.19 (d, J = 11.4 Hz, 1H), 3.91 (d, J = 11.4 Hz, 1H), 3.85 (s, 3H), 2.34 (s, 3H), 1.75 (s, 3H). 154 547.1 1H NMR (400 MHz, DMSO-d6) δ = 9.41-9.38 (m, 1H), 9.29 (s, 1H), 8.70 (s, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.95-7.91 (m, 2H), 7.75-7.38 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 5.60-5.53 (m, 1H), 4.93-4.86 (m, 6H), 4.82-4.77 (m, 2H), 4.23 (d, J = 11.2 Hz, 1H), 3.86 (d, J = 11.2 Hz, 1H), 1.70 (s, 3H) ppm 155 550.2 1H NMR (400 MHz, DMSO-d6) δ = 9.37-9.34 (m, 1H), 9.27 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 1.2 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.95- 7.93 (m, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.67-6.65 (m, 2H), 4.92-4.77 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 3.89-3.84 (m, 4H), 3.77-3.74 (m, 4H), 3.28-3.25 (m, 4H), 1.70 (s, 3H) ppm 156 499.1 1H NMR (400 MHz, METHANOL-d4) δ = 9.44-9.35 (m, 2H), 8.56 (d, J = 8.4 Hz, 1H), 8.19 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.95-7.93 (m, 1H), 7.86-7.76 (m, 2H), 7.36-7.27 (m, 2H), 7.17-7.15 (m, 1H), 4.96-4.76 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 3.90 (s, 3H), 3.86 (d, J = 11.6 Hz, 1 H), 1.69 (s, 3H) ppm 157 515.2 1H NMR (400 MHz, DMSO-d6) δ = 9.40 (s, 2H), 8.58 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 1.2 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.99-7.86 (m, 2H), 7.80 (s, 1H), 7.39 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.25-6.93 (m, 1H), 4.96- 4.76 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 3.91 (s, 3H), 3.86 (d, J = 11.2 Hz, 1H), 1.69 (s, 3H) ppm 158 493.2 1H NMR (400 MHz, DMSO-d6) δ = 9.51 (s, 1H), 9.48-9.39 (m, 1H), 9.04 (d, J = 5.2 Hz, 1H), 8.87-8.78 (m, 1H), 8.73 (d, J = 8.4 Hz, 1H), 8.45 (d, J = 5.2 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.97-7.94 (m, 1H), 7.90 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.03-4.82 (m, 8H), 4.73-4.52 (m, 1H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 1.71 (s, 3H) ppm 159 518.1 1H NMR (400 MHz, DMSO-d6) δ = 9.42-9.35 (m, 2H), 8.62 (d, J = 8.4 Hz, 1H), 8.28-8.17 (m, 2H), 7.95-7.93 (m, 1H), 7.84 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 3.2 Hz, 1H), 7.35-7.26 (m, 2H), 7.18 (d, J = 2.8 Hz, 1H), 4.94-4.81 (m, 5H), 4.31-4.28 (m, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 3.77-3.71 (m, 2H), 1.70 (s, 3H) ppm 160 501.15 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.49-9.38 (m, 2H), 8.88-8.72 (m, 2H), 8.55 (dd, J = 7.9, 1.0 Hz, 1H), 8.30 (s, 1H), 8.10-7.95 (m, 2H), 7.85 (s, 1H), 7.81-7.73 (m, 1H), 7.32 (d, J = 8.1 Hz, 1H), 6.69 (s, 1H), 5.16- 5.04 (m, 2H), 4.94-4.68 (m, 6H), 4.09 (t, J = 13.0 Hz, 1H), 3.86 (dd, J = 25.2, 12.5 Hz, 1H), 1.71 (d, J = 20.7 Hz, 3H). 162 489.2 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.35 (m, 2H), 8.61 (d, J = 8.8 Hz, 1H), 8.51-8.47 (m, 1H), 8.22-8.19 (m, 2H), 7.96-7.93(m, 1H), 7.75 (s, 1H), 7.50-7.23 (m, 3H), 4.93-4.76 (m, 4H), 4.26-4.16 (m, 1H), 4.04 (s, 3H), 3.87 (d, J = 11.2 Hz, 1H), 1.70 (s, 3H) ppm 163 532.3 1H NMR (400 MHz, DMSO-d6) δ = 9.45-9.41 (m, 2H), 8.73 (d, J = 8.6 Hz, 1H), 8.71-8.57(m, 2H), 8.20 (d, J = 1.2 Hz, 1H), 8.01-7.99 (m, 1H), 7.96-7.94 (m, 1H), 7.84 (s, 1H), 7.70-7.68 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 4.93-4.82 (m, 4H), 4.24 (d, J = 11.2 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H), 3.37 (s, 3H), 1.70 (s, 3H), 1.53 (s, 6H) ppm 164 475.3 1HNMR (400 MHz, DMSO-d6) δ = 9.48-9.33 (m, 2H), 8.79-8.78 (m, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.97-7.95 (m, 1H), 7.86-7.71 (m, 2H), 7.40 (s, 1H), 7.35-7.24 (m, 2H), 7.02-6.98 (m, 1H), 4.96-4.76 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 1.71 (s, 3H), ppm 165 543.2 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.42 (m, 2H), 8.85-8.83 (m, 1H), 8.78-8.76 (m, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.46 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.99-7.95 (m, 2H), 7.87 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 9.6 Hz, 1H), 4.94-4.83 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H), 3.15-3.08 (m, 1H), 1.71 (s, 3H), 1.40-1.35 (m, 2H), 0.92-0.88 (m, 2H) ppm 167 453.20 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.35-9.15 (m, 2H), 8.82-8.64 (m, 1H), 8.48-8.30 (m, 3H), 8.20-8.09 (m, 1H), 7.94-7.81 (m, 1H), 7.72-7.57 (m, 3H), 7.27 (d, J = 8.1 Hz, 1H), 5.02-4.69 (m, 4H), 4.22 (d, J = 11.5 Hz, 1H), 3.85 (d, J = 11.5 Hz, 1H), 1.68 (s, 3H). 168 499.20 .sup.1H NMR (400 MHz, DMSO-d6) δ 9.45-9.38 (m, 2H), 8.70 (d, J = 8.6 Hz, 1H), 8.62 (d, J = 8.6 Hz, 1H), 8.36 (d, J = 7.7 Hz, 1H), 8.28 (d, J = 1.8 Hz, 1H), 7.98 (dt, J = 8.0, 1.7 Hz, 1H), 7.89 (t, J = 7.8 Hz, 1H), 7.82 (s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 4.94-4.69 (m, 5H), 4.08 (t, J = 13.0 Hz, 1H), 3.95-3.78 (m, 3H), 1.70 (d, J = 20.7 Hz, 3H), 1.29 (q, J = 3.7 Hz, 2H), 1.00 (q, J = 3.7 Hz, 2H). 169 535.20 .sup.1H NMR (400 MHz, DMSO-d6) δ 9.43 (t, J = 1.4 Hz, 2H), 8.83-8.65 (m, 2H), 8.52 (dd, J = 7.9, 1.0 Hz, 1H), 8.29 (d, J = 1.9 Hz, 1H), 8.09-7.97 (m, 2H), 7.88-7.78 (m, 2H), 7.32 (d, J = 8.1 Hz, 1H), 6.47 (s, 1H), 4.92- 4.69 (m, 4H), 4.09 (t, J = 13.0 Hz, 1H), 3.85 (dd, J = 25.2, 12.5 Hz, 1H), 3.42 (d, J = 13.5 Hz, 2H), 2.98-2.80 (m, 2H), 1.70 (d, J = 20.7 Hz, 3H). 170 518.2 1H NMR (400 MHz, DMSO-d6) δ = 9.45-9.41 (m, 2H), 8.73 (d, J = 8.8 Hz, 1H), 8.61 (d, J = 8.8 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.40 (br s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.00-7.94 (m, 2H), 7.84 (s, 1H), 7.63-7.62 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.65 (br s, 1H), 4.93-4.82 (m, 4H), 4.24 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H), 1.52 (s, 6H) ppm 171 506.2 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.38 (m, 2H), 8.66 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.94-7.92 (m, 1H), 7.86 (s, 1H), 7.67-7.64 (m, 1H), 7.55-7.53 (m, 1H), 7.49 (d, J = 3.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 4.92-4.81 (m, 4H), 4.23-4.20 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.83 (s, 3H), 1.69(s, 3H) ppm 172 502.4 1H NMR (400 MHz, DMSO) δ = 9.44-9.34 (m, 2H), 8.65-8.57 (m, 1H), 8.31-8.27 (m, 1H), 8.26-8.16 (m, 2H), 7.98-7.91 (m, 1H), 7.85 (s, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.62-7.54 (m, 1H), 7.34-7.20 (m, 2H), 7.01- 6.95 (m, 1H), 4.93-4.85 (m, 2H), 4.82 (br d, J = 5.4 Hz, 2H), 4.22 (d, J = 11.2 Hz, 1H), 3.86 (d, J = 11.2 Hz, 1H), 3.76-3.73 (m, 3H), 2.47-2.45 (m, 3H), 1.72-1.69 (m, 3H) ppm 173 514.2 1H NMR (400 MHz, DMSO-d6) δ = 9.41-9.38 (m, 2H), 8.62 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.95-7.93 (m, 1H), 7.83-7.80 (m, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 3.6 Hz, 1H), 7.37-7.33 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 3.2 Hz, 1H), 4.92- 4.81 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 3.54- 3.49 (m, 1H), 1.70 (s, 3H), 1.12-1.08 (m, 2H), 0.99-0.96 (m, 2H) ppm 174 516.3 1H NMR (400 MHz, DMSO-d6) δ = 9.42-9.38 (m, 2H), 8.62 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 8.24-8.20 (m, 2H), 7.95 (d, J = 6.4 Hz, 1H), 7.83 (s, 1H), 7.77-7.71 (m, 2H), 7.65 (d, J = 3.2 Hz, 1H), 7.33-7.29 (m, 2H), 7.21 (d, J = 2.8 Hz, 1H), 4.93-4.81 (m, 5H), 4.23 (d, J = 11.2 Hz, 1H), 3.86 (d, J = 11.2 Hz, 1H), 1.70 (s, 3H), 1.49 (d, J = 6.8 Hz, 6H) ppm 175 521.3 1H NMR (400 MHz, MeOD) δ = 9.35-9.31 (m, 1H), 8.56-8.48 (m, 1H), 8.22-8.16 (m, 1H), 8.14-8.06 (m, 1H), 8.00-7.91 (m, 2H), 7.81-7.76 (m, 1H), 7.34-7.28 (m, 1H), 7.27-7.19 (m, 2H), 5.19-5.13 (m, 2H), 4.98- 4.95 (m, 2H), 4.94-4.93 (m, 2H), 4.86-4.83 (m, 3H), 4.44-4.33 (m, 1H), 4.26-4.18 (m, 1H), 3.95 (s, 3H), 3.94-3.89 (m, 1H), 1.77 (s, 3H) ppm 176 475.20 .sup.1H NMR (400 MHz, DMSO-d6) δ 9.59 (t, J = 5.9 Hz, 1H), 9.46 (s, 2H), 9.10 (t, J = 1.7 Hz, 1H), 8.79 (s, 1H), 8.75 (d, J = 8.7, 0.8 Hz, 1H), 8.62 (t, J = 1.8 Hz, 1H), 8.56 (d, J = 8.6 Hz, 1H), 7.93 (s, 1H), 4.94-4.78 (m, 2H), 2.41-2.30 (m, 1H), 1.71 (d, J = 20.9 Hz, 3H), 1.23-1.10 (m, 4H). 177 502.2 1H NMR (400 MHz, DMSO-d6) δ = 9.47-9.35 (m, 2H), 8.61 (d, J = 8.4 Hz, 1H), 8.42 (br s, 1H), 8.17 (s, 1H), 7.92 (br d, J = 7.4 Hz, 1H), 7.86- 7.76 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.32-7.22 (m, 2H), 7.19-7.11 (m, 2H), 4.93-4.76 (m, 4H), 4.21 (d, J = 11.2 Hz, 1H), 3.85 (br d, J = 11.6 Hz, 1H), 3.78 (s, 3H), 1.82 (s, 3H), 1.68 (s, 3H) ppm 178 502.3 1H NMR (400 MHz, DMSO-d6) δ = 9.47-9.32 (m, 2H), 8.62 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 3.2 Hz, 1H), 7.36-7.26 (m, 2H), 7.19 (d, J = 3.2 Hz, 1H), 4.98- 4.76 (m, 4H), 4.36-4.16 (m, 3H), 3.87 (d, J = 11.2 Hz, 1H), 1.70 (s, 3H), 1.41-1.37 (m, 3H) ppm 179 488.3 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.32 (m, 2H), 8.62 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 3.2 Hz, 1H), 7.38-7.27 (m, 2H), 7.20 (d, J = 2.8 Hz, 1H), 4.96- 4.76 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.90-3.83 (m, 4H), 1.70 (s, 3H) ppm 180 517.3 1H NMR (400 MHz, DMSO-d6) δ = 9.57-9.36 (m, 2H), 8.89-8.73 (m, 2H), 8.53 (d, J = 8.0 Hz, 1H), 8.48-8.43 (m, 1H), 8.41-8.33 (m, 1H), 8.22 (s, 1H), 8.10-8.01 (m, 1H), 8.00-7.94 (m, 1H), 7.88 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 9.6 Hz, 1H), 4.98-4.77 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.89-3.83 (m, 4H), 1.71 (s, 3H) ppm 181 477.2 1H NMR (400 MHz, DMSO-d6) δ = 9.55-9.52 (m, 1H), 9.36 (s, 1H), 9.16 (s, 1H), 9.08 (d, J = 2.0 Hz, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.36-8.33 (m, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.89 (s, 1H), 4.91- 4.85 (m, 2H), 4.80(d, J = 6 Hz, 2H), 4.29 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 2.31-2.27 (m, 1H), 1.71 (s, 3H), 1.16-1.10 (m, 4H) ppm. 182 489.2 1H NMR (400 MHz, DMSO) δ = 9.45-9.34 (m, 2H), 8.87-8.82 (m, 1H), 8.72-8.64 (m, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.97-7.93 (m, 2H), 7.91-7.81 (m, 1H), 7.63-7.53 (m, 1H), 7.34-7.26 (m, 1H), 4.95-4.80 (m, 4H), 4.27 (s, 1H), 4.15-4.11 (m, 3H), 3.87 (d, J = 11.6 Hz, 1H), 1.73-1.67 (m, 3H) ppm 184 505.3 1H NMR (400 MHz, DMSO-d6) δ = 9.38-9.35 (m, 1H), 9.33 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.42 (s, 1H), 8.18 (d, J = 1.2 Hz, 1H), 8.00-7.68 (m, 4H), 7.30 (d, J = 8.0 Hz, 1H), 4.92-4.78 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 4.15 (s, 3H), 3.87 (d, J = 11.6 Hz, 1H), 1.69 (s, 3H) ppm 185 527.3 1H NMR (400 MHz, DMSO-d6) δ = 9.39-9.36 (m, 1H), 9.21 (s, 1H), 8.46- 8.45 (m, 2H), 8.43 (s, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.95-7.92 (m, 1H), 7.57 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.49-5.29 (m, 1H), 5.05-4.98 (m, 1H), 4.92-4.81 (m, 2H), 4.75 (br d, J = 4.8 Hz, 2H), 4.22 (d, J = 11.2 Hz, 1H), 4.00 (s, 3H), 3.86 (d, J = 11.2 Hz, 1H), 2.86- 2.75 (m, 2H), 2.73-2.68 (m, 2H), 1.69 (s, 3H) ppm 186 521.2 1H NMR (400 MHz, DMSO-d6) δ = 9.36-9.33 (m, 1H), 9.25 (s, 1H), 8.66 (s, 1H), 8.50 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.92-7.90 (m, 1H), 7.68 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.55- 5.48 (m, 1H), 4.95-4.85 (m, 6H), 4.81-4.75 (m, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 11.2 Hz, 1H), 3.00-2.92 (m, 1H), 1.69 (s, 3H), 0.97- 0.89 (m, 4H) ppm 187 495.4 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.31 (m, 1H), 9.26 (s, 1H), 8.49 (d, J = 8.8 Hz, 1H), 8.35 (s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 5.81-5.63 (m, 1H), 5.08-4.69 (m, 8H), 4.31-4.12 (m, 1H), 3.86 (d, J = 11.6 Hz, 1H), 2.74-2.67 (m, 3H), 1.69 (s, 3H) ppm 188 495.4 1H NMR (400 MHz, DMSO-d6) δ = 9.39-9.36 (m, 1H), 9.26 (s, 1H), 8.71 (s, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.93 (d, J = 9.2 Hz, 2H), 7.70 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.65-5.47 (m, 1H), 4.93 (d, J = 7.2 Hz, 4H), 4.90-4.72 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 2.64 (s, 3H), 1.70 (s, 3H) ppm 189 478.20 .sup.1H NMR (300 MHz, DMSO-d6) δ 9.79 (t, J = 5.7 Hz, 1H), 9.14 (d, J = 2.0 Hz, 1H), 9.08 (dd, J = 8.9, 1.0 Hz, 1H), 8.96 (d, J = 9.0 Hz, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.45 (d, J = 7.4 Hz, 1H), 8.34 (s, 1H), 7.98 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 5.23 (d, J = 5.7 Hz, 2H), 5.01-4.84 (m, 2H), 4.36 (d, J = 11.5 Hz, 1H), 4.00 (d, J = 11.6 Hz, 1H), 2.36-2.28 (m, 1H), 1.79 (s, 3H), 1.24-1.05 (m, 4H). 192 499.2 1H NMR (400 MHz, DMSO-d6) δ = 9.57-9.54 (m, 1H), 9.31 (s, 1H), 9.09 (s, 1H), 8.84 (s, 1H), 8.62-8.57 (m, 2H), 8.07 (d, J = 8.8 Hz, 1H), 7.83- 7.53 (m, 2H), 4.86-4.73 (m, 4H), 4.15-4.06 (m, 4H), 3.96-3.86 (m, 1H), 1.71 (d, J = 20.8 Hz, 3H) ppm 193 505.2 1H NMR (400 MHz, DMSO-d6) δ = 9.42-9.38 (m, 1H), 9.31 (s, 1H), 8.85 (s, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.96-7.94 (m, 1H), 7.81-7.52 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 4.93-4.77(m, 4H), 4.23 (d, J = 11.2 Hz, 1H), 4.08-4.05 (m, 3H), 3.88- 3.85 (m, 1H), 1.70 (s, 3H) ppm 194 541.2 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.38 (m, 2H), 8.68 (d, J = 8.8 Hz, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 8.10 (s, 1H), 7.96-7.93 (m, 1H), 7.83 (s, 1H), 7.63-7.59 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.70-6.42 (m, 1H), 4.99- 4.86 (m, 6H), 4.82 (br d, J = 4.4 Hz, 2H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 1.70 (s, 3H) ppm 195 469.3 1H NMR (400 MHz, MeOD-d4) δ = 9.18 (s, 1H), 8.49 (d, J = 9.2 Hz, 1H), 8.21-8.13 (m, 2H), 7.91-7.89 (m, 1H), 7.76 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 5.84 (s, 1H), 4.91-4.90 (m, 4H), 4.20 (d, J = 11.6 Hz, 1H), 3.98- 3.89 (m, 4H), 2.79 (s, 3H), 1.76 (s, 3H) ppm 196 517 1H NMR (400 MHz, DMSO-d6) δ = 9.55-9.35 (m, 2H), 8.94-8.70 (m, 3H), 8.30 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 7.98-7.95 (m, 1H), 7.87 (s, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 7.2 Hz, 1H), 4.94-4.84 (m, 4H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 3.59 (s, 3H), 1.71 (s, 3H) ppm 197 525.3 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.37 (m, 1H), 9.22 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.97-7.94 (m, 1H), 7.60 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.96- 4.82 (m, 3H), 4.76 (br d, J = 5.6 Hz, 2H), 4.24 (d, J = 11.6 Hz, 1H), 4.02- 3.96 (m, 4H), 3.94 (d, J = 5.2 Hz, 2H), 3.88 (d, J = 11.6 Hz, 1H), 3.82- 3.77 (m, 1H), 2.39-2.33 (m, 2H), 1.70 (s, 3H) ppm 198 477.15 .sup.1H NMR (300 MHz, Chloroform-d) δ 9.12 (s, 1H), 8.92 (d, J = 8.3 Hz, 1H), 8.58-8.27 (m, 3H), 8.22-7.93 (m, 3H), 7.56 (t, J = 7.7 Hz, 1H), 7.45- 7.38 (m, 1H), 5.37 (s, 2H), 4.92 (s, 2H), 4.25 (d, J = 11.3 Hz, 1H), 4.05 (d, J = 11.0 Hz, 1H), 2.14 (s, 1H), 1.35 (s, 3H), 1.16 (d, J = 7.9 Hz, 2H), 1.01- 0.85 (m, 2H). 199 476.15 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.59-9.21 (m, 2H), 8.93 (d, J = 5.1 Hz, 1H), 8.25 (s, 1H), 8.14-7.85 (m, 3H), 7.30 (d, J = 8.1 Hz, 1H), 5.02- 4.57 (m, 4H), 4.08 (t, J = 13.0 Hz, 1H), 3.84 (dd, J = 25.2, 12.5 Hz, 1H), 2.42-2.20 (m, 1H), 1.69 (d, J = 20.7 Hz, 3H), 1.35-1.01 (m, 4H). 200 509.2 1H NMR (400 MHz, DMSO-d6) δ = 9.42-9.38 (m, 1H), 9.21 (s, 1H), 8.47- 8.42 (m, 2H), 8.40 (br s, 1H), 8.20 (d, J = 1.2 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.96-7.94 (m, 1H), 7.58 (s, 1H), 7.33-7.30 (m, 1H), 4.93-4.82 (m, 2H), 4.76-4.71 (m, 3H), 4.23 (d, J = 11.2 Hz, 1H), 4.02-3.98 (m, 3H), 3.87 (d, J = 11.6 Hz, 1H), 2.46-2.42 (m, 2H), 2.36-2.33 (m, 2H), 1.79-1.67 (m, 5H) ppm 201 504.2 1H NMR (400 MHz, DMSO) δ = 9.43-9.34 (m, 1H), 9.23 (s, 1H), 8.55- 8.43 (m, 2H), 8.27 (s, 1H), 8.06-7.93 (m, 2H), 7.57 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.56-5.44 (m, 1H), 4.95-4.83 (m, 5H), 4.80-4.70 (m, 3H), 4.13-4.04 (m, 4H), 3.90-3.82 (m, 1H), 1.76-1.61 (m, 3H) ppm 202 519.3 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.37 (m, 1H), 9.24 (s, 1H), 8.55- 8.42 (m, 2H), 8.20 (d, J = 1.2 Hz, 1H), 8.05-7.92 (m, 2H), 7.60 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.61-6.17 (m, 1H), 4.95-4.81 (m, 2H), 4.76 (d, J = 5.6 Hz, 2H), 4.56-4.54 (m, 2H), 4.23 (d, J = 11.6 Hz, 1H), 4.00 (s, 3H), 3.86 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm 203 513.3 1H NMR (400 MHz, DMSO-d6) δ = 9.37 (s, 1H), 9.21 (s, 1H), 8.46 (d, J = 8.8 Hz, 1H), 8.35 (s, 1H), 8.20 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.95 (br d, J = 7.2 Hz, 1H), 7.59 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.93-4.82 (m, 2H), 4.75 (d, J = 5.6 Hz, 2H), 4.24-4.16 (m, 3H), 3.98 (s, 3H), 3.86 (d, J = 11.6 Hz, 1H), 3.69-3.67 (m, 2H), 3.24 (s, 3H), 1.70 (s, 3H) ppm 204 495.3 1H NMR (400 MHz, MeOD-d4) δ = 9.40 (s, 1H), 8.94 (d, J = 5.2 Hz, 1H), 8.70 (s, 2H), 8.50 (d, J = 5.2 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.02 (s, 1H), 7.97-7.90 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.94 (s, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.21 (d, J = 11.2 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 1.77 (s, 3H), 1.68 (s, 2H), 1.66-1.61 (m, 2H) ppm 205 501.29 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.49 (d, J = 4.0 Hz, 2H), 8.79 (s, 2H), 8.51 (d, J = 7.7 Hz, 1H), 8.36 (s, 1H), 8.04 (t, J = 8.0 Hz, 2H), 7.95-7.80 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 5.25 (s, 1H), 5.05-4.67 (m, 4H), 4.16 (t, J = 13.0 Hz, 1H), 3.92 (dd, J = 25.1, 12.5 Hz, 1H), 1.97 (dt, J = 33.8, 6.6 Hz, 2H), 1.78 (d, J = 20.7 Hz, 3H), 1.62 (s, 3H), 0.81 (t, J = 7.3 Hz, 3H). 206 477.25 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.66 (s, 1H), 9.35 (t, 1H), 9.25 (s, 1H), 8.70 (s, 1H), 8.65 (s, 1H), 8.45 (d, J = 8.5 Hz, 1H), 8.29 (d, J = 8.6 Hz, 1H), 8.19 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 4.99- 4.79 (m, 4H), 4.23 (d, J = 11.5 Hz, 1H), 3.87 (d, J = 11.5 Hz, 1H), 2.38- 2.27 (m, 1H), 1.71 (s, 3H), 1.18-1.08 (m, 4H). 208 477.3 1H NMR (400 MHz, DMSO-d6) δ = 9.57 (s, 1H), 9.42 (s, 1H), 9.08 (d, J = 2.0 Hz, 1H), 8.71-8.66 (m, 1H), 8.64-8.60 (m, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.91-7.82 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 4.93-4.80 (m, 4H), 4.29 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 2.24 (s, 1H), 1.72 (s, 3H), 1.10-1.08 (m, 2H), 1.06-1.03 (m, 2H) ppm 210 492.2 1H NMR (400 MHz, DMSO-d6) δ = 9.58-9.55 (m, 1H), 9.40 (s, 1H), 9.08 (d, J = 2.0 Hz, 1H), 8.71-8.54 (m, 3H), 7.93-7.84 (m, 2H), 7.73-7.69 (m, 1H), 6.53 (d, J = 8.0 Hz, 1H), 4.94-4.81 (m, 4H), 4.30 (d, J = 11.6 Hz, 1H), 4.09-4.05 (m, 4H), 3.93 (d, J = 11.6 Hz, 1H), 2.43-2.35 (m, 2H), 1.73 (s, 3H) ppm 211 473.15 1H NMR (300 MHz, Chloroform-d) δ 9.70 (s, 1H), 9.39 (s, 1H), 9.12 (dd, J = 2.2, 1.2 Hz, 1H), 8.73-8.67 (m, 2H), 8.60-8.46 (m, 2H), 8.13 (s, 1H), 7.63 (t, J = 4.8 Hz, 1H), 5.11 (d, J = 4.9 Hz, 2H), 4.18 (t, J = 11.4 Hz, 1H), 4.00 (dd, J = 15.8, 12.1 Hz, 1H), 2.35-2.21 (m, 1H), 1.85 (d, J = 21.0 Hz, 3H), 1.40-1.30 (m, 2H), 1.30-1.20 (m, 2H). 212 473.15 .sup.1H NMR (400 MHz, Chloroform-d) δ 9.43 (s, 1H), 8.96-8.64 (m, 3H), 8.54 (d, J = 8.8 Hz, 1H), 8.43 (s, 1H), 8.17 (d, J = 1.8 Hz, 1H), 8.04-7.81 (m, 2H), 7.51 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 5.09-4.73 (m, 5H), 4.08 (t, J = 11.9 Hz, 1H), 3.82 (dd, J = 19.0, 12.1 Hz, 1H), 1.73 (d, J = 20.8 Hz, 3H), 1.62 (d, J = 6.5 Hz, 3H). 213 473.15 .sup.1H NMR (400 MHz, Chloroform-d) δ 9.44 (s, 1H), 9.05-8.90 (m, 2H), 8.68 (d, J = 7.8 Hz, 1H), 8.60-8.42 (m, 2H), 8.18 (s, 1H), 8.02-7.82 (m, 2H), 7.52 (d, J = 7.7 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 5.13-4.98 (m, 3H), 4.91-4.71 (m, 2H), 4.08 (t, J = 12.0 Hz, 1H), 3.82 (dd, J = 19.2, 12.1 Hz, 1H), 1.78-1.58 (m, 6H). 217 513 1H NMR (400 MHz, MeOD) δ = 9.33-9.25 (m, 1H), 8.85-8.78 (m, 1H), 8.70-8.53 (m, 2H), 8.44-8.33 (m, 1H), 8.10-8.06 (m, 1H), 7.93-7.87 (m, 1H), 7.85-7.80 (m, 1H), 7.27-7.13 (m, 1H), 4.84 (s, 2H), 4.83-4.80 (m, 2H), 4.15-4.06 (m, 1H), 3.87-3.75 (m, 1H), 3.19-3.12 (m, 1H), 2.54- 2.35 (m, 1H), 2.07-1.84 (m, 1H), 1.66 (s, 3H) ppm 218 513 1H NMR (400 MHz, MeOD) δ = 9.35-9.25 (m, 1H), 8.87-8.78 (m, 1H), 8.69-8.56 (m, 2H), 8.46-8.32 (m, 1H), 8.14-8.04 (m, 1H), 7.94-7.89 (m, 1H), 7.86-7.81 (m, 1H), 7.23-7.17 (m, 1H), 4.84 (s, 2H), 4.81 (d, J = 3.2 Hz, 2H), 4.15-4.07 (m, 1H), 3.87-3.81 (m, 1H), 3.20-3.12 (m, 1H), 2.53-2.37 (m, 1H), 2.08-1.90 (m, 1H), 1.66 (s, 3H) ppm 221 478.3 1H NMR (400 MHz, DMSO-d6) δ = 9.67-9.54 (m, 1H), 9.46 (s, 2H), 9.08 (d, J = 2.0 Hz, 1H), 8.84-8.70 (m, 2H), 8.60-8.50 (m, 2H), 7.93 (s, 1H), 4.96-4.76 (m, 4H), 4.29 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 2.38-2.28 (m, 1H), 1.72 (s, 3H), 1.20-1.02 (m, 4H) ppm 222 473.15 .sup.1H NMR (300 MHz, Chloroform-d) δ 9.63 (s, 1H), 9.37-9.29 (m, 1H), 9.07- 9.03 (m, 1H), 8.65 (t, J = 4.3 Hz, 2H), 8.47-8.42 (m, 2H), 8.10 (s, 1H), 7.72-7.63 (m, 1H), 5.01 (dd, J = 24.4, 4.0 Hz, 2H), 4.88 (m, 2H), 2.27- 2.17 (m, 1H), 1.84-1.75 (m, 3H), 1.28-1.23 (m, 2H), 1.22-1.15 (m, 2H). 223 480.20 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.54 (t, J = 5.7 Hz, 1H), 9.00-8.89 (m, 2H), 8.21-8.13 (m, 2H), 7.99-7.92 (m, 1H), 7.89-7.82 (m, 1H), 7.78- 7.70 (m, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.12 (d, J = 5.7 Hz, 2H), 4.95-4.78 (m, 2H), 4.22 (d, J = 11.5 Hz, 1H), 3.86 (d, J = 11.5 Hz, 1H), 3.17 (s, 6H), 1.70 (s, 3H). 224 509.3 1H NMR (400 MHz, MeOD) δ = 9.29 (s, 1H), 9.16-9.15 (m, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.62 (s, 1H), 8.57-8.55 (m, 1H), 7.97 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.67-7.65 (m, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.56-6.27 (m, 1H), 4.93 (s, 2H), 4.89-4.88 (m, 2H), 4.40-4.33(m, 1H), 4.16-4.11 (m, 1H), 3.19 (s, 6H) ppm 225 495.5 1H NMR (400 MHz, MeOD) δ = 9.15 (s, 1H), 8.44-8.36 (m, 1H), 8.29- 8.25 (m, 1H), 8.21-8.11 (m, 2H), 7.97-7.90 (m, 1H), 7.81-7.75 (m, 1H), 7.34-7.25 (m, 1H), 4.92 (br d, J = 3.6 Hz, 4H), 4.24-4.18 (m, 1H), 4.05 (s, 3H), 3.96-3.92 (m, 1H), 3.64-3.57 (m, 1H), 1.81-1.73 (m, 3H), 1.15- 1.07 (m, 2H), 1.05-1.00 (m, 2H) ppm 226 526.20 .sup.1H NMR (300 MHz, Chloroform-d) δ 9.28 (d, J = 2.5 Hz, 1H), 8.79-8.72 (m, 1H), 8.38 (d, J = 8.7 Hz, 1H), 8.08-7.90 (m, 3H), 7.76-7.65 (m, 2H), 7.63-7.55 (m, 1H), 6.73-6.68 (m, 1H), 6.38-5.95 (m, 1H), 5.04- 4.82 (m, 4H), 4.37 (t, J = 11.7 Hz, 1H), 4.02 (t, J = 11.4 Hz, 1H), 3.32- 3.11 (m, 6H). 227 509.3 1H NMR (400 MHz, MeOH) δ = 9.28 (s, 1H), 9.15-9.14 (m, 1H), 8.70- 8.67 (m, 1H), 8.62 (s, 1H), 8.56-8.54 (m, 1H), 7.96 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.69-7.65 (m, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.56-6.27 (m, 1H), 4.92 (s, 2H), 4.91-4.89 (m, 2H), 4.40-4.33 (m, 1H), 4.16-4.10 (m, 1H), 3.18 (s, 6H) ppm 228 507.3 1H NMR (400 MHz, MeOH) δ = 9.46 (s, 1H), 9.34 (s, 1H), 9.15-9.14 (m, 1H), 8.64-8.58 (m, 4H), 8.01 (s, 1H), 6.55-6.26 (m, 1H), 4.94 (s, 2H), 4.88 (br s, 2H), 4.40-4.33 (m, 1H), 4.16-4.10 (m, 1H), 2.33-2.28 (m, 1H), 1.23-1.21 (m, 2H), 1.19-1.17 (m, 2H) ppm 229 507.3 1H NMR (400 MHz, MeOD) δ = 9.47 (s, 1H), 9.34 (s, 1H), 9.15-9.14 (m, 1H), 8.65-8.58 (m, 4H), 8.02 (s, 1H), 6.55-6.26 (m, 1H), 4.94 (s, 2H), 4.89 (br s, 2H), 4.40-4.33 (m, 1H), 4.16-4.13 (m, 1H), 2.32-2.27 (m, 1H), 1.23-1.17 (m, 4H) ppm 231 440.3 1H NMR (400 MHz, DMSO-d6) δ = 9.45 (s, 1H), 9.42-9.39 (m, 1H), 8.77- 8.75 (m, 1H), 8.19-8.17 (m, 2H), 7.96-7.93 (m, 1H), 7.81 (s, 1H), 7.31- 7.29 (m, 2H), 4.93-4.81 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 2.35 (s, 3H), 1.70 (s, 3H) ppm 232 501.3 1H NMR (400 MHz, DMSO-d6) δ = 9.53 (s, 1H), 9.46-9.43 (m, 1H), 9.18 (d, J = 5.2 Hz, 1H), 8.85 (d, J = 8.4 Hz, 1H), 8.74-8.66 (m, 2H), 8.21 (d, J = 1.2 Hz, 1H), 8.00-7.87 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 4.97-4.80 (m, 4H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 2.21-2.11 (m, 3H), 1.71 (s, 3H) ppm 233 486.4 1H NMR (400 MHz, MeOD) δ = 9.32 (s, 1H), 8.64-8.53 (m, 2H), 8.41- 8.35 (m, 1H), 8.24 (s, 1H), 7.98-7.88 (m, 2H), 7.28 (d, J = 7.6 Hz, 1H), 7.16-7.06 (m, 1H), 4.95-4.90 (m, 3H), 4.83-4.76 (m, 1H), 4.28-4.20 (m, 1H), 4.12-4.03 (m, 1H), 3.94-3.83 (m, 1H), 1.80-1.66 (m, 3H), 1.34- 1.29 (m, 2H), 1.19-1.11 (m, 2H) ppm 235 515.3 1H NMR (400 MHz, DMSO-d6) δ = 9.45 (d, J = 0.8 Hz, 1H), 9.40-9.32 (m, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 5.2 Hz, 1H), 8.02 (s, 1H), 7.93-7.91 (m, 1H), 7.48-7.40 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.95- 4.74 (m, 4H), 4.26-4.14 (m, 5H), 3.86 (d, J = 11.6 Hz, 1H), 2.44-2.35 (m, 2H), 1.69 (s, 3H) ppm 236 511.1 1H NMR (400 MHz, MeOD) δ = 9.16 (s, 1H), 8.45-8.39 (m, 1H), 8.34 (s, 1H), 8.20-8.13 (m, 2H), 7.95-7.90 (m, 1H), 7.77 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.52-5.43 (m, 1H), 5.14-5.08 (m, 2H), 5.05-4.98 (m, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.60 (s, 2H), 4.23-4.19 (m, 1H), 4.13 (s, 3H), 3.95- 3.90 (m, 1H), 1.77 (s, 3H) ppm 237 524.30 .sup.1H NMR (300 MHz, Chloroform-d) δ 9.64 (s, 1H), 9.34 (s, 1H), 8.69-8.63 (m, 2H), 8.45 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.77-7.66 (m, 2H), 6.19 (td, J = 54.0, 8.9 Hz, 1H), 5.09-5.03 (d, J = 5.2 Hz, 2H), 4.93-4.88 (m, 2H), 4.45-4.31 (t, J = 11.5 Hz, 1H), 4.11-3.96 (t, J = 13.0 Hz, 1H), 2.29-2.18 (m, 1H), 1.28-1.18 (m, 4H). 238 473.30 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.53 (t, J = 5.8 Hz, 1H), 9.00-8.95 (m, 1H), 8.91 (d, J = 9.0 Hz, 1H), 8.30-8.24 (m, 1H), 8.15 (d, J = 1.0 Hz, 1H), 8.00-7.93 (m, 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.77-7.68 (m, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.90-6.85 (m, 1H), 5.20-5.05 (m, 2H), 4.90- 4.80 (m, 1H), 4.78-4.67 (m, 1H), 4.07 (t, J = 13.0 Hz, 1H), 3.91-3.76 (m, 1H), 3.17 (s, 6H), 1.69 (d, J = 20.7 Hz, 3H). 239 513.20 .sup.1H NMR (300 MHz, DMSO-d6) δ 9.62 (t, J = 5.8 Hz, 1H), 9.11 (dd, J = 9.0, 1.0 Hz, 1H), 8.98 (d, J = 9.0 Hz, 1H), 8.58 (d, J = 8.3 Hz, 1H), 8.45 (d, J = 7.5 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 8.13 (t, J = 8.0 Hz, 1H), 8.04 (dd, J = 7.9, 1.8 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 5.28-5.14 (m, 2H), 5.00-4.74 (m, 2H), 4.32 (t, J = 7.1 Hz, 2H), 4.15 (t, J = 13.0 Hz, 1H), 3.91 (dd, J = 25.1, 12.5 Hz, 1H), 2.73 (t, J = 8.0 Hz, 2H), 2.21 (p, J = 7.7 Hz, 2H), 1.76 (d, J = 20.7 Hz, 3H). 240 470.15 .sup.1H NMR (400 MHz, Chloroform-d) δ 8.96 (d, J = 9.0 Hz, 1H), 8.84 (dd, J = 9.1, 1.0 Hz, 1H), 8.42 (dd, J = 7.8, 1.0 Hz, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.83 (dt, J = 8.1, 1.6 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 5.8 Hz, 1H), 7.32 (dd, J = 7.8, 1.0 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 5.26 (d, J = 5.5 Hz, 2H), 4.93-4.75 (m, 2H), 4.07 (t, J = 11.7 Hz, 1H), 3.86 (dd, J = 17.1, 12.0 Hz, 1H), 2.15 (tt, J = 8.1, 4.8 Hz, 1H), 1.74 (d, J = 20.8 Hz, 3H), 1.26-1.16 (m, 2H), 1.09 (dt, J = 8.2, 3.2 Hz, 2H). 241 506.80 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.46-9.42 (m, 3H), 8.92 (t, J = 1.9 Hz, 1H), 8.79-8.74 (m, 2H), 8.59-8.54 (m, 2H), 7.91 (s, 1H), 7.25-6.65 (m, 1H), 4.83 (d, J = 5.3 Hz, 2H), 4.58-4.54 (m, 1H), 4.41-4.35 (m, 1H), 2.37 (dd, J = 12.3, 6.0 Hz, 1H), 1.17 (d, J = 5.4 Hz, 4H). 243 506.80 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.47-9.42 (m, 3H), 8.92 (t, J = 1.9 Hz, 1H), 8.83-8.74 (m, 2H), 8.59-8.55 (m, 2H), 7.93 (s, 1H), 7.24-6.65 (m, 1H), 4.84 (d, J = 5.3 Hz, 2H), 4.58-4.52 (m, 1H), 4.42-4.38 (m, 1H), 2.37 (dd, J = 12.3, 6.0 Hz, 1H), 1.17 (d, J = 5.4 Hz, 4H). 244 492.10 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.59 (s, 1H), 9.49 (m, 1H), 9.14 (s, 1H), 8.88-8.48 (m, 2H), 8.12 (m, 1H), 7.54 (d, J = 4.9 Hz, 1H), 5.13-4.71 (m, 4H), 4.36-4.08 (m, 5H), 3.98 (dd, J = 25.3, 12.7 Hz, 1H), 2.45 (t, J = 7.4 Hz, 2H), 1.78 (d, J = 20.9 Hz, 3H). 245 491.10 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.50-9.25 (m, 2H), 8.61 (d, J = 4.9 Hz, 1H), 8.24 (m, 1H), 7.95 (d, J = 12.5 Hz, 2H), 7.46 (d, J = 4.9 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 4.99-4.58 (m, 4H), 4.26-4.04 (m, 5H), 3.84 (dd, J = 25.2, 12.5 Hz, 1H), 2.39 (q, J = 7.4 Hz, 2H), 1.69 (d, J = 20.7 Hz, 3H). 246 505.3 1H NMR (400 MHz, MeOD) δ = 9.47-9.46 (m, 1H), 9.34 (s, 1H), 9.05 (d, J = 2.0 Hz, 1H), 8.64-8.58 (m, 4H), 8.00 (s, 1H), 6.25-5.97 (m, 1H), 4.94 (s, 2H), 4.86 (br s, 2H), 4.28 (d, J = 12.0 Hz, 1H), 3.77 (br d, J = 1.2 Hz, 1H), 2.33-2.28 (m, 1H), 1.23-1.20(m, 2H), 1.18-1.17 (m, 2H) ppm 248 472.3 1H NMR (400 MHz, MeOD) δ = 9.40-9.37 (m, 2H), 8.65 (s, 2H), 8.27 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.83-7.79 (m, 2H), 7.68-7.66 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.88-4.75 (m, 4H), 4.11- 4.04 (m, 1H), 3.89-3.79 (m, 1H), 3.15 (s, 6H), 1.72-1.67 (m, 3H) ppm 249 515.4 1H NMR (400 MHz, DMSO-d6) δ = 9.42-9.37 (m, 2H), 8.70-8.69 (m, 2H), 8.49-8.47 (m, 1H), 8.28 (s, 1H), 8.03-8.01 (m, 2H), 7.88-7.83 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 5.77 (s, 1H), 4.85-4.76 (m, 4H), 4.12-4.07 (m, 4H), 3.89-3.86 (m, 2H), 2.67-2.66 (m, 1H), 2.16-2.11 (m, 1H), 1.72-1.67 (m, 3H) ppm 251 461.2 1H NMR (400 MHz, DMSO-d6) δ = 9.30-9.27 (m, 1H), 9.16 (s, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 8.07-8.03 (m, 2H), 7.96-7.94 (m, 1H), 7.89-7.86 (m, 1H), 7.58 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.84-4.83 (m, 1H), 4.75- 4.70 (m, 3H), 4.12-4.01 (m, 1H), 3.94 (s, 3H), 3.88-3.79 (m, 1H), 3.74 (s, 3H), 1.68 (d, J = 20.4 Hz, 1H) ppm 252 469.20 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 9.49 (s, 1H), 9.37 (s, 1H), 9.11 (s, 1H), 8.74 (dd, J = 7.8, 2.5 Hz, 4H), 8.13 (s, 1H), 5.04 (s, 2H), 3.13-3.00 (m, 2H), 2.53-2.03 (m, 5H), 1.88 (d, J = 21.1 Hz, 3H), 1.35-1.24 (m, 4H). 