HK40006173A - Fused quadracyclic compounds, compositions and uses thereof - Google Patents

Description

Fused tetracyclic compounds, compositions and uses thereof

Related application

This application claims priority to U.S. provisional patent application No. 62/274,640, filed on 4/1/2016, the entire contents of which are incorporated herein by reference.

Background

p38 mitosis-promoter activated protein kinases (p38 MAPKs) transduce a variety of extracellular signals that cause inflammatory responses, cell division and differentiation, apoptosis, and cell motility. P38MAPK was originally thought to be an ideal target for anti-inflammatory therapeutics. However, the failure of more than a dozen chemically distinct compounds in the clinical phase suggests that p38MAPK may be a poor therapeutic target. Many of these compounds were found to have varying degrees of hepatotoxicity and were resistant to anti-inflammatory effects that occurred over several weeks. Later, failure in clinical trials due to unwanted side effects may not be unexpected because p38MAPK modulates the activity of more than 60 substrates.

one downstream substrate for p38MAPK is mitosis promoter activated protein kinase-2 (MAPKAPK or MK2) among other actions, MK2 regulates tumor necrosis factor α and biosynthesis of other cytokines in addition, MK2 is activated following DNA damage that causes cell cycle arrest, allowing cells to have the ability to repair their DNA and continue proliferation. MK2 also phosphorylates heat shock 27(Hsp27), a significant biomarker of cancer progression therefore, MK2 can be used as a potential anti-inflammatory and anti-cancer target to improve the efficacy of chemotherapy without affecting unwanted side effects of further upstream targets (i.e., p38 MAPK).

Thus, there is a continuing need to find and develop new compounds that inhibit MK2 and that may be useful therapeutic agents.

Disclosure of Invention

In certain embodiments, the present invention relates to compounds having the structure of formula (I) and pharmaceutically acceptable salts thereof:

wherein R is¹-R³、X¹-X³、X⁵-X⁷Z and n are as defined in the specification.

In certain embodiments, the present invention relates to compounds having the structure of formula (II):

wherein R is^1a、R^1b、R²、R³、X¹-X³、X⁶、X⁷And Z is as defined in the specification.

In some embodiments, the present invention relates to pharmaceutical compositions of a compound of formula (I) or formula (II) and a pharmaceutically acceptable carrier.

The invention also relates to methods of treating an MK 2-associated disorder comprising administering to a subject a compound of the invention.

The invention further relates to a method of inhibiting the proliferation of a cancer cell comprising contacting the cancer cell with a compound of the invention.

The invention also provides methods of inhibiting MK2 activity in a cell comprising contacting the cell with a compound of the invention.

The invention also provides methods of treating or preventing a metabolic disorder comprising administering to a subject a compound of the invention.

Detailed Description

In certain aspects, the present invention provides substituted fused tetracyclic compounds and pharmaceutical compositions thereof. In particular, the substituted fused tetracyclic compounds are useful as MK2 inhibitors, and thus, as anticancer, anti-inflammatory, or antidiabetic agents.

I. Compound (I)

In certain embodiments, the present invention relates to compounds having the structure of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

X¹、X²And X³Each occurrence is independently CR⁵Or N;

X⁵、X⁶and X⁷Each occurrence is independently CR⁷Or N;

R¹independently for each occurrence is H, halo, -OH, -CN, or optionally substituted alkyl, alkoxy, ether, carbamate, or ester;

R²is H, halo, -CN, alkyl or ester;

R³is H, alkyl or cycloalkyl;

R⁵is H, halo, -CN or optionally substituted alkyl, alkoxy, aryl, heteroaryl, carbamate, or ester;

R⁷is H, halo, -OH, -CN or optionally substituted alkyl, alkoxy, carbamate or ester;

z is halo or optionally substituted amino, alkylamino, heteroalkylamino, cycloalkylamino or heterocycloalkylamino; and is

n is an integer of 0 to 5.

In certain embodiments, the present invention relates to compounds having the structure of formula (II) or a pharmaceutically acceptable salt thereof:

wherein X¹Is N or CH;

X²and X³Each occurrence is independently CR⁵Or N;

R^1ais H, halo, -CN, -OH or optionally substituted alkyl;

R^1bis H, halo, -CN, -OH or optionally substituted alkyl;

R²is H or halo;

R⁵is H, halo or optionally substituted alkyl; and is

Z is halo or optionally substituted amino, alkylamino, heteroalkylamino, cycloalkylamino or heterocycloalkylamino.

In certain embodiments of formulas I and II, X¹Is N; and X²And X³Is CH. In certain embodiments of formulas I and II, X¹And X²Is N; and X³Is CH. In certain embodiments of formulas I and II, X¹And X³Is N; and X²Is CH. In certain embodiments of formulas I and II, X¹、X²And X³Is N.

In certain embodiments of formulas I and II, Z is halo, preferably bromo. In alternative embodiments, Z is optionally substituted amino, alkylamino, heteroalkylamino, cycloalkylamino or heterocycloalkylamino.

In certain embodiments of formulas I and II, Z is optionally substituted alkylamino, heterocycloalkylamino, cycloalkylamino, or-NR⁸R⁹(ii) a And R is⁸And R⁹Each independently is H or optionally substituted alkyl, cycloalkyl or heterocycloalkyl; or R⁸And R⁹Taken together with the bound N to form an optionally substituted 4-, 5-or 6-membered heterocyclic ring.

In certain embodiments of formulas I and II, Z isAnd is

R²⁰、R²¹、R²²And R²³Each independently is H, halo, hydroxy, amino, or optionally substituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, alkylamino, cycloalkyl, or heterocycloalkyl; or

R²³And R²⁰Combine to form an optionally substituted 3-, 4-, 5-or 6-membered ring;

R²¹and R²⁰Combine to form an optionally substituted 3-, 4-, 5-or 6-membered ring; or

R²¹And R²²The combination forms an optionally substituted 4-, 5-or 6-membered ring. In some embodiments, the optionally substituted 4-, 5-, or 6-membered ring comprises a heteroatom. In some embodiments, the heteroatom is N.

In certain embodiments of formulas I and II, Z is

In certain embodiments of formulas I and II, Z is

In certain embodiments of formulas I and II, Z isX²⁰Is CR²⁴R²⁶NH or O; and is

R²⁴、R²⁵、R²⁶And R²⁷Each independently is H, amino or optionally substituted alkyl, aminoalkyl, alkylaminoalkyl, alkylamino, cycloalkyl or heterocycloalkyl; or

R²⁴And R²⁶The combination forms an optionally substituted 4-, 5-or 6-membered ring. In some embodiments, the optionally substituted 4-, 5-, or 6-membered ring comprises a heteroatom. In some embodiments, the heteroatom is N.

In certain embodiments of formulas I and II, Z is

In certain embodiments of formulas I and II, Z isAnd R is²⁸And R²⁹Each independently is H, amino orOptionally substituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, alkylamino, cycloalkyl or heterocycloalkyl; or R²⁸And R²⁹The combination forms an optionally substituted 4-, 5-or 6-membered ring. In some embodiments, the optionally substituted 4-, 5-, or 6-membered ring comprises a heteroatom. In some embodiments, the heteroatom is N.

In certain embodiments of formulas I and II, Z is

In certain embodiments of formulas I and II, Z isAnd X²¹Is NH or O. In some embodiments, Z is

In certain embodiments of formulas I and II, Z is optionally substituted alkylamino, cycloalkylamino, or heterocycloalkylamino.

In certain embodiments of formulas I and II, Z is

In certain embodiments of formulas I and II, Z is

In certain embodiments of formula I, R¹Independently at each occurrence is fluoro, chloro, -CN, -O-R³¹、-OCF₃、-O-C(O)-NR³¹R³²OR-C (O) -OR³¹(ii) a And R is³¹And R³²Independently for each occurrence is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, aryl or aralkyl group. In certain preferred embodiments of formula I, R¹Is fluorine or-CN.

In certain embodiments of formula II, R^1aAnd R^1bIndependently at each occurrence is fluoro, chloro, -CN, -O-R³¹、-OCF₃、-O-C(O)-NR³¹R³²OR-C (O) -OR³¹(ii) a And R is³¹And R³²Independently for each occurrence is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, aryl or aralkyl group. In certain preferred embodiments of formula II, R^1aAnd R^1bIndependently at each occurrence is fluorine or-CN.

In certain embodiments of formulas I and II, R²is-C (O) -OR⁴¹(ii) a And R is⁴¹Is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, aryl or aralkyl group. In some embodiments, R²Is H or chlorine.

In certain embodiments of formula I, R³Is optionally substituted C_1-6Alkyl or C_3-6Cycloalkyl, preferably cyclopropyl. In some embodiments of formula I, R³Is H.

In certain embodiments of formulas I and II, R⁵Is optionally substituted alkyl, -O-C (O) -NR⁶¹R⁶²OR-C (O) -OR⁶¹；R⁶¹And R⁶²Independently for each occurrence is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, aryl or aralkyl group.