253 478.10 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 9.48 (s, 1H), 9.37 (s, 1H), 8.77 (d, J = 2.3 Hz, 1H), 8.71-8.58 (m, 3H), 8.56 (d, J = 2.3 Hz, 1H), 8.04 (s, 1H), 4.93 (s, 2H), 4.58 (dd, J = 6.5, 4.1 Hz, 2H), 2.60-2.46 (m, 1H), 2.38- 2.21 (m, 2H), 1.87 (s, 3H), 1.29-1.12 (m, 4H). 254 480.10 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 9.12 (d, J = 9.1 Hz, 1H), 9.03 (dd, J = 9.1, 1.0 Hz, 1H), 8.95-8.88 (m, 1H), 8.41-8.36 (m, 1H), 8.35-8.23 (m, 2H), 8.06-7.92 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 6.97 (t, J = 55.2 Hz, 1H), 5.31 (s, 2H), 4.93-4.82 (m, 2H), 4.16 (t, J = 12.3 Hz, 1H), 3.97 (dd, J = 20.0, 12.2 Hz, 1H), 1.81 (d, J = 20.6 Hz, 3H). 255 470.85 .sup.1H NMR (300 MHz, DMSO-d6) δ 9.56 (t, J = 5.8 Hz, 1H), 9.49 (s, 1H), 9.06 (dd, J = 8.9, 1.0 Hz, 1H), 8.84-8.79 (m, 2H), 8.27-8.24 (m, 2H), 7.96 (dt, J = 8.0, 1.7 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 5.16-5.14 (m, 2H), 4.90-4.70 (m, 2H), 4.08 (t, J = 13.0 Hz, 1H), 3.84 (dd, J = 25.1, 12.5 Hz, 1H), 2.42-2.34 (m, 1H), 1.69 (d, J = 20.7 Hz, 3H), 1.22-1.13 (m, 4H). 257 485.2 1HNMR (400 MHz, DMSO-d6) δ = 9.35-9.32 (m, 2H), 8.46 (s, 1H), 8.25 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.04-8.01 (m, 2H), 7.97-7.94 (m, 1H), 7.76-7.73 (m, 2H), 7.29 (d, J = 8.0 Hz, 1H), 4.87-4.70 (m, 4H), 4.19- 4.13 (m, 1H), 410-4.03 (m, 1H), 3.87-3.78 (m, 1H), 1.75 (d, J = 20.8 Hz, 1H) ppm 259 515.2 1H NMR (400 MHz, DMSO-d6) δ = 9.48 (s, 1H), 9.43-9.41 (m, 1H), 8.77- 8.75 (m, 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.37- 8.32 (m, 1H), 8.28 (s, 1H), 7.98-7.97 (m, 1H), 7.85 (s, 1H), 7.74 (d, J = 4.8 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 4.85-4.82 (m, 4H), 4.08 (s, 1H), 3.89-3.83 (m, 5H), 3.74-3.71 (m, 4H), 1.72-1.67 (m, 3H) ppm 260 486.2 1H NMR (400 MHz, DMSO-d6) δ = 9.47-9.39 (m, 3H), 8.89-8.82 (m, 2H), 8.76 (d, J = 8.8 Hz, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.28 (s, 1H), 8.20- 8.18 (m, 1H), 7.99-7.96 (m, 1H), 7.86 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.89-4.72 (m, 4H), 4.11-4.05 (m, 1H), 3.89-3.80 (m, 1H), 2.87 (d, J = 4.8 Hz, 3H), 1.72-1.67 (m, 3H) ppm 261 469.3 1H NMR (400 MHz, MeOD-d4) δ = 9.29-9.23 (m, 2H), 8.49 (d, J = 1.6 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.13 (s, 1H), 7.92-7.89 (m, 1H), 7.77 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 4.91-4.86 (m, 4H), 4.20 (d, J = 11.2 Hz, 1H), 4.05 (s, 3H), 3.93 (d, J = 11.6 Hz, 1H), 3.83 (s, 3H), 1.76 (s, 3H) ppm 262 491.2 1H NMR (400 MHz, MeOD) δ = 9.23 (s, 1H), 8.50 (s, 1H), 8.38-8.30 (m, 1H), 8.17-8.11 (m, 2H), 7.92-7.90 (m, 1H), 7.88-7.82 (m, 3H), 7.74- 7.71 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.93-4.87 (m, 4H), 4.19 (d, J = 11.6 Hz, 1H), 3.92 (d, J = 11.6 Hz, 1H), 1.75 (s, 3H), 1.53-1.48 (m, 2H), 1.25-1.21 (m, 2H) ppm 263 537 1H NMR (400 MHz, DMSO-d6) δ = 9.44-9.41 (m, 1H), 9.31 (s, 1H), 8.58 (s, 1H), 8.34 (d, J = 10 Hz, 1H), 8.17 (d, J = 10 Hz, 1H), 8.14 (s, 1H), 7.96- 7.93 (m, 1H), 7.83 (s, 1H), 7.66-7.64 (m, 1H), 7.42 (d, J = 7.6 Hz, 1H), 6.75-6.60 (m, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.0 (d, J = 16 Hz, 1H), 4.84 (d, J = 16 Hz, 1H), 4.77-4.76 (m, 2H), 4.27-4.15 (m, 2H), 4.06-4.03 (m, 4H), 2.40-2.33 (m, 2H) ppm 264 439.3 1H NMR (400 MHz, DMSO-d6) δ = 13.19-12.78 (m, 1H), 9.44-9.26 (m, 2H), 8.58-8.45 (m, 1H), 8.28-8.13 (m, 2H), 7.96-7.94 (m, 1H), 7.72 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.84-6.72 (m, 1H), 4.94-4.82 (m, 2H), 4.79 (d, J = 6.0 Hz, 2H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 2.30 (s, 3H), 1.70 (s, 3H) ppm 265 528.4 1H NMR (400 MHz, DMSO-d6) δ = 9.35-9.34 (m, 2H), 8.66-8.58 (m, 2H), 8.37-8.35 (m, 1H), 8.27-8.21 (m, 2H), 7.94 (d, J = 4.0 Hz, 2H), 7.82-7.79 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.85-4.75 (m, 4H), 4.15- 4.04 (m, 2H), 3.89-3.83 (m, 1H), 3.68-3.65 (m, 3H), 3.52-3.50 (m, 1H), 3.30 (s, 3H), 2.13-2.10 (m, 2H), 1.72-1.67 (m, 3H) ppm 266 528.4 1H NMR (400 MHz, DMSO-d6) δ = 9.36-9.34 (m, 2H), 8.68 (s, 1H), 8.58 (s, 1H), 8.37-8.34 (m, 1H), 8.27-8.21 (m, 2H), 8.02-7.96 (m, 2H), 7.82 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.85-4.75 (m, 4H), 4.15-4.08 (m, 2H), 3.89-3.83 (m, 1H), 3.68-3.65 (m, 3H), 3.54-3.50 (m, 1H), 3.30 (s, 3H), 2.14-2.08 (m, 2H), 1.72-1.67 (m, 3H) ppm 267 542.2 1H NMR (400 MHz, DMSO-d6) δ = 9.48 (s, 1H), 9.42-9.39 (m, 1H), 8.77 (d, J = 8.4 Hz, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.64 (d, J = 4.8 Hz, 1H), 8.27 (s, 1H), 7.98-7.96 (m, 1H), 7.85 (s, 1H), 7.78 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.88-4.81(m, 3H), 4.76-4.71 (m, 1H), 4.38-4.28 (m, 2H), 4.14-4.04 (m, 3H), 3.89-3.79 (m, 1H), 3.49-3.46 (m, 2H), 2.91 (s, 3H), 1.72-1.63 (m, 3H) ppm 268 486.2 1H NMR (400 MHz, DMSO-d6) δ = 9.43-9.39 (m, 2H), 8.69-8.63 (m, 2H), 8.53-8.42 (m, 1H), 8.27 (s, 1H), 8.19 (d, J = 4.4 Hz, 1H), 8.07 (d, J = 4 Hz, 1H), 7.97-7.95 (m, 1H), 7.78 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.88- 4.70 (m, 4H), 4.23-4.19(m, 1H), 4.18-4.04 (m, 1H), 3.88-3.79 (m, 1H), 1.68 (d, J = 20.4 Hz, 1H), 1.10-1.00 (m, 4H) ppm 269 502.2 1H NMR (400 MHz, DMSO-d6) δ = 9.44-9.41 (m, 1H), 9.33 (s, 1H), 8.63- 8.57 (m, 2H), 8.32-8.29 (m, 1H), 8.22-8.20 (m, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.82-7.77 (m, 2H), 4.94 (d, J = 16.8 Hz, 1H), 4.78-4.71 (m, 3H), 4.16-4.04 (m, 5H), 3.89-3.80 (m, 1H), 2.45-2.38 (m, 2H), 1.72-1.66 (m, 3H) ppm 270 509.2 1H NMR (400 MHz, DMSO-d6) δ = 9.44-9.41 (m, 1H), 9.33 (s, 1H), 8.63- 8.60 (m, 2H), 8.32-8.29 (m, 1H), 8.22-8.20 (m, 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.88-7.83 (m, 2H), 7.78-7.76 (m, 1H), 4.97-4.83 (m, 2H), 4.77 (d, J = 5.6 Hz, 2H), 4.23 (d, J = 11.6 Hz, 1H), 4.16-4.12 (m, 4H), 3.87 (d, J = 11.2 Hz, 1H), 2.45-2.40 (m, 2H), 1.70 (s, 3H) ppm 271 485.3 1H NMR (400 MHz, DMSO-d6) δ = 9.40 (s, 2H), 8.66 (d, J = 0.8 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.35 (d, J = 1.2 Hz, 1H), 8.28 (s, 1H), 7.95 (s, 2H), 7.89-7.79 (m, 2H), 7.35-7.28 (m, 1H), 6.29 (s, 1H), 4.92-4.69 (m, 4H), 4.14-4.03 (m, 1H), 3.91-3.77 (m, 1H), 1.70 (d, J = 20.8 Hz, 3H), 1.42-1.41 (m, 2H), 1.19-1.18 (m, 2H) ppm 272 508.2 1H NMR (400 MHz, DMSO-d6) δ = 9.36-9.32 (m, 2H), 8.24-8.17 (m, 2H), 7.99-7.92 (m, 2H), 7.82-7.80 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 4.88-4.76 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 4.14-4.10 (m, 4H), 3.87-3.84 (d, J = 11.6 Hz, 1H), 2.37-2.32 (m, 1H), 1.68 (s, 3H) ppm 273 520.1 1H NMR (400 MHz, MeOD) δ = 9.30 (s, 1H), 8.67-8.54 (m, 2H), 8.27- 8.23 (m, 1H), 8.09-8.08 (m, 1H), 7.96-7.91 (m, 2H), 7.76-7.73 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.89-6.87 (m, 1H), 4.92 (s, 2H), 4.91-4.89 (m, 1H), 4.81-4.80 (m, 1H), 4.15-4.02 (m, 1H), 3.96-3.81 (m, 1H), 3.50 (s, 6H), 1.73 (d, J = 20.4 Hz, 3H) ppm 274 475.20 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.31 (t, J = 5.9 Hz, 1H), 9.20 (d, J = 0.9 Hz, 1H), 8.44 (s, 1H), 8.17 (d, J = 1.7 Hz, 1H), 8.01-7.86 (m, 1H), 7.75 (d, J = 0.9 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 5.00-4.78 (m, 2H), 4.71 (d, J = 5.8 Hz, 2H), 4.23 (d, J = 11.5 Hz, 1H), 4.03 (s, 3H), 3.85 (d, J = 21.7 Hz, 4H), 1.70 (s, 3H). 275 463.20 .sup.1H-NMR (300 MHz, DMSO-d.sub.6) δ 9.50 (t, J = 5.8 Hz, 1H), 8.75 (dd, J = 9.1, 1.0 Hz, 1H), 8.44 (s, 1H), 8.29-8.20 (m, 2H), 7.95 (dt, J = 8.1, 1.7 Hz, 1H), 7.84 (s, 1H), 7.30 (d, J = 8.2 Hz, 1H), 5.05 (dd, J = 5.9, 2.8 Hz, 2H), 4.86 (dd, J = 15.6, 2.5 Hz, 1H), 4.73 (dd, J = 15.7, 4.4 Hz, 1H), 4.08 (t, J = 13.0 Hz, 1H), 4.00 (s, 3H), 3.93-3.80 (m, 1H), 3.79 (s, 3H), 1.69 (d, J = 20.7 Hz, 3H). LCMS (ESI) m/z [M + H].sup.+ = 271. 276 485.90 .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 8.97 (s, 1H), 8.94-8.83 (m, 2H), 8.28 (s, 2H), 7.91 (d, J = 5.2 Hz, 2H), 7.27 (d, J = 8.1 Hz, 1H), 5.21 (s, 2H), 4.84 (m, 2H), 4.26 (t, J = 7.5 Hz, 4H), 4.07 (t, J = 12.2 Hz, 1H), 3.94- 3.81 (m, 1H), 2.54 (p, J = 7.5 Hz, 2H), 1.75 (s, 3H). 277 429.20 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.53 (t, J = 5.8 Hz, 1H), 8.95 (dd, J = 9.0, 1.0 Hz, 1H), 8.58 (d, J = 9.1 Hz, 1H), 8.41-8.33 (m, 2H), 8.30-8.22 (m, 1H), 8.14 (s, 1H), 8.00-7.92 (m, 1H), 7.64-7.56 (m, 3H), 7.30 (d, J = 8.1 Hz, 1H), 5.17-5.09 (m, 2H), 4.90-4.82 (m, 1H), 4.78-4.68 (m, 1H), 4.07 (t, J = 13.0 Hz, 1H), 3.92-3.75 (m, 1H), 1.69 (d, J = 20.7 Hz, 3H). 278 650.30 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ9.53-9.43 (m, 2H), 8.80-8.66 (m, 2H), 8.31-8.25 (m, 1H), 8.08-7.95 (m, 2H), 7.92-7.78 (m, 2H), 7.39 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 5.05-4.85 (m, 4H), 4.31 (d, J = 11.5 Hz, 1H), 3.95 (d, J = 11.5 Hz, 1H), 3.79-3.68 (m, 10H), 3.63-3.45 (m, 4H), 3.30 (s, 3H), 2.72 (t, J = 6.6 Hz, 2H), 1.78 (s, 3H). 280 494.1 1H NMR (400 MHz, METHANOL-d4) δ = 9.45 (s, 1H), 9.31-9.20 (m, 1H), 8.68 (d, J = 0.8 Hz, 1H), 8.36 (d, J = 4.8 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.96 (s, 1H), 7.93-7.87 (m, 1H), 7.51-7.40 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 4.93-4.90 (m, 4H), 4.20 (d, J = 11.6 Hz, 1H), 3.92 (d, J = 11.2 Hz, 1H), 2.58-2.37 (m, 1H), 1.76 (s, 3H), 1.16-1.08 (m, 4H) ppm 284 534.3 1H NMR (400 MHz, DMSO-d6) δ = 9.48 (s, 1H), 9.44-9.41 (m, 1H), 8.80- 8.75 (m, 1H), 8.73-8.68 (m, 1H), 8.65 (d, J = 5.2 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.98-7.95 (m, 1H), 7.88 (s, 1H), 7.79 (d, J = 4.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.97-4.82 (m, 4H), 4.76 (br s, 2H), 4.24 (d, J = 11.6 Hz, 1H), 4.16-4.04 (m, 1H), 4.00-3.67 (m, 4H), 3.22-3.13 (m, 1H), 1.93 (d, J = 8.8 Hz, 1H), 1.71 (s, 3H) ppm 285 518.3 1H NMR (400 MHz, DMSO-d6) δ = 9.47 (s, 1H), 9.43-9.40 (m, 1H), 8.81- 8.72 (m, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 4.8 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.96-7.93 (m 1H), 7.86 (s, 1H), 7.67 (d, J = 4.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.12-4.96 (m, 1H), 4.95-4.79 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.58 (br s, 2H), 3.03-2.95 (m, 1H), 2.05 (br s, 2H), 1.70 (s, 3H), 1.47-1.38 (m, 2H) ppm 287 645.00 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.42 (d, J = 5.1 Hz, 2H), 8.73-8.58 (m, 2H), 8.20 (d, J = 1.7 Hz, 1H), 8.01-7.88 (m, 2H), 7.85-7.70 (m, 2H), 7.31 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 4.96-4.73 (m, 4H), 4.23 (d, J = 11.5 Hz, 1H), 3.87 (d, J = 11.5 Hz, 1H), 3.66 (d, J = 17.0 Hz, 8H), 2.84 (d, J = 11.0 Hz, 2H), 2.62 (t, J = 7.3 Hz, 1H), 2.21 (s, 3H), 2.01 (s, 2H), 1.71 (s, 3H), 1.65 (dd, J = 8.1, 3.3 Hz, 4H). 288 606.40 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.41 (s, 2H), 8.77-8.54 (m, 2H), 8.20 (s, 1H), 8.01-7.88 (m, 2H), 7.84-7.71 (m, 2H), 7.31 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 4.85 (dd, J = 19.0, 6.6 Hz, 4H), 4.23 (d, J = 11.5 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.78-3.51 (m, 10H), 3.24 (s, 3H), 2.64 (t, J = 6.5 Hz, 2H), 1.71 (s, 3H). 289 445.15 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.32 (t, J = 5.9 Hz, 1H), 9.24 (d, J = 0.9 Hz, 1H), 8.63 (s, 1H), 8.24-8.11 (m, 2H), 7.92 (d, 1H), 7.84-7.78 (m, 1H), 7.30 (d, J = 8.1 Hz, 1H), 5.00-4.62 (m, 4H), 4.23 (d, J = 11.5 Hz, 1H), 3.94 (s, 3H), 3.91 (d, 1H), 1.70 (s, 3H). 290 435.20 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 9.27-9.20 (m, 1H), 9.11-9.02 (m, 1H), 8.64-8.57 (m, 1H), 8.26-8.13 (m, 2H), 8.06-8.00 (m, 1H), 7.69- 7.53 (m, 3H), 4.93-4.90 (m, 2H), 4.88-4.83 (m, 2H), 4.20-4.07 (m, 1H), 4.02-3.89 (m, 1H), 1.77 (d, J = 20.7 Hz, 3H). 291 524.3 1H NMR (400 MHz, DMSO-d6) δ = 9.47-9.37 (m, 2H), 8.93 (s, 1H), 8.75- 8.70 (m, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.22-8.17 (m, 2H), 7.97-7.94 (m, 1H), 7.86 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.63-5.43 (m, 1H), 4.96- 4.77 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 4.00-3.57 (m, 5H), 2.36-2.15 (m, 2H), 1.71 (s, 3H) ppm 292 570.4 1H NMR (400 MHz, DMSO-d6) δ = 9.46 (s, 1H), 9.41-9.38 (m, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.58 (d, J = 4.8 Hz, 1H), 8.26 (s, 1H), 7.97-7.95 (m, 1H), 7.84 (s, 1H), 7.70 (d, J = 4.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 4.88-4.70 (m, 4H), 4.58-4.55 (m, 2H), 4.51-4.48 (m, 2H), 4.10-4.04 (m, 1H), 3.89 (br d, J = 5.6 Hz, 4H), 3.85-3.79 (m, 1H), 3.48-3.42 (m, 1H), 2.38-2.36 (m, 4H), 1.71-1.66 (m, 3H) ppm 293 460.3 1H NMR (400 MHz, METHANOL-d4) δ = 9.36 (s, 1H), 8.60 (s, 2H), 8.23- 8.21 (m, 2H), 8.08 (d, J = 4.0 Hz, 1H), 7.93-7.91 (m, 2H), 7.27 (d, J = 7.6 Hz, 1H), 4.92 (s, 2H), 4.90 (br d, J = 2.8 Hz, 1H), 4.81 (br d, J = 3.6 Hz, 1H), 4.10-4.04 (m, 1H), 3.92-3.84 (m, 4H), 1.75-1.70 (m, 3H) ppm 294 509.3 1H NMR (400 MHz, METHANOL-d4) δ = 9.43 (s, 1H), 9.18 (s, 1H), 8.61 (s, 1H), 8.16 (d, J = 0.8 Hz, 1H), 8.00-7.88 (m, 3H), 7.27 (d, J = 8.0 Hz, 1H), 6.91-6.88 (m, 1H), 4.93-4.89 (m, 4H), 4.29-4.17 (m, 5H), 3.92 (d, J = 11.6 Hz, 1H), 2.50-2.39 (m, 2H), 1.75 (s, 3H) ppm 295 484.30 1H NMR (400 MHz, MeOD) δ = 9.30 (s, 1H), 8.64-8.62 (m, 1H), 8.57- 8.55 (m, 1H), 8.25 (s, 1H), 7.95-7.93 (m, 2H), 7.85 (d, J = 7.2 Hz, 1H), 7.70-7.66 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.52-6.50 (m, 1H), 4.92 (s, 2H), 4.82-4.77 (m, 2H), 4.15-4.05 (m, 5H), 3.93-3.88 (m, 1H), 2.48- 2.41 (m, 2H), 1.76-1.71 (m, 3H) ppm 296 503.1 1H NMR (400 MHz, DMSO-d6) δ = 9.57-9.54 (m, 1H), 9.47 (s, 1H), 9.08- 9.07 (m, 1H), 8.72 (d, J = 8.0 Hz, 1H), 8.61 (s, 1H), 8.07-7.99 (m, 2H), 7.88 (s, 1H), 7.16-7.14 (m, 1H), 4.91-4.71 (m, 4H), 4.21-4.06 (m, 5H), 3.97-3.84 (m, 1H), 2.39-2.33 (m, 2H), 1.79-1.64 (m, 3H) ppm 297 469.2 1H NMR (400 MHz, DMSO-d6) δ = 9.37-9.33 (m, 2H), 8.61-8.59 (m, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.93-7.91 (m, 1H), 7.78 (s, 1H), 7.55 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.92-4.78 (m, 4H), 4.23-4.20 (m, 4H), 3.89-3.87 (m, 4H), 1.69 (s, 3H) ppm 299 501.4 1H NMR (400 MHz, MeOD) δ = 9.91 (s, 1H), 9.39 (s, 1H), 9.05 (s, 1H), 8.70 (d, J = 0.8 Hz, 2H), 8.18 (d, J = 1.6 Hz, 1H), 8.05 (s, 1H), 7.92 (d, J = 1.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.97-4.94 (m, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.21 (d, J = 11.2 Hz, 1H), 3.93 (d, J = 11.2 Hz, 1H), 2.22-2.12 (m, 3H), 1.77 (s, 3H) ppm 300 433.90 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 9.29 (s, 1H), 8.35-8.22 (m, 3H), 8.10- 7.97 (m, 2H), 7.74-7.61 (m, 3H), 7.41-7.27 (m, 1H), 5.01-4.97 (m, 1H), 4.94-4.90 (m, 2H), 4.90-4.82 (m, 1H), 4.24-4.08 (m, 1H), 4.06- 3.88 (m, 1H), 1.82 (d, J = 20.5 Hz, 3H). 301 471.00 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.59 (t, J = 5.9 Hz, 1H), 9.47 (d, J = 4.1 Hz, 2H), 9.10 (t, J = 1.8 Hz, 1H), 8.82-8.73 (m, 2H), 8.63 (t, J = 1.8 Hz, 1H), 8.56 (d, J = 8.6 Hz, 1H), 7.94 (s, 1H), 4.93-4.72 (m, 4H), 4.13 (t, J = 12.9 Hz, 1H), 3.91 (dd, J = 25.3, 12.6 Hz, 1H), 2.36 (dt, J = 8.5, 5.6 Hz, 1H), 1.72 (d, J = 20.9 Hz, 3H), 1.19-1.12 (m, 4H). 302 529.3 1H NMR (400 MHz, CDCl3) δ = 9.41 (s, 1H), 8.83 (d, J = 8.6 Hz, 1H), 8.68 (d, J = 7.5 Hz, 1H), 8.56 (d, J = 8.6 Hz, 1H), 8.30 (s, 2H), 8.21 (s, 1H), 8.03 (t, J = 7.8 Hz, 1H), 7.95-7.85 (m, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 5.07 (br d, J = 5.5 Hz, 2H), 4.94-4.70 (m, 2H), 4.20-3.93 (m, 6H), 3.84 (br dd, J = 12.1, 19.0 Hz, 1H), 2.37-2.22 (m, 2H), 1.80-1.71 (m, 3H), 1.67 (br d, J = 12.8 Hz, 2H) ppm 305 457.4 1H NMR (400 MHz, CHLOROFORM-d) δ = 9.25 (s, 1H), 8.38-8.36 (m, 1H), 8.28 (s, 1H), 8.12-8.10 (m, 2H), 7.91 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.99 (d, J = 5.2 Hz, 2H), 4.91-4.76 (m, 2H), 4.12-4.03 (m, 4H), 3.90-3.80 (m, 1H), 1.78-1.73 (m, 3H) ppm 306 524.5 1H NMR (400 MHz, DMSO-d6) δ = 9.47 (s, 1H), 9.43-9.39 (m, 1H), 8.79- 8.74 (m, 1H), 8.67 (d, J = 8.4 Hz, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.96-7.94 (m, 1H), 7.87 (s, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.60-5.39 (m, 1H), 4.94-4.81 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 4.01-3.59 (m, 5H), 2.33-2.15 (m, 2H), 1.70 (s, 3H) ppm 307 555.2 1H NMR (400 MHz, DMSO-d6) δ = 9.47 (s, 1H), 9.42-9.39 (m, 1H), 8.75 (d, J = 8.8 Hz, 1H), 8.64 (d, J = 8.8 Hz, 1H), 8.58 (d, J = 5.2 Hz, 1H), 8.28 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.69 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.22-5.03 (m, 2H), 4.92-4.70 (m, 4H), 4.11- 4.04 (m, 1H), 3.97-3.78 (m, 3H), 3.35 (s, 1H), 3.25-3.20 (m, 1H), 2.98- 2.88 (m, 1H), 2.82-2.76 (m, 1H), 2.02-1.93 (m, 1H), 1.90-1.80 (m, 1H), 1.77-1.63 (m, 4H), 1.40-1.31 (m, 1H) ppm 308 555.2 1H NMR (400 MHz, DMSO-d6) δ = 9.47 (s, 1H), 9.41-7.38 (m, 1H), 8.75 (d, J = 8.8 Hz, 1H), 8.64 (d, J = 8.8 Hz, 1H), 8.58 (d, J = 4.8 Hz, 1H), 8.27 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.69 (d, J = 4.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.24-5.01 (m, 2H), 4.93-4.69 (m, 4H), 4.11- 4.04 (m, 1H), 4.00-3.76 (m, 3H), 3.37-3.34 (m, 1H), 3.25-3.20 (m, 1H), 2.97-2.88 (m, 1H), 2.82-2.76 (m, 1H), 1.98-1.96 (m, 1H), 1.92-1.80 (m, 1H), 1.75-1.65 (m, 4H), 1.36-1.32 (m, 1H) ppm 309 526.4 1H NMR (400 MHz, MeOD) δ = 9.40 (s, 1H), 9.12 (d, J = 7.6 Hz, 1H), 8.86 (d, J = 8.8 Hz, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.48-8.38 (m, 2H), 8.19 (d, J = 1.6 Hz, 1H), 8.04 (s, 1H), 7.95-7.92 (m, 1H), 7.49-7.14 (m, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.58 (s, 2H), 4.21 (d, J = 11.2 Hz, 1H), 3.94 (d, J = 11.2 Hz, 1H), 1.75 (s, 3H) ppm 310 534.5 1H NMR (400 MHz, DMSO-d6) δ = 9.47 (s, 1H), 9.43-9.39 (m, 1H), 8.79- 8.72 (m, 1H), 8.65 (br s, 1H), 8.57 (d, J = 5.2 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.96-7.94 (m, 1H), 7.87 (s, 1H), 7.71 (d, J = 4.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.32-4.96 (m, 1H), 4.95-4.69 (m, 5H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (br d, J = 11.2 Hz, 2H), 3.78-3.44 (m, 3H), 2.02-1.96 (m, 1H), 1.95-1.87 (m, 1H), 1.70 (s, 3H) ppm 311 524.5 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.36 (m, 2H), 8.93 (s, 1H), 8.72 (d, J = 8.8 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.24-8.13 (m, 2H), 7.97- 7.94 (m, 1H), 7.86 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.64-5.44 (m, 1H), 4.96-4.76 (m, 4H), 4.23 (d, J = 11.2 Hz, 1H), 4.03-3.69 (m, 4H), 3.64- 3.59 (m, 1H), 2.34-2.12 (m, 2H), 1.71 (s, 3H) ppm 316 580.25 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51-9.34 (m, 2H), 8.83-8.65 (m, 3H), 8.44 (dt, J = 8.0, 1.4 Hz, 1H), 8.35 (d, J = 8.7 Hz, 1H), 8.21 (d, J = 1.8 Hz, 1H), 8.07-7.91 (m, 2H), 7.85 (s, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 4.99-4.75 (m, 4H), 4.23 (d, J = 11.4 Hz, 1H), 3.87 (d, J = 11.5 Hz, 1H), 3.65-3.50 (m, 4H), 3.51-3.41 (m, 4H), 3.23 (s, 3H), 1.71 (s, 3H). 317 575.35 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.42 (d, J = 3.2 Hz, 2H), 8.77-8.64 (m, 2H), 8.55-8.40 (m, 2H), 8.35 (d, J = 8.7 Hz, 1H), 8.21 (d, J = 1.7 Hz, 1H), 8.07-7.92 (m, 2H), 7.85 (s, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 5.02-4.72 (m, 4H), 4.23 (d, J = 11.4 Hz, 1H), 3.95-3.72 (m, 2H), 2.83 (d, J = 11.1 Hz, 2H), 2.21 (s, 3H), 2.04 (q, J = 11.9, 8.9 Hz, 2H), 1.87-1.76 (m, 2H), 1.71 (s, 3H), 1.63 (qd, J = 12.1, 3.9 Hz, 2H). 318 510 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.71-1.81 (m, 3 H) 3.88 (dd, J = 17.31, 12.02 Hz, 1 H) 4.09 (t, J = 11.69 Hz, 1 H) 4.67 (td, J = 13.06, 4.52 Hz, 2 H) 4.75-4.94 (m, 2 H) 5.01 (d, J = 5.29 Hz, 2 H) 6.11-6.52 (m, 1 H) 7.11-7.20 (m, 2 H) 7.27 (s, 8 H) 7.36 (br s, 1 H) 7.84 (d, J = 8.16 Hz, 1 H) 7.98 (s, 1 H) 8.11 (s, 1 H) 8.39 (s, 2 H) 8.65 (d, J = 9.92 Hz, 1 H) 9.30 (s, 1 H) ppm. 319 515.2 1H NMR (400 MHz, CDCl3) δ = 9.27-9.33 (m, 1H), 9.18-9.23 (m, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.26-8.31 (m, 1H), 8.12 (s, 1H), 8.02-8.07 (m, 1H), 7.83-7.89 (m, 1H), 7.34-7.38 (m, 1H), 7.19 (s, 1H), 4.99-5.05 (m, 2H), 4.76-4.93 (m, 2H), 4.06-4.14 (m, 1H), 3.89-3.95 (m, 4H), 3.82-3.89 (m, 1H), 3.69-3.75 (m, 4H), 1.83 (s, 3H) ppm 320 534.1 1HNMR (400 MHz, DMSO-d6) δ = 9.70-9.63 (m, 1H), 9.61-9.54 (m, 1H), 8.79-8.71 (m, 1H), 8.27-8.22 (m, 1H), 8.22-8.19 (m, 1H), 8.11- 8.02 (m, 1H), 7.99-7.90 (m, 1H), 7.65-7.50 (m, 1H), 7.36-7.25 (m, 1H), 7.11-7.00 (m, 1H), 4.95-4.79 (m, 5H), 4.42-4.34 (m, 2H), 4.26-4.18 (m, 1H), 3.97-3.90 (m, 2H), 3.86 (d, J = 11.6 Hz, 1H), 2.28 (s, 3H), 1.70 (s, 3H) ppm. 321 518.4 1H NMR (400 MHz, DMSO-d6) δ = 9.46 (s, 1H), 9.42-9.39 (m, 1H), 8.75 (d, J = 8.4 Hz, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 4.8 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.96-7.93 (m, 1H), 7.86 (s, 1H), 7.68 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.95-4.80 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.2 Hz, 3H), 3.57 (br d, J = 3.2 Hz, 2H), 1.70 (s, 5H), 0.8-0.75 (m, 1H), 0.22-0.19 (m, 1H) ppm. 322 536.4 1H NMR (400 MHz, DMSO-d6) δ = 9.53-9.36 (m, 2H), 8.76 (d, J = 8.4 Hz, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.20 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.87 (s, 1H), 7.73 (d, J = 4.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.96-4.78 (m, 4H), 4.70-4.52 (m, 2H), 4.23 (d, J = 11.6 Hz, 1H), 3.95 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 3.62-3.51 (m, 2H), 3.09-3.01 (m, 1H), 2.76-2.67 (m, 1H), 1.70 (s, 3H), 1.20 (d, J = 6.4 Hz, 3H) ppm 323 536.2 1H NMR (400 MHz, METHANOL-d4) δ = 9.32 (s, 1H), 8.62 (d, J = 8.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 2H), 8.22 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.06-7.97 (m, 3H), 7.94-7.92 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.90- 4.90 (m, 4H), 4.21 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.2 Hz, 1H), 3.59 (s, 4H), 3.39 (s, 3H), 1.76 (s, 3H) ppm 324 492.2 1H NMR (400 MHz, METHANOL-d4) δ = 9.33 (s, 1H), 8.62 (d, J = 8.8 Hz, 1H), 8.32-8.29 (m, 2H), 8.22 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.99-7.97 (m, 3H), 7.94-7.92 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.92- 4.91 (m, 4H), 4.21 (d, J = 11.2 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 2.95 (s, 3H), 1.76 (s, 3H) ppm 325 470.2 1H NMR (400 MHz, DMSO-d6) δ = 9.43 (s, 2H), 9.42 (br s, 1H), 8.77 (s, 1H), 8.74(d, J = 8.4 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.27 (s, 1H), 7.98- 7.96 (m, 1H), 7.85 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.88-4.81 (m, 3H), 4.75-4.74(m, 1H), 4.11-4.04 (m, 1H), 3.88-3.79 (m, 1H), 2.35-2.32 (m, 1H), 1.71-1.66 (m, 3H), 1.15-1.13 (m, 4H) ppm. 329 469.2 1H NMR (400 MHz, MeOD) δ = 8.31-8.30 (m, 1H), 8.21-8.19 (m, 2H), 8.15 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 5.2 Hz, 2H), 7.90-7.89 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 5.09 (s, 2H), 4.90 (s, 2H), 4.20 (d, J = 11.2 Hz, 1H), 4.03 (s, 3H), 3.93 (d, J = 11.6 Hz, 1H), 3.82-3.81 (m, 3H), 1.75 (s, 3H) ppm. 333 480.2 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.43 (m, 1H), 9.20 (s, 1H), 8.46 (d, J = 0.4, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 8.00-7.96(m, 1H), 7.79 (d, J = 10.4 Hz, 1H), 7.57 (s, 1H), 4.95 (d, J = 16.8 Hz, 1H), 4.77-4.71 (m, 3H), 4.16-4.04 (m, 1H), 3.97 (s, 3H), 3.90-3.78 (m, 1H), 3.76 (s, 3H), 1.75- 1.61 (m, 3H) ppm. 334 463.2 1H NMR (400 MHz, DMSO-d6) δ = 9.54-9.52 (m, 1H), 9.21 (s, 1H), 9.09- 9.08 (m, 1H), 8.62 (s, 1H), 8.46-8.42 (m, 1H), 8.35 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.60 (s, 1H), 4.86-4.74 (m, 4H), 4.16-4.09 (m, 1H), 3.98 (s, 3H), 3.93-3.83(m, 1H), 3.78 (s, 3H), 1.71 (d, J = 21.2, 3H) ppm 335 492.2 1H NMR (400 MHz, DMSO-d6) δ = 9.49-9.46 (m, 1H), 8.99 (d, J = 1.6 Hz, 1H), 8.81-8.78 (m, 1H), 8.55 (d, J = 9.2 Hz, 1H), 8.36 (d, J = 5.6 Hz, 1H), 8.31 (s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.94-7.92 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.41 (d, J = 6.0 Hz, 1H), 5.06 (d, J = 5.6 Hz, 2H), 4.92-4.81 (m, 2H), 4.23-4.14 (m, 5H), 3.87 (d, J = 11.6 Hz, 1H), 2.45-2.40 (m, 2H), 1.69 (s, 3H) ppm. 336 492.2 1H NMR (400 MHz, DMSO-d6) δ = 9.52-9.49 (m, 1H), 8.84 (s, 1H), 8.59- 8.58 (m, 2H), 8.51 (d, J = 5.2 Hz, 1H), 8.23 (s, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.95-7.92 (m, 1H), 7.42 (d, J = 5.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.09 (d, J = 6.0 Hz, 2H), 4.92-4.81 (m, 2H), 4.23 (d, J = 11.6 Hz, 1H), 4.16-4.12 (m, 4H), 3.87 (d, J = 11.2 Hz, 1H), 2.37-2.33(m, 2H), 1.68(s, 3H) ppm. 337 477.2 1H NMR (400 MHz, DMSO-d6) δ = 9.72 (d, J = 2.4 Hz, 1H), 9.46 (s, 1H), 9.42-9.40 (m, 1H), 9.21 (d, J = 1.2 Hz, 1H), 8.82 (d, J = 5.2 Hz, 1H), 8.19 (d, J = 1.2 Hz, 1H), 8.07 (d, J = 5.2 Hz, 1H), 7.97-7.94 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 4.97 93-4.81 (m, 4H), 4.24 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H), 2.34-2.30 (m, 1H), 1.69 (s, 3H), 1.15-1.12 (m, 4H) ppm. 338 462.2 1HNMR (400 MHz, DMSO-d6) δ = 9.33-9.30 (m, 1H), 9.26-9.20 (m, 2H), 8.43-8.35 (m, 2H), 8.25 (s, 1H), 7.96(d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.88-4.82 (m, 1H), 4.76-4.70 (m, 3H), 4.10- 4.04 (m, 1H), 3.96 (s, 3H), 3.88-3.80 (m, 1H), 3.77 (s, 3H), 1.71-1.61 (m, 3H) ppm. 339 536.3 1H NMR (400 MHz, DMSO-d6) δ = 9.47 (s, 1H), 9.44-9.40 (m, 1H), 8.79- 8.74 (m, 1H), 8.67 (d, J = 8.8 Hz, 1H), 8.57 (d, J = 4.8 Hz, 1H), 8.49 (s, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.97-7.95 (m, 1H), 7.87 (s, 1H), 7.68 (d, J = 5.2 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 4.96-4.81 (m, 4H), 4.24 (d, J = 11.6 Hz, 1H), 4.12 (br s, 1H), 3.90-3.51 (m, 5H), 3.30 (s, 3H), 2.16-2.07 (m, 2H), 1.71 (s, 3H) ppm 340 534.3 1H NMR (400 MHz, DMSO-d6) δ = 9.47 (s, 1H), 9.43-9.39 (m, 1H), 8.78- 8.73 (m, 1H), 8.70-8.60 (m, 1H), 8.57 (d, J = 5.2 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.97-7.94 (m, 1H), 7.87 (s, 1H), 7.71 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.95-4.70 (m, 6H), 4.23 (d, J = 11.2 Hz, 1H), 3.90-3.84 (m, 2H), 3.77-3.49 (m, 3H), 2.00-1.89 (m, 2H), 1.70 (s, 3H) ppm 341 524.2 1H NMR (400 MHz, DMSO-d6) δ = 9.47 (s, 1H), 9.43-9.39 (m, 1H), 8.80- 8.74 (m, 1H), 8.67 (d, J = 8.4 Hz, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.97-7.87 (m, 1H), 7.87 (s, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.60-5.39 (m, 1H), 4.95-4.80 (m, 4H), 4.23 (d, J = 11.2 Hz, 1H), 4.09-3.54 (m, 5H), 2.32-2.12 (m, 2H), 1.71 (s, 3H) ppm 342 477.2 1H NMR (400 MHz, DMSO-d6) δ = 9.67 (d, J = 2.0 Hz, 1H), 9.44 (s, 1H), 9.42-9.41 (m, 1H), 9.22 (s, 1H), 9.13 (d, J = 1.6 Hz, 1H), 8.71 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.97-7.95 (m, 1H), 7.92 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.93-4.81 (m, 4H), 4.24 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H), 2.34-2.31 (m, 1H), 1.70 (s, 3H), 1.19-1.12 (m, 4H) ppm. 343 462.2 1H NMR (400 MHz, DMSO-d6) δ = 9.39-9.36 (m, 1H), 9.20 (s, 1H), 8.46- 8.44 (m, 2H), 8.36 (s, 1H), 8.28 (s, 1H), 8.00-7.96 (m, 2H), 7.55 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.88-4.84 (m, 1H), 4.76-4.71 (m, 3H), 4.11- 4.04 (m, 1H), 3.97 (s, 3H), 3.69-3.79 (m, 1H), 3.75 (s, 3H), 168 (d, J = 12.4, 3H) ppm. 344 473.1 1H NMR (400 MHz, DMSO-d6) δ = 9.42 (s, 1H), 9.37-9.34 (m, 1H), 9.09 (s, 1H), 8.58 (s, 1H), 8.18 (d, J = 1.2 Hz, 1H), 8.00 (s, 1H), 7.95-7.92 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 4.94-4.80 (m, 2H), 4.77 (d, J = 6.0 Hz, 2H), 4.22 (d, J = 11.6 Hz, 1H), 4.07 (s, 3H), 3.86 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm 345 491.2 1H NMR (400 MHz, MeOD) δ = 9.21 (s, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.24 (s, 1H), 7.96-7.92(m, 2H), 7.86-7.85 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 4.88 (s, 3H), 4.81-4.76(m, 1H), 4.61-4.50 (m, 2H), 4.10-4.04 (m, 1H), 3.92-3.84 (m, 1H), 3.73 (s, 3H), 3.66-3.63(m, 2H), 2.47-2.46 (m, 2H), 1.76-1.70 (m, 3H) ppm. 346 490 1H NMR (400 MHz, DMSO-d6) δ = 9.63 (s, 1H), 9.42 (s, 2H), 8.73 (s, 2H), 8.21 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 3.2 Hz, 1H), 8.01-7.93 (m, 1H), 7.88 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 3.2 Hz, 1H), 4.97-4.81 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.97 (s, 3H), 3.87 (d, J = 11.6 Hz, 1H), 1.71 (s, 3H) ppm. 347 484.2 1H NMR (400 MHz, MeOH) δ = 9.63 (s, 1H), 9.36 (s, 1H), 8.85 (s, 1H), 8.23 (s, 1H), 7.93-7.91 (m, 2H), 7.66-7.63(m, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.45(d, J = 8.4 Hz, 1H), 4.90 (s, 3H), 4.80 (d, J = 3.2 Hz, 1H), 4.14-4.03 (m, 5H), 3.91-3.86 (m, 1H), 2.46-2.42 (m, 2H), 1.75-1.69 (m, 3H) ppm. 348 498.1 1H NMR (400 MHz, DMSO-d6) δ = 9.41 (s, 1H), 9.36-9.33 (m, 1H), 8.61 (d, J = 4.8 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.98 (s, 1H), 7.93-7.90 (m, 1H), 7.46 (d, J = 4.