In certain embodiments of formulas I and II, R⁷is-O-C (O) -NR⁷¹ ₂OR-C (O) -OR⁷¹(ii) a And R is⁷¹Is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, aryl or aralkyl group.

In certain embodiments of formula I, n is 0,1, or 2.

In certain embodiments, the compounds of the present invention may be prodrugs of compounds of formula I or formula II, for example, where the hydroxy group in the parent compound is present as an ester or carbonate, or the carboxylic acid present in the parent compound is present as an ester. In certain such embodiments, the prodrug is metabolized in vivo to the active parent compound (e.g., hydrolysis of the ester to the corresponding hydroxy or carboxylic acid).

In certain embodiments, the compounds of the present invention may be racemic. In certain embodiments, the compounds of the present invention may be enriched in one enantiomer. For example, a compound of the invention can have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% ee or greater. The compounds of the invention have more than one stereogenic center. Thus, the compounds of the present invention may be enriched in one or more diastereomers. For example, a compound of the invention may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% de or greater.

In certain embodiments, as described in detail below, the present invention relates to methods of treating or preventing cancer or an inflammatory disorder with a compound of formula I or formula II, or a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutic agent may be enriched to provide predominantly one enantiomer of a compound (e.g., a compound of formula I or II). An enantiomerically enriched mixture may comprise, for example, at least 60 mol% of one enantiomer, or more preferably at least 75 mol%, 90 mol%, 95 mol% or even 99 mol%. In certain embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance constitutes less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in a composition or mixture of compounds. For example, if a composition or mixture of compounds contains 98 grams of the first enantiomer and 2 grams of the second enantiomer, it is said to contain 98 mol% of the first enantiomer and only 2% of the second enantiomer.

In certain embodiments, the therapeutic agent may be enriched to provide predominantly one diastereomer of the compound (e.g., a compound of formula I or II). A diastereomerically enriched mixture may comprise, for example, at least 60 mol% of one diastereomer, or more preferably at least 75 mol%, 90 mol%, 95 mol%, or even 99 mol%.

In certain embodiments, the present invention provides pharmaceutical formulations suitable for treating cancer, inflammatory disorders in a human patient comprising an effective amount of any compound of formula I or formula II and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical formulation may be used to treat or prevent a condition or disease as described herein. In certain embodiments, the pharmaceutical formulation has sufficiently low pyrogen activity for use in a human patient.

Compounds of any of the above structures may be used in the manufacture of medicaments for the treatment of any of the diseases or conditions disclosed herein.

Exemplary compounds of formula I and formula II are depicted in the examples and table 1. The compounds disclosed in the examples and table 1 are to be understood as encompassing both the free base and the conjugate acid. For example, the compounds in the examples and table 1 may be depicted as complexes or salts with trifluoroacetic acid or hydrochloric acid, but compounds in their respective free base forms or in salt forms with other acids are also within the scope of the invention. The compounds may be isolated in the form of the free base, in the form of a salt (e.g., hydrochloride salt), or in both forms. In the chemical structures shown below, standard chemical abbreviations are sometimes used.

Table 1: exemplary Compounds of formula I and formula II

Use of MK2 inhibitors

In certain aspects, the invention provides methods of treating cancer comprising administering to a subject, e.g., a therapeutically effective amount of a compound of formula I or formula II.

In certain embodiments, the cancer may be one or a variant of: acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), adrenocortical carcinoma, AIDS-related cancers (Kaposi sarcoma and lymphoma), anal carcinoma, appendiceal carcinoma, atypical teratoid/rhabdoidTumors, basal cell carcinoma, cholangiocarcinoma (including extrahepatic), bladder carcinoma, bone carcinoma (including osteosarcoma and malignant fibrous histiocytoma), brain tumor (e.g., astrocytoma, brain and spinal cord tumors, brain stem glioma, central nervous system atypical teratoid/rhabdoid tumor, central nervous system embryonal tumor, craniopharyngioma, ependymoma, medulloblastoma, intermediate differentiated pineal parenchymal tumor, supratentorial primitive neuroectodermal tumor, and pineal blastoma), breast carcinoma, bronchial tumor, berkitt's lymphoma (burkitt lymphoma), basal cell carcinoma, cholangiocarcinoma (including extrahepatic), bladder carcinoma, bone carcinoma (including osteosarcoma and malignant fibrous histiocytoma), carcinoid tumor, carcinoma of unknown primary central nervous system (e.g., atypical teratoid/rhabdoid tumor, embryoma and lymphoma), Cervical cancer, childhood cancer, chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma (mycosis fungoides and sezary Syndrome), bile duct (extrahepatic), Ductal Carcinoma In Situ (DCIS), embryonal carcinoma (central nervous system), endometrial carcinoma, ependymoma, esophageal cancer, sensitive neuroblastoma, Ewing' S Sarcoma (Ewing Sarcoma) family of tumors, ectogenital cytoma, extrahepatic cholangiocarcinoma, ocular cancer (e.g., intraocular melanoma, retinoblastoma), fibrohistiocytoma of bone (including malignant and osteosarcoma), gallbladder cancer, Stomach (gasteric or Stomach) cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), Germ Cell tumors (extracranial, extragonadal, ovarian), gestational trophoblastic tumors, glioblastoma, glioma, hairy Cell leukemia, head and neck cancer, heart cancer, hepatocellular (liver) cancer, glomerulo-proliferation disorders, Langerhans cells (Langerhans cells), hodgkin's lymphoma (hodgkin lymphoma), hypopharyngeal cancer, intraocular melanoma, islet Cell tumors (endocrine, pancreatic), kaposi's sarcoma, kidney (including kidney cells), Langerhans Cell histobulbar-proliferation disorders, laryngeal cancer, leukemia (including Acute Lymphoblastic Leukemia (ALL), Acute Myelogenous Leukemia (AML), chronic gonorrhoea, lymphoblastic leukemia, and other cancersBarbaltic leukemia (CLL), Chronic Myelogenous Leukemia (CML), hairy Cell leukemia, lip and oral cavity cancers, liver cancer (primary), Lobular Carcinoma In Situ (LCIS), lung cancer (non-small cells and small cells), lymphoma (AIDS-related, Berkitt's, cutaneous T-cells (mycosis fungoides and sezary syndrome), Hodgkin, non-Hodgkin, primary Central Nervous System (CNS), male breast cancer, malignant fibrous histiocytoma and osteosarcoma of bone, medulloblastoma, melanoma (including intraocular (eye)), Merkel Cell Carcinoma, mesothelioma (malignant), occult primary metastatic squamous neck cancer, midline Carcinoma involving the NUT gene, oral cancer, multiple endocrine neoplasia, multiple myeloma/plasma Cell neoplasia, mycosis fungoides, myelodysplastic syndrome, Myelodysplastic/myeloproliferative neoplasms, Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), myeloma and multiple myeloma, myeloproliferative disorders (chronic), nasal and paranasal sinus cancers, nasopharyngeal cancers, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancers, oral cancers, lip and oropharyngeal cancers, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancers (e.g., epithelium, germ cell tumors, and low malignant potential tumors), pancreatic cancers (including islet cell tumors), papillomatosis, paragangliomas, paranasal sinuses and nasal cavity cancers, parathyroid cancers, penile cancers, pharyngeal cancers, pheochromocytoma, intermediate differentiated pineal parenchymal tumors, pineal blastomas, and supratentorial primary neuroectodermal tumors, pituitary tumors, plasmacytoma/multiple myeloma, Pleuropulmonoblastoma, breast carcinoma in gestation, primary Central Nervous System (CNS) lymphoma, prostate cancer, rectal cancer, renal cell (kidney) carcinoma, carcinoma of renal pelvis and ureter, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, sarcoma (e.g., ewing's sarcoma family tumor, kaposi's sarcoma, soft tissue sarcoma, uterine sarcoma), sezary syndrome, skin cancer (e.g., melanoma, merkel cell carcinoma, non-melanoma), small cell lung cancer, small bowel cancer, soft tissue sarcoma, squamous cell carcinoma, occult primary squamous neck carcinoma, metastatic Stomach (Stomach or gasteric) carcinoma, supratentorial primary neuroectodermal tumor, T-tencell lymphoma, and T-cell lymphomaLymphocytoma (cutaneous, mycosis fungoides and sezary syndrome), testicular cancer, laryngeal cancer, thymoma and thymus cancer, thyroid cancer, transitional cell carcinoma of renal pelvis and ureter, trophoblastic tumor (gestational period), unknown primary childhood-uncommon cancer, transitional cell carcinoma of ureter and renal pelvis, cancer of urethra, uterine cancer, endometrium, uterine sarcoma, Fahrenheit macroglobulinemia [ (B) andmacroloballinemia) and Wilms Tumor (Wilms Tumor).

In certain embodiments, the cancer is a KRAS-dependent or BRAF-dependent cancer.

In certain embodiments, the cancer is a solid tumor. The individual is typically one who has been diagnosed with a cancerous tumor or who has previously been treated for a cancerous tumor (e.g., where the tumor has been previously removed by surgery). The cancerous tumor may be a primary tumor and/or a secondary (e.g., metastatic) tumor.