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.93-4.80 (m, 2H), 4.76 (d, J = 6.0 Hz, 2H), 4.22 (d, J = 11.2 Hz, 1H), 4.17-4.13 (m, 4H), 3.86 (d, J = 11.6 Hz, 1H), 2.41-2.34 (m, 2H), 1.69 (s, 3H) ppm 349 467.1 1H NMR (400 MHz, MeOD-d4) δ = 8.90 (s, 1H), 8.77 (s, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.28-8.26 (m, 2H), 8.15 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 5.17 (s, 2H), 4.92-4.81 (m, 2H), 4.20 (d, J = 11.2 Hz, 1H), 4.13 (s, 3H), 3.92 (d, J = 11.2 Hz, 1H), 1.74 (s, 3H) ppm 351 491 1H NMR (400 MHz, MeOD-d4) δ = 8.61-8.60 (m, 2H), 8.50-8.49 (m, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.68-7.64 (m, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.30-7.28 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 5.17 (s, 2H), 4.92-4.81 (m, 2H), 4.20 (d, J = 11.2 Hz, 1H), 4.16-4.12 (m, 4H), 3.92 (d, J = 11.2 Hz, 1H), 2.49-2.42 (m, 2H), 1.76 (s, 3H) ppm 352 539.1 1H NMR (400 MHz, DMSO-d6) δ = 9.49-9.46(m, 1H), 9.42 (s, 1H), 8.93 (s, 1H), 8.73 (d, J = 8.4 Hz, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.14(s, 1H), 8.01 (s, 1H), 7.96 (d, J = 10.4 Hz, 1H), 7.87 (s, 1H), 6.88-6.59 (m, 1H), 5.00- 4.96 (m, 1H), 4.86-4.82(m, 3H), 4.30-4.20 (m, 1H), 4.18-4.16 (m, 4H), 4.12 (s, 1H), 2.46-2.43 (m, 2H) ppm. 353 498.2 1H NMR (400 MHz, DMSO-d6) δ = 9.44-9.29 (m, 2H), 8.68 (s, 1H), 8.17 (d, J = 1.2 Hz, 1H), 8.08 (s, 1H), 7.98-7.90 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 4.95-4.80 (m, 2H), 4.75 (d, J = 6.0 Hz, 2H), 4.26-4.12 (m, 5H), 3.86 (d, J = 11.6 Hz, 1H), 2.46-2.40 (m, 2H), 1.70 (s, 3H) ppm 354 472 1H NMR (400 MHz, DMSO-d6) δ = 9.38 (s, 1H), 9.36-9.33 (m, 1H), 8.82- 8.79 (m, 1H), 8.47-8.45 (m, 1H), 8.40 (s, 1H), 8.17 (d, J = 1.2 Hz, 1H), 7.96-7.90 (m, 2H), 7.33-7.25 (m, 2H), 4.93-4.81 (m, 2H), 4.76 (br d, J = 6.0 Hz, 2H), 4.22 (d, J = 11.6 Hz, 1H), 4.18 (s, 3H), 3.86 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm 355 487 1H NMR (400 MHz, DMSO-d6) δ = 9.90 (s, 1H), 9.50 (s, 1H), 9.45-9.42 (m, 1H), 9.14 (s, 1H), 8.82 (d, J = 8.4 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 8.02-7.89 (m, 2H), 7.44-7.11 (m, 2H), 4.96- 4.78 (m, 4H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 1.71 (s, 3H) ppm 356 492 1H NMR (400 MHz, MeOD-d4) δ = 8.68 (s, 1H), 8.62-8.61 (m, 1H), 8.55- 8.52 (m, 2H), 8.27 (s, 1H), 8.17 (s, 1H), 7.93-7.92 (m, 1H), 7.83 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.18 (s, 2H), 4.92-4.81 (m, 2H), 4.27-4.19 (m, 5H), 3.92 (d, J = 11.2 Hz, 1H), 2.58-2.50 (m, 2H), 1.77 (s, 3H) ppm 357 466 1H NMR (400 MHz, MeOD-d4) δ = 8.48-8.46 (m, 2H), 8.25-8.16 (m, 5H), 7.92-7.90 (m, 2H), 7.29-7.27 (m, 1H), 7.15-7.13 (m, 1H), 5.17 (s, 2H), 4.92-4.81 (m, 2H), 4.20 (d, J = 11.2 Hz, 1H), 4.00 (s, 3H), 3.92 (d, J = 11.2 Hz, 1H), 1.76 (s, 3H) ppm 358 487 1H NMR (400 MHz, MeOD) δ = 9.32 (s, 1H), 9.02 (d, J = 5.2 Hz, 1H), 8.71-8.63 (m, 3H), 8.07 (d, J = 1.6 Hz, 1H), 7.93 (s, 1H), 7.84-7.82 (m, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.91-6.64 (m, 1H), 4.85 (s, 2H), 4.82 (d, J = 3.2 Hz, 2H), 4.12 (d, J = 11.6 Hz, 1H), 3.84 (d, J = 11.6 Hz, 1H), 1.67 (s, 3H) ppm 359 505.2 1H NMR (400 MHz, MeOD) δ = 9.36 (s, 1H), 8.88 (d, J = 8.8 Hz, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.52 (br s, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.00-7.91 (m, 3H), 7.45 (d, J = 6.8 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.93 (s, 2H), 4.91 (d, J = 3.2 Hz, 2H), 4.42-4.37(m, 4H), 4.29- 4.26 (m, 1H), 4.22 (d, J = 11.2 Hz, 1H), 3.94 (d, J = 11.6 Hz, 1H), 2.98 (s, 3H), 1.76 (s, 3H) ppm. 360 479.2 1H NMR (400 MHz, MeOD) δ = 9.27 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.55 (d, J = 8.8 Hz, 1H), 8.17(d, J = 1.6 Hz, 1H), 7.94-7.91 (m, 2H), 7.81 (d, J = 7.2 Hz, 1H), 7.67-7.65 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 4.91-4.90 (m, 4H), 4.21 (d, J = 11.2 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 3.18 (s, 6H), 1.76 (s, 3H) ppm. 361 505.1 1H NMR (400 MHz, MeOD) δ = 9.31 (s, 1H), 8.72 (d, J = 8.8 Hz, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.01-7.93 (m, 2H), 7.80 (d, J = 7.2 Hz, 1H), 7.67-7.64 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 4.95-4.92 (m, 4H), 4.23 (d, J = 11.2 Hz, 1H), 3.95 (d, J = 11.2 Hz, 1H), 3.61-3.57 (m, 4H), 2.17-2.05 (m, 4H), 1.79 (s, 3H) ppm 362 536.3 1H NMR (400 MHz, METHANOL-d4) δ = 9.48 (d, J = 0.8 Hz, 1H), 9.43- 9.40 (m, 1H), 8.77-8.75 (m, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.61 (d, J = 4.8 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.96-7.94 (m, 1H), 7.87 (s, 1H), 7.73 (d, J = 5.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.93-4.82 (m, 4H), 4.67-4.58 (m, 2H), 4.23 (d, J = 11.6 Hz, 1H), 3.97-3.94 (m, 1H), 3.88 (d, J = 11.2 Hz, 1H), 3.61-3.52 (m, 2H), 3.09-3.02 (m, 1H), 2.76-2.70 (m, 1H), 1.70 (s, 3H), 1.21 (d, J = 6.4 Hz, 3H) ppm 363 536.2 1H NMR (400 MHz, DMSO-d6) δ = 9.47 (s, 1H), 9.45-9.35 (m, 1H), 8.76 (d, J = 8.8 Hz, 1H), 8.68-8.56 (m, 2H), 8.20 (d, J = 1.2 Hz, 1H), 8.02- 7.92 (m, 1H), 7.87 (s, 1H), 7.73 (d, J = 4.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.96-4.74 (m, 5H), 4.44 (br d, J = 12.0 Hz, 1H), 4.23 (d, J = 11.6 Hz, 1H), 4.05-3.92 (m, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.81-3.73 (m, 1H), 3.69-3.61 (m, 1H), 3.56-3.43 (m, 1H), 3.28-3.20 (m, 1H), 1.70 (s, 3H), 1.25 (d, J = 6.4 Hz, 3H) ppm. 364 457.2 1H NMR (400 MHz, DMSO-d6) δ 9.41 (t, J = 6.0 Hz, 1H), 9.33 (s, 1H), 8.62-8.51 (m, 2H), 8.24 (d, J = 1.8 Hz, 1H), 7.99 (dd, J = 8.1, 1.8 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.69 (s, 1H), 7.35 (d, J = 8.1 Hz, 1H), 4.95 (d, J = 16.0 Hz, 1H), 4.88 (d, J = 16.1 Hz, 1H), 4.82 (d, J = 5.8 Hz, 2H), 4.27 (d, J = 11.4 Hz, 1H), 3.91 (d, J = 11.5 Hz, 1H), 3.85 (s, 3H), 1.74 (s, 3H). 365 491.3 1H NMR (400 MHz, DMSO-d6) δ 9.39 (d, J = 11.6 Hz, 2H), 8.74 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.39 (dd, J = 8.5, 1.7 Hz, 1H), 8.27 (d, J = 8.7 Hz, 1H), 8.23 (d, J = 1.7 Hz, 1H), 7.99 (dd, J = 8.1, 1.7 Hz, 1H), 7.89 (s, 1H), 7.45 (d, J = 5.2 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 4.99-4.79 (m, 4H), 4.26 (d, J = 11.4 Hz, 1H), 4.18 (t, J = 7.5 Hz, 4H), 3.91 (d, J = 11.6 Hz, 1H), 2.40 (d, J = 7.6 Hz, 1H), 1.74 (s, 3H). 366 535.4 1H NMR (400 MHz, DMSO-d6) δ 9.37 (d, J = 5.0 Hz, 2H), 8.71 (s, 1H), 8.61 (s, 1H), 8.40 (dd, J = 8.7, 1.6 Hz, 1H), 8.29-8.20 (m, 2H), 8.06 (s, 1H), 7.99 (dd, J = 8.0, 1.8 Hz, 1H), 7.87 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 4.95 (d, J = 16.0 Hz, 1H), 4.88 (d, J = 15.9 Hz, 1H), 4.82 (d, J = 5.8 Hz, 2H), 4.35 (d, J = 4.3 Hz, 0H), 4.26 (d, J = 11.4 Hz, 1H), 4.18 (s, 1H), 3.91 (d, J = 11.5 Hz, 1H), 3.73 (d, J = 11.6 Hz, 2H), 3.68 (dd, J = 11.7, 4.3 Hz, 1H), 3.57 (q, J = 8.8 Hz, 1H), 2.15 (td, J = 8.7, 8.3, 4.3 Hz, 2H), 1.74 (s, 3H). 367 468.2 1H NMR (400 MHz, DMSO-d6) δ 9.31 (t, J = 5.9 Hz, 1H), 9.21 (s, 1H), 8.27-8.19 (m, 2H), 8.14-8.05 (m, 2H), 7.97 (dd, J = 8.0, 1.7 Hz, 1H), 7.92 (dd, J = 8.6, 1.7 Hz, 1H), 7.64 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 4.95 (d, J = 16.0 Hz, 1H), 4.88 (d, J = 16.0 Hz, 1H), 4.84-4.73 (m, 2H), 4.26 (d, J = 11.5 Hz, 1H), 3.99 (s, 3H), 3.91 (d, J = 11.6 Hz, 1H), 3.79 (s, 3H), 1.74 (s, 3H). 368 483.3 1H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.61 (s, 1H), 8.44 (s, 1H), 8.37 (dd, J = 8.7, 1.7 Hz, 1H), 8.30 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.83 (s, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.44 (d, J = 8.2 Hz, 1H), 4.90 (d, J = 15.9 Hz, 1H), 4.85-4.74 (m, 3H), 4.16-4.05 (m, 5H), 3.88 (dd, J = 25.2, 12.5 Hz, 1H), 2.44-2.36 (m, 2H), 1.73 (d, J = 20.7 Hz, 3H). 369 490.3 1H NMR (500 MHz, DMSO-d6) δ 9.42-9.33 (m, 2H), 8.61 (s, 1H), 8.42- 8.34 (m, 3H), 8.26-8.18 (m, 3H), 7.98 (dd, J = 8.1, 1.7 Hz, 1H), 7.84 (s, 1H), 7.72-7.65 (m, 1H), 7.45 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 6.64 (s, 1H), 6.44 (d, J = 8.3 Hz, 1H), 4.91 (q, J = 15.9 Hz, 3H), 4.80 (d, J = 6.0 Hz, 2H), 4.26 (d, J = 11.5 Hz, 1H), 4.08 (td, J = 7.4, 4.3 Hz, 5H), 3.91 (d, J = 11.5 Hz, 1H), 1.74 (s, 3H). 370 484.3 1H NMR (400 MHz, DMSO-d6) δ 9.36 (d, J = 6.3 Hz, 2H), 8.69-8.62 (m, 2H), 8.38-8.22 (m, 3H), 8.01 (dd, J = 8.0, 1.9 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 6.4 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 4.94-4.72 (m, 4H), 4.18 (dt, J = 12.2, 7.4 Hz, 4H), 4.10 (d, J = 13.0 Hz, 1H), 3.88 (dd, J = 24.9, 12.5 Hz, 1H), 2.45 (ddq, J = 11.3, 7.4, 3.7 Hz, 2H), 1.73 (d, J = 20.7 Hz, 3H) 371 491.3 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 2H), 8.70-8.62 (m, 2H), 8.35 (dd, J = 8.6, 1.6 Hz, 1H), 8.29-8.20 (m, 2H), 8.02-7.90 (m, 2H), 7.86 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 4.95 (d, J = 16.0 Hz, 1H), 4.88 (d, J = 15.9 Hz, 1H), 4.81 (d, J = 5.8 Hz, 2H), 4.26 (d, J = 11.5 Hz, 1H), 4.18 (dt, J = 12.5, 7.5 Hz, 5H), 3.91 (d, J = 11.5 Hz, 1H), 2.52-2.39 (m, 3H), 1.74 (s, 3H), 1.08 (d, J = 6.1 Hz, 2H). 372 492.2 1H NMR (400 MHz, DMSO-d6) δ = 9.83 (d, J = 1.6 Hz, 1H), 9.43 (s, 1H), 9.39-9.33 (m, 1H), 9.19 (s, 1H), 8.35 (d, J = 6.0 Hz, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.42 (d, J = 6.0 Hz, 1H), 4.95-4.84 (m, 2H), 4.80 (d, J = 5.6 Hz, 2H), 4.25-4.12 (m, 5H), 3.86 (d, J = 11.6 Hz, 1H), 2.45-2.39 (m, 2H), 1.69 (s, 3H) ppm. 373 521.1 1H NMR (400 MHz, DMSO-d6) δ = 9.48-9.36 (m, 2H), 8.72-8.58 (m, 2H), 8.21 (s, 1H), 8.04-7.90 (m, 2H), 7.85-7.73 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.00-4.78 (m, 4H), 4.24 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H), 3.82-3.71 (m, 4H), 3.65-3.55 (m, 4H), 1.71 (s, 3H) ppm 374 510 1H NMR (400 MHz, CDCl3) δ = 9.28 (s, 1H), 9.20 (s, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.04-8.03 (m, 2H), 7.96 (s, 1H), 7.83- 7.81 (m, 1H), 7.48-7.44 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 5.62-5.47 (m, 1H), 5.00 (d, J = 5.2 Hz, 2H), 4.99-4.88 (m, 2H), 4.53-4.48 (m, 2H), 4.37-4.31 (m, 2H), 4.15 (d, J = 11.2 Hz, 1H), 3.96 (d, J = 11.2 Hz, 1H), 1.77 (s, 3H) ppm 375 539.5 1H NMR (400 MHz, DMSO-d6) δ = 9.50-9.47 (m, 1H), 9.42 (s, 1H), 8.93 (s, 1H), 8.73 (d, J = 8.8 Hz, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.14 (s, 1H), 8.01 (s, 1H), 7.96 (d, J = 10.4 Hz, 1H), 7.87 (s, 1H), 6.88-6.59 (m, 1H), 5.00-4.96 (m, 1H), 4.86-4.82 (m, 3H), 4.30-4.22 (m, 1H), 4.19-4.16 (m, 4H), 4.16-4.10 (m, 1H), 2.46-2.42 (m, 2H) ppm. 376 536.5 1H NMR (400 MHz, DMSO-d6) δ = 9.49 (s, 1H), 9.44-9.41 (m, 1H), 8.77 (d, J = 8.8 Hz, 1H), 8.68-8.60 (m, 2H), 8.20 (d, J = 1.6 Hz, 1H), 7.96- 7.93 (m, 1H), 7.89 (s, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.94-4.85 (m, 2H), 4.83 (d, J = 6.0 Hz, 2H), 4.78-4.78 (m, 1H), 4.44 (d, J = 12.4 Hz, 1H), 4.22 (d, J = 11.2 Hz, 1H), 3.98-3.95 (m, 1H), 3.88 (s, 1H), 3.75 (s, 1H), 3.66-3.62 (m, 1H), 3.55-3.43 (m, 1H), 3.29- 3.21 (m, 1H), 1.70 (s, 3H), 1.25 (d, J = 6.8 Hz, 3H) ppm. 377 492.1 1H NMR (400 MHz, DMSO-d6) δ = 9.67 (d, J = 2.4 Hz, 1H), 9.45-9.39 (m, 2H), 9.12 (s, 1H), 8.53-8.51(m, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.96-7.93 (m, 2H), 7.46 (d, J = 4.8 Hz, 1H), 7.31-7.29 (m, 1H), 4.89-4.80 (m, 4H), 4.24-4.20 (m, 1H), 4.17-4.13 (m, 4H), 3.87 (d, J = 11.6 Hz, 1H), 2.37- 2.35 (m, 2H), 1.69 (s, 3H) ppm 378 519.1 1H NMR (400 MHz, MeOD-d4) δ = 9.68 (s, 1H), 8.96-8.81 (m, 2H), 8.61- 8.46 (m, 2H), 8.35 (s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.09-7.98 (m, 1H), 7.97-7.88 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.02 (s, 2H), 4.91 (d, J = 2.4 Hz, 2H), 4.37-4.29 (m, 2H), 4.20 (d, J = 11.2 Hz, 1H), 3.94 (d, J = 11.6 Hz, 1H), 2.78-2.69 (m, 2H), 2.30-2.19 (m, 2H), 1.76 (s, 3H) ppm. 379 536.3 1H NMR (400 MHz, METHANOL-d4) δ = 9.39 (s, 1H), 8.75-8.73 (m, 1H), 8.68-8.66 (m, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.01 (s, 1H), 7.96-7.93 (m, 1H), 7.77 (d, J = 4.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.95 (s, 2H), 4.94 (d, J = 3.6 Hz, 2H), 4.24-4.18 (m, 2H), 3.95 (d, J = 11.6 Hz, 1H), 3.91-3.65 (m, 4H), 3.42 (s, 3H), 2.30-2.11 (m, 2H), 1.78 (s, 3H) ppm 380 506.2 1H NMR (400 MHz, MeOD) δ = 9.36 (s, 1H), 8.75-8.67 (m, 1H), 8.67- 8.61 (m, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.99 (s, 1H), 7.96-7.90 (m, 1H), 7.71 (d, J = 5.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 4.94 (s, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 3.68 (br s, 4H), 2.13-2.01 (m, 4H), 1.77 (s, 3H) ppm 381 521.3 1H NMR (400 MHz, DMSO-d6) δ = 9.31-9.28 (m, 1H), 8.91 (s, 1H), 8.20- 8.17 (m, 2H), 7.95-7.92 (m, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.33-7.27 (m, 2H), 6.17 (d, J = 6.8 Hz, 1H), 4.94-4.80 (m, 2H), 4.71 (s, 2H), 4.69-4.61 (m, 2H), 4.23 (d, J = 11.6 Hz, 1H), 3.98- 3.94 (m, 2H), 3.87 (d, J = 11.6 Hz, 1H), 3.40 (s, 3H), 2.54 (br s, 2H), 1.70 (s, 3H) ppm 384 491.2 1H NMR (400 MHz, DMSO-d6) δ = 9.67 (d, J = 2.0 Hz, 1H), 9.39-9.37 (m, 2H), 8.96 (d, J = 1.6 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.96-7.93 (m, 1H), 7.89 (s, 1H), 7.70-7.66 (m, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.46 (d, J = 8.0 Hz, 1H), 4.93-4.79 (m, 4H), 4.22 (d, J = 11.2 Hz, 1H), 4.07-4.03 (m, 4H), 3.86 (d, J = 11.6 Hz, 1H), 2.38-2.34(m, 2H), 1.69 (s, 3H) ppm. 385 492.2 1H NMR (400 MHz, DMSO-d6) δ = 9.65 (d, J = 2 Hz, 1H), 9.42-9.38 (m, 2H), 9.04 (d, J = 1.6 Hz, 1H), 8.66 (s, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.98- 7.94 (m, 2H), 7.90 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.93-4.80 (m, 4H), 4.24-4.14 (m, 5H), 3.86 (d, J = 11.6 Hz, 1H), 2.44-2.41 (m, 2H), 1.69 (s, 3H) ppm 386 467.1 1H NMR (400 MHz, DMSO-d6) δ = 9.74 (d, J = 3, 1H), 9.46-9.41 (m, 2H), 9.18 (d, J = 2, 1H), 9.08 (s, 1H), 8.41(s, 1H), 8.19 (d, J = 1.6, 1H), 7.97-7.91 (m, 2H), 7.30 (d, J = 8, 1H), 4.93-4.81 (m, 4H), 4.23(d, J = 11.6, 1H), 4.08 (s, 3H), 3.86(d, J = 11.6, 1H), 1.69(s, 3H) ppm. 387 507.2 1H NMR (400 MHz, DMSO-d6) δ = 9.48-9.38 (m, 2H), 8.73 (d, J = 8.8 Hz, 1H), 8.61 (d, J = 8.8 Hz, 1H), 8.47 (d, J = 7.2 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.08-8.04 (m, 1H), 7.97-7.94 (m, 1H), 7.86 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.95-4.86 (m, 2H), 4.83 (d, J = 4.8 Hz, 2H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 3.43 (s, 3H), 2.17 (s, 3H), 1.71 (s, 3H) ppm. 388 466.4 1H NMR (400 MHz, MeOD) δ = 9.38 (s, 1H), 9.20 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.29-8.24 (m, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.95- 7.88 (m, 3H), 7.27 (d, J = 8.0 Hz, 1H), 7.17-7.11 (m, 1H), 4.92-4.89 (m, 4H), 4.19 (d, J = 11.6 Hz, 1H), 4.00 (s, 3H), 3.92 (d, J = 11.6 Hz, 1H), 1.78- 1.71 (m, 3H) ppm 389 508.2 1H NMR (400 MHz, DMSO-d6) δ = 9.45-9.31 (m, 2H), 8.65-8.63(m, 1H), 8.51-8.45 (m, 2H), 8.20 (d, J = 1.6 Hz, 1H), 7.96-7.94 (m, 1H), 7.78 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.99-4.73 (m, 4H), 4.52-4.43 (m, 2H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.63-3.54 (m, 2H), 3.21 (s, 3H), 1.70 (s, 3H) ppm. 390 503.2 1H NMR (400 MHz, METHANOL-d4) δ = 9.37 (s, 1H), 8.72-8.62 (m, 2H), 8.46 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.04-7.72 (m, 3H), 7.30 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 9.6 Hz, 1H), 4.94-4.91 (m, 4H), 4.21 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 1.77 (s, 3H) ppm. 391 505.2 1H NMR (400 MHz, DMSO-d6) δ = 9.43-9.40 (m, 2H), 8.74 (d, J = 8.8 Hz, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.33 (d, J = 7.6 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 8.03-7.99 (m, 1H), 7.97-7.94 (m, 1H), 7.84 (s, 1H), 7.75-7.73 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.93-4.81 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.89-3.84 (m, 3H), 3.17-3.15 (m, 2H), 1.71 (s, 3H) ppm. 392 504.1 1H NMR (400 MHz, DMSO-d6) δ = 9.45-9.37 (m, 2H), 8.68 (d, J = 8.8 Hz, 1H), 8.32 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 8.18 (s, 1H), 8.01-7.94 (m, 2H), 7.83 (s, 1H), 7.58-7.54 (m, 2H), 7.32- 7.29 (m, 1H), 4.93-4.81 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.88-3.85 (m, 1H), 3.75-3.73 (m, 2H), 3.12-3.10 (m, 2H), 1.70 (s, 3H) ppm. 393 504.1 1H NMR (400 MHz, DMSO-d6) δ = 9.45-9.37 (m, 2H), 8.68 (d, J = 8.8 Hz, 1H), 8.32 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 8.18 (s, 1H), 8.01-7.94 (m, 2H), 7.83 (s, 1H), 7.58-7.54 (m, 2H), 7.32- 7.29 (m, 1H), 4.93-4.81 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.88-3.85 (m, 1H), 3.75-3.73 (m, 2H), 3.12-3.10 (m, 2H), 1.70 (s, 3H) ppm. 394 536.3 1H NMR (EW18644-416-P1A, 400 MHz, METHANOL-d4) δ = 9.34 (s, 1H), 8.93 (s, 1H), 8.64-8.57 (m, 2H), 8.18 (d, J = 1.6 Hz, 1H), 7.98 (s, 1H), 7.96-7.86 (m, 2H), 7.30 (d, J = 8.4 Hz, 1H), 4.93 (s, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.32-4.25 (m, 2H), 4.21 (d, J = 11.6 Hz, 1H), 4.01-3.97 (m, 2H), 3.93 (d, J = 11.6 Hz, 1H), 3.65 (d, J = 6.4 Hz, 2H), 3.41 (s, 3H), 3.15- 3.08 (m, 1H), 1.77 (s, 3H) ppm 395 486.1 1H NMR (400 MHz, DMSO-d6)δ = 9.59-9.56 (m, 1H), 9.43 (s, 1H), 9.10 (s, 1H), 8.94 (s, 1H), 8.72 (d, J = 8.4 Hz, 1H), 8.62 (s, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.90 (s, 1H), 4.94-4.69 (m, 4H), 4.22-4.08 (m, 5H), 4.01-3.81 (m, 1H), 2.49-2.40 (m, 2H), 1.72 (d, J = 20.4 Hz, 3H) ppm 396 506.3 1H NMR (400 MHz, DMSO-d6) δ = 9.45-9.37 (m, 2H), 8.68 (d, J = 8.4 Hz, 1H), 8.39-8.17 (m, 4H), 7.96-7.94 (m, 1H), 7.82 (s, 1H), 7.64-7.49 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 4.95-4.77 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.22 (s, 3H), 2.00-1.73 (m, 3H), 1.70 (s, 3H) ppm. 397 521.3 1H NMR (400 MHz, METHANOL-d4) δ = 9.41 (s, 1H), 8.93 (d, J = 5.2 Hz, 1H), 8.82-8.80 (m, 1H), 8.73-8.71 (m, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.02 (s, 1H), 7.96-7.93 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 4.96 (s, 2H), 4.93 (d, J = 3.6 Hz, 2H), 4.23 (d, J = 11.6 Hz, 1H), 4.14-4.10 (m, 2H), 3.95 (d, J = 11.2 Hz, 1H), 3.70-3.63 (m, 2H), 3.30- 3.26 (m, 1H), 2.16-2.05 (m, 4H), 1.78 (s, 3H) ppm 398 503.2 1H NMR (400 MHz, DMSO-d6) δ = 9.50-9.47 (m, 1H), 9.42 (s, 1H), 8.92 (s, 1H), 8.72 (d, J = 8.4 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 8.00 (s, 1H), 7.85 (s, 1H), 7.80 (d, J = 10.4 Hz, 1H), 4.96 (d, J = 16.0 Hz, 1H), 4.83-4.80 (m, 2H), 4.76-4.75 (m, 1H), 4.18-4.15 (m, 4H), 4.08-4.05 (m, 1H), 3.89-3.83 (m, 1H), 2.47-2.39 (m, 2H), 1.72-1.67 (m, 3H) ppm. 399 510.3 1H NMR (400 MHz, DMSO-d6) δ = 9.50-9.47 (m, 1H), 9.41 (s, 1H), 8.92 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 7.79 (d, J = 10.4 Hz, 1H), 4.98-4.85 (m, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.25(d, J = 11.6 Hz, 1H), 4.18-4.16 (m, 4H), 3.89 (d, J = 11.6 Hz, 1H), 2.45-2.41 (m, 2H), 1.71 (s, 3H) ppm. 400 453.2 1H NMR (400 MHz, DMSO-d6) δ = 9.50-9.48 (m, 1H), 9.39 (s, 1H), 8.67 (d, J = 8.0 Hz, 1H), 8.33-8.29 (m, 3H), 8.11 (s, 1H), 7.83 (s, 1H), 7.80- 7.78 (m, 1H), 7.60-7.56 (m, 3H), 4.99-4.84 (m, 2H), 4.82 (br d, J = 5.6 Hz, 2H), 4.25 (d, J = 11.6 Hz, 1H), 3.89 (d, J = 11.6 Hz, 1H), 1.72 (s, 3H) ppm 401 485.3 1H NMR (400 MHz, DMSO-d6) δ = 9.48-9.34 (m, 2H), 8.92 (s, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.27 (s, 1H), 8.07-7.92 (m, 2H), 7.84 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.93-4.69 (m, 4H), 4.19-4.15 (m, 4H), 4.11-4.04 (m, 1H), 3.92-3.78 (m, 1H), 2.46-2.40 (m, 2H), 1.78- 1.59 (m, 3H) ppm 403 534.4 1H NMR (400 MHz, CHLOROFORM-d) δ = 9.32 (s, 1H), 8.67 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.44 (d, J = 8.8 Hz, 1H), 8.03-8.02 (m, 2H), 7.86 (d, J = 5.2 Hz, 1H), 7.81-7.80 (m, 1H), 7.39-7.38 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 5.01 (d, J = 5.2 Hz, 2H), 4.91 (s, 4H), 4.88 (s, 2H), 4.42 (s, 4H), 4.16 (d, J = 11.2 Hz, 1H), 3.97 (d, J = 11.2 Hz, 1H), 1.77 (s, 3H) ppm 404 528.5 1H NMR (400 MHz, CDCl3-d) δ = 9.31 (s, 2H), 8.57 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.04-8.03 (m, 3H), 7.84-7.81 (m, 1H), 7.41- 7.40 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 5.02 (d, J = 5.2 Hz, 2H), 4.89 (s, 2H), 4.60-4.54 (m, 4H), 4.16 (d, J = 11.2 Hz, 1H), 3.97 (d, J = 11.2 Hz, 1H), 1.78 (s, 3H) ppm 405 481.3 1H NMR (400 MHz, MeOD-d4) δ = 9.14 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.13 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.94-7.92 (m, 1H), 7.81 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.92 (d, J = 3.6 Hz, 2H), 4.59-4.55 (m, 4H), 4.247-4.19 (m, 3H), 3.93 (d, J = 11.2 Hz, 1H), 2.38- 2.35 (m, 2H), 1.77 (s, 3H) ppm 406 477.3 1H NMR (400 MHz, CDCl3) δ = 9.61 (s, 1H), 9.33-9.30 (m, 1H), 8.62- 8.59 (m, 2H), 8.42-8.40 (m, 1H), 8.04-8.03 (m, 2H), 7.84-7.81 (m, 1H), 7.42-7.41 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 5.02 (d, J = 5.2 Hz, 2H), 4.89 (s, 2H), 4.16 (d, J = 11.6 Hz, 1H), 3.97 (d, J = 11.6 Hz, 1H), 2.22-2.19 (m, 1H), 1.78 (s, 3H), 1.25-1.23 (m, 2H), 1.18-1.16 (m, 2H) ppm 407 480.2 1H NMR (400 MHz, MeOD-d4) δ = 9.33 (s, 1H), 8.90 (s, 1H), 8.64 (d, J = 1.6 Hz, 2H), 8.18-8.17 (m, 2H), 7.98 (s, 1H), 7.94-7.92 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.93 (s, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.94 (d, J = 11.6 Hz, 1H), 3.26 (s, 6H), 1.76 (s, 3H) ppm 408 451.3 1H NMR (400 MHz, CDCl3) δ = 9.67 (s, 1H), 9.32 (s, 1H), 8.69 (d, J = 8.8 Hz, 1H), 8.59 (s, 1H), 8.45-8.43 (m, 1H), 8.07 (s, 1H), 8.04 (s, 1H), 7.84- 7.81 (m, 1H), 7.44-7.43 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 5.02 (d, J = 5.2 Hz, 2H), 4.89 (s, 2H), 4.16 (d, J = 11.2 Hz, 1H), 3.96 (d, J = 11.6 Hz, 1H), 2.70 (s, 3H), 1.78 (s, 3H) ppm 409 522.4 1H NMR (400 MHz, MeOD-d4) δ = 9.33 (s, 1H), 8.95 (s, 1H), 8.63-8.58 (m, 2H), 8.17 (s, 1H), 7.98 (s, 1H), 7.94-7.91 (m, 2H), 7.30 (d, J = 8.4 Hz, 1H), 4.93 (s, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.49-4.45 (m, 1H), 4.43- 4.40 (m, 2H), 4.22 (d, J = 11.2 Hz, 1H), 4.07-4.03 (m, 2H), 3.94 (d, J = 11.6 Hz, 1H), 3.38 (s, 3H), 1.76 (s, 3H) ppm 410 494.2 1H NMR (400 MHz, METHANOL-d4)δ = 9.24 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.39 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.93- 7.80 (m, 3H), 7.69 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 5.05 (s, 1H), 4.84-4.81 (m, 4H), 4.12 (d, J = 11.6 Hz, 1H), 3.83 (d, J = 11.2 Hz, 1H), 1.67 (s, 3H), 1.56 (s, 6H) ppm 412 509.3 1H NMR (400 MHz, DMSO-d6) δ = 9.46 (s, 1H), 9.42-9.39 (m, 1H), 8.72 (d, J = 8.4 Hz, 1H), 8.47 (br s, 1H), 8.18 (s, 1H), 8.04-8.00 (m, 2H), 7.95- 7.93 (m, 1H), 7.83 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.16-7.14 (m, 1H), 4.92-4.81 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 4.16-4.13 (m, 4H), 3.86 (d, J = 11.6 Hz, 1H), 2.37-2.33 (m, 2H), 1.69 (s, 3H) ppm 413 429.1 1H NMR (400 MHz, MeOD-d4) δ = 9.31 (s, 1H), 9.09-9.04 (m, 1H), 8.63- 8.56 (m, 2H), 8.23-8.14 (m, 3H), 7.98 (s, 1H), 7.59-7.52 (m, 3H), 4.94 (s, 2H), 4.85 (br s, 1H), 4.83 (d, J = 3.6 Hz, 1H), 4.17-4.06 (m, 1H), 4.00- 3.87 (m, 1H), 1.87-1.63 (m, 3H) ppm. 414 492.3 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.36 (m, 1H), 9.33 (s, 1H), 9.18 (d, J = 1.6 Hz, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.19 (s, 1H), 7.97-7.93 (m, 2H), 7.78 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.92- 4.78 (m, 4H), 4.23-4.16 (m, 5H), 3.87 (d, J = 11.6 Hz, 1H), 2.46-2.41 (m, 2H), 1.70 (s, 3H) ppm 415 506.6 1H NMR (400 MHz, MeOD-d4) δ = 9.33 (s, 1H), 8.87 (s, 1H), 8.66-8.63 (m, 2H), 8.18-8.17 (m, 1H), 8.00-7.98 (m, 2H), 7.94-7.92 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.93 (s, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.94 (d, J = 11.6 Hz, 1H), 3.66-3.61 (m, 4H), 2.12-2.09 (m, 4H), 1.76 (s, 3H) ppm 416 522.2 1HNMR (400 MHz, METHANOL-d4) δ = 9.37 (s, 1H), 8.70-8.63 (m, 2H), 8.55 (d, J = 5.2 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.99 (s, 1H), 7.94-7.91 (m, 1H), 7.78 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.96-4.90 (m, 4H), 4.21 (d, J = 11.2 Hz, 1H), 3.94 (d, J = 2.8 Hz, 1H), 3.92 (d, J = 4.4 Hz, 4H), 3.83-3.78 (m, 4H), 1.77 (s, 3H) ppm 417 477.4 1H NMR (400 MHz, METHANOL-d4) δ = 9.39 (s, 1H), 8.78 (d, J = 7.2 Hz, 1H), 8.74-8.66 (m, 2H), 8.35 (d, J = 7.2 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.00 (s, 1H), 7.94-7.92 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.94 (s, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.93 (s, 1H), 2.43- 2.32 (m, 1H), 1.77 (s, 3H), 1.29-1.23 (m, 2H), 1.21-1.13 (m, 2H) ppm. 418 521.2 1H NMR (400 MHz, DMSO-d6) δ = 9.42-9.36 (m, 2H), 8.68 (d, J = 8.8 Hz, 1H), 8.37-8.31 (m, 2H), 8.31-8.27 (m, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.96-7.94 (m, 1H), 7.85 (s, 1H), 7.68-7.60 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 4.94-4.79 (m, 8H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.07 (s, 3H), 1.70 (s, 3H) ppm. 419 522.2 1H NMR (400 MHz, METHANOL-d4) δ = 9.35 (s, 1H), 8.86 (d, J = 8.4 Hz, 1H), 8.68-8.61 (m, 2H), 8.18 (d, J = 1.6 Hz, 1H), 8.06-8.05 (m, 1H), 8.00 (s, 1H), 7.94-7.93 (m, 1H), 7.65-7.63 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.22 (d, J = 7.2 Hz, 2H), 4.97-4.94 (m, 4H), 4.92 (d, J = 4.0 Hz, 2H), 4.21 (d, J = 11.2 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 3.29 (s, 3H), 1.77 (s, 3H) ppm 420 491.3 1H NMR (400 MHz, METHANOL-d4) δ = 9.40 (s, 1H), 8.89 (d, J = 5.2 Hz, 1H), 8.82 (d, J = 8.8 Hz, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.18 (d, J = 1.2 Hz, 1H), 8.02 (s, 1H), 7.93-7.92 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 4.94 (s, 2H), 4.92 (d, J = 3.2 Hz, 2H), 4.21 (d, J = 11.2 Hz, 1H), 3.96-3.90 (m, 2H), 2.65-2.53 (m, 2H), 2.52-2.41 (m, 2H), 2.25- 2.12 (m, 1H), 2.09-1.98 (m, 1H), 1.77 (s, 3H) ppm 421 504.3 1H NMR (400 MHz, DMSO-d6) δ = 9.45-9.37 (m, 2H), 8.66 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.21 (s, 2H), 8.14 (d, J = 7.2 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.60-7.50 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 4.98-4.76 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 11.2 Hz, 1H), 3.78-3.65 (m, 3H), 3.21-3.18 (m, 2H), 2.31 (s, 3H), 1.71 (s, 3H) ppm 422 536.3 .sup.1H NMR (400 MHz, METHANOL-d4) δ = 9.37 (s, 1H), 8.76-8.62 (m, 2H), 8.50 (d, J = 5.0 Hz, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.93 (dd, J = 1.7, 8.1 Hz, 1H), 7.74 (d, J = 5.1 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.95-4.91 (m, 4H), 4.27-4.12 (m, 2H), 3.90-3.62 (m, 4H), 3.93 (d, J = 11.3 Hz, 1H), 3.40 (s, 3H), 2.27-2.11 (m, 2H), 1.77 (s, 3H) ppm 423 467.1 .sup.1H NMR (400 MHz, DMSO-d6) δ = 9.46 (s, 1H), 9.42 (br t, J = 5.7 Hz, 1H), 9.30 (s, 1H), 8.78 (d, J = 8.7 Hz, 1H), 8.61 (d, J = 8.8 Hz, 1H), 8.49 (s, 1H), 8.20 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.31 (d, J = 8.3 Hz, 1H), 4.94-4.81 (m, 4H), 4.23 (d, J = 11.4 Hz, 1H), 4.10 (s, 3H), 3.87 (d, J = 11.6 Hz, 1H), 1.71 (s, 3H) ppm 424 480.2 .sup.1H NMR (400 MHz, DMSO-d6) δ = 9.47 (s, 1H), 9.41 (br t, J = 5.7 Hz, 1H), 8.76 (d, J = 8.6 Hz, 1H), 8.69-8.63 (m, 1H), 8.56 (d, J = 4.9 Hz, 1H), 8.20 (s, 1H), 7.98-7.93 (m, 1H), 7.86 (s, 1H), 7.66 (d, J = 4.9 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 4.94-4.81 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.25 (s, 6H), 1.70 (s, 3H) ppm 427 505.2 .sup.1H NMR (400 MHz, DMSO-d6) δ = 9.50-9.40 (m, 2H), 8.80-8.68 (m, 3H), 8.28-8.19 (m, 2H), 7.97 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.97-4.77 (m, 4H), 4.71-4.61 (m, 2H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.15 (s, 3H), 1.71 (s, 3H) ppm 428 446.3 .sup.1H NMR (400 MHz, MeOD) δ = 9.30 (s, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.23- 8.14 (m, 3H), 8.09 (s, 1H), 7.95 (s, 1H), 7.69 (brd, J = 10.6 Hz, 1H), 7.60- 7.51 (m, 3H), 4.97-4.88 (m, 4H), 4.10-3.99 (m, 1H), 3.94-3.81 (m, 1H), 1.82-1.64 (m, 3H) ppm 429 485.2 .sup.1H NMR (400 MHz, DMSO-d6) δ = 9.46 (s, 1H), 9.41-7.38 (m, 1H), 8.75 (d, J = 8.8 Hz, 1H), 8.61-8.53 (m, 2H), 8.27 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.71-7.70 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.90-4.70 (m, 4H), 4.18-4.14 (m, 4H), 4.11-4.04 (m, 1H), 3.91-3.79 (m, 1H), 2.42- 2.35 (m, 2H), 1.74-1.65 (m, 3H) ppm 430 522.2 .sup.1H NMR (400 MHz, METHANOL-d4) δ = 9.37 (s, 1H), 8.65 (s, 2H), 8.50 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.98 (s, 1H), 7.96-7.90 (m, 1H), 7.80 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.96-4.89 (m, 4H), 4.48-4.36 (m, 3H), 4.21 (d, J = 11.6 Hz, 1H), 4.06 (br d, J = 6.8 Hz, 2H), 3.93 (d, J = 11.2 Hz, 1H), 3.38 (s, 3H), 1.77 (s, 3H) ppm 431 495.2 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.37 (m, 2H), 8.52 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.95-7.93 (m, 1H), 7.85-7.83 (m, 1H), 7.78-7.76 (m, 1H), 7.49-7.44 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.11-7.07 (m, 1H), 4.92-4.79 (m, 5H), 4.23-4.13 (m, 3H), 3.86 (d, J = 11.6 Hz, 1H), 3.74-3.71 (m, 2H), 1.69 (s, 3H) ppm 432 484.2 1H NMR (400 MHz, MeOD) δ = 9.40 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.12-8.04 (m, 2H), 7.99 (s, 1H), 7.95-7.88 (m, 1H), 7.55-7.51 (m, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.94 (s, 2H), 4.91 (d, J = 4.0 Hz, 2H), 4.20 (d, J = 11.6 Hz, 1H), 4.07 (s, 3H), 3.92 (d, J = 11.6 Hz, 1H), 1.76 (s, 3H) ppm 434 534.3 1H NMR (400 MHz, DMSO-d6) δ = 9.45-9.37 (m, 2H), 8.97 (s, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.52-8.41 (m, 2H), 8.20 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.74-7.65 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 4.93-4.80 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.57 (s, 3H), 1.71 (s, 3H) ppm 435 522.5 1H NMR (400 MHz, MeOD-d4) δ = 9.33 (s, 1H), 8.99 (s, 1H), 8.61-8.56 (m, 2H), 8.32 (s, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.98 (s, 1H), 7.96-7.91 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.93-4.90 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 3.94 (d, J = 11.6 Hz, 1H), 3.87-3.85 (m, 4H), 3.75-3.72 (m, 4H), 1.76 (s, 3H) ppm 437 491.3 1H NMR (400 MHz, DMSO-d6) δ = 9.49-9.38 (m, 2H), 8.72 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.26-8.18 (m, 2H), 7.96 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.44 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.14 (s, 1H), 4.97-4.80 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 4.06-4.02 (m, 4H), 3.88 (d, J = 11.6 Hz, 1H), 2.38-2.32 (m, 2H), 1.71 (s, 3H) ppm 438 442.3 1H NMR (400 MHz, DMSO-d6) δ = 9.46 (s, 1H), 9.38-9.36 (m, 1H), 8.91- 8.80 (m, 2H), 8.18 (s, 1H), 8.14-8.07 (m, 2H), 8.02 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.94-4.82 (m, 2H), 4.78 (d, J = 6.0 Hz, 2H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm 439 442.1 1H NMR (400 MHz, DMSO-d6) δ = 9.53-9.24 (m, 3H), 8.83-8.81 (m, 1H), 8.54-8.52 (m, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.95-7.93 (m, 1H), 7.67-7.64 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.95-4.81 (m, 2H), 4.77 (d, J = 6.0 Hz, 2H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 1.71 (s, 3H) ppm 440 442.1 1H NMR (400 MHz, DMSO-d6) δ = 9.39 (s, 1H), 9.38-9.35 (m, 1H), 8.79- 8.78 (m, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.18 (s, 1H), 8.11-8.07 (m, 1H), 7.98 (s, 1H), 7.95-7.93 (m, 1H), 7.70-7.66 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.95-4.81 (m, 2H), 4.77 (d, J = 6.0 Hz, 2H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 1.71 (s, 3H) ppm 441 491.3 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.35 (m, 2H), 8.76 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.99-7.92 (m, 2H), 7.84 (s, 1H), 7.58-7.57 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.98-4.77(m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.99-3.98 (m, 4H), 3.88 (d, J = 11.6 Hz, 1H), 2.41-2.39 (m, 2H), 1.71 (s, 3H) ppm. 442 522.4 1HNMR (400 MHz, METHANOL-d4) δ = 9.34 (s, 1H), 8.62-8.55 (m, 2H), 8.17 (d, J = 1.6 Hz, 1H), 7.98 (s, 1H), 7.93-7.91 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 4.92 (d, J = 3.6 Hz, 4H), 4.24-4.19 (m, 5H), 3.96- 3.91 (m, 4H), 2.45-2.37 (m, 2H), 1.76 (s, 3H) ppm. 443 523.3 1H NMR (400 MHz, DMSO-d6) δ = 9.51 (s, 1H), 9.43 (m, 1H), 8.83 (d, J = 8.6 Hz, 1H), 8.50 (d, J = 8.6 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.96 (m, 1H), 7.91-7.82 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 4.98-4.78 (m, 4H), 4.23 (d, J = 11.4 Hz, 1H), 3.87 (d, J = 11.4 Hz, 1H), 3.59 (s, 3H), 1.71 (s, 3H) ppm 444 451.3 1HNMR (400 MHz, METHANOL-d4) δ = 9.40 (s, 1H), 8.86 (d, J = 5.6 Hz, 1H), 8.79-8.67 (m, 2H), 8.44 (d, J = 5.2 Hz, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.95-7.92 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.94 (s, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 2.83 (s, 3H), 1.77 (s, 3H) ppm 445 548.5 1H NMR (400 MHz, DMSO-d6) δ = 9.45-9.35 (m, 2H), 8.69 (d, J = 8.6 Hz, 1H), 8.51-8.48 (m, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 1.4 Hz, 1H), 7.96 (m, 1H), 7.84 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.68-7.60 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.98-4.76 (m, 4H), 4.48 (m, 1H), 4.33-4.12 (m, 4H), 3.87 (m, 2H), 3.22 (s, 3H), 1.70 (s, 3H) ppm 446 484.3 1H NMR (400 MHz, DMSO-d6) δ = 9.50 (s, 1H), 9.42 (t, J = 6.0 Hz, 1H), 8.77 (d, J = 8.7 Hz, 1H), 8.39 (d, J = 2.5 Hz, 1H), 8.22-8.18 (m, 1H), 8.09 (dd, J = 1.8, 8.5 Hz, 1H), 7.95 (dd, J = 1.6, 8.1 Hz, 1H), 7.87 (s, 1H), 7.38 (d, J = 5.1 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 4.95-4.79 (m, 4H), 4.23 (d, J = 11.5 Hz, 1H), 3.91 (s, 3H), 3.87 (d, J = 11.5 Hz, 1H), 1.71 (s, 3H) ppm 447 476.4 1H NMR (400 MHz, METHANOL-d4) δ = 9.38 (s, 1H), 9.04 (d, J = 7.6 Hz, 1H), 8.81 (d, J = 8.8 Hz, 1H), 8.69 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.02 (s, 1H), 7.93-7.92 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.89-6.88 (m, 1H), 4.94 (s, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.95 (d, J = 11.2 Hz, 1H), 1.77 (s, 3H) ppm 448 517 1H NMR (400 MHz, MeOD-d4) δ = 9.36 (s, 1H), 9.16 (s, 1H), 8.80-8.78 (m, 1H), 8.69-8.67 (m, 1H), 8.42 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.95-7.93 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.94 (s, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.94 (d, J = 11.2 Hz, 1H), 3.87 (s, 3H), 1.77 (s, 3H) ppm 449 520.2 1H NMR (400 MHz, METHANOL-d4) δ = 9.32 (br s, 1H), 8.63-8.55 (m, 2H), 8.42 (dd, J = 2.2, 11.0 Hz, 1H), 8.22-8.13 (m, 2H), 8.10-7.76 (m, 3H), 7.31 (d, J = 8.2 Hz, 1H), 4.93 (s, 4H), 4.22 (d, J = 11.4 Hz, 1H), 3.95 (d, J = 11.4 Hz, 1H), 1.78 (s, 3H) ppm 450 493 1H NMR (400 MHz, DMSO-d6) δ = 9.53-9.47 (m, 1 H), 9.46-9.38 (m, 1 H), 8.97-8.73 (m, 4 H), 8.53-8.36 (m, 2 H), 8.25-8.15 (m, 1 H), 8.01- 7.95 (m, 1 H), 7.94-7.88 (m, 1 H), 7.40-7.23 (m, 1 H), 5.00-4.72 (m, 4 H), 4.30-4.16 (m, 1 H), 3.94-3.83(m, 1 H), 2.95-2.80 (m, 3 H), 1.80- 1.59 (m, 3 H) ppm 451 436.2 1H NMR (400 MHz, METHANOL-d4) δ = 9.40 (s, 1H), 8.78-8.74 (m, 2H), 8.71 (d, J = 8.4 Hz, 1H), 8.33-8.26 (m, 3H), 8.20 (d, J = 1.6 Hz, 1H), 8.02 (s, 1H), 7.96-7.94 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.96 (s, 2H), 4.93 (d, J = 3.6 Hz, 2H), 4.23 (d, J = 11.6 Hz, 1H), 3.95 (d, J = 11.6 Hz, 1H), 1.79 (s, 3H) ppm 452 516.2 1H NMR (400 MHz, DMSO-d6) δ = 9.41 (s, 2H), 9.12 (s, 1H), 8.69 (d, J = 8.8 Hz, 1H), 8.64-8.62 (m, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.21 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.89-7.81 (m, 2H), 7.59 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 7.2 Hz, 1H), 4.96-4.78 (m, 4H), 4.24 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H), 3.56 (s, 3H), 1.72 (s, 3H) ppm 454 469.1 1H NMR (400 MHz, DMSO-d6) δ = 9.39 (t, J = 5.2 Hz, 1H), 9.21 (s, 1H), 8.46 (d, J = 8.8 Hz, 1H), 8.37 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.02-7.93 (m, 2H), 7.57 (s, 1H), 7.31 (d, J = 8.2 Hz, 1H), 4.95-4.81 (m, 2H), 4.76 (br d, J = 5.9 Hz, 2H), 4.23 (d, J = 11.4 Hz, 1H), 3.98 (s, 3H), 3.87 (d, J = 11.4 Hz, 1H), 3.76 (s, 3H), 1.70 (s, 3H) ppm 456 491.3 1HNMR (400 MHz, DMSO-d6) δ = 9.40-9.34 (m, 1H), 9.28 (s, 1H), 9.00 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.42-8.40(m, 1H), 8.21- 8.15 (m, 2H), 7.95-7.93(m, 1H), 7.71 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.46 (d, J = 9.2 Hz, 1H), 4.94-4.81 (m, 2H), 4.80-4.75 (m, 2H), 4.23 (d, J = 11.2 Hz, 1H), 4.07-4.03 (m, 4H), 3.87 (d, J = 11.6 Hz, 1H), 2.39- 2.35 (m, 2H), 1.70 (s, 3H) ppm 459 475.2 1HNMR (400 MHz, DMSO-d6) δ = 9.45-9.39 (m, 2H), 8.80 (d, J = 7.2 Hz, 1H), 8.73-8.68 (m, 2H), 8.43 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.97-7.95(m, 1H), 7.87-7.82 (m, 2H), 7.32 (d, J = 7.6 Hz, 1H), 6.84 (s, 1H), 4.95-4.85 (m, 2H), 4.82 (d, J = 4.4 Hz, 2H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 1.71 (s, 3H) ppm 460 509.9 1H NMR (400 MHz, DMSO-d6) δ = 9.46 (s, 1H), 9.45-9.42 (m, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.43 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.11- 8.01 (m, 2H), 7.96-7.94 (m, 1H), 7.83 (s, 1H), 7.78-7.71 (m, 1H), 7.45- 7.41 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.97-4.79 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 2.81 (d, J = 4.8 Hz, 3H), 1.70 (s, 3H) ppm. 462 469.3 1H NMR (400 MHz, DMSO-d6) δ = 9.37-9.36 (m, 1H), 9.25 (s, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 1.2 Hz, 1H), 8.09 (s, 1H), 7.94-7.91 (m, 2H), 7.69 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.88-4.76 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 4.06 (s, 3H), 3.87 (d, J = 11.2 Hz, 1H), 3.72 (s, 3H), 1.69 (s, 3H) ppm 464 507.5 1H NMR (400 MHz, MeOD) δ = 9.35 (s, 1H), 8.76-8.72 (m, 1H), 8.72- 8.68 (m, 1H), 8.67-8.62 (m, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.14-8.09 (m, 1H), 8.00 (s, 1H), 7.95-7.92 (m, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 4.94 (s, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 3.19 (d, J = 10.4 Hz, 6H), 1.77 (s, 3H) ppm 465 534.6 1H NMR (400 MHz, MeOD) δ = 9.30 (s, 1H), 8.69-8.63 (m, 1H), 8.60- 8.55 (m, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.00-7.90 (m, 3H), 7.76-7.71 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.93-4.89 (m, 4H), 4.21 (d, J = 11.2 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 3.75 (br s, 4H), 2.72- 2.68 (m, 4H), 2.44 (s, 3H), 1.77 (s, 3H) ppm 466 493.2 1H NMR (400 MHz, MeOD) δ = 9.37 (s, 1H), 8.98 (d, J = 8.8 Hz, 1H), 8.82 (d, J = 7.6 Hz, 1H), 8.68 (d, J = 8.0 Hz, 1H), 8.26-8.21 (m, 1H), 8.20- 8.13 (m, 2H), 8.01 (s, 1H), 7.95-7.92 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.94 (s, 2H), 4.92 (br d, J = 4.0 Hz, 2H), 4.21 (d, J = 11.2 Hz, 1H), 3.93 (d, J = 11.2 Hz, 1H), 3.06 (s, 3H), 1.77 (s, 3H) ppm 467 510.2 1H NMR (400 MHz, DMSO-d6) δ = 9.44-9.39 (m, 2H), 8.68 (d, J = 8.4 Hz, 1H), 8.53-8.51 (m, 1H), 8.45-8.43 (m, 2H), 8.33 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.96-7.94 (m, 1H), 7.82 (s, 1H), 7.48-7.47 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.93-4.80 (m, 4H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 2.81 (d, J = 4.8 Hz, 3H), 1.70 (s, 3H) ppm. 468 536.3 1H NMR (400 MHz, MeOD-d4) δ = 9.32 (s, 1H), 8.67-8.66 (m, 1H), 8.62 (d, J = 8.4 Hz, 1H), 8.41-8.34 (m, 1H), 8.23 (d, J = 8.74 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.02-7.91 (m, 3H), 7.65 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.92-4.87 (m, 4H), 4.21 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.2 Hz, 1H), 3.60 (s, 4H), 3.38 (s, 3H), 1.76 (s, 3H) ppm. 469 486.2 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.42 (m, 2H), 8.77-8.74 (m, 2H), 8.65 (d, J = 8.8 Hz, 1H), 8.50-8.44 (m, 1H), 8.24-8.20 (m, 2H), 7.97-7.50 (m, 1H), 7.88 (d, J = 5.6 Hz, 2H), 7.31 (d, J = 8.8 Hz, 1H), 7.26-6.98 (m, 1H), 4.93-4.82(m, 4H), 4.23(d, J = 11.6 Hz, 1H), 3.93-3.80(m, 1H), 1.70 (s, 3H) ppm. 470 429.2 1H NMR (400 MHz, DMSO-d6) δ = 9.43-9.38 (m, 2H), 9.28 (d, J = 1.6 Hz, 1H), 8.67 (d, J = 8.8 Hz, 1H), 8.64-8.61 (m, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.96-7.94 (m, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.30 (s, 1H), 4.94-4.85 (m, 2H), 4.81 (d, J = 6.0 Hz, 2H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 1.70 (s, 3H), 1.34-1.29 (m, 2H), 1.20-1.14 (m, 2H) ppm. 472 480.3 1HNMR (400 MHz, MeOD-d4) δ = 9.22-9.14 (m, 1H), 9.13-9.07 (m, 2H), 8.49-8.41 (m, 1H), 8.17 (s, 1H), 8.05-7.97 (m, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.86-7.81 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.90 (d, J = 3.2 Hz, 2H), 4.89-4.88 (m, 2H), 4.20 (d, J = 11.2 Hz, 1H), 3.92 (d, J = 11.6 Hz, 1H), 3.27-3.24 (m, 6H), 1.75 (s, 3H) ppm 474 533 1HNMR (400 MHz, METHANOL-d4) δ = 9.40 (s, 1H), 8.64 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.18 (s, 1H), 8.05-8.01 (m, 1H), 7.95-7.89 (m, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.53-7.45 (m, 1H), 7.33-7.21 (m, 2H), 4.95 (s, 2H), 4.91 (d, J = 2.8 Hz, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.99 (d, J = 12.8 Hz, 2H), 3.95-3.89 (m, 1H), 3.64 (d, J = 11.2 Hz, 2H), 3.30 (s, 2H), 3.22-3.07 (m, 2H), 2.98 (s, 3H), 1.80-1.73 (m, 3H) ppm 475 534.2 1H NMR (400 MHz, MeOD-d4) δ = 9.25 (s, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.44-8.20 (m, 1H), 8.17 (s, 1H), 8.11-8.08 (m, 1H), 8.01-7.95 (m, 1H), 7.93-7.90 (m, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 4.91- 4.90 (m, 4H), 4.39-4.37 (m, 2H), 4.21 (d, J = 11.2 Hz, 1H), 4.00-3.99 (m, 2H), 3.93 (d, J = 11.6 Hz, 1H), 2.38 (s, 3H), 1.76 (s, 3H) ppm 476 504.1 1H NMR (400 MHz, MeOD-d4) δ = 9.31 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.20-8.18 (m, 2H), 7.96-7.84 (m, 3H), 7.84 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.92-4.90 (m, 4H), 4.21 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 3.65 (s, 2H), 3.32 (s, 3H), 1.77 (s, 3H) ppm. 477 502.3 1H NMR (400 MHz, DMSO-d6) δ = 9.58 (s, 1H), 9.44-9.40 (m, 1H), 9.32 (s, 1H), 8.73-8.69 (m, 2H), 8.65-8.61 (m, 2H), 8.21 (d, J = 1.6 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.01-7.94 (m, 3H), 7.73 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 4.96-4.78 (m, 4H), 4.24 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H), 1.71 (s, 3H) ppm 478 486.2 1H NMR (400 MHz, DMSO-d6) δ = 9.55 (d, J = 1.2 Hz, 1H), 9.45 (s, 1H), 9.43-9.38 (m, 1H), 8.86-8.83 (m, 1H), 8.76 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.97-7.94 (m, 1H), 7.91-7.85 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.24-6.91 (m, 1H), 4.95-4.80 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm 479 507.2 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.35 (m, 2H), 8.67 (d, J = 8.8 Hz, 1H), 8.50 (s, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.25-8.17 (m, 2H), 7.96- 7.94 (m, 1H), 7.87-7.76 (m, 2H), 7.62-7.58 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.74-6.18 (m, 1H), 4.94-4.76 (m, 8H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm. 480 519.2 1H NMR (400 MHz, DMSO-d6) δ = 9.42-9.39 (m, 1H), 9.36 (s, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.13 (s, 1H), 8.05-8.01 (m, 2H), 7.96-7.94 (m, 1H), 7.78 (s, 1H), 7.33-7.27 (m, 2H), 4.93-4.85 (m, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.22 (d, J = 11.6 Hz, 1H), 4.05 (s, 3H), 3.95 (s, 3H), 3.86 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm. 481 483.1 1H NMR (400 MHz, DMSO-d6) δ = 9.43-9.34 (m, 2H), 8.54 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 1.2 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.95-7.93 (m, 1H), 7.86-7.77 (m, 1H), 7.77 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.14-7.11 (m, 1H), 6.93-6.92 (m, 1H), 4.94-4.76 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 3.88-3.84 (m, 4H), 1.70 (s, 3H) ppm. 482 466.2 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.36 (m, 2H), 9.05 (d, J = 1.6 Hz, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.45 (d, J = 2.8 Hz, 1H), 8.43 (br s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.20-8.15 (m, 2H), 7.97-7.92 (m, 1H), 7.85 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 4.95-4.77 (m, 4H), 4.26-4.19 (m, 1H), 3.94 (s, 3H), 3.86 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm 483 492.2 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.35 (m, 2H), 8.73-8.68 (m, 2H), 8.66-8.60 (m, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.37 (br s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 8.02-7.93 (m, 2H), 7.84 (s, 1H), 7.69-7.61 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.96-4.75 (m, 4H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 2.83 (d, J = 4.4 Hz, 3H), 1.71 (s, 3H) ppm 484 518.2 1HNMR (400 MHz, DMSO-d6) δ = 9.41-9.36 (m, 2H), 8.69 (d, J = 8.0 Hz, 1H), 8.50 (s, 1H), 8.43-8.39 (m, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.96-7.94 (m, 1H), 7.84 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.65-7.62 (m, 1H), 7.31 (d, J = 7.6 Hz, 1H), 4.93-4.81 (m, 4H), 4.36-4.32 (m, 2H), 4.24-4.16 (m, 1H), 4.10-4.06 (m, 2H), 3.86 (d, J = 11.6 Hz, 1H), 2.29-2.26 (m, 2H), 1.70 (s, 3H) ppm. 485 504.2 1H NMR (400 MHz, DMSO-d6) δ = 9.51-9.29 (m, 2H), 8.68 (d, J = 8.4 Hz, 1H), 8.59-8.50 (m, 2H), 8.41 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H), 7.97- 7.95 (m, 1H), 7.85 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.98-4.77 (m, 4H), 4.56 (s, 2H), 4.24 (s, 1H), 3.87 (d, J = 7.2 Hz, 1H), 3.12 (s, 3H), 1.71 (s, 3H) ppm. 487 509.2 1H NMR (400 MHz, DMSO-d6) δ = 9.57-9.54 (m, 1H), 9.42-9.37 (m, 1H), 9.07 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.87 (s, 1H), 7.37-7.30 (m, 1H), 7.12-7.11 (m, 1H), 6.39-6.35 (m, 1H), 4.93-4.80 (m, 4H), 4.29 (d, J = 11.6 Hz, 1H), 3.95-3.89 (m, 5H), 2.52 (s, 1H), 2.38-2.34 (m, 1H), 1.72 (s, 3H) ppm. 488 466.1 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.32 (m, 2H), 8.61 (d, J = 8.8 Hz, 1H), 8.39-8.25 (m, 2H), 8.23-8.12 (m, 2H), 7.94(d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 4.98-4.73 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 3.98 (s, 3H), 3.86 (d, J = 11.6 Hz, 1H), 1.69 (s, 3H) ppm. 489 466.3 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.38 (m, 2H), 8.79 (s, 1H), 8.61- 8.56 (m, 2H), 8.18 (d, J = 1.2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.95-7.93 (m, 1H), 7.82 (s, 1H), 7.30-7.27 (m, 2H), 4.92-4.80 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 3.94 (s, 3H), 3.86 (d, J = 11.6 Hz, 1H), 1.69 (s, 3H) ppm. 490 506.2 1H NMR (400 MHz, DMSO-d6) δ = 9.41-9.38 (m, 2H), 8.68 (d, J = 8.8 Hz, 1H), 8.41 (br s, 1H), 8.37-8.30 (m, 3H), 8.20 (d, J = 1.2 Hz, 1H), 7.96- 7.94 (m, 1H), 7.82 (s, 1H), 7.64-7.60 (m, 1H), 7.57-7.55 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.93-4.80 (m, 4H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 3.02-2.94 (m, 6H), 1.70 (s, 3H) ppm 491 519.2 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.35 (m, 2H), 8.65 (d, J = 8.0 Hz, 1H), 8.22-8.14 (m, 2H), 8.12 (s, 1H), 7.98-7.91 (m, 1H), 7.83 (s, 1H), 7.65-7.59 (m, 1H), 7.56-7.50 (m, 1H), 7.30 (d, J = 8.4 Hz, 1H), 4.95-4.77 (m, 4H), 4.27 (s, 3H), 4.22 (d, J = 11.2 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.59 (s, 3H), 1.70 (s, 3H) ppm. 492 466.2 1HNMR (400 MHz, DMSO-d6) δ = 9.45-9.37 (m, 2H), 8.76-8.64 (m, 2H), 8.25-8.18 (m, 2H), 7.97-7.94 (m, 1H), 7.93-7.88 (m, 1H), 7.83 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.95-4.84 (m, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.23 (d, J = 11.6 Hz, 1H), 4.04 (s, 3H), 3.87 (d, J = 11.6 Hz, 1H), 1.71 (s, 3H) ppm 493 475.2 1HNMR (400 MHz, DMSO-d6) δ = 9.38-9.35 (m, 1H), 9.24 (s, 1H), 8.97 (s, 1H), 8.88-8.83 (m, 2H), 8.50 (d, J = 8.4 Hz, 1H), 8.23-8.18 (m, 2H), 7.96-7.93 (m, 1H), 7.80 (s, 1H), 7.60-7.53 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.17-7.11 (m, 1H), 4.95-4.83 (m, 2H), 4.83-4.74 (m, 2H), 4.23 (d, J = 11.5 Hz, 1H), 3.88 (d, J = 11.2 Hz, 1H), 1.71 (s, 3H) ppm 494 435.2 1H NMR (400 MHz, METHANOL-d4) δ = 8.51 (d, J = 8.8 Hz, 1H), 8.25- 8.21 (m, 3H), 8.15 (d, J = 2.0 Hz, 1H), 7.91-7.88 (m, 1H), 7.84-7.81 (m, 2H), 7.53-7.51 (m, 2H), 7.49-7.45 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H), 5.15 (s, 2H), 4.89 (d, J = 3.6 Hz, 2H), 4.20 (d, J = 11.2 Hz, 1H), 3.92 (d, J = 11.6 Hz, 1H), 1.74 (s, 3H) ppm 495 504.2 1H NMR (400 MHz, DMSO-d6) δ = 9.44-9.41 (m, 2H), 8.72 (d, J = 8.4 Hz, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.41-8.39 (m, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.22 (d, J = 1.2 Hz, 1H), 7.98-7.96 (m, 1H), 7.83-7.81 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 4.94-4.82 (m, 4H), 4.57 (s, 2H), 4.24 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 11.2 Hz, 1H), 3.12 (s, 3H), 1.71 (s, 3H) ppm 496 491.2 1H NMR (400 MHz, DMSO-d6) δ = 9.50-9.31 (m, 2H), 8.74-8.54 (m, 2H), 8.21 (s, 1H), 7.98-7.95 (m, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.82 (s, 1H), 7.72-7.70 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 4.95-4.80 (m, 4H), 4.24 (d, J = 11.6 Hz, 1H), 4.09-4.05 (m, 4H), 3.88 (d, J = 11.6 Hz, 1H), 2.43-2.33 (m, 2H), 1.71 (s, 3H) ppm 497 492.2 1HNMR (400 MHz, DMSO-d6) δ = 9.40-9.37 (m, 1H), 9.25 (s, 1H), 8.63 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.26-8.20 (m, 2H), 8.00-7.94 (m, 2H), 7.66 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.11-5.07 (m, 1H), 4.94-4.77 (m, 2H), 4.78 (br d, J = 5.2 Hz, 2H), 4.24 (d, J = 11.6 Hz, 1H), 4.02-3.96 (m, 3H), 3.89-3.83 (m, 2H), 2.44-2.35 (m, 2H), 1.71 (s, 3H) ppm. 498 504.1 1H NMR (400 MHz, DMSO-d6) δ = 9.40-9.37 (m, 1H), 9.32 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.28-8.24 (m, 3H), 8.20 (d, J = 1.2 Hz, 1H), 7.97-7.94 (m, 1H), 7.74 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.93-4.89 (m, 2H), 4.80 (d, J = 6.0 Hz, 2H), 4.24 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.66 (s, 2H), 3.18 (s, 3H), 1.70 (s, 3H) ppm. 499 502.4 1H NMR (400 MHz, MeOD) δ = 9.23 (s, 1H), 9.18 (s, 1H), 9.14 (d, J = 1.6 Hz, 1H), 8.56 (d, J = 4.4 Hz, 1H), 8.53-8.51 (m, 2H), 8.33 (d, J = 8.0 Hz, 1H), 8.18 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.95-7.93 (m, 1H), 7.86 (s, 1H), 7.61-7.60 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.92-4.90 (m, 4H), 4.22 (d, J = 11.2 Hz, 1H), 3.95 (d, J = 11.6 Hz, 1H), 1.77 (s, 3H). ppm 500 486.1 1HNMR (400 MHz, MeOD-d4) δ = 9.31 (s, 1H), 9.05 (d, J = 2.0 Hz, 1H), 8.65-8.57 (m, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.41 (s, 1H), 8.34 (d, J = 7.2 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.75-7.63 (m, 2H), 6.89 (s, 1H), 4.95-4.89 (m, 4H), 4.26 (d, J = 11.6 Hz, 1H), 3.97 (d, J = 11.6 Hz, 1H), 1.78 (s, 3H) ppm. 501 453.1 1HNMR (400 MHz, MeOD-d4) δ = 9.30 (s, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 8.04-7.88 (m, 3H), 7.30 (d, J = 8.4 Hz, 1H), 6.82 (s, 1H), 4.93 (s, 4H), 4.30 (s, 3H), 4.22 (d, J = 11.6 Hz, 1H), 3.94 (d, J = 10.8 Hz, 1H), 2.32 (s, 3H), 1.78 (s, 3H) ppm 504 475.1 1H NMR (400 MHz, DMSO-d6) δ = 9.42-9.39 (m, 1H), 9.32 (s, 1H), 9.13 (s, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.56 (s, 1H), 8.21 (d, J = 1.2 Hz, 1H), 8.14-7.90 (m, 3H), 7.75-7.72 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.94- 4.83 (m, 2H), 4.80 (br d, J = 5.6 Hz, 2H), 4.24 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 11.2 Hz, 1H), 1.71 (s, 3H) ppm 506 492.3 1H NMR (400 MHz, MeOD-d4) δ = 9.36 (s, 1H), 8.64 (s, 2H), 8.47 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 1.2 Hz, 1H), 7.98 (s, 1H), 7.93-7.91 (m, 1H), 7.76 (d, J = 4.8 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.93-4.90 (m, 4H), 4.27- 4.19 (m, 5H), 3.93 (d, J = 11.6 Hz, 1H), 2.47-2.43 (m, 2H), 1.77 (s, 3H) ppm 507 466.3 1H NMR (400 MHz, MeOD) δ = 9.37 (s, 1 H), 8.60 (d, J = 8.8 Hz, 1 H), 8.52 (s, 1 H), 8.36 (d, J = 4.8 Hz, 1 H), 8.16-8.13 (m, 2 H), 7.96 (s, 1H), 7.91-7.86 (m, 1 H), 7.83 (d, J = 4.8 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 4.95-4.93 (m, 2 H), 4.91 (d, J = 3.6 Hz, 2 H), 4.21 (d, J = 11.6 Hz, 1 H), 4.03 (s, 3H), 3.93 (d, J = 11.2 Hz, 1 H), 1.75 (s, 3H) ppm. 508 435.1 1HNMR (400 MHz, DMSO-d6) δ = 9.60 (s, 1H), 9.52 (s, 1H), 9.45-9.38 (m, 1H), 8.50 (s, 1H), 8.26 (d, J = 7.2 Hz, 2H), 8.21 (s, 1H), 8.00-7.93 (m, 1H), 7.80 (s, 1H), 7.58-7.44 (m, 3H), 7.32 (d, J = 8.0 Hz, 1H), 4.96-4.83 (m, 2H), 4.80 (d, J = 5.6 Hz, 2H), 4.24 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H), 1.71 (s, 3H) ppm 509 453.1 1HNMR (400 MHz, MeOD-d4) δ = 9.18 (s, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.27 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.92-7.90 (m, 1H), 7.86-7.80 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 4.91 (d, J = 3.6 Hz, 2H), 4.89 (s, 2H), 4.20 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.2 Hz, 1H), 3.90 (s, 3H), 2.62 (s, 3H), 1.76 (s, 3H) ppm 510 466.2 1H NMR (400 MHz, MeOD) δ = 9.68-9.61 (m, 1H), 9.10-8.99 (m, 1H), 8.96-8.81 (m, 2H), 8.35-8.21 (m, 2H), 8.18 (d, J = 2.0 Hz, 1H), 7.96- 7.93 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.85-6.77 (m, 1H), 5.02 (s, 2H), 4.93 (d, J = 2.8 Hz, 2H), 4.22 (d, J = 11.6 Hz, 1H), 3.96 (d, J = 11.6 Hz, 1H), 3.81 (s, 3H), 1.81-1.75 (m, 3H) ppm 511 435.1 1HNMR (400 MHz, DMSO-d6) δ = 9.45-9.39 (m, 2H), 9.39 (d, J = 2.4 Hz, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.98-7.92 (m, 3H), 7.87 (s, 1H), 7.61-7.55 (m, 2H), 7.53-7.48 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.95-4.85 (m, 2H), 4.81 (d, J = 6.0 Hz, 2H), 4.23 (d, J = 11.6 Hz, 1H), 3.89-3.86 (m, 1H), 1.70 (s, 3H) ppm 512 466.2 1HNMR (400 MHz, MeOD-d4) δ = 9.36 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.30 (d, J = 5.6 Hz, 1H), 8.23-8.13 (m, 2H), 7.99 (s, 1H), 7.94-7.91 (m, 1H), 7.77-7.71 (m, 1H), 7.58 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.96-4.90 (m, 4H), 4.20 (d, J = 11.6 Hz, 1H), 3.99 (s, 3H), 3.93 (d, J = 11.6 Hz, 1H), 1.76 (s, 3H) ppm 513 481.1 1H NMR (400 MHz, MeOD-d4) δ = 9.20 (s, 1H), 8.58 (s, 1H), 8.47-8.45 (m, 1H), 8.36 (s, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.95-7.91 (m, 2H), 7.83 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 5.68-5.61 (m, 1H), 5.09 (s, 2H), 5.08 (s, 2H), 4.92 (d, J = 3.6 Hz, 2H), 4.89 (s, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 1.77 (s, 3H) ppm. 515 501.2 1H NMR (400 MHz, DMSO-d6) δ = 9.47 (s, 1H), 9.39-9.38 (m, 1H), 8.71 (d, J = 5.6 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.93-7.92 (m, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.80 (s, 1H), 7.36-7.35 (m, 1H), 7.30-7.17 (m, 2H), 4.96- 4.73 (m, 4H), 4.21 (d, J = 3.6 Hz, 1H), 3.91-3.81 (m, 4H), 1.68 (s, 3H) ppm. 516 483.2 1H NMR (400 MHz, DMSO-d6) δ = 9.46-9.38 (m, 2H), 8.65 (s, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 1.6, 1H), 7.82 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.32-7.29 (m, 1H), 7.34-7.22 (m, 2H), 4.94-4.80 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.82 (d, J = 1.6 Hz, 3H), 1.70 (s, 3H) ppm. 517 483.2 1H NMR (400 MHz, DMSO-d6) δ = 9.43-9.33 (m, 2H), 8.57 (d, J = 8.2 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 1.6, 1H), 7.79 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.38-7.27 (m, 2H), 7.26-7.21 (m, 1H), 4.93-4.76 (m, 4H), 4.21 (d, J = 11.6 Hz, 1H), 3.88-3.83 (m, 4H), 1.69 (s, 3H) ppm. 518 471.2 1HNMR (400 MHz, DMSO-d6) δ = 9.42-9.39 (m, 2H), 8.72 (d, J = 8.8 Hz, 1H), 8.44 (s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 1.3 Hz, 1H), 8.06-8.02 (m, 2H), 7.96-7.94 (m, 1H), 7.84 (s, 1H), 7.48-7.42 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.93-4.81 (m, 4H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm 519 485.2 1HNMR (400 MHz, DMSO-d6) δ = 9.43-9.31 (m, 2H), 8.69-8.61 (m, 2H), 8.21-8.10(m, 2H), 7.96-7.94 (m, 1H), 7.78-7.76 (m, 1H), 7.66 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.93-4.78 (m, 4H), 4.24-4.19 (m, 1H), 3.87 (d, J = 11.6 Hz, 1H), 2.11 (s, 3H), 1.70 (s, 3H) ppm. 520 437.1 1H NMR (400 MHz, DMSO-d6) δ = 9.74 (d, J = 1.2 Hz, 1H), 9.47 (s, 1H), 9.44-9.41 (m, 1H), 8.85-8.76 (m, 3H), 8.60 (d, J = 8.8 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.96-7.94 (m, 1H), 7.90 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.93-4.83 (m, 4H), 4.23 (d, J = 11.6 Hz, 1H), 3.87 (br d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm 521 485.2 1HNMR (400 MHz, DMSO-d6) δ = 9.46 (s, 1H), 9.42-9.36 (m, 1H), 8.72 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.98-7.91 (m, 2H), 7.86- 7.77 (m, 3H), 7.75-7.66 (m, 2H), 7.61 (s, 0.3H), 7.47 (s, 0.5H), 7.33 (s, 0.2H), 7.29 (d, J = 8.0 Hz, 1H), 4.94-4.75 (m, 4H), 4.21 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 1.69 (s, 3H) ppm 522 435.2 1H NMR (400 MHz, DMSO-d6) δ = 9.61 (s, 1H), 9.34-9.31 (m, 1H), 8.27- 8.16 (m, 3H), 8.08 (d, J = 1.6 Hz, 1H), 7.95-7.86 (m, 3H), 7.58-7.51 (m, 2H), 7.50-7.45 (m, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.97-4.77 (m, 4H), 4.23 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 1.70 (s, 3H) ppm. 525 464.2 1HNMR (400 MHz, DMSO-d6) δ = 9.53-9.30 (m, 2H), 8.66 (d, J = 8.4 Hz, 1H), 8.39-8.21 (m, 4H), 8.09 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.66-7.51 (m, 3H), 7.43 (d, J = 8.0 Hz, 1H), 6.98-6.55 (m, 1H), 5.01-4.74 (m, 4H), 4.36-4.09 (m, 2H) ppm