In certain embodiments, the subject is a mammal, such as a human.

In certain embodiments, the cancer is associated with a tissue of the bladder, bone marrow, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, skin, or thyroid.

In certain embodiments, the method of treating cancer further comprises administering radiation therapy in combination.

In some embodiments, the method of treating cancer further comprises administering one or more additional chemotherapeutic agents in combination.

Chemotherapeutic agents that may be administered in combination with the compounds of the present invention include: ABT-263, aminoglutethimide (amitriptamide), amsacrine (amsacrine), anastrozole (anastrozole), asparaginase (asparaginase), AZD5363, BCG (Bacillus Calmette-Guerin vacine, bcg), bicalutamide (bicalutamide), bleomycin (bleomycin), bortezomib (bortezomib), buserelin (buserelin), buserelin (busulfan), camptothecin (campothricin), capecitabine (capicitabine), carboplatin (carboplatin), carfilzomib (carmustine), carmustine (carmustine), chlorambucil (chloacetic acid), chloroquine (cisplatin), cisplatin, cladribine (clinoptilodine), chlorambucil (cloxacillin), cyproconazole (clofibrate), cyproconazole (clobetamethamphetamine), cyproconazole (clofibrate), meclomethamphetamine (monocrotamycin), mechlorvinphos (clofibrate), meclocycline (clofibrate), mechlorvinpocetine (clofibrate), mechlorvinpocetine (clofibrate), mechlorvinpoclad (clofibrate), mechlorvinpocetine), mechlorvinpoclad (clofibrate), meclofen), mechlorvinpoclad (cloxacin (clofibrate), mechlorvinpoclad, Hexadiene estrol (dienestrol), diethylstilbestrol (diethylstilbestrol), docetaxel (docetaxel), doxorubicin (doxorabicin), famicin (epirubicin), estradiol (estradiol), estramustine (estramustine), etoposide (etoposide), everolimus (everolimus), exemestane (exemestane), filgrastim (filgrastim), fludarabine (fludarabine), fluhydrocortisone (fluucortisone), fluorouracil (fluouracil) and 5-fluorouracil, fluoromethyltestosterone (fluoxymatrione), flutamide (flutamidamide), gemcitabine (gemcitabine), genistein (genistein), sertraline (goserelin), hydroxyurea (hydroxyurea), idarubicin (ifosfamide), fludioxonil (fludioxonil), levofloxacin (levofloxacin), levofloxacin (levofoline), flunaridine (flunarine), flunarizine (flunarizine), flunarizine (valoriginine (valorine), flunarine (valoridonil), flunaridine (valorine), flunarine (valorine), flunaridine), flunarine (valorine), flunarine (valorine (valoridonil), flunarine (valbutine), flunarine (val, LY2603618, methyldichloroethylamine (mechlorethamine), medroxyprogesterone (medroxyprogesterone), megestrol (megestrol), melphalan (melphalan), mercaptopurine (mercaptoprine), mesna (mesna), metformin (metformin), methotrexate (methotrexate), miltefosine (miltefosine), mitomycin (mitomycin), mitotane (mitotane), mitoxantrone (mitoxantrone), MK2206, nilutamide (nilutamide), nocodazole (nocodazole), octreotide (octreotide), oxaliplatin (oxaliplatin), paclitaxel (paclitaxel), paclitaxel (paclitaxel), pamidronate (pemetrexestatin), pazopanib (papanicolamide), piperacillin (piperacillin), Prothromazine (PF), thiopefurazosin (04691502), thiomycin (piperacillin), streptomycin (piperacillin), thiomycin (piperacillin), thiomycin (propinebrodenticide), thiomycin (piperazines), thiocillin (propinebrodenticins (piperazines), thiocillin (propineb (piperazines), thioprin (sorafen (piperazines), thioprin), thiocillin (sorafen (piperazines), thiocillin (sorafen (propineb), sorafenib), sorafen (sorafenib), sorafe, Sunitinib (sunitinib), suramin (suramin), tamoxifen (tamoxifen), temozolomide (temozolomide), temsirolimus (temsirolimus), teniposide (teniposide), testosterone (teststerone), thalidomide (thalidomide), thioguanine (thioguanine), thiotepa (thiotepa), titanocene dichloride (titanocene dichloride), topotecan (topotecan), trametinib (trametinib), trastuzumab (trastuzumab), tretinoin (tretinoin), vinblastine (vinblastastine), vincristine (vinchristinine), digoxin (vindesine), vinorelbine (vinorelbine) and vorinostat, saratin. For example, chemotherapeutic agents that may be administered in combination with the compounds of the present invention include: aminoglutethimide, amsacrine, anastrozole, asparaginase, bcg, bicalutamide, bleomycin, bortezomib, buserelin, busulfan, camptothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronic acid, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, actinomycin D, daunomycin, desmopramycin, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, famicin, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluorometholone, flutamide, gemcitabine, genistein, sertraline, hydroxyurea, idarubicin, ifolin, ifosfamide, imatinib, interferon, Irinotecan, riliezomib, letrozole, leucovorin, salisperine, levamisole, lomustine, lonidamine, methyldichloroethylamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronic acid, pentastatin, pirifocine, plicamycin, pomalidomide, porfiil sodium, procarbazine, raltitrexed, rituximab, sorafenib, streptozotocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, and vinorelbine. In certain embodiments, the chemotherapeutic agent is cisplatin. In certain embodiments, the other chemotherapeutic agent is a CHK1 inhibitor.

A number of combination therapies have been developed to treat cancer. In certain embodiments, the compounds of the present invention may be administered in combination with a combination therapy. Examples of combination therapies that can be administered in combination with the compounds of the present invention are included in table 2.

Table 2: exemplary combination therapies for the treatment of cancer.

In some embodiments, the co-administered chemotherapeutic agent is an immunooncology therapeutic agent, e.g., an inhibitor of CTLA-4, indoleamine 2, 3-dioxygenase, and/or PD-1/PD-L1.

In certain embodiments, the combined administration of an MK2 inhibitor of formula I or formula II with one or more other therapeutic agents (e.g., one or more other chemotherapeutic agents) provides improved efficacy relative to the administration of an MK2 inhibitor (e.g., a compound of formula I or II) or each individual administration of one or more other therapeutic agents. In certain such embodiments, the co-administration provides an additive effect, where additive effect refers to the sum of the effects of each of the MK2 inhibitor and the one or more other therapeutic agents administered individually. In certain embodiments, co-administration produces a synergistic effect.

In certain embodiments, the MK2 inhibitor and one or more other chemotherapeutic agents are administered simultaneously. In alternative embodiments, one or more other chemotherapeutic agents are administered within about 5 minutes to within about 168 hours before or after administration of the MK2 inhibitor.

In certain embodiments, the present invention provides a method of inhibiting the proliferation of a cancer cell comprising contacting a cancer cell with an effective amount of a compound of formula I or formula II.

The invention also provides methods of inhibiting MK2 activity in a cell, comprising contacting the cell with a compound of formula I or formula II. In certain embodiments, the cell is a cancer cell. The method may be performed in vivo or in vitro.

The invention also provides a method of treating or preventing a metabolic disorder comprising administering to a subject a compound of formula I or II. In certain embodiments, the metabolic disorder is diabetes, insulin resistance, obesity, or metabolic syndrome. In some embodiments, the diabetes is type I, type II, or gestational diabetes. In some embodiments, the treatment or prevention affects hepatic glucose breakdown or glucose neogenesis in the individual. In some embodiments, the treating or preventing reduces hepatic glucose production, hyperglycemia, fatty liver, insulin resistance-related inflammation, insulin resistance-related dyslipidemia, or any combination thereof, in the individual.

in certain embodiments, such as methods of treating diabetes, the methods further comprise co-administration of one or more other antidiabetic agents including, but not limited to, sulfonylureas, biguanides, α -glucosidase inhibitors, Thiazolidinediones (TZD), dipeptidyl peptidase inhibitors (DPP-4 inhibitors), non-sulfonylurea insulin secretagogues, glucagon-like peptide-1 analogs (GLP-1 analogs), and insulin, more particularly, antidiabetic agents including, but not limited to, metformin, glyburide (glyburide), glimepiride (glimepiridide), glipizide (glitazoide), glipizide (glipizide), chlorpropamide (chlorpropamide), gliclazide (gliclazide), acarbose (acarbose), miglitol (miglitol), pioglitazone (pioglitazone), troglitazone (troglitazone), glitazone (glitazoline), glitazoline (glitazoline), glitazone (gliptin), glitazone (glitazone), glitazone (gliptin), gliptin (glitazone), gliptin (gliptin), gliptin (gliptin), gliptin (gliptin).

Pharmaceutical compositions

In certain embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula I or II and a pharmaceutically acceptable carrier.

The compositions and methods of the invention can be used to treat an individual in need thereof. In certain embodiments, the subject is a mammal, e.g., a human or non-human mammal. Upon administration to an animal (e.g., a human), the composition or compound is preferably administered in the form of a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, such as water or physiological buffered saline, or other solvents or vehicles, such as glycols, glycerol, oils (e.g., olive oil), or injectable organic esters. In preferred embodiments, the aqueous solution is pyrogen-free or substantially pyrogen-free when the pharmaceutical composition is for human administration, particularly for invasive administration routes (i.e., routes that prevent transmission or diffusion through epithelial barriers, such as injection or implantation). The excipient may be selected, for example, to achieve delayed release of the agent or to selectively target one or more cells, tissues, or organs. The pharmaceutical compositions may be in dosage unit form, such as tablets, capsules (including both dispersion and gelatin capsules), granules, lyophilizates for reconstitution, powders, solutions, syrups, suppositories, injections and the like. The composition may also be present in a transdermal delivery system (e.g., a skin patch). The compositions may also be presented in a solution suitable for topical administration, such as eye drops.

A pharmaceutically acceptable carrier can contain a physiologically acceptable agent for, e.g., stabilizing a compound (e.g., a compound of the invention), increasing its solubility, or increasing its absorption. The physiologically acceptable agent includes, for example, carbohydrates (e.g., glucose, sucrose, or dextran), antioxidants (e.g., ascorbic acid or glutathione), chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical compositions (formulations) may also be liposomes or other polymeric matrices into which, for example, the compounds of the invention may be incorporated. Liposomes, for example, comprising phospholipids or other lipids, are relatively simple nontoxic, physiologically acceptable and metabolizable carriers to prepare and administer.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) maltose; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution (Ringer's solution); (19) ethanol; (20) a phosphate buffer solution; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

Pharmaceutical compositions (formulations) can be administered to a subject by any of several routes of administration, including, for example, orally (e.g., drenches such as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including dispersion capsules and gelatin capsules), concentrated injections, powders, granules, pastes for administration to the tongue); absorption through the oral mucosa (e.g., sublingually); transanal, rectal, or vaginal (e.g., in the form of a pessary, cream, or foam); parenteral (including intramuscular, intravenous, subcutaneous, or intrathecal, in the form of, for example, sterile solutions or suspensions); transnasally; intraperitoneal administration; subcutaneous injection; transdermal (e.g., in the form of a patch applied to the skin); and topically (e.g., in the form of a cream, ointment, or spray applied to the skin, or in the form of eye drops). The compounds may also be formulated for inhalation. In certain embodiments, the compound may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. nos. 6,110,973, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, and patents cited therein.

The formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, this amount ranges from about 1% to about 99%, preferably from about 5% to about 70%, most preferably from about 10% to about 30% active ingredient by 100%.

Methods of preparing such formulations or compositions include the step of admixing an active compound, such as a compound of the present invention, with a carrier and, optionally, one or more accessory ingredients. Generally, the formulations are prepared by: the compound of the present invention is uniformly and thoroughly mixed with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, the product is shaped.

Formulations of the present invention suitable for oral administration may be in the form of: capsules (including dispersible capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilizates, powders, granules; or as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as elixirs or syrups; or in the form of soft tablets (using inert bases such as gelatin and glycerol, or sucrose and acacia) and/or in the form of mouthwashes and the like, each containing a predetermined amount of a compound of the invention as active ingredient. The compositions or compounds may also be administered in the form of a bolus, lick, or paste.

To prepare solid dosage forms for oral administration (capsules (including both dispersion and gelatin capsules), tablets, pills, sugar-coated tablets, powders, granules, and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers (e.g., sodium citrate or dicalcium phosphate) and/or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) slow solvents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; and (11) a colorant. In the case of capsules (including dispersion-type capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

Tablets may be prepared by compression or moulding, optionally containing one or more accessory ingredients. Compressed tablets may be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrating agents (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agents. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions (e.g., sugar-coated tablets, capsules (including dispersible capsules and gelatin capsules), pills, and granules) can optionally be scored or prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical compounding art. It may also be formulated, for example, with hydroxypropylmethylcellulose in varying proportions to provide the desired release properties, other polymer matrices, liposomes and/or microspheres to provide slow or controlled release of the active ingredient therein. It may be sterilized, for example, by filtration through a bacteria-retaining filter or by the inclusion of a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately prior to use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may, if appropriate, also be in microencapsulated form containing one or more of the abovementioned excipients.

Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophilizates for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and derivatives thereof; solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyethylene oxide sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations of pharmaceutical compositions for rectal, vaginal or urethral administration may be presented as suppositories which can be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which are solid at room temperature but liquid at body temperature and therefore can melt in the rectum or vaginal cavity and release the active compound.

Formulations of pharmaceutical compositions for administration to the oral cavity may be presented as a mouthwash, or an oral spray or an oral ointment.

Alternatively or additionally, the composition may be formulated for delivery through a catheter, stent, guidewire, or other intraluminal device. Delivery by the device is particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine.

Formulations suitable for vaginal administration also include pessary, tampon, cream, gel, paste, foam or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants which may be required.

Ointments, pastes, creams and gels may contain, in addition to the active compound, excipients, for example animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the active compound, excipients, for example lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays can additionally contain conventional propellants, such as chlorofluorohydrocarbons and unsubstituted volatile hydrocarbons, such as butane and propane.

Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. The dosage forms may be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate of flux can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, ophthalmic ointments, powders, solutions, and the like are also encompassed within the scope of the invention. Exemplary ophthalmic formulations are described in U.S. publication Nos. 2005/0080056, 2005/0059744, 2005/0031697, and 2005/004074, and U.S. patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, the liquid ophthalmic formulation has properties similar to those of tears, aqueous humor, or vitreous humor or is compatible with the fluid. Preferably, the route of administration is topical (e.g., topical administration, such as eye drops, or administration via an implant).

The phrase "parenteral administration and administeration" as used herein means modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with: one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions; or a sterile powder that can be reconstituted into a sterile injectable solution or dispersion immediately prior to use, which can contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). For example, proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size (in the case of dispersants) and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, p-hydroxybenzoic acid, chlorobutanol, phenol sorbic acid, and the like. Isotonic agents, for example, sugars, sodium chloride, and the like may also be desirably included in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In some cases, to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials that have poor water solubility. The rate of drug absorption then depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of the drug is achieved by dissolving or suspending the parenterally administered drug form in an oil vehicle.

Injectable depot forms are prepared by forming microencapsulated matrices of the subject compounds in biodegradable polymers (e.g., polylactide-polyglycolide). Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

For use in the methods of the invention, the active compounds may be administered per se or in the form of pharmaceutical compositions containing, for example, from 0.1% to 99.5% (more preferably from 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

The method of introduction may also be provided by a replaceable or biodegradable device. Various slow release polymeric devices have been developed in recent years for controlled delivery of drugs, including protein biopharmaceuticals, and tested in vivo. Various biocompatible polymers (including hydrogels), including biodegradable and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.

The actual dosage amount of the active ingredient in the pharmaceutical composition can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, but which is not toxic to the patient.

The dosage value selected will depend upon a variety of factors including the activity of the particular compound or combination of compounds or esters, salts or amides thereof employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, body weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, to achieve a desired therapeutic effect, a physician or veterinarian can initially start a dosage of a pharmaceutical composition or compound that is less than the desired value and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" is meant a concentration of the compound sufficient to elicit the desired therapeutic effect. It will generally be appreciated that the effective amount of the compound will vary according to the weight, sex and medical history of the individual. Other factors that affect an effective amount can include, but are not limited to, the severity of the patient's condition, the disorder being treated, a stabilizer for the compound, and, if desired, another type of therapeutic agent to be administered with the compound of the invention. A greater total dose can be delivered by multiple administrations of the agent. Methods for determining potency and dosage are known to those skilled in the art (Isselbacher et al (1996) Harrison's Principles of Internalmedicine 13 th edition, 1814-1882, incorporated herein by reference).

In general, a suitable daily dose of active compound for use in the compositions and methods of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. The effective dose will generally depend on the factors described above.

If desired, an effective daily dose of the active compound may be administered in 1,2,3,4, 5,6 or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. In certain embodiments of the invention, the active compound may be administered twice or three times daily. In a preferred embodiment, the active compound will be administered once daily.

Generally, the patient receiving such treatment is any desired animal, including primates (particularly humans) and other mammals (e.g., horses, cattle, pigs, and sheep); and poultry and pets.

In certain embodiments, the compounds of the present invention may be used alone or administered in combination with another type of therapeutic agent. The phrase "co-administration," as used herein, refers to any form of administration of two or more different therapeutic compounds, such that the second compound is administered while the previously administered therapeutic compound is still effective in vivo (e.g., both compounds are effective simultaneously in a patient, which may include a synergistic effect of both compounds). For example, different therapeutic compounds may be administered in the same formulation or in separate formulations in parallel or sequentially. In certain embodiments, different therapeutic compounds may be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or 1 week of each other. Thus, the individual receiving the treatment may benefit from the combined effect of different therapeutic compounds.