    Example 29: (R)-4-Cyano-N-((2-(3-(dimethylamino)-2-oxopyridin-1(2H)-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide

    [1221] ##STR00657##

    Step 1: (R)-4-Cyano-N-((2-(3-(dimethylamino)-2-oxopyridin-1(2H)-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide

    [1222] To a solution of (R)—N-((2-chloro-1,6-naphthyridin-7-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide (30 mg, 76.37 umol) and 3-(dimethylamino)pyridin-2(1H)-one (21.10 mg, 152.73 umol) in dioxane (1 mL) was added Cs.sub.2CO.sub.3 (74.65 mg, 229.10 umol) and XantPhos Pd G3 (7.24 mg, 7.64 umol). The mixture was stirred at 100° C. for 12 hrs under N.sub.2. The mixture was diluted with H.sub.2O (10 mL) and extracted with EA (10 mL*2). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by reverse phase prep-HPLC (0.1% FA condition) to give the title compound (12.66 mg, 22.61 umol, 29.61% yield, FA salt) as a yellow solid.

    [1223] LCMS (ESI) m/z: [M+H].sup.+=495.4.

    [1224] .sup.1H NMR (400 MHz, MeOD) δ=9.39 (s, 1H), 8.65 (d, J=8.8 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.91-7.89 (m, 2H), 7.60-7.58 (m, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.93-6.91 (m, 1H), 6.46-6.43 (m, 1H), 4.92 (s, 2H), 4.90 (d, J=4.0 Hz, 2H), 4.21 (d, J=11.6 Hz, 1H), 3.93 (d, J=11.6 Hz, 1H), 2.85 (s, 6H), 1.75 (s, 3H) ppm.

    [1225] Chiral SFC: Cellucoat-MeOH+ACN(DEA)-40-3 mL-35T.lcm, Rt=0.908 min, ee value=100%.

    [1226] The following examples in Table 20 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Examples 29.

    TABLE-US-00021 TABLE 20 Compounds of the Invention LCMS # (m/z) 1H NMR 142 498.4 1H NMR (400 MHz, DMSO-d6) δ = 9.48-9.45 (m, 1H), 8.75 (d, J = 4.4 Hz, 1H), 8.50 (d, J = 9.6 Hz, 1H), 8.30-8.27 (m, 1H), 8.18-8.13 (m, 2H), 8.05 (s, 1H), 7.95-7.92 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.01 (d, J = 5.6 Hz, 2H), 4.94-4.80 (m, 2H), 4.22 (d, J = 11.6 Hz, 1H), 4.02-3.98 (m, 4H), 3.86 (d, J = 11.6 Hz, 1H), 2.42-2.34 (m, 2H), 1.69 (s, 3H) ppm 219 530.5 1H NMR (400 MHz, METHANOL-d4) δ = 8.29 (d, J = 9.6 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 7.94-7.87 (m, 3H), 7.68 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.06-6.76 (m, 1H), 5.04 (s, 2H), 4.90 (s, 2H), 4.84 (s, 2H), 4.37-4.35 (m, 2H), 4.20 (d, J = 11.6 Hz, 1H), 4.11 (t, J = 5.6 Hz, 2H), 3.92 (d, J = 11.6 Hz, 1H), 1.75 (s, 3H) ppm 220 530.4 1H NMR (400 MHz, DMSO-d6) δ = 9.36-9.33 (m, 1H), 9.14 (s, 1H), 9.08 (d, J = 2.8 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.96-7.94 (m, 1H), 7.71 (s, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.57 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.25- 6.92 (m, 1H), 4.94-4.81 (m, 2H), 4.79 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 4.32-4.30 (m, 2H), 4.23 (d, J = 11.2 Hz, 1H), 4.12-4.05 (m, 2H), 3.86 (d, J = 11.6 Hz, 1H), 1.69 (s, 3H)ppm 279 512 1H NMR (400 MHz, DMSO-d6) δ = 9.36-9.33 (m, 1H), 9.22 (s, 1H), 8.55 (d, J = 9.2 Hz, 1H), 8.25 (s, 1H), 7.96-7.94 (m, 1H), 7.52-7.47 (m, 2H), 7.30 (d, J = 8.0 Hz, 1H), 4.87-4.73 (m, 4H), 4.12-4.07 (m, 3H), 3.88- 3.82 (m, 1H), 3.61-3.57 (m, 2H), 2.45-2.43 (m, 1H), 1.71-1.66 (m, 3H), 0.77-0.75 (m, 4H) ppm 282 492.2 1H NMR (400 MHz, MeOH) δ = 9.43-9.36 (m, 1H), 8.69-8.61 (m, 1H), 8.17-8.13 (m, 1H), 8.05-7.99 (m, 1H), 7.94-7.87 (m, 2H), 7.87-7.81 (m, 1H), 7.31-7.24 (m, 1H), 7.24-7.19 (m, 1H), 6.49-6.38 (m, 1H), 4.94- 4.92 (m, 2H), 4.91-4.89 (m, 2H), 4.23-3.87 (m, 2H), 2.13-2.02 (m, 1H), 1.79-1.73 (m, 3H), 1.02-0.89 (m, 2H), 0.74-0.66 (m, 2H) ppm 283 507 1H NMR (400 MHz, MeOD) δ = 9.40 (s, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 1.2 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1 H), 7.95-7.89 (m, 2H), 7.43-7.41 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.46-6.38 (m, 2H), 4.95-4.93 (m, 2H), 4.93-4.91 (m, 2H), 4.22 (d, J = 11.2 Hz, 1H), 4.03-4.01 (m, 4H), 3.94 (d, J = 11.2 Hz, 1H), 2.36-2.32 (m, 2H), 1.77 (s, 3H) ppm 303 490.1 1HNMR (400 MHz, MeOD-d4) δ = 9.20-9.13 (m, 1H), 8.98 (s, 1H), 8.32- 8.27 (m, 1H), 8.07-8.02 (m, 1H), 8.01-7.95 (m, 1H), 7.85-7.78 (m, 2H), 7.73-7.65 (m, 1H), 7.64-7.59 (m, 1H), 7.58-7.43 (m, 2H), 7.18-7.12 (m, 1H), 5.30-5.23 (m, 2H), 4.95 (d, J = 5.1 Hz, 2H), 4.91-4.85 (m, 2H), 4.20-4.10 (m, 1H), 4.01-3.91 (m, 1H), 1.81-1.75 (m, 3H) ppm 312 483.2 1H NMR (400 MHz, DMSO-d6) δ = 9.41-9.29 (m, 1H), 9.14 (s, 1H), 8.61- 8.55 (m, 1H), 8.43-8.36 (m, 1H), 8.22-8.16 (m, 1H), 7.98-7.89 (m, 1H), 7.50 (s, 1H), 7.34-7.27 (m, 1H), 4.94-4.80 (m, 2H), 4.77-4.66 (m, 2H), 4.27-4.18 (m, 1H), 4.04-3.98 (m, 2H), 3.90-3.83 (m, 1H), 3.47- 3.43 (m, 2H), 2.66-2.60 (m, 1H), 1.70(s, 3H), 0.72-0.69 (m, 4H) ppm 313 497.3 1H NMR (400 MHz, DMSO-d6) δ = 9.36-9.33 (m, 1H), 9.15-9.13 (m, 1H), 8.56 (d, J = 9.2 Hz, 1H), 8.38 (d, J = 9.2 Hz, 1H), 8.19 (d, J = 1.2 Hz, 1H), 7.95-7.92 (m, 1H), 7.49 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.93-4.86 (m, 2H), 4.73 (br d, J = 4.4 Hz, 2H), 4.47-4.42 (m, 1H), 4.23 (d, J = 11.6 Hz, 1H), 4.09-4.05 (m, 2H), 3.87 (d, J = 11.6 Hz, 1H), 3.61-3.57 (m, 2H), 2.28-2.23 (m, 2H), 2.04-1.99 (m, 2H), 1.70-1.64 (m, 5H) ppm 315 497.2 1H NMR (400 MHz, CD3OD) δ = 9.13 (s, 1H), 8.37-8.26 (m, 1H), 8.18 (s, 1H), 8.14-8.07 (m, 1H), 7.96-7.87 (m, 1H), 7.72 (s, 1H), 7.36-7.18 (m, 1H), 4.95-4.92 (m, 2H), 4.86-4.85 (m, 2H), 4.25-4.18 (m, 1H), 4.13-4.05 (m, 2H), 3.97-3.90 (m, 1H), 3.49-3.44 (m, 2H), 2.81-2.68 (m, 1H), 2.14-2.05 (m, 2H), 1.79-1.74 (m, 3H), 0.88-0.81 (m, 2H), 0.79- 0.70 (m, 2H) ppm 350 511.1 1H NMR (400 MHz, MeOD-d4) δ = 9.13 (s, 1H), 8.28 (d, J = 10.2 Hz, 1H), 8.17 (s, 1H), 8.03 (d, J = 10.2 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.30 (d, J = 7.6 Hz, 1H), 4.97-4.81 (m, 4H), 4.81-4.80 (m, 1H), 4.22 (d, J = 11.2 Hz, 1H), 4.11-4.08 (m, 2H), 3.94 (d, J = 11.2 Hz, 1H), 3.52- 3.49 (m, 2H), 2.29-2.17 (m, 2H), 2.14-2.11 (m, 4H), 1.77-1.73 (m, 5H) ppm 471 442.3 1H NMR (400 MHz, DMSO-d6) δ = 9.39-9.33 (m, 1H), 9.23 (s, 1H), 8.62 (d, J = 8.8 Hz, 1H), 8.51 (d, J = 9.2 Hz, 1H), 8.18 (s, 1H), 7.94-7.91 (m, 1H), 7.58 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.92-4.75 (m, 4H), 4.22 (d, J = 11.6 Hz, 1H), 4.12-4.08 (m, 2H), 3.86 (d, J = 11.2 Hz, 1H), 2.67-2.63 (m, 2H), 2.08-2.04 (m, 2H), 1.69 (s, 3H) ppm

    Example 30: (R)-4-Cyano-4-methyl-N-((2-(6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridin-2(1H)-yl)-1,6-naphthyridin-7-yl)methyl)isochromane-6-carboxamide

    [1227] ##STR00658##

    Step 1: (R)-4-Cyano-4-methyl-N-((2-(6-methyl-5-oxo-3,4,5,6-tetrahydro-2,6-naphthyridin-2(1H)-yl)-1,6-naphthyridin-7-yl)methyl)isochromane-6-carboxamide

    [1228] To a mixture of 2-methyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1(2H)-one (30 mg, 107.83 umol, TFA salt) in DMSO (1 mL) was added (R)—N-((2-chloro-1,6-naphthyridin-7-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide (28.24 mg, 71.88 umol) and DIEA (46.45 mg, 359.42 umol, 62.60 uL).

    [1229] The mixture was stirred at 120° C. for 16 hrs. The mixture was poured into H.sub.2O (15 mL) and extracted with EA/MeOH=10/1 (15 mL*3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=10/1, Rf=0.3) to afford a yellow solid. The yellow solid was further purified by reverse phase column (0.1% FA condition). The product fraction was concentrated under reduced pressure to remove MeCN and lyophilized to give the title compound (8.23 mg, 15.81 umol, 22.0% yield) as a white solid.

    [1230] LCMS (ESI) m/z: [M+H].sup.+=521.3.

    [1231] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.31-9.28 (m, 1H), 8.91 (s, 1H), 8.20-8.17 (m, 2H), 7.95-7.92 (m, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.38 (d, J=9.2 Hz, 1H), 7.33-7.27 (m, 2H), 6.17 (d, J=6.8 Hz, 1H), 4.94-4.80 (m, 2H), 4.71 (5, 2H), 4.69-4.61 (d, 2H), 4.23 (d, J=11.6 Hz, 1H), 3.98-3.94 (i, 2H), 3.87 (d, J=11.6 Hz, 1H), 3.40 (m, 3H), 2.54 (brs, 2H), 1.70 (d, 3H) ppm.

    [1232] Chiral SFC: Cellucoat-MeOH+ACN(DEA)-40-3 mL-35T, Rt=1.153 min, ee %=100%.

    [1233] The following examples in Table 21 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Examples 30.