In certain embodiments, the combined administration of a compound of the invention and one or more other therapeutic agents (e.g., one or more other chemotherapeutic agents) provides improved efficacy relative to each individual administration of the compound of the invention (e.g., a compound of formula I or Ia) or one or more other therapeutic agents. In certain such embodiments, the combined administration provides an additive effect, wherein additive effect refers to the sum of each of the effects of the individual administration of a compound of the invention and one or more other therapeutic agents.

The invention includes the use of pharmaceutically acceptable salts of the compounds of the invention in the compositions and methods of the invention. The term "pharmaceutically acceptable salt" as used herein includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic and other acids. Pharmaceutically acceptable salt forms may include forms in which the ratio of molecules comprising salt is other than 1: 1. For example, a salt may comprise more than one inorganic or organic acid molecule per base molecule, such as two hydrochloric acid molecules per molecule of a compound of formula I or formula II. As another example, a salt may comprise less than one molecule of an inorganic or organic acid per molecule of base, e.g., two molecules of a compound of formula I or formula II per molecule of tartaric acid.

In other embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkyl ammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benzylamine, benzathine, betaine, calcium hydroxide, choline, dinonol, diethanolamine, diethylamine, 2- (diethylamino) ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4- (2-hydroxyethyl) morpholine, piperazine, potassium, 1- (2-hydroxyethyl) pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.

The pharmaceutically acceptable acid addition salts may also be present in the form of various solvates, for example with water, methanol, ethanol, dimethylformamide and the like. Mixtures of the solvates may also be prepared. The source of the solvate may be from the solvent of the crystallization, which is either intrinsic in the solvent of the preparation or crystallization or extrinsic to the solvent.

Wetting agents, emulsifying agents and lubricating agents (e.g., sodium lauryl sulfate and magnesium stearate), as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

examples of pharmaceutically acceptable antioxidants include (1) water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like, (2) oil soluble antioxidants such as ascorbyl palmitate, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), lecithin, propyl gallate, α -tocopherol, and the like, and (3) metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Definition of

The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbyl C (O) -, preferably alkyl C (O) -.

The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and can be represented, for example, by the formula hydrocarbyl C (O) NH-.

The term "acyloxy" is art recognized and refers to a group represented by the general formula hydrocarbyl C (O) O-, preferably alkyl C (O) O-.

The term "alkoxy" refers to an alkyl, preferably a lower alkyl, group having an oxygen attached thereto. Representative alkoxy groups include methoxy, -OCF₃Ethoxy, propoxy, tert-butoxy and the like.

The term "cycloalkyloxy" refers to a cycloalkyl group having an oxygen attached thereto.

The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

The term "alkylaminoalkyl" refers to an alkyl group substituted with an alkylamino group.

The term "alkenyl" as used herein refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls," the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl. The substituents may be present on one or more carbons that may or may not be included in one or more double bonds. Further, the substituents include all those contemplated for alkyl groups, as discussed below, except for stability constraints. For example, substitution of alkenyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl or heteroaryl groups is contemplated.

"alkyl" or "alkane" is a fully saturated straight or branched chain nonaromatic hydrocarbon. Generally, unless otherwise defined, straight or branched chain alkyl groups have from 1 to about 20, preferably from 1 to about 10 carbon atoms. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. C₁-C₆Straight-chain or branched alkyl is also referred to as "lower alkyl".

In addition, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. If not otherwise specified, such substituents can include, for example, halogen, hydroxy, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, and the likeAcid esters, amino, amido, amidine, imine, cyano, nitro, azido, mercapto, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that the substituted moiety on the hydrocarbon chain may itself be substituted as desired. For example, substituents of substituted alkyl groups may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate) and silyl groups, as well as ethers, alkyl thiols, carbonyl (including ketones, aldehydes, carboxylates and esters), -CF₃CN, -CN, etc. Exemplary substituted alkyl groups are described below. Cycloalkyl may be further alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF₃And CN, etc.

The term "C_x-y"when used in conjunction with a chemical moiety (e.g., acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy) is intended to include groups containing from x to y carbons in the chain. For example, the term "C_x-yAlkyl "refers to a substituted or unsubstituted saturated hydrocarbon group containing x to y carbons in the chain (including straight chain and branched alkyl groups), including haloalkyl groups, such as trifluoromethyl and 2,2, 2-trifluoroethyl, and the like. C₀Alkyl indicates hydrogen (if the group is in the terminal position), bond (if it is in the interior). The term "C_2-yAlkenyl "and" C_2-yAlkynyl "refers to a substituted or unsubstituted, unsaturated aliphatic radical analog similar in length and possible substitution to the alkyl groups described above, but containing at least one double or triple bond, respectively.

The term "alkylamino" as used herein refers to an amino group substituted with at least one alkyl group.

The term "alkylthio" as used herein refers to an alkyl-substituted thiol group and may be represented by the general formula alkyl S-.

The term "alkynyl" as used herein refers to aliphatic groups containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls" which refer to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. The substituents may be present on one or more carbons that may or may not be included in one or more triple bonds. Further, the substituents include all those contemplated for alkyl groups, as discussed above, except for stability constraints. For example, substitution of alkynyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl or heteroaryl groups is contemplated.

The term "amide" as used herein refers to a group

Wherein each R is¹⁰Independently represent hydrogen or a hydrocarbyl group, or two R¹⁰Together with the N atom to which they are attached, form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, such as moieties that can be represented by:

wherein each R is¹⁰Independently represent hydrogen or a hydrocarbyl group, or two R¹⁰Together with the N atom to which they are attached, form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

The term "aminoalkyl" as used herein refers to an alkyl group substituted with an amino group.

The term "aralkyl" as used herein refers to an alkyl group substituted with an aryl group.

The term "aryl" as used herein includes substituted or unsubstituted monocyclic aromatic groups in which each atom in the ring is carbon. Preferably, the ring is a 5 to 7 membered ring, more preferably a 6 membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

The term "carbamate" is art-recognized and refers to a group

Wherein R is⁹And R¹⁰Independently represent hydrogen or a hydrocarbyl group (e.g. alkyl), or R⁹And R¹⁰Together with intervening atoms, form a heterocyclic ring having from 4 to 8 carbons in the ring structure.

The terms "carbocycle" and "carbocyclic", as used herein, refer to a saturated or unsaturated ring in which each atom in the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include cycloalkane rings in which all carbon atoms are saturated and cycloalkenes which contain at least one double bond. "carbocycle" includes 5 to 7 membered monocyclic rings and 8 to 12 membered bicyclic rings. Each ring of the bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycles include bicyclic molecules that share 1,2, or 3 or more atoms between the two rings. The term "fused carbocyclic ring" refers to bicyclic carbocyclic rings in which each ring shares two adjacent atoms with another ring. Each of the fused carbon rings may be selected from saturated, unsaturated, and aromatic rings. In exemplary embodiments, an aromatic ring (e.g., phenyl) may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Included within the definition of carbocycle are any combination of saturated, unsaturated and aromatic bicyclic rings, if valency permits. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo [2.2.1] heptane, 1, 5-cyclooctadiene, 1,2,3, 4-tetrahydronaphthalene, bicyclo [4.2.0] oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocyclic rings include decahydronaphthalene, naphthalene, 1,2,3, 4-tetrahydronaphthalene, bicyclo [4.2.0] octane, 4,5,6, 7-tetrahydro-1H-indene and bicyclo [4.1.0] hept-3-ene. The "carbocycle" may be substituted at any one or more positions capable of carrying a hydrogen atom.

"cycloalkyl" is a fully saturated cyclic hydrocarbon. "cycloalkyl" includes monocyclic and bicyclic rings. Typically, monocyclic cycloalkyl groups have 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise defined. The second ring of the bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl groups include bicyclic molecules that share 1,2, or 3 or more atoms between the two rings. The term "fused cycloalkyl" refers to bicyclic cycloalkyl groups in which each of the rings shares two adjacent atoms with the other ring. The second ring of the fused bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. "cycloalkenyl" is a cyclic hydrocarbon containing one or more double bonds.

The term "carbocyclylalkyl" as used herein refers to an alkyl group substituted with a carbocyclic group.

The term "carbonate" is art recognized and refers to the group-OCO₂-R¹⁰Wherein R is¹⁰Represents a hydrocarbon group.

The term "carboxy" as used herein refers to a compound of the formula-CO₂And H represents a group.

The term "ester" as used herein refers to the group-C (O) OR¹⁰Wherein R is¹⁰Represents a hydrocarbon group.

The term "ether" as used herein refers to a hydrocarbyl group linked to another hydrocarbyl group through an oxygen. Thus, the ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. The ethers may be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which may be represented by the general formula alkyl-O-alkyl.

The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo, and iodo.

The term "heteroaralkyl" ("heptalkyl" and "heteroaralkyl") as used herein refers to an alkyl group substituted with a heteroaryl group.

The term "heteroalkyl," as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein two heteroatoms are not adjacent.

The term "heteroalkylamino" as used herein refers to an amino group substituted with a heteroalkyl group.

The terms "heteroaryl" and "heteroaryl" include substituted or unsubstituted aromatic monocyclic ring structures, preferably 5 to 7 membered, more preferably 5 to 6 membered, which ring structures comprise at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is a heteroaromatic ring, e.g., the other rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur.

The terms "heterocyclyl", "heterocyclic" ("heterocyclic" and "heterocyclic") refer to a substituted or unsubstituted non-aromatic ring structure, preferably a 3 to 10 membered ring, more preferably a 3 to 7 membered ring, which ring structure includes at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocycle" also include polycyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is a heterocycle, e.g., the other rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclic groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. The heterocyclic group may also be substituted by oxo. For example, "heterocyclyl" encompasses both pyrrolidine and pyrrolidone.

The term "heterocycloalkyl" as used herein refers to an alkyl group substituted with a heterocyclic group.

The term "heterocycloalkylamino" as used herein refers to an amino group substituted with a heterocycloalkyl group.

The term "hydrocarbyl" as used herein refers to a group bonded through a carbon atom and not having an ═ O or ═ S substituent, and which typically has at least one carbon-hydrogen bond and (predominantly) a carbon backbone, but may optionally include heteroatoms. Thus, for purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl may be considered hydrocarbyl groups, but substituents such as acetyl (which has an ═ O substituent on the connecting carbon) and ethoxy (which is connected through oxygen rather than carbon) are not hydrocarbyl groups. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term "hydroxyalkyl" as used herein refers to an alkyl group substituted with a hydroxyl group.

The term "lower" when used in conjunction with a chemical moiety (e.g., acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy) is intended to include groups in which 10 or fewer, preferably 6 or fewer, non-hydrogen atoms are present in the substituent. "lower alkyl" refers to, for example, alkyl groups containing 10 or fewer, preferably 6 or fewer, carbon atoms. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy substituents as defined herein are each lowercarbonyl, lowercacyloxy, lowercalkyl, lowercalkenyl, lowercalkynyl or lowercalkoxy, whether occurring alone or in combination with other substituents, for example in the listing of hydroxyalkyl and aralkyl groups (in which case, for example, when counting carbon atoms in an alkyl substituent, atoms within an aryl group are not counted).

The term "oxo" as used herein isRefers to a carbonyl group. Where an oxo substituent is present on an otherwise saturated group, such as an oxo-substituted cycloalkyl (e.g., 3-oxo-cyclobutyl), the substituted group is still intended to be a saturated group. Where a group is said to be substituted by "oxo", this may mean that the carbonyl moiety (i.e., -C (═ O) -) replaces the methylene unit (i.e., -CH)₂-)。

The terms "polycyclic" ("polycyclyl", "polycycle" and "polycylic") refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are "fused rings". Each ring of the polycyclic ring may be substituted or unsubstituted. In certain embodiments, each ring of the polycyclic ring contains from 3 to 10, preferably from 5 to 7, atoms in the ring.

The term "silyl" refers to a silicon moiety to which three hydrocarbyl moieties are attached.

The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It is understood that "substitution" or "substitution with … …" includes the implicit premise that the substitution will be consistent with the allowed valences of the substituted atom and substituent, and that the substitution will result in a stable compound, e.g., that it will not spontaneously transform (e.g., by rearrangement, cyclization, elimination, etc.). The term "substituted" as used herein is intended to include all permissible substituents of organic compounds. Broadly, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For suitable organic compounds, the permissible substituents may be one or more and may be the same or different. For purposes of the present invention, a heteroatom (e.g., nitrogen) may have a hydrogen substituent that meets the valence requirements of the heteroatom and/or any permissible substituents of organic compounds described herein. Substituents may include any of the substituents described herein, for example, halogen, hydroxy, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, thiol, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be appreciated by those skilled in the art that the substituents may themselves be substituted as desired. Unless specifically stated as "unsubstituted," chemical moieties referred to herein are understood to include substituted variations. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variations.

The term "sulfate" is art recognized and refers to the group-OSO₃H or a pharmaceutically acceptable salt thereof.

The term "sulfonamide" is art recognized and refers to a group represented by the general formula:

wherein R is⁹And R¹⁰Independently represent hydrogen or a hydrocarbyl group (e.g. alkyl), or R⁹And R¹⁰Together with intervening atoms, form a heterocyclic ring having from 4 to 8 carbons in the ring structure.

The term "sulfoxide" is art recognized and refers to the group-S (O) -R¹⁰Wherein R is¹⁰Represents a hydrocarbon group.

The term "sulfonate" is art recognized and refers to the group SO₃H or a pharmaceutically acceptable salt thereof.

The term "sulfone" is art recognized and refers to the group-S (O)₂-R¹⁰Wherein R is¹⁰Represents a hydrocarbon group.

The term "thioalkyl" as used herein refers to an alkyl group substituted with a thiol group.

The term "thioester" as used herein"means a group-C (O) SR¹⁰or-SC (O) R¹⁰Wherein R is¹⁰Represents a hydrocarbon group.

The term "thioether", as used herein, is equivalent to an ether, wherein oxygen is replaced by sulfur.

The term "urea" is art recognized and may be represented by the general formula

Wherein R is⁹And R¹⁰Independently represent hydrogen or a hydrocarbyl group (e.g. alkyl), or R⁹And R¹⁰At each occurrence, together with the intervening atoms, form a heterocyclic ring having from 4 to 8 carbons in the ring structure.

"protecting group" refers to a group of atoms that masks, reduces, or prevents the reactivity of a functional group when attached to a reactive functional group in a molecule. In general, the protecting group can be selectively removed during the synthetic process, if desired. Examples of protecting Groups are found in Green (Greene) and Wuss (Wuts), protecting Groups in Organic Chemistry (Protective Groups in Organic Chemistry), 3 rd edition, 1999, John Wiley's father, John Wiley & Sons, New York (NY) and Harrison et al, summary of Synthetic Organic Methods (Compendium of Synthetic Organic Methods), volumes 1-8, 1971-1996, John Wiley's son, New York. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC"), and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers (e.g., ethylene glycol and propylene glycol derivatives), and allyl ethers.

As used herein, a therapeutic agent that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the incidence of the disorder or condition in a treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to an untreated control sample.

The term "treatment" includes prophylactic and/or therapeutic treatment. The term "prophylactic or therapeutic" treatment is art-recognized and includes the administration of one or more subject compositions to a subject. If it is administered prior to clinical expression of the unwanted condition (e.g., a disease or other unwanted state of the host animal), the treatment is prophylactic (i.e., it protects the host from the unwanted condition), whereas if it is administered after expression of the unwanted condition, the treatment is therapeutic (i.e., it is intended to reduce, ameliorate or stabilize the existing unwanted condition or its side effects).

The term "prodrug" is intended to encompass compounds that are converted under physiological conditions to the therapeutically active agents of the invention (e.g., compounds of formula I). A common method of making prodrugs is to include one or more selective moieties that hydrolyze under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the invention. In certain embodiments, some or all of the compounds of formula I in the formulations indicated above may be replaced by the corresponding suitable prodrugs, for example, wherein the hydroxy group in the parent compound is present as an ester or carbonate, or the carboxylic acid present in the parent compound is present as an ester.

The term "MK 2-associated disorder" is a disorder or condition in which MK2 plays a role in the incidence or symptoms of a disease or disorder. For example, MK 2-related disorders include, but are not limited to, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, angiogenic disorders, infectious diseases, neurodegenerative diseases, and viral diseases.

The term "inflammatory disorder" or "inflammatory disease" as used herein includes diseases and disorders that are caused by or primarily by inflammation, as well as diseases and disorders in which inflammation plays a role in the incidence or symptoms of the disease or disorder, the spread of the disease or disorder, the worsening of the symptoms of the disease or disorder, and/or the worsening of prognosis or survival time for the patient due to the disease or disorder.

Examples of the invention

Examples of compounds of formula (I) or formula (II) or pharmaceutically acceptable salts thereof having useful biological activity are described below. The preparation of these compounds can be accomplished by those skilled in the art of organic synthesis using known techniques and methods.

A. Chemical synthesis

The general procedures used in the methods to prepare the compounds of the present invention are described below.