    TABLE-US-00022 TABLE 21 Compounds of the Invention LCMS # (m/z) 1H NMR 382 530.3 1H NMR (400 MHz, DMSO-d6) δ = 9.32-9.29 (m, 1H), 8.98 (s, 1H), 8.36- 8.35 (m, 1H), 8.28 (d, J = 9.6 Hz, 1H), 8.18 (d, J = 1.2 Hz, 1H), 7.94- 7.92 (m, 1H), 7.69 (s, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.25-6.97 (m, 1H), 5.10 (s, 2H), 4.92-4.81 (m, 2H), 4.69 (br d, J = 5.2 Hz, 2H), 4.29-4.21 (m, 5H), 3.87 (d, J = 11.6 Hz, 1H), 1.69 (s, 3H) ppm 383 492.2 1H NMR (400 MHz, DMSO-d6) δ = 9.31 (s, 1H), 8.64-8.57 (m, 2H), 8.49 (brs, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.97-7.86 (m, 4H), 7.29 (d, J = 8.0 Hz, 1H), 4.92 (brd, J = 5.6 Hz, 5H), 4.21 (d, J = 11.2 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 1.76 (s, 3H), 1.54-1.51 (m, 2H), 1.27-1.24 (m, 2H) ppm 425 498.5 1H NMR (400 MHz, MeOD) δ = 9.15 (s, 1H), 8.52 (d, J = 4.4 Hz, 1H), 8.48 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.93- 7.90 (m, 1H), 7.72 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.91 (d, J = 3.2 Hz, 2H), 4.86 (br s, 2H), 4.20 (d, J = 11.2 Hz, 1H), 4.11-4.07 (m, 4H), 3.93 (d, J = 11.6 Hz, 1H), 2.50-2.43 (m, 2H), 1.76 (s, 3H) ppm 426 480.5 1H NMR (400 MHz, MeOD) δ = 9.16 (s, 1H), 8.57 (d, J = 2.8 Hz, 1H), 8.50 (d, J = 9.2 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.93- 7.90 (m, 1H), 7.73 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.99 (d, J = 3.2 Hz, 1H), 4.91 (d, J = 3.6 Hz, 2H), 4.87 (brs, 2H), 4.20 (d, J = 11.6 Hz, 1H), 4.03-3.99 (m, 4H), 3.93 (d, J = 11.2 Hz, 1H), 2.47-2.39 (m, 2H), 1.76 (s, 3H) ppm 453 494.3 1HNMR (400 MHz, METHANOL-d4) δ = 8.83 (d, J = 2.8 Hz, 1H), 8.19- 8.08 (m, 2H), 7.93-7.90 (m, 1H), 7.46 (s, 1H), 7.36-7.25 (m, 3H), 4.91 (d, J = 3.6 Hz, 2H), 4.82-4.74 (m, 4H), 4.23-4.13 (m, 3H), 3.93 (d, J = 11.6 Hz, 1H), 3.73 (d, J = 1.6 Hz, 3H), 2.86 (s, 2H), 1.76 (s, 3H) ppm 455 494.3 1HNMR (400 MHz, METHANOL-d4) δ = 8.83 (s, 1H), 8.18-8.07 (m, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.34-7.28 (m, 2H), 4.91 (d, J = 3.6 Hz, 2H), 4.81-4.77 (m, 4H), 4.24-4.12 (m, 3H), 3.93 (d, J = 11.6 Hz, 1H), 3.83-3.72 (m, 3H), 2.86-2.81 (m, 2H), 1.76 (s, 3H) ppm 457 494.5 1H NMR (400 MHz, MeOD) δ = 8.85 (s, 1H), 8.35-8.33 (m, 1H), 8.16-8.13 (m, 2H), 7.91-7.89 (m, 1H), 7.49 (s, 1H), 7.38-7.35(m, 1H), 7.28-7.26 (m, 2H), 4.96 (s, 2H), 4.90 (d, J = 3.2 Hz, 2H), 4.78 (s, 2H), 4.21 (d, J = 11.2 Hz, 1H), 4.03-4.01 (m, 2H), 3.93 (d, J = 11.2 Hz, 1H), 3.79-3.78 (m, 3H), 2.71 (brs, 2H), 1.76 (s, 3H) ppm. 458 494.5 1H NMR (400 MHz, MeOD) δ = 8.82-8.81 (m, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 8.13-8.08 (m, 1H), 7.91-7.89 (m, 1H), 7.45 (s, 1H), 7.33 (s, 1H), 7.30- 7.26 (m, 2H), 4.89 (s, 2H), 4.77 (s, 2H), 4.21-4.17 (m, 1H), 4.05 (s, 2H), 3.93-3.89 (m, 1H), 3.82 (s, 3H), 2.72 (s, 2H), 1.75 (d, J = 1.2 Hz, 3H) ppm. 461 480.2 1H NMR (400 MHz, MeOD-d4) δ = 8.85 (s, 1H), 8.29 (s, 1H), 8.19-8.12 (m, 2H), 7.93-7.91 (m, 1H), 7.51 (s, 1H), 7.34-7.26 (m, 2H), 7.01 (d, J = 9.2 Hz, 1H), 4.91 (d, J = 3.2 Hz, 2H), 4.83-4.75 (m, 4H), 4.74-4.64 (m, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.6 Hz, 1H), 3.85 (s, 3H), 1.77 (s, 3H) ppm. 473 425.3 1HNMR (400 MHz, DMSO-d6) δ = 9.44-9.41 (m, 1H), 9.38 (s, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.75 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.21 (s, 1H), 8.15-8.13 (m, 1H), 7.98-7.93 (m, 2H), 7.73 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.68-6.67(m, 1H), 4.95-4.84 (m, 2H), 4.83-4.79 (m, 2H), 4.24 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H), 1.71 (s, 3H) ppm 486 480.2 1H NMR (400 MHz, DMSO-d6) δ = 9.32-9.30 (m, 1H), 8.95 (s, 1H), 8.28- 8.15 (m, 2H), 7.94-7.91 (m, 1H), 7.48-7.39 (m, 2H), 7.36-7.25 (m, 2H), 6.17 (d, J = 1.6 Hz, 1H), 5.01 (s, 2H), 4.94-4.80 (m, 2H), 4.67 (d, J = 3.2, 2H), 4.30-4.18 (m, 5H), 3.86 (d, J = 11.6 Hz, 1H), 1.69 (s, 3H) ppm. 502 540.3 1H NMR (400 MHz, Chloroform-d) δ 8.71 (s, 1H), 8.13 (s, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.62 (s, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.93 (s, 1H), 5.35 (s, 1H), 4.90 (d, J = 5.7 Hz, 2H), 4.85 (d, J = 4.6 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 4.13 (d, J = 11.3 Hz, 1H), 3.87 (d, J = 11.3 Hz, 1H), 3.68 (s, 2H), 2.15-1.15 (m, 14H) 503 439 1H NMR (400 MHz, MeOD) δ = 9.23 (s, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.95- 7.90 (m, 1H), 7.80 (s, 1H), 7.29 (d, J = 8.2 Hz, 1H), 6.42 (d, J = 2.8 Hz, 1H), 4.91 (br d, J = 3.8 Hz, 4H), 4.20 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 11.2 Hz, 1H), 2.37 (s, 3H), 1.76 (s, 3H) ppm 505 439.2 1HNMR (400 MHz, DMSO-d6) δ = 9.43-9.31 (m, 2H), 8.69-8.61 (m, 2H), 8.21-8.10(m, 2H), 7.96-7.94 (m, 1H), 7.78-7.76 (m, 1H), 7.66 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.93-4.78 (m, 4H), 4.24-4.19 (m, 1H), 3.87 (d, J = 11.6 Hz, 1H), 2.11 (s, 3H), 1.70 (s, 3H) ppm. 514 428.3 1H NMR (400 MHz, DMSO-d6) δ = 9.30-9.27 (m, 1H), 8.85 (s, 1H), 8.19 (s, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.95-7.93 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 6.92 (d, J = 9.2 Hz, 1H), 4.95-4.79 (m, 2H), 4.66-4.64 (m, 2H), 4.23 (d, J = 11.6 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.11-3.09 (m, 1H), 2.56-2.52 (m, 2H), 1.96 (br s, 4H), 1.90-1.76 (m, 1H), 1.70 (s, 3H) ppm

    Example 31: (R)—N-((2-(6-(Azetidin-1-yl)pyridin-2-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide

    [1234] ##STR00659##

    Step 1: 1-(6-Chloropyridin-2-yl)-1H-pyrazol-3-ol

    [1235] Methyl prop-2-ynoate (1.29 g, 15.32 mmol, 1.28 mL) was added dropwise to a solution of (6-chloro-2-pyridyl)hydrazine (2 g, 13.93 mmol) in t-BuOH (10 mL) at 20° C. t-BuOK (3.13 g, 27.86 mmol) was then added at 0° C. before stirring at 20° C. for 16 hrs. The reaction was quenched by adding water (100 mL) and the mixture was adjusted to pH 9 with 1 N HCl solution, forming a yellow precipitate. The solid was collected by filtration, washed with water (20 mL) and dried to give the title compound (1.6 g, 8.18 mmol, 58.72% yield).

    [1236] LCMS (ESI) m/z: [M+H].sup.+=196.1.

    [1237] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.38-8.36 (m, 1H), 7.83-7.71 (m, 1H), 7.57-7.48 (m, 1H), 7.21-7.11 (m, 1H), 6.06-5.89 (m, 1H), 4.71 (br s, 1H) ppm.

    Step 2: 2-(3-(Benzyloxy)-1H-pyrazol-1-yl)-6-chloropyridine

    [1238] NaH (173.21 mg, 4.33 mmol, 60% purity) was added portion wise to a solution of 1-(6-chloropyridin-2-yl)-1H-pyrazol-3-ol (0.77 g, 3.94 mmol) in DMF (10 mL) at 0° C. The mixture was stirred at 0° C. for 15 mins. (Bromomethyl)benzene (673.27 mg, 3.94 mmol, 467.55 uL) was added dropwise at 0° C. and the mixture was stirred at 60° C. for 1 hr. The reaction was quenched by pouring into water (50 mL), forming a yellow precipitate was formed. The solid was collected by filtration, washed with water (20 mL) and dried. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=3/1) to give the title compound (0.5 g, 1.75 mmol, 44.45% yield).

    [1239] LCMS (ESI) m/z: [M+H].sup.+=286.1.

    [1240] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=8.38-8.36 (m, 1H), 7.76-7.67 (m, 2H), 7.55-7.46 (m, 2H), 7.44-7.34 (m, 4H), 7.14-7.05 (m, 1H), 6.00-5.97 (m, 1H), 5.32 (s, 2H) ppm.

    Step 3: 3-(Benzyloxy)-1-(6-chloropyridin-2-yl)-1H-pyrazole-4-carbaldehyde

    [1241] POCl.sub.3 (429.30 mg, 2.80 mmol, 260.18 uL) was added dropwise to a solution of DMF (204.64 mg, 2.80 mmol, 215.41 uL) at −10° C. and the mixture was stirred at 0° C. for 15 mins. 2-(3-(Benzyloxy)-1H-pyrazol-1-yl)-6-chloropyridine (0.2 g, 699.97 umol) was added portion wise at 0° C. The mixture was then stirred at 70° C. for 1 hr. The reaction was quenched by adding sat. NaHCO.sub.3 (20 mL) and a yellow precipitate was formed. The solid was collected by filtration, washed with water (10 mL) and dried to give the title compound (0.21 g, 669.35 umol, 95.63% yield).

    [1242] LCMS (ESI) m/z: [M+H].sup.+=314.1.

    [1243] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=9.92 (s, 1H), 8.91 (s, 1H), 7.84-7.74 (m, 2H), 7.57-7.49 (m, 2H), 7.45-7.36 (m, 3H), 7.26-7.24 (m, 1H), 5.46 (s, 2H) ppm.

    Step 4: 1-(6-Chloropyridin-2-yl)-3-hydroxy-1H-pyrazole-4-carbaldehyde

    [1244] TFA (3.39 g, 29.71 mmol, 2.20 mL) was added dropwise to a solution of 3-(benzyloxy)-1-(6-chloropyridin-2-yl)-1H-pyrazole-4-carbaldehyde (110 mg, 350.61 umol) in toluene (2.2 mL). The mixture was stirred at 20° C. for 48 hrs. The reaction mixture was concentrated under vacuum. The residue was triturated with MTBE (5 mL) to give the title compound (50 mg, crude) as yellow solid.

    [1245] LCMS (ESI) m/z: [M+H].sup.+=224.0.

    Step 5: 1-(6-Chloropyridin-2-yl)-4-formyl-1H-pyrazol-3-yl trifluoromethanesulfonate

    [1246] To a solution of 1-(6-chloropyridin-2-yl)-3-hydroxy-1H-pyrazole-4-carbaldehyde (40 mg, 178.88 umol) in DCM (3 mL) was added TEA (54.30 mg, 536.64 umol) and dropwise Tf.sub.2O (75.70 mg, 268.32 umol). The mixture was stirred at 20° C. for 1 hr. The reaction was quenched by adding water (50 mL) and the products were extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/1) to give the title compound (30 mg, crude) as a yellow oil.

    Step 6: tert-Butyl (3-(1-(6-chloropyridin-2-yl)-4-formyl-1H-pyrazol-3-yl)prop-2-yn-1-yl)carbamate

    [1247] A mixture of tert-butyl prop-2-yn-1-ylcarbamate (13.74 mg, 88.56 umol), 1-(6-chloropyridin-2-yl)-4-formyl-1H-pyrazol-3-yl trifluoromethanesulfonate (30 mg, 84.35 umol), Et.sub.3N (85.35 mg, 843.46 umol), CuI (1.61 mg, 8.43 umol) and Pd(PPh.sub.3).sub.2Cl.sub.2 (5.92 mg, 8.43 umol) in CH.sub.3CN (2 mL) was de-gassed and purged with N.sub.2. The mixture was stirred at 70° C. for 2 hours under N.sub.2. The reaction mixture was quenched by adding (water 30 mL) and the products were extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether/Ethyl acetate=1/1) to give the title compound (40 mg, crude) as a yellow oil.

    [1248] LCMS (ESI) m/z: [M+Na].sup.+=383.1.

    Step 7: tert-Butyl ((2-(6-chloropyridin-2-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)methyl)carbamate

    [1249] To a solution of tert-butyl (3-(1-(6-chloropyridin-2-yl)-4-formyl-1H-pyrazol-3-yl)prop-2-yn-1-yl)carbamate (40 mg, 110.87 umol) in t-BuOH (2 mL) was added NH.sub.4OAc (12.82 mg, 166.30 umol) and AgOTf (5.70 mg, 22.17 umol) under N.sub.2. The mixture was stirred at 20° C. for 16 hrs. The reaction was quenched by addition of NaHCO.sub.3 (0.2 g), and the mixture was stirred at 20° C. for 30 mins. The resulting mixture was filtered and the solid was washed with ethyl acetate (30 mL*3). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=0/1) to give the title compound (35 mg, crude) as a yellow solid.

    [1250] LCMS (ESI) m/z: [M+H].sup.+=360.1.

    [1251] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=9.27 (s, 1H), 9.24-9.14 (m, 1H), 8.28-8.18 (m, 1H), 7.97-7.84 (m, 1H), 7.53 (s, 1H), 7.45-7.36 (m, 1H), 5.48-5.29 (m, 1H), 4.58-4.48 (m, 2H), 1.48 (s, 9H) ppm.

    Step 8: tert-Butyl ((2-(6-(azetidin-1-yl)pyridin-2-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)methyl)carbamate

    [1252] Azetidine (15.23 mg, 266.81 umol) and DIEA (114.94 mg, 889.36 umol) were added dropwise to a solution of tert-butyl ((2-(6-chloropyridin-2-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)methyl)carbamate (32 mg, 88.94 umol) in DMSO (2 mL). The mixture was stirred at 120° C. for 16 hrs. The reaction mixture was cooled to 20° C. and poured into water (20 mL). The products were extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with water (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (22 mg, crude) as a yellow oil.

    [1253] LCMS (ESI) m/z: [M+H].sup.+=381.2.

    Step 9: (2-(6-(Azetidin-1-yl)pyridin-2-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)methanamine

    [1254] TFA (410.67 mg, 3.60 mmol, 266.67 uL) was added to a solution of tert-butyl ((2-(6-(azetidin-1-yl)pyridin-2-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)methyl)carbamate (20 mg, 52.57 umol) in DCM (2 mL). The mixture was stirred at 20° C. for 1 hr. The solvent was evaporated by a flow of N.sub.2 gas to give the title compound (12 mg, crude) as a yellow oil, which was used in the next step without further purification.

    [1255] LCMS (ESI) m/z: [M+H].sup.+=281.2.

    Step 10: (R)—N-((2-(6-(Azetidin-1-yl)pyridin-2-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide

    [1256] To a solution of (2-(6-(azetidin-1-yl)pyridin-2-yl)-2H-pyrazolo[4,3-c]pyridin-6-yl)methanamine (12 mg, 42.81 umol) in DCM (2 mL) was added (R)-4-cyano-4-methylisochromane-6-carboxylic acid (11.16 mg, 51.37 umol), DIEA (27.66 mg, 214.04 umol), HOBt (6.94 mg, 51.37 umol) and EDCI (9.85 mg, 51.37 umol). Water (30 mL) was added and the products were extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (10 ml*3), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% NH.sub.3.H.sub.2O condition) to give the title compound (4.44 mg, 9.26 umol, 21.63% yield) as a yellow solid.

    [1257] LCMS (ESI) m/z: [M+H].sup.+=480.2.

    [1258] .sup.1H NMR (400 MHz, DMSO-d6) δ=9.38 (s, 1H), 9.30-9.22 (m, 2H), 8.21-8.15 (m, 1H), 7.95-7.90 (m, 1H), 7.80-7.73 (m, 1H), 7.46 (s, 1H), 7.43-7.37 (m, 1H), 7.32-7.26 (m, 1H), 6.51-6.43 (m, 1H), 4.93-4.81 (m, 2H), 4.72-4.65 (m, 2H), 4.27-4.21 (m, 1H), 4.11-4.07 (m, 4H), 3.90-3.84 (m, 1H), 2.42-2.38 (m, 2H), 1.70 (s, 3H) ppm.

    [1259] The following examples in Table 22 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 31.

    TABLE-US-00023 TABLE 22 Compounds of the Invention # LCMS (m/z) 1H NMR 524 424.1 1HNMR (400 MHz, DMSO-d6) δ = 9.39 (s, 1H), 9.29-9.22 (m, 2H), 8.18 (d, J = 1.6 Hz, 1H), 8.10 (d, J = 7.6 Hz, 2H), 7.95-7.91 (m, 1H), 7.65-7.59 (m, 2H), 7.53-7.47 (m, 2H), 7.29 (d, J = 8.0 Hz, 1H), 4.95-4.80 (m, 2H), 4.69 (d, J = 5.6 Hz, 2H), 4.22 (d, J = 11.4 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 1.70 (s, 3H) ppm

    Example 32: (R)-4-Cyano-N-((6-(2-methoxyphenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methyl)-4-methylisochromane-6-carboxamide

    [1260] ##STR00660##

    Step 1: tert-Butyl (3-(4-formylpyridin-3-yl)prop-2-yn-1-yl)carbamate

    [1261] A mixture of 3-bromopyridine-4-carbaldehyde (15 g, 80.64 mmol), tert-butyl prop-2-yn-1-ylcarbamate (13.14 g, 84.67 mmol), Et.sub.3N (81.60 g, 806.43 mmol, 112.25 mL), CuI (1.54 g, 8.06 mmol) and Pd(PPh.sub.3).sub.2Cl.sub.2 (5.66 g, 8.06 mmol) in CH.sub.3CN (120 mL) was stirred at 80° C. for 2 hrs under N.sub.2. The reaction mixture was quenched by addition of water (300 mL) and extracted with ethyl acetate (300 mL*3). The combined organic phase was washed with brine (300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=1/1) to give the title compound (18 g, 69.15 mmol, 85.75% yield) as a brown oil.

    [1262] LCMS (ESI) m/z: [M+H].sup.+=261.1.

    [1263] .sup.1HNMR (400 MHz, CDCl.sub.3) δ=10.48 (s, 1H), 8.66 (s, 1H), 8.78-8.68 (m, 1H), 7.78-7.62 (m, 1H), 4.88 (br s, 1H), 4.32-4.18 (m, 2H), 1.46 (s, 9H) ppm.

    Step 2: tert-Butyl ((2,6-naphthyridin-3-yl)methyl)carbamate

    [1264] To a solution of tert-butyl (3-(4-formylpyridin-3-yl)prop-2-yn-1-yl)carbamate (17 g, 65.31 mmol) in t-BuOH (60 mL) was added NH.sub.4OAc (7.55 g, 97.97 mmol) and AgOTf (3.36 g, 13.06 mmol). The mixture was stirred at 20° C. for 16 hrs. The reaction mixture was quenched by addition of NaHCO.sub.3 (22 g), and the reaction mixture was stirred at 20° C. for 30 mins. The mixture was filtered and the filter cake was washed with ethyl acetate (30 mL*3). The combined organic phases were concentrated under reduced pressure and the residue was purified by column chromatography (SiO.sub.2, Petroleum ether/Ethyl acetate=0/1) to give the title compound (8.5 g, 32.39 mmol, 49.59% yield) as a yellow oil.

    [1265] LCMS (ESI) m/z: [M+H].sup.+=260.1.

    [1266] .sup.1HNMR (400 MHz, CDCl.sub.3) δ=9.36-9.25 (m, 2H), 8.75-8.61 (m, 1H), 7.82-7.71 (m, 1H), 5.46 (br s, 1H), 4.64-4.62 (m, 2H), 1.46 (s, 9H) ppm.

    Step 3: tert-Butyl ((5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methyl)carbamate

    [1267] A mixture of tert-butyl ((2,6-naphthyridin-3-yl)methyl)carbamate (8 g, 30.85 mmol) and PtO.sub.2 (700.59 mg, 3.09 mmol) in MeOH (80 mL) was degassed and purged with H.sub.2 3 times. The mixture was stirred at 20° C. for 16 hrs under H.sub.2 atmosphere (15 psi). The reaction was filtered and the filter cake was washed with MeOH (50 mL*2). The filtrate was concentrated under vacuum and the residue was purified by column chromatography (SiO.sub.2, DCM:MeOH=10/1) to give crude product (5 g) as a black oil. The crude product was purified by reversed-phase HPLC (0.1% FA condition). The desired fraction was adjusted to pH 9 with sat. NaHCO.sub.3 and extracted with DCM (200 mL*3). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (3.8 g, 14.43 mmol, 46.77% yield) as a yellow oil.

    [1268] LCMS (ESI) m/z: [M+H].sup.+=264.2.

    [1269] .sup.1HNMR (400 MHz, CDCl.sub.3) δ=8.26 (s, 1H), 6.92 (s, 1H), 5.46 (br s, 1H), 4.37-4.35 (m, 2H), 3.98 (s, 2H), 3.17-3.13 (m, 2H), 2.79-2.75 (m, 2H), 1.46 (s, 9H) ppm.

    Step 4: tert-Butyl ((6-(2-methoxyphenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methyl)carbamate

    [1270] A mixture of tert-butyl ((5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methyl)carbamate (100 mg, 379.75 umol), 1-bromo-2-methoxy-benzene (213.08 mg, 1.14 mmol, 142.05 uL), BINAP (47.29 mg, 75.95 umol), Pd.sub.2(dba).sub.3 (34.77 mg, 37.97 umol) and Cs.sub.2CO.sub.3 (371.18 mg, 1.14 mmol) in dioxane (3 mL) was degassed and purged with N.sub.2 3 times. The mixture was stirred at 110° C. for 3 hrs under N.sub.2 atmosphere.

    [1271] The mixture was poured into water (40 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (80 mg, 155.90 umol, 41.06% yield) as a yellow solid.

    [1272] LCMS (ESI) m/z: [M+H].sup.+=370.1

    Step 5: (6-(2-methoxyphenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methanamine hydrochloride

    [1273] To a solution of tert-butyl ((6-(2-methoxyphenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methyl)carbamate (35 mg, 94.73 umol) in MeOH (0.5 mL) was added HCl/dioxane (4 M, 0.5 mL). The mixture was stirred at 20° C. for 2 hrs. The solvent was removed under vacuum to give the title compound (30 mg, crude) as a yellow oil.

    [1274] LCMS (ESI) m/z: [M+H].sup.+=270.2.

    Step 6: (R)-4-Cyano-N-((6-(2-methoxyphenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methyl)-4-methylisochromane-6-carboxamide

    [1275] To a solution of (6-(2-methoxyphenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)methanamine hydrochloride (30 mg, 98.10 umol) and ((R)-4-cyano-4-methylisochromane-6-carboxylic acid (27.70 mg, 127.53 umol) in DCM (1 mL) was added EDCI (28.21 mg, 147.15 umol), DIEA (63.40 mg, 490.51 umol, 85.44 uL) and HOBt (19.88 mg, 147.15 umol). The mixture was stirred at 25° C. for 16 hrs. The mixture was poured into water (30 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine (20 mL, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 um; mobile phase: [water (10 mM NH.sub.4HCO.sub.3)-ACN]; B %: 26%-56%, 8 min) to give the title compound (15.64 mg, 31.70 umol, 32.31% yield) as an off-white solid.

    [1276] LCMS (ESI) m/z: [M+H]+=469.3

    [1277] .sup.1H NMR (400 MHz, METHANOL-d.sub.4) δ=8.31 (s, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.90-7.81 (m, 1H), 7.29-7.20 (m, 2H), 7.08-6.96 (m, 3H), 6.94-6.86 (m, 1H), 4.89 (d, J=3.2 Hz, 2H), 4.67 (m, 2H), 4.23 (s, 2H), 4.19 (d, J=11.6 Hz, 1H), 3.91 (d, J=11.6 Hz, 1H), 3.87 (m, 3H), 3.42-3.35 (m, 2H), 3.03-2.94 (m, 2H), 1.74 (s, 3H) ppm.

    [1278] The following examples in Table 23 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 32.

    TABLE-US-00024 TABLE 23 Compounds of the Invention # LCMS (m/z) 1H NMR 209 495.4 1H NMR (400 MHz, DMSO-d6) δ = 9.25-9.13 (m, 1H), 8.39-8.31 (m, 1H), 8.17-8.08 (m, 2H), 7.79 (s, 2H), 7.36-7.21 (m, 2H), 5.55-5.42 (m, 1H), 4.94-4.81 (m, 2H), 4.61-4.47 (m, 2H), 4.38-4.27 (m, 1H), 4.26-4.17 (m, 1H), 3.95-3.77 (m, 2H), 2.95-2.82 (m, 2H), 2.08-1.93 (m, 1H), 1.69 (s, 3H), 1.47-1.35 (m, 3H), 1.01-0.82 (m, 3H) ppm 230 497.5 1H NMR (400 MHz, MeOD) δ = 8.31 (s, 1H), 8.16-8.09 (m, 1H), 7.88-7.84 (m, 1H), 7.54 (d, J = 9.6 Hz, 1H), 7.30-7.23 (m, 2H), 6.91 (d, J = 9.6 Hz, 1H), 4.90 (br s, 2H), 4.67 (s, 2H), 4.55-4.50 (m, 2H), 4.19 (d, J = 11.6 Hz, 1H), 4.08-4.00 (m, 1H), 3.96-3.88 (m, 1H), 3.73-3.65 (m, 2H), 2.99-2.91 (m, 2H), 1.76-1.74 (m, 3H), 1.14-1.10 (m, 2H), 0.96-0.88 (m, 2H) ppm 234 496.5 1H NMR (400 MHz, MeOD) δ = 8.11 (d, J = 2.0 Hz, 1H), 7.87-7.85 (m, 1H), 7.60 (s, 1H), 7.36-7.32 (m, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.18 (d, J = 8.0 Hz, 1H), 5.72 (d, J = 7.6 Hz, 1H), 4.90 (br s, 2H), 4.85-4.85 (m, 2H), 4.76 (s, 2H), 4.19 (d, J = 11.6 Hz, 1H), 3.99-3.96 (m, 2H), 3.95-3.89 (m, 5H), 3.22-3.19 (m, 2H), 2.34-2.26 (m, 2H), 1.74 (s, 3H) ppm 247 497.3 1H NMR (400 MHz, MeOD) δ = 8.11 (d, J = 1.6 Hz, 1H), 7.8-7.85 (m, 1H), 7.62 (s, 1H), 7.49 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.03 (s, 1H), 4.89 (d, J = 3.6 Hz, 2H), 4.86-4.86 (m, 2H), 4.81 (s, 2H), 4.19 (d, J = 11.6 Hz, 1H), 4.07-3.99 (m, 6H), 3.91 (d, J = 11.6 Hz, 1H), 3.26-3.23 (m, 2H), 2.46-2.36 (m, 2H), 1.74 (s, 3H) ppm 258 513.4 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.38 (s, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.80-7.72 (m, 2H), 7.59-7.52 (m, 1H), 7.17-7.12 (m, 2H), 6.26-6.23 (m, 1H), 4.87 (s, 2H), 4.73 (d, J = 4.8 Hz, 2H), 4.43 (s, 2H), 4.22-4.11 (m, 5H), 3.94 (d, J = 11.2 Hz, 1H), 3.61-3.58 (m, 2H), 2.99-2.97 (m, 2H), 2.45-2.33 (m, 2H), 1.77 (s, 3H) ppm 286 440.1 1HNMR (400 MHz, DMSO-d6) δ = 9.27-9.14 (m, 1H), 8.37-8.31 (m, 1H), 8.16-8.11 (m, 2H), 7.93-7.88 (m, 1H), 7.59-7.51 (m, 1H), 7.31-7.26 (m, 1H), 7.22 (s, 1H), 6.96-6.87 (m, 1H), 6.67-6.60 (m, 1H), 4.93-4.81 (m, 2H), 4.68 (s, 2H), 4.60-4.51 (m, 2H), 4.27-4.19 (m, 1H), 3.89-3.83 (m, 3H), 2.89-2.84 (m, 2H), 1.69 (s, 3H)ppm 298 496.3 1HNMR (400 MHz, DMSO-d6) δ = 8.54-8.46 (m, 1H), 8.34 (s, 1H), 8.14-8.13 (m, 1H), 7.91-7.86 (m, 1H), 7.49-7.44 (m, 1H), 7.32 (s, 1H), 7.29-7.27 (m, 1H), 7.02 (s, 1H), 4.91 (br s, 2H), 4.75-4.72 (m, 2H), 4.60 (s, 2H), 4.26-4.17 (m, 2H), 4.08 (s, 4H), 3.96-3.90 (m, 3H), 2.98-2.94 (m, 2H), 2.47-2.39 (m, 2H), 1.77 (s, 3H) ppm 304 490.5 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.40 (s, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.80-7.78 (m, 1H), 7.66-7.62 (m, 2H), 7.14 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.62-6.34 (m, 1H), 4.87 (s, 2H), 4.76-4.74 (m, 4H), 4.14 (d, J = 11.2 Hz, 1H), 3.95-3.91 (m, 3H), 2.99-2.96 (m, 2H), 1.76 (s, 3H) ppm 314 526.3 1H NMR (400 MHz, DMSO-d6) δ = 9.28-9.17 (m, 1H), 8.34 (s, 1H), 8.14 (m, 1H), 7.95-7.86 (m, 1H), 7.66 (s, 1H), 7.53 (s, 1H), 7.31-7.26 (m, 1H), 7.22 (s, 1H), 4.92-4.81 (m, 2H), 4.66(s, 2H), 4.61-4.50(m, 2H), 4.25-4.19 (m, 1H), 3.89-3.80 (m, 3H), 3.71-3.65 (m, 4H), 3.46-3.42 (m, 4H), 2.91-2.82 (m, 2H), 1.66 (s, 3H) ppm 326 484.2 1H NMR (400 MHz, DMSO-d6) δ = 9.22-9.19 (m, 1H), 8.34 (s, 1H), 8.17-8.12 (m, 2H), 7.92-7.85 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.21 (s, 1H), 6.12(d, J = 6.0 Hz, 1H), 4.94-4.78 (m, 2H), 4.71 (s, 2H), 4.61-4.48 (m, 2H), 4.21 (d, J = 11.6 Hz, 1H), 3.90-3.79 (m, 3H), 3.05 (s, 6H), 2.85-2.82 (m, 2H), 1.68 (s, 3H) ppm. 327 481.2 1H NMR (400 MHz, MeOD) δ = 8.35 (s, 1H), 8.32 (br s, 1H), 8.12 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 6.8 Hz, 1H), 7.87-7.85 (m, 1H), 7.32 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 6.4 Hz, 1H), 4.89 (d, J = 3.2 Hz, 2H), 4.83 (s, 2H), 4.67(s, 2H), 4.20 (d, J = 11.6 Hz, 1H), 3.98-3.96 (m, 2H), 3.92 (d, J = 11.6 Hz, 1H), 2.97-2.94 (m, 2H), 2.04-2.01 (m, 1H), 1.74 (s, 3H), 1.14-1.12 (m, 2H), 1.06-1.04(m, 2H) ppm. 328 481.2 1H NMR (400 MHz, MeOD) δ = 8.32 (s, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.96 (s, 1H), 7.88-7.85 (m, 1H), 7.74 (s, 1H), 7.31(s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.89 (d, J = 3.6 Hz, 2H), 4.73 (s, 2H), 4.67 (s, 2H), 4.20 (d, J = 11.6 Hz, 1H), 3.92-3.89 (m, 3H), 2.96-2.93 (m, 2H), 2.02-1.97 (m, 1H), 1.74 (s, 3H), 1.01-0.95 (m, 4H) ppm. 330 526.2 1H NMR (400 MHz, DMSO-d6) δ = 9.22-9.19 (m, 1H), 8.34 (s, 1H), 8.14 (d, J = 1.2 Hz, 1H), 7.94-7.87 (m, 2H), 7.28 (d, J = 8.4 Hz, 1H), 7.21 (s, 1H), 6.21 (d, J = 6.0 Hz, 1H), 4.91-4.80 (m, 2H), 4.70 (s, 2H), 4.60-4.52 (m, 2H), 4.21 (d, J = 11.2 Hz, 1H), 3.93-3.75 (m, 3H), 3.62 (s, 8H), 2.85-2.82 (m, 2H), 1.68 (s, 3H) ppm. 331 510.2 1H NMR (400 MHz, DMSO-d6) δ = 9.34-9.12 (m, 1H), 8.40-8.27 (m, 1H), 8.14 (d, J = 1.2 Hz, 1H), 7.95-7.82 (m, 2H), 7.36-7.14 (m, 2H), 6.20-6.07 (m, 1H), 4.93-4.78 (m, 2H), 4.71 (s, 2H), 4.62-4.47 (m, 2H), 4.27-4.15 (m, 1H), 3.84-3.83 (m, 3H), 3.50-3.43 (m, 4H), 2.83-2.82 (m, 2H), 1.92-1.82 (m, 4H), 1.68 (s, 3H) ppm. 332 496.2 1HNMR (400 MHz, DMSO-d6) δ = 9.32-9.11 (m, 1H), 8.41-8.30 (m, 2H), 8.14 (s, 1H), 7.94-7.85 (m, 2H), 7.32-7.25 (m, 1H), 7.19 (s, 1H), 6.22-6.15 (m, 1H), 4.96-4.87 (m, 2H), 4.69 (s, 2H), 4.59-4.50 (m, 2H), 4.27-4.17 (m, 1H), 3.97-3.90 (m, 4H), 3.88 (s, 1H), 2.87-2.80 (m, 2H), 2.24-2.19 (m, 2H), 1.69 (s, 3H) ppm 402 495.5 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.35 (s, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.79-7.76 (m, 1H), 7.57-7.36(m, 1H), 7.35-7.31 (m, 1H), 7.18 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.01 (d, J = 8.0 Hz, 1H), 5.68 (d, J = 7.6 Hz, 1H), 4.87 (s, 2H), 4.72 (d, J = 4.8 Hz, 2H), 4.69 (s, 2H), 4.14 (d, J = 11.6 Hz, 1H), 3.99-3.95 (m, 4H), 3.94 (d, J = 11.2 Hz, 1H), 3.87-3.84 (m, 2H), 2.96-2.89 (m, 2H), 2.38-2.31 (m, 2H), 1.76 (s, 3H) ppm.

    Example 33: (R)-4-cyano-4-methyl-N-((6-phenylthiazolo[5,4-c]pyridazin-3-yl)methyl)isochromane-6-carboxamide

    [1279] ##STR00661##

    Step 1: 3-Chlorothiazolo[5,4-c]pyridazine-6(5H)-thione

    [1280] A mixture of 3,6-dichloropyridazin-4-amine (5.00 g, 30.490 mmol, 1.00 equiv) and potassium ethyl xanthogenate (14.78 g, 121.957 mmol, 4.00 equiv) in DMF (10 mL) was stirred at 130° C. for 12 h. The resulting mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL×3). The combined organic layers were washed with brine (100 mL×1), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (4.8 g, 79.67%) as a white solid that was used directly without further purification.

    [1281] LCMS (ESI) m/z [M+H].sup.+=204.

    Step 2: 3,6-Dichlorothiazolo[5,4-c]pyridazine

    [1282] A mixture of 3-chlorothiazolo[5,4-c]pyridazine-6(5H)-thione (2.00 g, 9.820 mmol, 1.00 equiv) in sulfonyl chloride (3.00 mL) was stirred for 2 h at 0 degrees C. under nitrogen atmosphere. The residue was neutralized to pH 9 with saturated aq. Na.sub.2CO.sub.3. The resulting mixture was extracted with CH.sub.2Cl.sub.2 (1 L×3) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford intermediate 3 (1.3 g, 61.68%) as a white solid which was used directly without further purification.

    [1283] LCMS (ESI) m/z [M+H]+=206.

    Step 3: 3-Chloro-6-phenylthiazolo[5,4-c]pyridazine

    [1284] To a stirred mixture of 3,6-dichlorothiazolo[5,4-c]pyridazine (800.00 mg, 3.883 mmol, 1.00 equiv) and Cs.sub.2CO.sub.3 (2530.15 mg, 7.765 mmol, 2.00 equiv) in dioxane (4.00 mL) and H.sub.2O (1.00 mL) was added Pd(dppf)Cl.sub.2 (284.10 mg, 0.388 mmol, 0.10 equiv). The resulting mixture was stirred for 2.5 h at room temperature. The resulting mixture was diluted with water (30.0 mL) and extracted with EtOAc (30.0 mL×3). The combined organic layers were washed with brine (25.0 mL×1), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (320 mg, 29.95%) as a white solid.

    [1285] LCMS (ESI) m/z [M+H].sup.+=248.

    Step 4: 6-Phenylthiazolo[5,4-c]pyridazine-3-carbonitrile

    [1286] To a stirred mixture of 3-chloro-6-phenylthiazolo[5,4-c]pyridazine (310.00 mg, 1.252 mmol, 1.00 equiv) and Zn(CN).sub.2 (293.97 mg, 2.503 mmol, 2.00 equiv) in DMF (4.00 mL) were added Pd.sub.2(dba).sub.3 (229.21 mg, 0.250 mmol, 0.20 equiv) and XPhos (238.65 mg, 0.501 mmol, 0.40 equiv). The reaction mixture was stirred at 40° C. under nitrogen atmosphere for 2 h. The resulting mixture was diluted with water (30.0 mL) and extracted with EtOAc (30.0 mL×3). The combined organic layers were washed with brine (25.0 mL×1), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 100% EtOAc in petroleum ether to give the title compound (150 mg, 48.29%) as a yellow solid.

    [1287] LCMS (ESI) m/z [M+H].sup.+=239.

    Step 5: (6-Phenylthiazolo[5,4-c]pyridazin-3-yl)methanamine

    [1288] To a stirred mixture of 6-phenylthiazolo[5,4-c]pyridazine-3-carbonitrile (130.00 mg, 0.546 mmol, 1.00 equiv) in DCM (4.00 mL) was added DIBAL-H (77.59 mg, 0.546 mmol, 1.00 equiv) dropwise at 0° C. The mixture was stirred for 30 min. The resulting mixture was diluted with water (30.0 mL) and extracted with EtOAc (30.0 mL×3). The combined organic layers were washed with brine (25.0 mL×1), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, elution gradient 0 to 100% EtOAc in petroleum ether, to give the title compound (40 mg, 29.05%) as an off-white solid.

    [1289] LCMS (ESI) m/z [M+H].sup.+=243.