Scheme 1

4-bromo-1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, S2. to a solution of 4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (120g,588mmol,1.0eq.) in MeCN (1200mL) at 0 deg.C was added DMAP (7.2g,58mmol,0.1eq.) followed by (Boc)₂O (141g,647mmol,1.1 eq.). The mixture was stirred at 25 ℃ for 2 hr. The mixture was concentrated and the residue was dissolved in ethyl acetate (2.0L). The solution was washed with ice 1M HCl (200 mL. multidot.2), saturated NaHCO₃Aqueous solution (200mL) and brine (100 mL). Passing the organic phase over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to yield crude 4-bromo-1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (174g) as a yellow oil, which was used in the next step without further purification. TLC R_f0.77 (petroleum ether: ethyl acetate: 5: 1). 1H NMR (400MHz, chloroform-d) δ 7.29(d, J1.8 Hz,1H),6.77(d,J＝1.3Hz,1H),3.82(s,3H),1.56(s,9H)。

4- (4-cyanophenyl) -1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, S3. 4-bromo-1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (131g,432mmol,1.0eq.), (4-cyanophenyl) boronic acid (95.3g,648.5mmol,1.5eq.), Na₂CO₃(91g,864mmol,2.0 eq.) and (Boc)₂O(141g,648mmol,1.5eq.)、Pd(dppf)Cl₂(15.8g,21.6mmol,0.05eq.) in dioxane/H₂The suspension in O (4.9L,10:1) was degassed and then in N₂Heating to 80 deg.C to 100 deg.C for 12 hr. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (3.0L) and brine (500 mL). Subjecting the organic layer to anhydrous Na₂SO₄Dried, filtered and concentrated to give crude 4- (4-cyanophenyl) -1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as yellow oil (150g), which was used in the next step without further purification. ESI [ M + H ]]＝327.2

4- (4-cyanophenyl) -1H-pyrrole-2-carboxylic acid methyl ester, S4. A solution of 4- (4-cyanophenyl) -1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (150g, crude) in TFA (500mL) was stirred at 50 ℃ for 2 hr. The solution was concentrated under reduced pressure. MeOH (300mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give methyl 4- (4-cyanophenyl) -1H-pyrrole-2-carboxylate (80g,353mmol) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 12.30(br.s.,1H),7.84(d, J ═ 8.4Hz,2H),7.79-7.69(m,3H),7.33(br.s.,1H),3.80(s, 3H). ESI [ M + H ] ═ 227.1

Scheme 2

5-bromo-2-nitrobenzoic acid, S6. A suspension of 3-bromobenzoic acid (249g,1.24mol,1.0eq.) in concentrated sulfuric acid (800mL) was cooled at 0 ℃. Concentrated nitric acid (57.1mL,1.2mol) was added dropwise and the mixture was warmed to 20 ℃ and stirred for 1 hr. The mixture was poured into ice water (2L). The precipitate was collected by filtration, washed with water (1000mL × 2) and dried to give 5-bromo-2-nitrobenzoic acid (280g,1.14mol, 91.94% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 14.12(br.s.,1H),8.00(d, J1.8 Hz,1H),7.98-7.90(m, 2H).

(5-bromo-2-nitrophenyl) methanol, S7. to a solution of 5-bromo-2-nitrobenzoic acid (280g,1.14mol,1.0eq.) in THF (1.5L), BH was added dropwise over 30 minutes₃-Me₂S in THF (119.7mL,1.05eq.) at 10M. After addition, the mixture was heated to 70 ℃ and held for 3 hr. The mixture was cooled to 0 ℃, slowly quenched with MeOH (100mL) and then concentrated in vacuo. To the residue was added petroleum ether/ethyl acetate (1000mL,10:1) and stirred for 1 hr. The precipitate was collected by filtration to give (5-bromo-2-nitrophenyl) methanol (160g,689mmol, 60.49% yield) as a white solid. 1H NMR (400MHz, chloroform-d) δ 7.98-7.91(m,2H),7.55(dd, J1.8, 8.8Hz,1H),4.97(br.s.,2H),2.77(br.s., 1H). ESI [ M + H ]]＝232.2/234.2

Methyl 1- (5-bromo-2-nitrobenzyl) -4- (4-cyanophenyl) -1H-pyrrole-2-carboxylate, s8 to a solution of (5-bromo-2-nitrophenyl) methanol (80g,344mmol,1.0eq.) and TEA (48.8g,482mmol,1.40eq.) in DCM (1.5L) at 0 ℃ was added MsCl (41.4g,362mmol,1.05eq.) and the mixture was stirred at 20 ℃ for 0.5 hr. Subsequently 4- (4-cyanophenyl) -1H-pyrrole-2-carboxylic acid methyl ester (74.1g,327 mmo) was added to the solution at 0 deg.Cl,0.95eq.), followed by addition of tetrabutylammonium hydroxide (35.8g,34.5mmol,0.1eq.) and NaOH (69g,1724mmol,5.0 eq.) to H₂Solution in O (210 mL). The mixture was stirred at 20 ℃ for 10hr and then diluted with ice water (500mL) and DCM (2000 mL). Separating the organic layer over anhydrous Na₂SO₄Dried, filtered and concentrated. EtOH (200mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give methyl 1- (5-bromo-2-nitrobenzyl) -4- (4-cyanophenyl) -1H-pyrrole-2-carboxylate (127g,239mmol, 69.3% yield) as an off white solid. TLC: r_f0.32 (petroleum ether: ethyl acetate: 4: 1). 1H NMR (400MHz, DMSO-d6) δ 8.08(d, J8.8 Hz,1H),8.00(d, J1.8 Hz,1H),7.84-7.76(m,5H),7.55(d, J1.8 Hz,1H),6.71(d, J1.3 Hz,1H),5.86(s,2H),3.29(s, 3H). ESI [ M + H ]]＝440.1/442.1

1- (2-amino-5-bromobenzyl) -4- (4-cyanophenyl) -1H-pyrrole-2-carboxylic acid methyl ester, S9. 1- (5-bromo-2-nitrobenzyl) -4- (4-cyanophenyl) -1H-pyrrole-2-carboxylic acid methyl ester (125g,284mmol,1.00eq.), Fe (79g,1420mmol,5.0eq.) and NH₄Cl (76g,1420mmol,5.0eq.) in EtOH (800mL), H₂The suspension in O (400mL) and THF (800mL) was heated to 80 ℃ and held for 2 hr. The mixture was concentrated to dryness and to the residue was added hot THF (5.0L). The mixture was filtered and the filtrate was concentrated. EtOH (300mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give methyl 1- (2-amino-5-bromobenzyl) -4- (4-cyanophenyl) -1H-pyrrole-2-carboxylate (106g,242mmol, 85.54% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 7.88(br.s.,1H),7.85-7.68(m,4H),7.50(br.s.,1H),7.09(d, J ═ 7.9Hz,1H),6.62(d, J ═ 8.4Hz,1H),6.33(br.s.,1H),5.37(br.s.,4H),3.73(br.s., 3H). ESI [ M + H ]]＝410.2/412.2

4-(7-Bromo-11-oxo-10, 11-dihydro-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Azadipine-2-yl) benzonitrile, S10, to a suspension of methyl 1- (2-amino-5-bromobenzyl) -4- (4-cyanophenyl) -1H-pyrrole-2-carboxylate (105g,256mmol,1.0eq.) in toluene (1.5L) at 0 deg.C is added Me₃Al (2M in toluene, 500mL, 3.9eq.) and the mixture was stirred at 20 ℃ for 10 hr. The mixture was poured into 1M ice HCl (300mL) and extracted with hot EtOAc/THF (1:1,500mL 4). Subjecting the organic layer to anhydrous Na₂SO₄Dried, filtered and concentrated. EtOH (100mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give 4- (7-bromo-11-oxo-10, 11-dihydro-5H-benzo [ e ] as a white solid]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile (86g,166mmol, 65% yield). 1HNMR (400MHz, DMSO-d6) δ 10.30(s,1H),7.73(s,4H),7.66(dd, J ═ 2.0,4.2Hz,2H),7.50(dd, J ═ 2.2,8.4Hz,1H),7.27(d, J ═ 1.8Hz,1H),7.13(d, J ═ 8.8Hz,1H),5.21(s, 2H). ESI [ M + H ]]＝378.2/380.2

4- (7-bromo-11-chloro-5H-benzo [ e)]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile, S11, by reacting 4- (7-bromo-11-oxo-10, 11-dihydro-5H-benzo [ e ] at 100 DEG C]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile (6.2g,16mol,1.0eq.) in POCl₃The solution in (100mL) was stirred for 2 hr. The solution was concentrated under reduced pressure to give crude 4- (7-bromo-11-chloro-5H-benzo [ e ] as a dark brown oil]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile (16g, crude), which was used in the next step without further purification.

4- (7-bromo-9H-benzo [ e ]]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, S12, to 4- (7-bromo-11-chloro-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile (2g,4.4mmol,1eq.) in THF/dioxane (1:1,40mL)To the solution of (a) was added TEA to adjust pH 7. Formyl hydrazine (8g,133mmol,30.0eq.) was then added and the mixture was heated to 120 ℃ in a sealed tube and held for 10 hr. The mixture was concentrated to dryness and the residue was dissolved in hot EtOAc/THF (1:1, 2.0L). The solution was washed with ice 1M HCl (100 mL. multidot.2), saturated NaHCO₃Aqueous solution (100mL) and brine (100 mL). Passing the organic phase over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. MeOH (10mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give 4- (7-bromo-9H-benzo [ e ] as a yellow solid]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile (900mg,2.2mmol, 50.4% yield). 1H NMR (400MHz, DMSO-d6) δ 9.25(s,1H),7.97(br.s.,1H),7.82-7.76(m,6H),7.70(d, J ═ 8.5Hz,1H),7.28(s,1H),5.33(s, 2H). ESI [ M + H ]]＝402.1/404.1

General procedure A-Ullmann Reaction (Ullmann Reaction).