    Step 6: (R)-4-Cyano-4-methyl-N-((6-phenylthiazolo[5,4-c]pyridazin-3-yl)methyl)isochromane-6-carboxamide

    [1290] To a stirred mixture of (R)-4-cyano-4-methylisochromane-6-carboxylic acid (16.14 mg, 0.025 mmol, 1.00 equiv) and (6-phenylthiazolo[5,4-c]pyridazin-3-yl)methanamine (18 mg, 0.025 mmol, 1.00 equiv) in DMF (1.50 mL) were added HATU (22.55 mg, 0.021 mmol, 1.00 equiv) and DIEA (24.00 mg, 0.062 mmol, 3.00 equiv). The resulting mixture was stirred for 1 h at room temperature. Without any additional work-up, the mixture was purified by prep-HPLC (Column: Xselect CSH F-Phenyl OBD column, 19*250, Sum; Mobile Phase A: Water (0.05% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 27 B to 55 B in 10 min, 55 B to B in min, B to B in min, B to B in min, B to B in min; 254/220 nm; RT.sub.1:8.4; RT.sub.2; Injection Volume: mL; Number of Runs;) to give the title compound (6.0 mg, 31.71%) as a white solid.

    [1291] LCMS (ESI) m/z [M+H].sup.+=443.05.

    [1292] .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 8.32-8.24 (m, 2H), 8.22 (s, 1H), 8.16 (d, J=1.8 Hz, 1H), 7.91 (dd, J=8.1, 1.8 Hz, 1H), 7.66 (dt, J=14.7, 7.1 Hz, 3H), 7.30 (d, J=8.2 Hz, 1H), 5.09 (s, 2H), 4.92 (s, 2H), 4.22 (d, J=11.4 Hz, 1H), 3.94 (d, J=11.4 Hz, 1H), 1.77 (s, 3H).

    Example 34: (S)—N-((2-(6-Cyclopropylpyrazin-2-yl)pyrido[3,4-b]pyrazin-7-yl)methyl)-4-fluoro-4-methylisochromane-6-carboxamide

    [1293] ##STR00662## ##STR00663##

    Step 1: (4,5-Diaminopyridin-2-yl)methanol

    [1294] To a stirred mixture of methyl 4,5-diaminopyridine-2-carboxylate (8.00 g, 47.856 mmol, 1.00 equiv) in THF (80 mL) was added LiBH4 (2M in THF, 119.64 mL, 239.280 mmol, 5.00 equiv) dropwise at 0° C. The resulting mixture was stirred for 13 h at room temperature. The mixture was quenched with sat. aq. NaHCO.sub.3 (500 mL) and concentrated under vacuum to give a crude product. The crude product was purified by aluminum oxide column chromatography, eluted with DCM/MeOH from 20/1 to 2/1 to give the title compound (6 g, 90.10%) as an off-white solid.

    [1295] LCMS (ESI) m/z: [M+H]+=140.

    Step 2: 7-(Hydroxymethyl)pyrido[3,4-b]pyrazin-2-ol

    [1296] To a solution of (4,5-diaminopyridin-2-yl)methanol (5.00 g, 35.930 mmol, 1.00 equiv) in n-BuOH (500.00 mL) was added ethyl glyoxylate (7.70 g, 37.727 mmol, 1.05 equiv, 50%). The resulting mixture was stirred for 8 h at 100° C. The reaction was cooled and filtered, and the filtrate was concentrated to give the title compound (3.1 g, 48.70%) as a yellow solid that was used directly without further purification.

    [1297] LCMS (ESI) m/z: [M+H]+=178.

    Step 3: (2-Oxo-1,2-dihydropyrido[3,4-b]pyrazin-7-yl)methyl acetate

    [1298] To a solution of 7-(hydroxymethyl)pyrido[3,4-b]pyrazin-2-ol (3.10 g, 17.498 mmol, 1.00 equiv) and DMAP (1068.85 mg, 8.749 mmol, 0.50 equiv) in DCM (50 mL) were added TEA (2.66 g, 26.287 mmol, 1.50 equiv) and Ac2O (5.36 g, 52.503 mmol, 3.00 equiv). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography eluted with DCM/MeOH=50/1 to give the title compound (3.1 g, 80.82%) as a yellow solid.

    [1299] LCMS (ESI) m/z: [M+H]+=220.

    Step 4: (2-Chloropyrido[3,4-b]pyrazin-7-yl)methyl acetate

    [1300] To a solution of PPh.sub.3 (5.80 g, 22.112 mmol, 4.8 equiv) in toluene (100.00 mL) was added trichloroisocyanuric acid (1.71 g, 7.371 mmol, 1.60 equiv). The resulting mixture was stirred for 24 h at room temperature. To the above mixture, (2-oxo-1,2-dihydropyrido[3,4-b]pyrazin-7-yl)methyl acetate (1.53 g, 6.97 mmol, 1.00 equiv) was added. The resulting mixture was stirred for an additional 5 h at 110° C. The mixture was concentrated and the residue was purified by silica gel column chromatograph eluting with PE/EA from 50/1 to 8/1 to give the title compound (610 mg, 55.72%) as an off-white solid.

    [1301] LCMS (ESI) m/z: [M+H]+=238.

    Step 5: (2-(6-Cyclopropylpyrazin-2-yl)pyrido[3,4-b]pyrazin-7-yl)methyl acetate

    [1302] To a stirred solution of (2-chloropyrido[3,4-b]pyrazin-7-yl)methyl acetate (250.00 mg, 1.052 mmol, 1.00 equiv) and Sn.sub.2Me.sub.6 (413.60 mg, 1.262 mmol, 1.20 equiv) in dioxane (2.00 mL) was added Pd(PPh.sub.3).sub.4 (121.57 mg, 0.105 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 2 h under nitrogen atmosphere. To the above mixture was added additional (2-chloropyrido[3,4-b]pyrazin-7-yl)methyl acetate (250.00 mg, 1.052 mmol, 1.00 equiv) at room temperature and the resulting mixture was stirred overnight at 100° C. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography, eluting with PE/EtOAc (12:1) to give the title compound (298 mg, crude) as a light yellow solid.

    [1303] (LCMS (ESI) m/z [M+H]+=321.

    Step 6: (2-(6-Cyclopropylpyrazin-2-yl)pyrido[3,4-b]pyrazin-7-yl)methanol

    [1304] To a stirred solution of (2-(6-cyclopropylpyrazin-2-yl)pyrido[3,4-b]pyrazin-7-yl)methyl acetate (285.00 mg, 0.887 mmol, 1.00 equiv) in MeOH (5.00 mL) was added K.sub.2CO.sub.3 (245.15 mg, 1.774 mmol, 2.00 equiv). The resulting mixture was stirred at 60° C. for 2 h. The solid was filtered off and the filtrate was concentrated under vacuum to give the title compound (48 mg, 30.32%) as a light yellow solid that was used directly without further purification.

    [1305] (LCMS (ESI) m/z [M+H]+=280.

    Step 7: (2-(6-Cyclopropylpyrazin-2-yl)pyrido[3,4-b]pyrazin-7-yl)methyl methanesulfonate

    [1306] To a stirred solution (2-(6-cyclopropylpyrazin-2-yl)pyrido[3,4-b]pyrazin-7-yl)methanol (270.00 mg, 0.967 mmol, 1.00 equiv) and TEA (195.64 mg, 1.934 mmol, 2.00 equiv) in DCM (5.00 mL) was added MsCl (166.10 mg, 1.451 mmol, 1.50 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:1) to give the title compound (115 mg, 33.29%) as a light yellow solid.

    [1307] (LCMS (ESI) m/z [M+H].sup.+=358.

    Step 8: 2-((2-(6-Cyclopropylpyrazin-2-yl)pyrido[3,4-b]pyrazin-7-yl)methyl)isoindoline-1,3-dione

    [1308] To a stirred solution of (2-(6-cyclopropylpyrazin-2-yl)pyrido[3,4-b]pyrazin-7-yl)methyl methanesulfonate (105.00 mg, 0.294 mmol, 1.00 equiv) in DMF (2.00 mL) was added potassium 1,3-dioxoisoindolin-2-ide (108.84 mg, 0.588 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with water (10 mL) and the precipitated solids were collected by filtration and washed with H.sub.2O (3×10 mL). The resulting solid was dried under vacuum to give the title compound (69 mg, 57.50%) as a light yellow solid.

    [1309] (LCMS (ESI) m/z [M+H].sup.+=409.

    Step 9: (2-(6-Cyclopropylpyrazin-2-yl)pyrido[3,4-b]pyrazin-7-yl)methanamine

    [1310] To a stirred solution of 2-((2-(6-cyclopropylpyrazin-2-yl)pyrido[3,4-b]pyrazin-7-yl)methyl)isoindoline-1,3-dione (60.00 mg, 0.147 mmol, 1.00 equiv) in EtOH (5.00 mL) was added hydrazine hydrate (0.50 mL) at room temperature. The resulting mixture was stirred for 2 h at 80° C. under nitrogen atmosphere. The resulting mixture was concentrated under vacuum to the title compound (72 mg, crude) as a light yellow solid that was used directly without further purification.

    [1311] (LCMS (ESI) m/z [M+H].sup.+=279.

    Step 10: (S)—N-((2-(6-Cyclopropylpyrazin-2-yl)pyrido[3,4-b]pyrazin-7-yl)methyl)-4-fluoro-4-methylisochromane-6-carboxamide

    [1312] To a stirred solution of (S)-4-fluoro-4-methylisochromane-6-carboxylic acid (20.00 mg, 0.095 mmol, 1.00 equiv) and HATU (43.41 mg, 0.114 mmol, 1.20 equiv) in DMF (2.00 mL) were added DIEA (36.89 mg, 0.285 mmol, 3.00 equiv) and (2-(6-cyclopropylpyrazin-2-yl)pyrido[3,4-b]pyrazin-7-yl)methanamine (29.13 mg, 0.105 mmol, 1.10 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature. Without any additional work-up, the mixture was purified by prep-HPLC to give the title compound (20 mg, 44.68%) as a light yellow solid.

    [1313] LCMS (ESI) m/z: [M+H]+=471.20.

    [1314] 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.55 (s, 1H), 9.46 (t, J=5.8 Hz, 1H), 9.40 (s, 1H), 8.85 (s, 1H), 8.28 (d, J=1.8 Hz, 1H), 8.02-7.90 (m, 2H), 7.31 (d, J=8.0 Hz, 1H), 4.95-4.81 (m, 3H), 4.79-4.69 (m, 1H), 4.08 (t, J=13.0 Hz, 1H), 3.85 (dd, J=25.1, 12.5 Hz, 1H), 2.43-2.31 (m, 1H), 1.70 (d, J=20.7 Hz, 3H), 1.29-1.09 (m, 4H).

    [1315] The following examples in Table 24 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 34.

    TABLE-US-00025 TABLE 24 Compounds of the Invention # LCMS (m/z) 1H NMR 143 513.20 .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 9.97 (s, 1H), 9.47 (d, J = 0.8 Hz, 1H), 8.55 (dd, J = 8.4, 0.8 Hz, 1H), 8.39 (dd, J = 7.6, 0.9 Hz, 1H), 8.29-8.24 (m, 1H), 8.06-7.90 (m, 3H), 7.30 (d, J = 8.1 Hz, 1H), 4.97 (s, 2H), 4.86-4.76 (m, 2H), 4.37-4.29 (m, 2H), 4.10 (t, J = 12.3 Hz, 1H), 3.98-3.83 (m, 1H), 2.79-2.69 (m, 2H), 2.32-2.18 (m, 2H), 1.75 (d, 3H). 161 463.10 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.42 (t, J = 5.9 Hz, 1H), 9.31 (d, J = 1.2 Hz, 2H), 8.49 (s, 1H), 8.28 (d, J = 1.7 Hz, 1H), 7.97 (dt, J = 8.0, 1.7 Hz, 1H), 7.63 (d, J = 0.9 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.87 (dd, J = 15.9, 2.5 Hz, 1H), 4.85-4.69 (m, 3H), 4.08 (t, J = 13.0 Hz, 1H), 4.00 (s, 3H), 3.85 (dd, J = 25.3, 12.5 Hz, 1H), 3.79 (s, 3H), 1.70 (d, J = 20.7 Hz, 3H). 183 487.05 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.88 (s, 1H), 9.66-9.56 (m, 2H), 9.13-9.06 (m, 1H), 8.62 (d, J = 4.9 Hz, 2H), 8.04-7.98 (m, 1H), 7.66 (d, J = 5.0 Hz, 1H), 4.95-4.71 (m, 4H), 4.26-4.08 (m, 5H), 3.92 (dd, J = 25.3, 12.7 Hz, 1H), 2.46-2.31 (m, 2H), 1.72 (d, J = 20.9 Hz, 3H). 190 486.20 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.86 (s, 1H), 9.56 (s, 1H), 9.45 (t, J = 5.9 Hz, 1H), 8.60 (d, J = 4.9 Hz, 1H), 8.31-8.24 (m, 1H), 8.01-7.91 (m, 2H), 7.66 (d, J = 5.0 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 4.92-4.82 (m, 3H), 4.77-4.71 (m, 1H), 4.19 (t, J = 7.5 Hz, 4H), 4.08 (t, J = 13.0 Hz, 1H), 3.84 (dd, J = 25.2, 12.5 Hz, 1H), 2.44-2.32 (m, 2H), 1.69 (d, J = 20.7 Hz, 3H). 207 503.25 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.57 (d, J = 0.8 Hz, 1H), 9.49-9.38 (m, 2H), 8.27 (s, 1H), 8.11-8.06 (m, 1H), 8.01-7.91 (m, 2H), 7.31 (d, J = 8.1 Hz, 1H), 7.25-7.17 (m, 1H), 4.92-4.81 (m, 3H), 4.78-4.68 (m, 1H), 4.23-4.17 (m, 3H), 4.10-4.02 (m, 1H), 3.85 (dd, J = 25.1, 12.6 Hz, 1H), 2.43-2.32 (m, 2H), 1.70 (d, J = 20.7 Hz, 3H). 214 485.30 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.90 (s, 1H), 9.50 (s, 1H), 9.48-9.39 (m, 1H), 8.28 (s, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.93-7.64 (m, 3H), 7.31 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 4.97-4.62 (m, 4H), 4.21-3.96 (m, 5H), 3.85 (dd, J = 24.9, 12.6 Hz, 1H), 2.45-2.22 (m, 2H), 1.70 (d, J = 20.7 Hz, 3H). 215 504.20 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.59 (d, J = 12.5 Hz, 2H), 9.40 (s, 1H), 9.08 (s, 1H), 8.61 (s, 1H), 8.12-7.97 (m, 2H), 7.20 (s, 1H), 4.97-4.71 (m, 4H), 4.27-4.12 (m, 5H), 3.91 (dd, J = 25.2, 12.6 Hz, 1H), 2.45-2.31 (m, 2H), 1.71 (d, J = 20.9 Hz, 3H). 216 486.30 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.90 (s, 1H), 9.67-9.57 (m, 1H), 9.51 (s, 1H), 9.10 (d, J = 2.1 Hz, 1H), 8.63 (s, 1H), 7.96 (s, 1H), 7.90-7.67 (m, 2H), 6.61 (d, J = 8.0 Hz, 1H), 4.97-4.71 (m, 4H), 4.26-4.02 (m, 5H), 3.92 (dd, J = 25.3, 12.6 Hz, 1H), 2.45-2.26 (m, 2H), 1.72 (d, J = 20.9 Hz, 3H). 256 459.05 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 9.54-9.39 (m, 3H), 8.28 (d, J = 1.8 Hz, 1H), 8.02-7.93 (m, 1H), 7.92-7.81 (m, 2H), 7.66-7.53 (m, 1H), 7.37-7.24 (m, 2H), 7.22-7.11 (m, 1H), 4.94-4.80 (m, 3H), 4.73 (dd, J = 15.8, 4.5 Hz, 1H), 4.08 (t, J = 13.0 Hz, 1H), 3.98-3.76 (m, 4H), 1.70 (d, J = 20.7 Hz, 3H). 463 435.9 1H NMR (400 MHz, DMSO-d.sub.6) δ = 9.71 (s, 1H), 9.49 (s, 1H), 9.47-9.41 (m, 1H), 8.43-8.34 (m, 2H), 8.20 (d, J = 1.6 Hz, 1H), 7.99-7.93 (m, 1H), 7.90 (s, 1H), 7.67-7.59 (m, 3H), 7.36-7.27 (m, 1H), 5.01-4.79 (m, 4H), 4.29-4.16 (m, 1H), 3.89-3.85 (m, 1H), 1.70 (s, 3H) ppm.

    Examples 35 and 36: (R)-4-Cyano-N-((2-(4-fluoro-3-methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide and (R)-4-cyano-N-((2-(4-fluoro-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide

    [1316] ##STR00664##

    Step 1: (R)—N-((2-(3-Bromo-4-fluoro-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide

    [1317] A mixture of (R)—N-((2-chloro-1,6-naphthyridin-7-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide (30 mg, 76.37 umol), 3-bromo-4-fluoro-1H-pyrazole (62.99 mg, 381.85 umol) and DIEA (98.70 mg, 763.70 umol, 133.02 uL) in DMSO (0.5 mL) was stirred at 120° C. for 2 hrs. The reaction was poured into water (4 mL) and extracted with EA (4 mL*3). The combined organic layers were dried by Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA condition) to give the title compound (30 mg, 56.38 umol, 73.83% yield,) as a white solid.

    [1318] LCMS (ESI) m/z: [81 BrM+H]+=523.1.

    [1319] 1 HNMR (400 MHz, DMSO-d6) δ=9.45-9.42 (m, 1H), 9.41 (s, 1H), 9.08 (d, J=4.8 Hz, 1H), 8.78 (d, J=8.8 Hz, 1H), 8.23-8.16 (m, 2H), 7.97-7.94 (m, 1H), 7.71 (s, 1H), 7.32 (d, J=8.4 Hz, 1H), 4.95-4.83 (m, 2H), 4.81 (d, J=6.0 Hz, 2H), 4.24 (d, J=11.2 Hz, 1H), 3.88 (d, J=11.6 Hz, 1H), 1.71 (s, 3H) ppm.

    Step 2: (R)-4-Cyano-N-((2-(4-fluoro-3-methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide and (R)-4-cyano-N-((2-(4-fluoro-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide

    [1320] A mixture of (R)—N-((2-(3-bromo-4-fluoro-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)-4-cyano-4-methylisochromane-6-carboxamide (30 mg, 57.54 umol), methylboronic acid (4.13 mg, 69.05 umol), K.sub.3PO.sub.4 (36.64 mg, 172.62 umol) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (37.50 mg, 57.54 umol) in dioxane (1 mL) was degassed and purged with N.sub.2 3 times. The mixture was stirred at 60° C. for 2 hrs under N.sub.2 atmosphere. The reaction was poured into 4 mL of H.sub.2O and extracted with EA (4 mL*3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 38%-68%, 10 min) to give (R)-4-cyano-N-((2-(4-fluoro-3-methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide (2.83 mg, 5.35 umol, 9.30% yield, FA salt) as a yellow solid and (R)-4-cyano-N-((2-(4-fluoro-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide (4.77 mg, 9.44 umol, 16.41% yield, FA salt) as a yellow solid.

    (R)-4-cyano-N-((2-(4-fluoro-3-methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide

    [1321] LCMS (ESI) m/z: [M+H]+=457.3.

    [1322] 1HNMR (400 MHz, METHANOL-d4) δ=9.23 (s, 1H), 8.65 (d, J=4.8 Hz, 1H), 8.58 (d, J=9.2 Hz, 1H), 8.24 (d, J=9.2 Hz, 1H), 8.17 (s, 1H), 7.93-7.90 (m, 1H), 7.80 (s, 1H), 7.29 (d, J=8.0 Hz, 1H), 4.91 (d, J=3.2 Hz, 2H), 4.89 (s, 2H), 4.21 (d, J=11.6 Hz, 1H), 3.93 (d, J=11.2 Hz, 1H), 2.34 (s, 3H), 1.77 (s, 3H) ppm.

    (R)-4-cyano-N-((2-(4-fluoro-1H-pyrazol-1-yl)-1,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide

    [1323] LCMS (ESI) m/z: [M+H]+=443.2.

    [1324] 1 HNMR (400 MHz, METHANOL-d4) 5=9.26 (s, 1H), 8.75 (d, J=4.8 Hz, 1H), 8.62 (d, J=8.8 Hz, 1H), 8.30 (d, J=8.8 Hz, 1H), 8.17 (s, 1H), 7.93-7.90 (m, 1H), 7.86-7.80 (m, 2H), 7.29 (d, J=8.0 Hz, 1H), 4.91 (d, J=3.6 Hz, 2H), 4.90 (s, 2H), 4.21 (d, J=11.2 Hz, 1H), 3.93 (d, J=11.2 Hz, 1H), 1.77 (s, 3H) ppm.

    Example 37: Methyl 1-(7-(((R)-4-cyano-4-methylisochromane-6-carboxamido)methyl)-1,6-naphthyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate

    [1325] ##STR00665##

    Step 1: tert-Butyl 5-(7-cyano-1,6-naphthyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

    [1326] To a mixture of 2-chloro-1,6-naphthyridine-7-carbonitrile (400 mg, 2.11 mmol) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (848.03 mg, 2.74 mmol) in dioxane (4 mL) and H.sub.2O (0.4 mL) was added [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (137.50 mg, 210.97 umol) and K.sub.3PO.sub.4 (1.34 g, 6.33 mmol). The mixture was purged with N.sub.2 for 1 min and the resulting mixture was stirred at 80° C. for 2 hrs. The reaction mixture was diluted with H.sub.2O (30 mL) and extracted with EA (40 mL*3). The combined organic layers were washed with brine (30 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was slurried in MeOH (8 mL), and the precipitate was collected by filtration and dried. Further purification by column chromatography (SiO.sub.2, PE:EtOAc=20:1-1:1) gave the title compound (460 mg, 1.37 mmol, 64.82% yield) as a yellow solid.

    [1327] LCMS (ESI) m/z: [M+H]+=337.2.

    Step 2: tert-Butyl 1-(7-cyano-1,6-naphthyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate

    [1328] To a mixture of t-BuOK (70.05 mg, 624.28 umol) in DMSO (2 mL) was added trimethylsulfoxonium iodide (137.39 mg, 624.28 umol) at 0° C. and the mixture was stirred at 25° C. for 30 min. The mixture was then added to the solution of tert-butyl 5-(7-cyano-1,6-naphthyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (210 mg, 624.28 umol) dissolved in DMSO (1 mL) and the resulting mixture was stirred at 45° C. for 4 hrs. The reaction mixture was diluted with H.sub.2O (30 mL) and extracted with EA (40 mL*3). The combined organic layers were washed with brine (30 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=20:1-1:1) to give the title compound (80 mg, 215.17 umol, 34.47% yield) as a colorless oil.

    [1329] LCMS (ESI) m/z: [M+H]+=351.2.

    [1330] 1H NMR (400 MHz, CDCl.sub.3) δ=9.21 (s, 1H), 8.30-8.19 (m, 2H), 7.71-7.40 (m, 1H), 4.32-4.25 (m, 1H), 4.24-4.14 (m, 1H), 3.76-3.52 (m, 1H), 3.20-2.96 (m, 1H), 2.18-(m, 1H), 1.97-1.82 (m, 2H), 1.78-1.60 (m, 1H), 1.54-1.46 (m, 10H) ppm.

    Step 3: 2-(3-Azabicyclo[4.1.0]heptan-1-yl)-1,6-naphthyridine-7-carbonitrile

    [1331] To a mixture of tert-butyl 1-(7-cyano-1,6-naphthyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (120 mg, 342.45 umol) in DCM (2 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL) at 0° C. and the mixture was stirred at 25° C. for 1 hr. The reaction mixture was poured into sat. NaHCO.sub.3 (20 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (85 mg, crude) as a yellow solid.

    Step 4: Methyl 1-(7-cyano-1,6-naphthyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate

    [1332] To a mixture of 2-(3-azabicyclo[4.1.0]heptan-1-yl)-1,6-naphthyridine-7-carbonitrile (85 mg, 339.60 umol) and TEA (171.82 mg, 1.70 mmol, 236.34 uL) in DCM (1 mL) was added methyl chloroformate (96.27 mg, 1.02 mmol, 78.91 uL) dropwise at 0° C., and the mixture was stirred at 25° C. for 2 hrs. The reaction mixture was diluted with H.sub.2O (30 mL) and extracted with EA (40 mL*3). The combined organic layers were washed with brine (30 mL*2), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=20:1-1:1) to give the title compound (55 mg, 173.78 umol, 51.17% yield) as a colorless oil.

    [1333] LCMS (ESI) m/z: [M+H]+=309.1.

    [1334] 1H NMR (400 MHz, DMSO-d6) δ=9.43 (d, J=0.8 Hz, 1H), 8.60 (d, J=8.8 Hz, 1H), 8.52 (s, 1H), 7.76-7.60 (m, 1H), 4.35-4.15 (m, 2H), 3.64 (s, 3H), 3.63-3.50 (m, 1H), 3.16-2.97 (m, 1H), 2.18-2.06 (m, 1H), 1.96-1.78 (m, 2H), 1.54-1.53 (m, 1H), 1.10-1.08 (m, 1H) ppm.

    Step 5: Methyl 1-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate

    [1335] To a mixture of methyl 1-(7-cyano-1,6-naphthyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (55 mg, 178.38 umol) in MeOH (10 mL) was added TEA (36.10 mg, 356.76 umol, 49.66 uL) and Boc.sub.2O (58.40 mg, 267.57 umol, 61.47 uL). The mixture was purged with N.sub.2 and Raney-Ni (76.41 mg, 891.89 umol) was added. The mixture was then purged with H.sub.2 3 times and the resulting mixture was stirred at 25° C. under H.sub.2 (15 psi) for 2 hrs. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO.sub.2, PE:EtOAc=20:1-1:1) to give the title compound (35 mg, 84.27 umol, 47.24% yield) as a colorless oil.

    [1336] LCMS (ESI) m/z: [M+H]+=413.2.

    Step 6: Methyl 1-(7-(aminomethyl)-1,6-naphthyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate

    [1337] To a solution of methyl 1-(7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (35 mg, 84.85 umol) in DCM (3 mL) was added TFA (1 mL) at 0° C. The mixture was stirred at 25° C. for 1 hr. The reaction mixture was poured into sat. NaHCO.sub.3 (20 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (28 mg, crude) as a yellow solid.

    [1338] LCMS (ESI) m/z: [M+H]+=313.2.

    Step 7: Methyl 1-(7-(((R)-4-cyano-4-methylisochromane-6-carboxamido)methyl)-1,6-naphthyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate

    [1339] To a solution of (R)-4-cyano-4-methylisochromane-6-carboxylic acid (23.37 mg, 107.57 umol) in DCM (1 mL) was added EDCI (22.34 mg, 116.53 umol), HOBt (15.75 mg, 116.53 umol) and DIEA (34.76 mg, 268.92 umol, 46.84 uL). Methyl 1-(7-(aminomethyl)-1,6-naphthyridin-2-yl)-3-azabicyclo[4.1.0]heptane-3-carboxylate (28 mg, 89.64 umol) was then added and the mixture was stirred at 25° C. for 2 hrs. The reaction mixture was poured into NaHCO.sub.3 (30 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by prep-HPLC (0.1% FA condition) to give the title compound (5.30 mg, 10.36 umol, 11.56% yield) as a white solid.

    [1340] LCMS (ESI) m/z: [M+H]+=512.2.

    [1341] 1H NMR (400 MHz, DMSO-d6) δ=9.41-9.32 (m, 1H), 9.28 (s, 1H), 8.45 (d, J=8.8 Hz, 1H), 8.19 (d, J=1.6 Hz, 1H), 7.94 (d, J=1.6, 1H), 7.64 (s, 1H), 7.51-7.39 (m, 1H), 7.31 (d, J=8.4 Hz, 1H), 4.94-4.81 (m, 2H), 4.77 (d, J=5.6 Hz, 2H), 4.33-4.19 (m, 2H), 4.18-4.07 (m, 1H), 3.87 (d, J=11.2 Hz, 1H), 3.61 (s, 3H), 3.52-3.43 (m, 1H), 3.13-2.97 (m, 1H), 2.14-2.04 (m, 1H), 1.88-1.76 (m, 2H), 1.70 (s, 3H), 1.53-1.43 (m, 1H), 1.04-0.96 (m, 1H) ppm.

    Example 38. Assay for ATPase Catalytic Activity of BRM and BRG-1

    [1342] The ATPase catalytic activity of BRM or BRG-1 was measured by an in vitro biochemical assay using ADP-Glo™ (Promega, V9102). The ADP-Glo™ kinase assay is performed in two steps once the reaction is complete. The first step is to deplete any unconsumed ATP in the reaction. The second step is to convert the reaction product ADP to ATP, which will be utilized by the luciferase to generate luminesce and be detected by a luminescence reader, such as Envision.

    [1343] The assay reaction mixture (10 μL) contains 30 nM of BRM or BRG-1, 20 nM salmon sperm DNA (from Invitrogen, UltraPure™ Salmon Sperm DNA Solution, cat #15632011), and 400 μM of ATP in the ATPase assay buffer, which comprises of 20 mM Tris, pH 8, 20 mM MgCl.sub.2, 50 mM NaCl, 0.1% Tween-20, and 1 mM fresh OTT (Pierce™ OTT (Dithiothreitol), cat #20290). The reaction is initiated by the addition of the 2.5 μL ATPase solution to 2.5 μL ATP/DNA solution on low volume white Proxiplate-384 plus plate (PerkinElmer, cat #6008280) and incubates at room temperature for 1 hour. Then following addition of 5 μL of ADP-Glo™ Reagent provided in the kit, the reaction incubates at room temperature for 40 minutes. Then 10 μL of Kinase Detection Reagent provided in the kit is added to convert ADP to ATP, and the reaction incubates at room temperature for 60 minutes. Finally, luminescence measurement is collected with a plate-reading luminometer, such as Envision.

    [1344] BRM and BRG-1 were synthesized from high five insect cell lines with a purity of greater than 90%. IC.sub.50 data for compounds 1-126 from the ATPase catalytic activity assay described herein are shown in Table 25 below.

    TABLE-US-00026 TABLE 25 BRM and BRG-1 Inhibition Data for Compounds of the Invention BRM BRM BRG1 BRG1 ATPase: IC50 Max % ATPase: Max % Compound # (uM) Inhibition IC50 (uM) Inhibition 1 +++ 90 + 56 2 +++ 96 + 65 3 ++++ 99 + 78 4 +++ 97 + 74 5 + 64 + 12 6 +++ 95 + 44 7 + 81 + 12 8 + 73 + 9 9 +++ 95 + 56 10 + 71 + 30 11 + 82 + 26 12 + 79 + 22 13 + 84 + 44 14 ++ 94 + 64 15 ++ 94 + 64 16 +++ 94 + 51 17 +++ 94 + 58 18 ++++ 93 + 87 19 +++ 97 ++ 89 20 ++ 83 + 41 21 + 78 + 31 22 + 70 + 31 23 ++ 85 + 35 24 +++ 94 + 65 25 +++ 94 + 68 26 ++++ 100 +++ 90 27 +++ 97 + 62 28 ++++ 98 ++ 86 29 +++ 98 + 69 30 +++ 92 + 35 31 +++ 96 + 73 32 + 89 + 55 33 +++ 98 + 78 34 +++ 94 + 53 35 ++ 91 + 47 36 + 64 + 44 37 + 76 + 21 38 ++++ 97 + 86 39 + 75 + 28 40 +++ 96 + 67 41 ++ 85 + 55 42 +++ 97 ++ 84 43 + 68 + 34 44 +++ 97 + 69 45 ++++ 96 ++ 79 46 + 78 + 29 47 +++ 90 + 47 48 + 67 + 11 49 +++ 84 + 26 50 +++ 90 + 53 51 ++++ 99 +++ 94 52 +++ 86 + 34 53 +++ 88 + 48 54 +++ 81 + 42 55 +++ 82 + 33 56 ++++ 98 +++ 92 57 +++ 85 + 37 58 +++ 92 ++ 50 59 +++ 93 ++ 56 60 +++ 93 ++ 75 61 +++ 85 + 25 62 +++ 90 + 42 63 ++++ 99 ++ 84 64 +++ 87 + 36 65 +++ 90 + 39 66 +++ 99 ++ 76 67 +++ 97 ++ 84 68 ++++ 98 +++ 91 69 +++ 90 ++ 50 70 +++ 94 ++ 55 71 +++ 89 + 42 72 ++++ 94 +++ 91 73 +++ 84 + 44 74 ++++ 98 +++ 87 75 +++ 97 ++ 54 76 +++ 98 + 91 77 +++ 99 ++ 102 78 ++++ 96 ++ 79 79 +++ 96 ++ 74 80 +++ 83 + 29 81 ++++ 98 +++ 90 82 +++ 88 + 38 83 ++++ 101 ++++ 99 84 +++ 89 ++ 53 85 ++++ 98 + 77 86 +++ 96 + 62 87 ++ 88 + 87 88 +++ 96 + 73 89 + 76 + 15 90 + 82 + 24 91 ++++ 97 ++ 85 92 +++ 95 + 64 93 ++++ 99 +++ 93 94 + 83 + 45 95 ++++ 99 +++ 93 96 + 84 + 20 97 +++ 93 + 47 98 ++++ 97 + 81 99 + 63 + 22 100 ++ 83 + 25 101 ++++ 98 ++ 78 102 +++ 93 + 56 103 +++ 94 + 71 104 ++ 84 + 33 105 ++++ 98 ++ 87 106 + 80 + 32 107 + 71 + 16 108 ++++ 99 ++ 91 109 + 75 + 11 110 ++++ 99 ++ 86 111 ++++ 101 +++ 93 112 +++ 94 + 55 113 + 79 + 32 114 ++ 86 + 42 115 + 84 + 19 116 + 76 + 22 117 + 74 + 27 118 + 89 + 40 119 + 81 + 18 120 + 8 + 0 121 + 81 + 44 122 +++ 94 + 62 123 +++ 96 + 74 124 ++++ 97 + 98 125 +++ 98 ++ 86 126 +++ 95 + 51 127 ++++ 96 ++ 74 128 +++ 82 + 39 129 ++++ 100 ++++ 98 130 ++++ 97 +++ 90 131 +++ 83 + 25 132 +++ 97 ++ 71 133 ++++ 102 ++++ 98 134 ++++ 101 ++++ 97 135 ++++ 103 ++++ 98 136 +++ 83 + 25 137 +++ 88 + 39 138 ++++ 101 +++ 94 139 ++++ 100 +++ 94 140 +++ 94 ++ 48 141 ++++ 100 +++ 96 142 ++++ 98 +++ 88 143 ++++ 103 +++ 89 144 ++++ 102 +++ 95 145 +++ 94 ++ 65 146 +++ 98 +++ 80 147 ++++ 101 +++ 90 148 +++ 90 + 32 149 +++ 95 ++ 67 150 ++++ 99 ++++ 97 151 +++ 93 ++ 56 152 +++ 96 ++ 85 153 +++ 87 + 37 154 ++++ 101 +++ 95 155 +++ 96 ++ 67 156 ++++ 99 +++ 97 157 ++++ 99 +++ 96 158 +++ 96 ++ 75 159 ++++ 99 +++ 95 160 +++ 93 ++ 62 161 +++ 94 ++ 53 162 +++ 91 ++ 59 163 ++++ 98 +++ 87 164 +++ 92 ++ 68 165 ++++ 97 +++ 80 166 +++ 91 + 40 167 +++ 93 ++ 69 168 ++++ 99 +++ 93 169 ++++ 98 +++ 91 170 +++ 96 ++ 80 171 ++++ 98 +++ 92 172 ++++ 99 ++++ 97 173 ++++ 98 +++ 94 174 ++++ 98 +++ 95 175 ++++ 97 +++ 86 176 ++++ 98 ++ 83 177 +++ 94 ++ 66 178 ++++ 99 +++ 96 179 ++++ 99 +++ 96 180 ++++ 100 +++ 99 181 ++++ 100 +++ 97 182 ++++ 99 +++ 95 183 ++++ 98 +++ 82 184 +++ 94 ++ 67 185 ++++ 99 +++ 87 186 ++++ 97 ++ 66 187 +++ 88 + 42 188 +++ 93 + 41 189 ++++ 99 +++ 93 190 ++++ 98 +++ 89 191 ++++ 97 ++ 76 192 +++ 94 ++ 60 193 ++++ 99 ++ 86 194 +++ 93 ++ 60 195 +++ 84 + 47 196 +++ 86 + 59 197 +++ 89 + 59 198 +++ 94 ++ 76 199 +++ 85 + 14 200 +++ 97 ++ 71 201 ++++ 99 ++ 76 202 ++++ 94 ++ 67 203 +++ 84 + 26 204 ++++ 97 ++ 82 205 +++ 91 ++ 52 206 ++++ 99 +++ 85 207 ++++ 98 +++ 89 208 ++++ 98 +++ 92 209 +++ 89 ++ 51 210 ++++ 99 +++ 96 211 +++ 97 ++ 82 212 +++ 89 + 39 213 +++ 97 ++ 63 214 ++++ 99 +++ 93 215 ++++ 97 +++ 90 216 ++++ 98 +++ 90 217 ++++ 98 ++ 79 218 ++++ 99 ++ 79 219 +++ 94 ++ 57 220 +++ 92 + 47 221 ++++ 99 +++ 88 222 ++++ 98 ++ 83 223 ++++ 101 ++++ 101 224 ++++ 101 ++++ 100 225 +++ 92 ++ 72 226 +++ 98 +++ 85 227 ++++ 99 +++ 94 228 ++++ 100 +++ 98 229 ++++ 100 +++ 90 230 +++ 97 ++ 62 231 +++ 91 + 46 232 ++++ 98 +++ 85 233 +++ 98 ++ 74 234 +++ 96 ++ 49 235 ++++ 99 +++ 72 236 ++++ 100 +++ 90 237 ++++ 100 +++ 92 238 ++++ 100 ++++ 96 239 ++++ 101 +++ 93 240 ++++ 101 +++ 89 241 +++ 97 ++ 63 242 +++ 94 ++ 51 243 +++ 81 + 9 244 +++ 88 + 25 245 +++ 96 ++ 75 246 +++ 88 + 23 247 +++ 93 + 65 248 ++++ 98 +++ 100 249 +++ 97 ++ 71 250 +++ 87 + 25 251 ++++ 100 +++ 91 252 +++ 87 + 33 253 +++ 92 ++ 57 254 ++++ 99 ++ 77 255 ++++ 100 +++ 90 256 ++++ 98 ++ 76 257 +++ 92 ++ 65 258 +++ 96 +++ 75 259 ++++ 99 +++ 88 260 +++ 83 + 42 261 +++ 94 ++ 61 262 ++++ 102 ++++ 99 263 ++++ 101 +++ 98 264 +++ 98 ++ 72 265 ++++ 104 ++++ 99 266 ++++ 103 +++ 96 267 ++++ 103 +++ 88 268 +++ 97 ++ 67 269 ++++ 104 +++ 97 270 ++++ 104 ++++ 98 271 ++++ 104 +++ 95 272 ++++ 104 +++ 95 273 +++ 98 ++ 64 274 +++ 93 ++ 45 275 ++++ 96 ++ 77 276 ++++ 98 +++ 95 277 +++ 96 ++ 69 278 ++++ 101 +++ 96 279 +++ 83 ++ 67 280 +++ 96 +++ 82 281 +++ 92 + 48 282 +++ 87 + 45 283 +++ 96 ++ 63 284 ++++ 99 +++ 93 285 ++++ 98 +++ 92 286 +++ 85 + 43 287 ++++ 99 ++ 99 288 ++++ 101 +++ 98 289 +++ 90 + 41 290 +++ 94 ++ 53 291 ++++ 100 ++++ 97 292 ++++ 99 +++ 94 293 +++ 88 + 33 294 ++++ 100 +++ 86 295 ++++ 100 +++ 93 296 ++++ 100 +++ 88 297 +++ 96 ++ 66 298 ++++ 99 +++ 82 299 ++++ 99 ++ 78 300 +++ 99 ++ 63 301 ++++ 96 +++ 86 302 +++ 93 ++ 58 303 +++ 96 +++ 87 304 +++ 86 + 38 305 +++ 87 + 40 306 ++++ 99 +++ 94 307 ++++ 98 +++ 97 308 ++++ 99 ++++ 96 309 ++++ 97 +++ 82 310 ++++ 97 +++ 84 311 ++++ 99 +++ 95 312 +++ 83 + 46 313 +++ 92 ++ 72 314 ++++ 96 +++ 83 315 +++ 81 + 33 316 +++ 98 + 92 317 +++ 100 + 96 318 +++ 107 ++ 55 319 ++++ 104 +++ 92 320 +++ 107 ++ 80 321 ++++ 105 +++ 95 322 ++++ 106 ++++ 97 323 +++ 108 ++ 76 324 +++ 105 ++ 81 325 ++++ 101 +++ 90 326 +++ 97 ++ 70 327 +++ 89 + 48 328 ++++ 99 ++ 81 329 ++++ 100 +++ 86 330 +++ 93 ++ 64 331 +++ 97 ++ 73 332 +++ 96 ++ 67 333 ++++ 100 ++ 79 334 +++ 96 ++ 61 335 ++++ 101 +++ 84 336 ++++ 99 +++ 92 337 +++ 99 ++ 63 338 +++ 97 ++ 56 339 ++++ 100 +++ 95 340 ++++ 99 +++ 91 341 ++++ 100 +++ 93 342 ++++ 97 ++ 80 343 ++++ 101 ++ 78 344 +++ 94 ++ 57 345 +++ 81 + 25 346 ++++ 102 ++++ 94 347 ++++ 100 +++ 79 348 ++++ 99 ++ 72 349 ++++ 100 +++ 87 350 +++ 96 + 54 351 ++++ 101 +++ 95 352 ++++ 99 +++ 89 353 ++++ 93 +++ 82 354 +++ 79 + 39 355 +++ 93 ++ 74 356 ++++ 97 +++ 95 357 ++++ 97 +++ 87 358 +++ 92 ++ 67 359 +++ 89 + 39 360 ++++ 99 + 99 361 ++++ 98 + 98 362 ++++ 99 + 98 363 ++++ 98 +++ 94 364 +++ 90 ++ 62 365 ++++ 99 +++ 98 366 ++++ 99 ++++ 99 367 ++++ 102 +++ 93 368 ++++ 103 +++ 96 369 ++++ 104 ++++ 95 370 ++++ 103 +++ 96 371 ++++ 104 ++++ 97 372 +++ 93 + 47 373 ++++ 103 ++++ 100 374 ++++ 101 +++ 94 375 ++++ 100 ++++ 101 376 +++ 98 ++ 79 377 ++++ 98 ++ 89 378 ++++ 100 +++ 99 379 ++++ 100 +++ 94 380 ++++ 101 ++++ 98 381 ++++ 101 ++++ 98 382 +++ 98 ++ 77 383 ++++ 98 ++ 79 384 ++++ 101 ++++ 100 385 ++++ 98 +++ 91 386 ++++ 98 +++ 94 387 +++ 97 ++ 73 388 +++ 97 ++ 71 389 +++ 93 ++ 56 390 ++++ 100 ++++ 97 391 ++++ 96 ++ 81 392 ++++ 100 +++ 95 393 ++++ 99 ++++ 96 394 ++++ 101 +++ 93 395 +++ 92 ++ 62 396 +++ 74 + 32 397 +++ 93 ++ 66 398 ++++ 98 +++ 91 399 ++++ 100 +++ 98 400 +++ 96 ++ 68 401 ++++ 97 +++ 91 402 ++++ 96 ++ 74 403 ++++ 99 +++ 91 404 +++ 93 +++ 78 405 +++ 85 ++ 55 406 ++++ 100 +++ 93 407 ++++ 99 +++ 97 408 +++ 91 ++ 65 409 ++++ 96 +++ 95 410 +++ 93 ++ 75 411 +++ 91 ++ 50 412 ++++ 99 +++ 98 413 +++ 92 ++ 51 414 +++ 91 ++ 67 415 ++++ 99 ++++ 95 416 ++++ 99 +++ 95 417 ++++ 97 +++ 91 418 +++ 90 + 51 419 +++ 93 ++ 64 420 ++++ 98 +++ 89 421 +++ 84 + 37 422 ++++ 99 ++++ 97 423 ++++ 98 +++ 89 424 ++++ 99 ++++ 96 425 ++++ 98 +++ 93 426 +++ 97 ++ 78 427 ++++ 99 +++ 87 428 +++ 97 ++ 65 429 ++++ 99 +++ 93 430 ++++ 100 +++ 92 431 +++ 86 ++ 53 432 ++++ 98 +++ 88 433 +++ 96 ++ 59 434 ++++ 100 ++++ 92 435 ++++ 100 +++ 93 436 ++++ 100 +++ 85 437 ++++ 99 +++ 87 438 +++ 84 + 28 439 +++ 88 + 36 440 +++ 88 + 40 441 +++ 97 ++ 80 442 ++++ 96 ++ 75 443 +++ 96 +++ 82 444 +++ 93 ++ 67 445 +++ 96 ++ 72 446 +++ 87 + 44 447 +++ 95 ++ 84 448 ++++ 97 +++ 93 449 +++ 92 + 50 450 +++ 96 ++ 73 451 +++ 93 ++ 58 452 ++++ 97 +++ 98 453 +++ 91 ++ 61 454 ++++ 97 +++ 88 455 +++ 94 ++ 75 456 +++ 95 ++ 80 457 +++ 95 ++ 61 458 +++ 95 ++ 74 459 ++++ 97 +++ 86 460 +++ 98 ++ 75 461 +++ 93 ++ 65 462 +++ 93 ++ 71 463 ++++ 98 ++ 82 464 +++ 88 + 48 465 ++++ 99 +++ 89 466 ++++ 99 ++ 79 467 ++++ 99 +++ 86 468 ++++ 100 ++ 80 469 ++++ 98 +++ 85 470 +++ 97 ++ 82 471 +++ 96 + 63 472 +++ 86 + 51 473 +++ 96 + 72 474 +++ 93 + 53 475 ++++ 99 +++ 98 476 +++ 94 ++ 63 477 +++ 88 + 49 478 +++ 95 ++ 63 479 +++ 96 ++ 72 480 +++ 93 ++ 73 481 ++++ 98 +++ 95 482 +++ 90 ++ 55 483 +++ 93 ++ 72 484 +++ 96 ++ 77 485 +++ 93 ++ 82 486 +++ 95 + 70 487 ++++ 100 +++ 95 488 ++++ 101 +++ 91 489 +++ 97 ++ 76 490 +++ 93 + 40 491 +++ 98 ++ 76 492 ++++ 99 +++ 91 493 +++ 96 ++ 68 494 ++++ 99 +++ 90 495 ++++ 99 +++ 88 496 ++++ 100 ++++ 92 497 ++++ 100 ++++ 97 498 +++ 98 +++ 83 499 +++ 85 + 29 500 ++++ 95 ++ 83 501 +++ 85 + 47 502 +++ 89 ++ 70 503 +++ 94 + 72 504 +++ 84 + 44 505 +++ 96 ++ 72 506 ++++ 97 +++ 96 507 ++++ 97 +++ 77 508 +++ 90 + 46 509 +++ 93 ++ 54 510 +++ 89 + 64 511 ++++ 96 ++ 79 512 ++++ 97 ++ 80 513 +++ 87 + 36 514 +++ 95 + 59 515 +++ 90 ++ 68 516 +++ 96 ++ 77 517 ++++ 98 +++ 88 518 +++ 96 ++ 72 519 ++++ 96 +++ 90 520 +++ 88 ++ 53 521 +++ 85 + 34 522 +++ 97 ++ 83 523 +++ 90 ++ 58 524 +++ 95 + 50 525 +++ 97 ++ 69 526 +++ 90.7 ++ 61.2 “+” indicates inhibitory effect of >1 μM; “++” indicates inhibitory effect of 0.5-1 μM; “+++” indicates inhibitory effect of 0.1-0.5 μM, “++++” indicates inhibitory effect of <0.1 μM

    Example 39. Synthesis of Compound A

    [1345] BRG1/BRM Inhibitor compound A has the structure:

    ##STR00666##

    [1346] Compound A was synthesized as shown in Scheme 1 below.

    ##STR00667##

    [1347] The ATPase catalytic activity of BRM or BRG-1 in the presence of Compound A was measured by the in vitro biochemical assay using ADP-Glo™ (Promega, V9102) described above. Compound A was found to have an IC.sub.50 of 10.4 nM against BRM and 19.3 nM against BRG1 in the assay.

    Example 40. Effects of BRG1/BRM ATPase Inhibition on the Growth of Uveal Melanoma and Hematological Cancer Cell Lines

    [1348] Procedure: Uveal melanoma cell lines (92-1, MP41, MP38, MP46), prostate cancer cell lines (LNCAP), lung cancer cell lines (NCI-H1299), and immortalized embryonic kidney lines (HEK293T) were plated into 96 well plates with growth media (see Table 5). BRG1/BRM ATPase inhibitor, Compound A, was dissolved in DMSO and added to the cells in a concentration gradient from 0 to 10 micromolar at the time of plating. Cells were incubated at 37 degrees Celsius for 3 days. After three days of treatment, the media was removed from the cells and 30 microliters of TrypLE (Gibco) was added to cells for 10 minutes. Cells were detached from the plates and resuspended with the addition of 170 microliters of growth media. Cells from two DMSO-treated control wells were counted, and the initial number of cells plated at the start of the experiment, were re-plated into fresh-compound containing plates for an additional four days at 37 degrees Celsius. At day 7, cells were harvested as described above. On day 3 and day 7, relative cell growth was measured by the addition of Cell-titer glo (Promega) and luminescence was measured on an Envision plate reader (Perkin Elmer). The concentration of compound at which each cell line's growth was inhibited by 50% (GI.sub.50), was calculated using Graphpad Prism, and is plotted below. For multiple myeloma cell lines (OPM2, MM1S, LP1), ALL cell lines (TALL1, JURKAT, RS411), DLBCL cell lines (SUDHL6, SUDHL4, DB, WSUDLCL2, PFEIFFER), AML cell lines (OCIAML5), MDS cell lines (SKM1), ovarian cancer cell lines (OV7, TYKNU), esophageal cancer cell lines (KYSE150), rhabdoid tumor lines (RD, G402, G401, HS729, A204), liver cancer cell lines (HLF, HLE, PLCRPF5), and lung cancer cell lines (SW1573, NCIH2444), the above methods were performed with the following modifications: Cells were plated in 96 well plates, and the next day, BRG1/BRM ATPase inhibitor, Compound A, was dissolved in DMSO and added to the cells in a concentration gradient from 0 to 10 micromolar. At the time of cell splitting on days 3 and 7, cells were split into new 96 well plates, and fresh compound was added four hours after re-plating.

    [1349] Table 26 lists the tested cell lines and growth media used.

    TABLE-US-00027 TABLE 26 Cell Lines and Growth Media Cell Line Source Growth Media 92-1 SIGMA RPMI1640 + 20% FBS A204 ATCC McCoy's 5A + 10% FBS DB ATCC RPMI1640 + 10% FBS G401 ATCC McCoy's 5A + 10% FBS G402 ATCC McCoy's 5A + 10% FBS HEK293T ATCC DMEM + 10% FBS HLE JCRB DMEM + 10% FBS HLF JCRB DMEM + 10% FBS HS729 ATCC DMEM + 10% FBS JURKAT ATCC RPMI1640 + 10% FBS KYSE150 DSMZ RPMI1640/Ham's F12 + 10% FBS LNCAP ATCC RPMI1640 + 10% FBS LP1 DSMZ IMDM + 20% FBS MM1S ATCC RPMI1640 + 10% FBS MP38 ATCC RPMI1640 + 20% FBS MP41 ATCC RPMI1640 + 20% FBS MP46 ATCC RPMI1640 + 20% FBS NCIH1299 ATCC RPMI1640 + 10% FBS NCIH2444 ATCC RPMI1640 + 20% FBS OCIAML5 DSMZ alpha-MEM + 20% FBS + 10 ng/ml GM-CSF OPM2 DSMZ RPMI1640 + 10% FBS OV7 ECACC DMEM/Ham's F12 (1:1) + 2 mM Glutamine + 10% FBS + 0.5 ug/ml hydrocortisone + 10 ug/ml insulin PFEIFFER ATCC RPMI1640 + 10% FBS PLCPRF5 ATCC EMEM + 10% FBS RD ATCC DMEM + 10% FBS RS411 ATCC RPMI1640 + 10% FBS SKM1 JCRB RPMI1640 + 10% FBS SUDHL4 DSMZ RPMI1640 + 10% FBS SUDHL6 ATCC RPMI1640 + 20% FBS SW1573 ATCC DMEM + 10% FBS TALL1 JCRB RPMI1640 + 10% FBS TYKNU JCRB EMEM + 20% FBS WSUDLCL2 DSMZ RPMI1640 + 10% FBS

    [1350] Results: As shown in FIG. 1, the uveal melanoma and hematologic cancer cell lines were more sensitive to BRG1/BRM inhibition than the other tested cell lines. Inhibition of the uveal melanoma and hematologic cancer cell lines was maintained through day 7.

    Example 41. Comparison of BRG1/BRM Inhibitors to Clinical PKC and MEK Inhibitors in Uveal Melanoma Cell Lines

    [1351] Procedure: Uveal melanoma cell lines, 92-1 or MP41, were plated in 96 well plates in the presence of growth media (see Table 26). BAF ATPase inhibitors (Compound A), PKC inhibitor (LXS196; MedChemExpress), or MEK inhibitor (Selumetinib; Selleck Chemicals) were dissolved in DMSO and added to the cells in a concentration gradient from 0 to 10 micromolar at the time of plating. Cells were incubated at 37 degrees Celsius for 3 days. After three days of treatment, cell growth was measured with Cell-titer glow (Promega), and luminescence was read on an Envision plate reader (Perkin Elmer).

    [1352] Results: As shown in FIG. 2A and FIG. 2B, Compound A showed comparable growth inhibition of uveal melanoma cells as the clinical PKC and MEK inhibitors. Further, compound A was found to result in a faster onset of inhibition than the clinical PKC and MEK inhibitors.

    Example 42. Synthesis of Compound B

    [1353] BRG1/BRM Inhibitor Compound B has the structure:

    ##STR00668##

    [1354] Compound B was synthesized as shown in Scheme 2 below.

    ##STR00669##

    Step 1: Preparation of (S)-1-(methylsulfonyl)-N-(4-(methylthio)-1-oxo-1-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)butan-2-yl)-1H-pyrrole-3-carboxamide (Compound B)

    [1355] ##STR00670##

    [1356] To a mixture of (2S)-2-amino-4-methylsulfanyl-N-[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]butanamide (2 g, 4.75 mmol, HCl salt) and 1-methylsulfonylpyrrole-3-carboxylic acid (898.81 mg, 4.75 mmol) in DMF (20 mL) was added EDCI (1.37 g, 7.13 mmol), HOBt (962.92 mg, 7.13 mmol), and DIEA (2.46 g, 19.00 mmol, 3.31 mL) and the mixture was stirred at 25° C. for 3 hours. The mixture was poured into H.sub.2O (100 mL) and the precipitate was collected by filtration. The solid was triturated in MeOH (20 mL) and the precipitate was collected by filtration. The solid was dissolved in DMSO (10 mL) and then the mixture was poured into MeOH (50 mL) and the formed precipitate was collected by filtration and lyophilized to give Compound B (2.05 g, 3.66 mmol, 77.01% yield) as a white solid. LCMS (ESI) m/z [M+H].sup.+=555.9. .sup.1H NMR (400 MHz, DMSO) δ 12.49 (s, 1H), 8.68-8.66 (m, 2H), 8.46 (d, J=7.2 Hz, 1H), 8.31-8.30 (m, 1H), 8.02-8.00 (m, 1H), 7.94-7.96 (m, 1H), 7.83 (s, 1H), 7.73-7.74 (m, 3H), 7.61-7.57 (m, 1H), 7.31-7.29 (m, 1H), 6.79-6.77 (m, 1H), 4.74-4.69 (m, 1H), 3.57 (s, 3H), 2.67-2.53 (m, 2H), 2.13-2.01 (m, 5H). SFC: AS-3-MeOH (DEA)-40-3 mL-35T.lcm, t=0.932 min, ee %=100%.

    Example 43. Effects of BRG1/BRM ATPase Inhibition on the Growth of Uveal Melanoma, Hematological Cancer, Prostate Cancer, Breast Cancer, and Ewing's Sarcoma Cell Lines

    [1357] Procedure: All cell lines described above in Example 28 were also tested as described above with Compound B. In addition, the following cell lines were also tested as follows. Briefly, for Ewing's sarcoma cell lines (CADOES1, RDES, SKES1), retinoblastoma cell lines (WERIRB1), ALL cell lines (REH), AML cell lines (KASUMI1), prostate cancer cell lines (PC3, DU145, 22RV1), melanoma cell lines (SH4, SKMEL28, WM115, COL0829, SKMEL3, A375), breast cancer cell lines (MDAMB415, CAMA1, MCF7, BT474, HCC1419, DU4475, BT549), B-ALL cell lines (SUPB15), CML cell lines (K562, MEGO1), Burkitt's lymphoma cell lines (RAMOS2G64C10, DAUDI), mantle cell lymphoma cell lines (JEKO1, REC1), bladder cancer cell lines (HT1197), and lung cancer cell lines (SBC5), the above methods were performed with the following modifications: Cells were plated in 96 well plates, and the next day, BRG1/BRM ATPase inhibitor, Compound B, was dissolved in DMSO and added to the cells in a concentration gradient from 0 to 10 micromolar. At the time of cell splitting on days 3 and 7, cells were split into new 96 well plates, and fresh compound was added four hours after re-plating.

    [1358] Table 27 lists the tested cell lines and growth media used.

    TABLE-US-00028 TABLE 27 Cell Lines And Growth Media Cell Line Source Growth Media 22RV1 ATCC RPMI1640 + 10% FBS A375 ATCC DMEM + 10% FBS BT474 ATCC Hybricare medium + 1.5 g/L sodium bicarbonate + 10% FBS BT549 ATCC RPMI1640 + 0.023 IU/ml insulin + 10% FBS CADOES1 DSMZ RPMI1640 + 10% FBS CAMA1 ATCC EMEM + 10% FBS COLO829 ATCC RPMI1640 + 10% FBS DAUDI ATCC RPMI1640 + 10% FBS DU145 ATCC EMEM + 10% FBS DU4475 ATCC RPMI1640 + 10% FBS HCC1419 ATCC RPMI1640 + 10% FBS HT1197 ATCC EMEM + 10% FBS JEKO1 ATCC RPMI1640 + 20% FBS K562 ATCC IMDM + 10% FBS KSUMI1 ATCC RPMI1640 + 10% FBS MCF7 ATCC EMEM + 0.01 mg/ml bovine insulin + 10% FBS MDAMB415 ATCC Leibovitz's L-15 + 2 mM L-glutamine + 10 mcg/ml insulin + 10 mcg/ml glutathione + 15% FBS MEG01 ATCC RPMI1640 + 10% FBS PC3 ATCC F-12K + 10% FBS RAMOS2G64C10 ATCC RPMI1640 + 10% FBS RDES ATCC RPMI1640 + 15% FBS REC1 ATCC RPMI1640 + 10% FBS REH ATCC RPMI1640 + 10% FBS SBC5 JCRB EMEM + 10% FBS SH4 ATCC DMEM + 10% FBS SKES1 ATCC McCoy's 5A + 15% FBS SKMEL28 ATCC EMEM + 10% FBS SKMEL3 ATCC McCoy's 5A + 15% FBS SUPB15 ATCC IMDM + 4 mM L-glutamine + 1.5 g/L sodium bicarbonate + 0.05 mM 2-mercaptoethanol + 20% FBS WERIRB1 ATCC RPMI1640 + 10% FBS WM115 ATCC EMEM + 10% FBS

    [1359] Results: As shown in FIG. 3, the uveal melanoma, hematologic cancer, prostate cancer, breast cancer, and Ewing's sarcoma cell lines were more sensitive to BRG1/BRM inhibition than the other tested cell lines. Inhibition of the uveal melanoma, hematologic cancer, prostate cancer, breast cancer, and Ewing's sarcoma cell lines was maintained through day 7.

    Example 44. Effects of BRG1/BRM ATPase Inhibition on the Growth of Cancer Cell Lines

    [1360] Procedure: A pooled cell viability assay was performed using PRISM (Profiling Relative Inhibition Simultaneously in Mixtures) as previously described (“High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines”, Yu et al, Nature Biotechnology 34, 419-423, 2016), with the following modifications. Cell lines were obtained from the Cancer Cell Line Encyclopedia (CCLE) collection and adapted to RPMI-1640 medium without phenol red, supplemented with 10% heat-inactivated fetal bovine serum (FBS), in order to apply a unique infection and pooling protocol to such a big compendium of cell lines. A lentiviral spin-infection protocol was executed to introduce a 24 nucleotide-barcode in each cell line, with an estimated multiplicity of infection (MOI) of 1 for all cell lines, using blasticidin as selection marker. Over 750 PRISM cancer cell lines stably barcoded were then pooled together according to doubling time in pools of 25. For the screen execution, instead of plating a pool of 25 cell lines in each well as previously described (Yu et al.), all the adherent or all the suspension cell line pools were plated together using T25 flasks (100,000 cells/flask) or 6-well plates (50,000 cells/well), respectively. Cells were treated with either DMSO or compound in a 8-point 3-fold dose response in triplicate, starting from a top concentration of 10 μM. As control for assay robustness, cells were treated in parallel with two previously validated compounds, the pan-Raf inhibitor AZ-628, and the proteasome inhibitor bortezomib, using a top concentration of 2.5 μM and 0.039 μM, respectively.

    [1361] Following 3 days of treatment with compounds, cells were lysed, genomic DNA was extracted, barcodes were amplified by PCR and detected with Next-Generation Sequencing. Cell viability was determined by comparing the counts of cell-line specific barcodes in treated samples to those in the DMSO-control and Day 0 control. Dose-response curves were fit for each cell line and corresponding area under the curves (AUCs) were calculated and compared to the median AUC of all cell lines (FIG. 4). Cell lines with AUCs less than the median were considered most sensitive.

    Example 45. Effects of BRG1/BRM ATPase Inhibitors on the Growth of Uveal Melanoma Cell Lines

    [1362] Procedure: Uveal melanoma cell lines (92-1, MP41, MP38, MP46) and Non-small cell lung cancer cells (NCIH1299) were plated into 96 well plates with growth media (see Table 27). BRG1/BRM ATPase inhibitor, compound 67, was dissolved in DMSO and added to the cells in a concentration gradient from 0 to 10 micromolar at the time of plating. Cells were incubated at 37° C. for 3 days. After three days of treatment, cell growth was measured with Cell-titer glow (Promega), and luminescence was read on an Envision plate reader (Perkin Elmer).

    [1363] Results: As shown in FIG. 5, Compound B resulted in potent growth inhibition in the uveal melanoma cell lines.

    Example 46. Comparison of BRG1/BRM Inhibitors to Clinical PKC and MEK Inhibitors in Uveal Melanoma Cell Lines

    [1364] Procedure: Uveal melanoma cell lines, 92-1 or MP41, were plated in 96 well plates in the presence of growth media (see Table 27). BAF ATPase inhibitor (Compound B), PKC inhibitor (LXS196; MedChemExpress), and MEK inhibitor (Selumetinib; Selleck Chemicals) were dissolved in DMSO and added to the cells in a concentration gradient from 0 to 10 micromolar at the time of plating. Cells were incubated at 37° C. for 3 days. After three days of treatment, cell growth was measured with Cell-titer glow (Promega), and luminescence was read on an Envision plate reader (Perkin Elmer).

    [1365] Results: As shown in FIG. 6A and FIG. 6B, compound B showed more potent effects on growth inhibition of uveal melanoma cells as compared to the clinical PKC and MEK inhibitors. Further, Compound B was found to result in a faster onset of growth inhibition than the clinical PKC and MEK inhibitors.

    Example 47. BRG1/BRM ATPase Inhibitors are Effective at Inhibiting the Growth of PKC Inhibitor-Resistant Cells

    [1366] Procedure: MP41 uveal melanoma cells were made resistant to the PKC inhibitor (LXS196; MedChemExpress), by long-term culture in growth media (see Table 27) containing increasing concentrations of the compound, up to 1 micromolar. After 3 months, sensitivity of the parental MP41 cells and the PKC inhibitor (PKCi)-resistant cells to the PKC inhibitor (LXS196) or the BRG1/BRM ATPase inhibitor (Compound B) was tested in a 7-day growth inhibition assay as described above in Example 9.

    [1367] Results: While the PKCi-resistant cells could tolerate growth at higher concentrations of LXS196 than could the parental MP41 cell line (FIG. 7A), the BRG1/BRM ATPase inhibitor (Compound B) still resulted in strong growth inhibition of both the PKCi-resistant and parental cell lines (FIG. 7B). The PKCi-resistant cells were more sensitive to Compound B than were the parental MP41 cells (FIG. 7B).

    Example 48. Synthesis of Compound C

    [1368] ##STR00671##

    Step 1: Preparation of 6-fluoropyridine-2-carbonyl chloride (Intermediate B)

    [1369] ##STR00672##

    [1370] To a cooled (0° C.) solution of 6-fluoropyridine-2-carboxylic acid (50.00 g, 354.36 mmol) in dichloromethane (500 mL) and N,N-dimethylformamide (0.26 mL, 3.54 mmol) was added oxalyl chloride (155.10 ml, 1.77 mol). After complete addition of oxalyl chloride, the reaction mixture was warmed to room temperature and stirred for an additional 0.5 h. The mixture was concentrated under vacuum to give Intermediate B (56.50 g) as a white solid, which was used to next step without further purification.

    Step 2: Preparation of 2-chloro-1-(6-fluoro-2-pyridyl)ethenone (Intermediate C)

    [1371] ##STR00673##

    [1372] To a cooled (0°) mixture of Intermediate B (56.00 g, 351.00 mmol) in 1,4-dioxane (800 mL) was added in a dropwise manner a solution of 2 M trimethylsilyl diazomethane in hexanes (351 mL). The resulting reaction mixture was stirred at 25° C. for 10 h. The reaction mixture was subsequently quenched with a solution of 4 M HCl in 1,4-dioxane (500 mL). After stirring for 2 h, the reaction solution was concentrated under vacuum to give an oil. The residue was diluted with saturated aqueous NaHCO.sub.3 (500 mL) and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine (300 mL×2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give Intermediate C (35.50 g) as a white solid, which was used to next step directly. LCMS (ESI) m/z: [M+H].sup.+=173.8.

    Step 3: Preparation of 4-(6-fluoro-2-pyridyl)thiazol-2-amine (Intermediate E)

    [1373] ##STR00674##

    [1374] To a solution of Intermediate C (35.50 g, 204.53 mmol) and thiourea (14.01 g, 184.07 mmol) in a mixture of MeOH (250 mL) and H.sub.2O (250 mL) at room temperature was added NaF (3.56 g, 84.82 mmol). After stirring for 0.5 h, the reaction mixture was partially concentrated under vacuum to remove MeOH, and the resulting solution was acidified to pH ˜3 with aqueous 2 M HCl. After 15 min, the solution was extracted with ethyl acetate (200 mL×3), the organic layers were discarded and the aqueous phase was alkalized with NaHCO.sub.3 (500 mL) and stirred for 30 min, then extracted with ethyl acetate (325 mL*3), the combined organic layers were washed with brine (225 mL*3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether (300 mL) and stirred at 25° C. for 10 min and filtered. The resultant solids were dried under vacuum to give Intermediate E (28.00 g, 143.43 mmol, 70.13% yield, 100% purity) as a white solid. LCMS (ESI) m/z: [M+H].sup.+=195.8; .sup.1H NMR (400 MHz, DMSO-d6) δ 8.00-7.96 (m, 1H), 7.72 (d, J=7.2 Hz, 1H), 7.24 (s, 1H), 7.16 (s, 2H), 7.02 (d, J=8.0 Hz, 1H).

    Step 4: Preparation of tert-butyl N-[2-[[4-(6-fluoro-2-pyridyl)thiazol-2-yl]amino]-2-oxo-ethyl]carbamate (Intermediate G)

    [1375] ##STR00675##

    [1376] To a solution of N-Boc-glycine (5.92 g, 33.81 mmol), HATU (12.86 g, 33.81 mmol), and DIEA (15.89 g, 122.94 mmol, 21.41 mL) in dichloromethane (100 mL) was added Intermediate E (6.00 g, 30.74 mmol). After stirring for 2 h, the reaction mixture was concentrated and subsequently diluted with water (100 mL) and extracted with ethyl acetate (60 mL×4). The combined organic layers were washed with brine (100 mL×2), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with a 1:1 mixture of petroleum ether and MeOH (40 mL). After stirring at 25° C. for 20 min, the suspension was filtered, the filter cake was washed with MTBE (20 mL) and dried in vacuo to give Intermediate G (7.7 g, 21.63 mmol, 70.4% yield, 99.0% purity) as a white solid. LCMS (ESI) m/z: [M+H].sup.+=353.1.

    Step 5: Preparation of 2-((4-(6-fluoropyridin-2-yl)thiazol-2-yl)amino)-2-oxoethan-1-aminium chloride (Intermediate H)

    [1377] ##STR00676##

    [1378] A solution of Intermediate G (5.40 g, 15.32 mmol) in 4 M HCl in 1,4-dioxane (35 mL) was stirred at 25° C. for 1.5 h. The mixture was concentrated under vacuum to give Intermediate H (4.42 g) as a white solid, which was used to next step directly without further purification. LCMS (ESI) m/z: [M+H].sup.+=252.9.

    Step 6: Preparation of 1-tert-butyl-N-[2-[[4-(6-fluoro-2-pyridyl)thiazol-2-yl]amino]-2-oxo-ethyl]pyrrole-3-carboxamide (Intermediate J)

    [1379] ##STR00677##

    [1380] To a solution of Intermediate H (3.00 g, 10.39 mmol), 1-tert-butylpyrrole-3-carboxylic acid (1.74 g, 10.39 mmol), and DIEA (6.71 g, 51.95 mmol, 9.05 mL) in dichloromethane (40 mL) was sequentially added HOBt (1.68 g, 12.47 mmol) and EDCI (2.39 g, 12.47 mmol). After stirring for 4 h, the mixture was concentrated under vacuum. The residue was diluted with water (250 mL) and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with brine (300 mL×3), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting solids were triturated with a 1:1 mixture of MTBE/ethyl acetate (400 mL) and after 30 min, the suspension was filtered. The solids were washed with MTBE (85 mL×3) and then dried under vacuum to give Intermediate J (3.10 g, 7.64 mmol, 73.6% yield, 99.0% purity) as a white solid.

    [1381] LCMS (ESI) m/z: [M+H].sup.+=402.3.

    [1382] .sup.1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.18-8.15 (m, 1H), 8.09-8.08 (m, 1H), 7.87-7.83 (m, 2H), 7.52 (s, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.97 (m, 1H), 6.47 (s, 1H), 4.10 (d, J=5.6 Hz, 2H), 1.49 (s, 9H).

    Step 7: Preparation of 1-(tert-butyl)-N-(2-((4-(6-(cis-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound C)

    [1383] ##STR00678##

    [1384] To a solution of Intermediate J (0.100 g, 0.249 mmol) in DMSO (1 mL) was added DIEA (0.130 mL, 0.747 mmol) and cis-2,6-dimethylmorpholine (0.057 g, 0.498 mmol) and the mixture was stirred at 120° C. After 12 h, the solution was cooled to room temperature and reaction mixture was diluted with MeOH (3 mL). The residue was purified by prep-HPLC (0.1% TFA; column: Luna C18 150*25 5 u; mobile phase: [water (0.075% TFA)-ACN]; B %: 30%-60%, 2 min). The appropriate fractions were collected and lyophilized to give Compound C (0.079 g, 0.129 mmol, 51.94% yield, 100% purity) as a white solid.

    [1385] LCMS (ESI) m/z: [M+H].sup.+=497.5.

    [1386] .sup.1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.17-8.14 (m, 1H), 7.75 (s, 1H), 7.63-7.59 (m, 1H), 7.51 (s, 1H), 7.25 (d, J=7.2 Hz, 1H), 6.96 (s, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.47 (s, 1H), 4.24 (d, J=12.4 Hz, 2H), 4.08 (d, J=5.6 Hz, 2H), 3.64-3.61 (m, 2H), 2.44-2.38 (m, 2H), 1.49 (s, 9H), 1.18 (d, J=5.6 Hz, 6H).

    Example 49. BRG1/BRM ATPase Inhibitors Cause Uveal Melanoma Tumor Growth Inhibition in Vivo

    [1387] Procedure: Nude mice (Envigo) were engrafted subcutaneously in the axillary region with 5×10.sup.6 92-1 uveal melanoma cells in 50% Matrigel. Tumors were grown to a mean of ˜200 mm.sup.3, at which point mice were grouped and dosing was initiated. Mice were dosed once daily by oral gavage with vehicle (20% 2-Hydroxypropyl-β-Cyclodextrin) or increasing doses of Compound C. Tumor volumes and body weights were measured over the course of 3 weeks, and doses were adjusted by body weight to achieve the proper dose in terms of mg/kg. At this time, animals were sacrificed, and tumors were dissected and imaged.

    [1388] Results: Treatment with Compound C led to tumor growth inhibition in a dose-dependent manner with tumor regression observed at the highest (50 mg/kg) dose. (FIG. 8A and FIG. 8B). All treatments were well tolerated with no body weight loss observed (FIG. 8C).

    OTHER EMBODIMENTS

    [1389] While the invention has been described in connection with specific embodiments thereof, it will be understood that invention is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

    [1390] Other embodiments are in the claims.