4- (12- (4-cyanophenyl) -9H-benzo [ e ]]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]T-butyl diazepine-7-yl piperazine-1-carboxylate, S13, prepared by reacting 4- (7-bromo-9H-benzo [ e ]]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile (30.0mg,74umol,1.0eq.), piperazine-1-carboxylic acid tert-butyl ester (41mg,223umol,3.0eq.), K₃PO₄A mixture of (47mg,223umol,3.0eq.), L-proline (4.2mg,37.2umol,0.5eq.) and CuI (14mg,74umol,1.0eq.) in DMSO (2mL) was degassed and treated at 100 ℃ under N₂Stirring for 12 hr. The mixture was diluted with ethyl acetate/THF (2:1,20mL) and filtered. The filtrate was washed with brine (5mL) and anhydrous Na₂SO₄Dried, filtered and concentrated to give 4- (12- (4-cyanophenyl) -9H-benzo [ e ] as a yellow solid]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]T-butyl diazepine-7-yl) piperazine-1-carboxylate (30mg, crude), which was used in the next step without further purification. ESI [ M + H ]]＝508.2

4- (7- (piperazin-1-yl) -9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 1-oriented 4- (12- (4-cyanophenyl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]T-butyl diazepine-7-yl piperazine-1-carboxylate (30mg,59.1umol,1.0eq.) in CH₂Cl₂(2mL) to the solution was added CF₃COOH (2mL) and the mixture was stirred at 40 ℃ for 30 min. The mixture was concentrated to dryness and the residue was purified by preparative HPLC to give 4- (7- (piperazin-1-yl) -9H-benzo [ e) as a yellow solid]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile (15mg,27.9umol, 47.2% yield). 1HNMR (400MHz, DMSO-d6) δ 9.13(s,1H),8.85(br.s.,2H),7.80-7.68(m,5H),7.57(d, J ═ 8.8Hz,1H),7.24(dd, J ═ 2.0,17.2Hz,2H),7.14(dd, J ═ 2.4,8.8Hz,1H),5.21(s,2H),3.23(br.s.,4H),2.52(br.s., 4H). ESI [ M + H ]]＝408.1

Scheme 3

General procedure C

((1- (12- (4-cyanophenyl) -9H-benzo [ e ]]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-7-yl) azetidin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester, S16. trans-4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Azadizepine-12-yl) benzonitrile (25mg,62.1umol,1.0eq.) to a solution in DMSO (2.0mL) was added tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate (17.6mg,74umol,1.2eq., HCl), pyrrolidine-2-carboxylic acid (3.6mg,31umol,0.5eq.), CuI (5.9mg,31umol,0.5eq.), and K₃PO₄(40mg,186umol,3.0 eq.). The mixture was heated at 100 ℃ under N₂Stirred for 12hr and then filtered. The filtrate was concentrated and passed through preparative TLC (SiO)₂DCM: MeOH ═ 20:1) purification, giving ((1- (12- (4-cyanophenyl) -9H-benzo [ e) a yellow oil]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-7-yl) azetidin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester (30mg,34.5umol, 55.5% yield, 60% purity), which was used in the next step without further purification. ESI [ M + H ]]＝522.3

4- (7- (3- ((methylamino) methyl) azetidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 11. a reaction of ((1- (12- (4-cyanophenyl) -9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-7-yl) azetidin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester (30.0mg,57.51umol,1.0eq.) in CF₃The solution in COOH (1.5mL) was stirred at 50 ℃ for 0.5hr and then concentrated under reduced pressure to give crude 4- (7- (3- ((methylamino) methyl) azetidin-1-yl) -9H-benzo [ e ] as a yellow oil]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile (30.00mg, crude, TFA), which was used in the next step without further purification. ESI [ M + H ]]＝422.1。

4- (7- (3- ((dimethylamino) methyl) azetidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 12, to 4- (7- (3- ((methylamino) methyl) azetidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile (30.0mg,71.17umol,1.0eq.) to a solution in MeOH (2.0mL) was added HCHO (57.7mg,711.7umol,10.0eq.) and the mixture was stirred at 15 deg.C for 2 hr. Followed byPost addition of NaBH₃CN (6.71mg,106.7umol,1.5eq.) and the mixture was stirred at 15 ℃ for 14 hr. The mixture was concentrated under reduced pressure and purified by preparative HPLC to give 4- (7- (3- ((dimethylamino) methyl) azetidin-1-yl) -9H-benzo [ e ] as a white solid]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile (6.0mg,13.6umol, 19.1% yield, 99% purity). 1HNMR (400MHz, methanol-d 4) δ 9.12(br.s.,1H),7.78-7.62(m,5H),7.51(d, J ═ 8.7Hz,1H),7.25(br.s.,1H),6.71(d, J ═ 2.4Hz,1H),6.61(dd, J ═ 2.4,8.7Hz,1H),5.17(s,2H),4.21(t, J ═ 7.8Hz,2H),3.82-3.74(m,2H),3.54(d, J ═ 7.3Hz,2H),3.29-3.23(m,1H),2.95(s, 6H). ESI [ M + H ]]＝436.2

Scheme 5

General procedure E

4- (7- (2- ((dimethylamino) methyl) morpholinyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, S18. synthesized using general procedure A with N, N-dimethyl-1- (morpholin-2-yl) methylamine instead of piperazine-1-carboxylic acid tert-butyl ester. ESI [ M + H ] ═ 466.2

(S) -4- (7- (2- ((dimethylamino) methyl) morpholinyl) -9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Azadipine-12-yl) benzonitrile, 23, isolation of 4- (7- (2- ((dimethylamino) methyl) morpholinyl) -9H-benzo [ e ] by SFC]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, thereby yielding (S) -4- (7- (2- ((dimethylamino) methyl) morpholinyl) -9H as a white solid-benzo [ e ]]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile. 1H NMR (400MHz, methanol-d)₄)δ＝9.01(s,1H),7.74-7.68(m,2H),7.68-7.63(m,2H),7.61(s,1H),7.54(d,J＝8.8Hz,1H),7.21(d,J＝4.4Hz,2H),7.10(dd,J＝2.2,8.8Hz,1H),5.18(s,2H),4.10(d,J＝9.7Hz,1H),4.00(t,J＝9.3Hz,1H),3.87-3.78(m,1H),3.72(d,J＝11.5Hz,1H),3.64(d,J＝11.9Hz,1H),3.17-3.01(m,2H),2.90(dt,J＝3.1,11.9Hz,1H),2.76(s,6H),2.59(t,J＝11.0Hz,1H)。ESI[M+H]＝466.2

Scheme 7

General procedure G

((trans-1- (12- (4-cyanophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-7-yl) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamic acid benzyl ester, S22. synthesized using general procedure A using ((trans-4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamic acid benzyl ester in place of piperazine-1-carboxylic acid tert-butyl ester. ESI [ M + H ] ═ 586.2

4- (7- (trans-3-hydroxy-4- ((methylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 72, to ((trans-1- (12- (4-cyanophenyl) -9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Benzyl diazepine-7-yl) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamate (30mg,20umol,1.0eq.) to a solution in DCM (2.0mL) was added TMSI (20.5mg,102.4umol,14uL,5.0 eq.). Stirring the mixture at 26 deg.C for 0.5hrAnd then concentrated. The residue was purified by acidic preparative HPLC to give 4- (7- (trans-3-hydroxy-4- ((methylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e) as a yellow solid]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile (1.93mg,3.28umol, 16% yield).¹H NMR (400MHz, methanol-d)₄)δ＝9.00(s,1H),7.77-7.70(m,2H),7.70-7.64(m,2H),7.62(s,1H),7.50(d,J＝8.8Hz,1H),7.23(s,1H),6.80(d,J＝2.2Hz,1H),6.70(dd,J＝2.6,8.8Hz,1H),5.18(s,2H),4.30(q,J＝6.6Hz,1H),3.78-3.64(m,2H),3.27-3.10(m,4H),2.77(s,3H),2.62-2.52(m,1H)。ESI[M+H]＝452.1

Scheme 8

General procedure H

4- (7- (4-hydroxypiperidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, S23. synthesized using general procedure A using piperidin-4-ol in place of tert-butyl piperazine-1-carboxylate. ESI [ M + H ] ═ 423.2

4- (7- (4-oxopiperidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, S24 to a solution of 4- (7- (4-hydroxypiperidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile (690mg,1.6mmol,1.0eq.) in DCM (20mL) was added Dess-Martin (898mg,2.1mmol,1.3eq.) in one portion and the mixture was stirred at 20 ℃ for 16 hr. After completion of the reaction, the mixture was filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (DCM: MeOH ═ 20:1, Rf ═ 0.50) to give 4- (7- (4-oxopiperidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile as a yellow solid (600mg, 78.8% yield, 90% purity). 1HNMR (400MHz, DMSO-d6) δ 9.14-9.07(m,1H),7.80-7.68(m,5H),7.57-7.49(m,1H),7.27(d, J ═ 2.6Hz,1H),7.20(d, J ═ 1.8Hz,1H),7.13(dd, J ═ 2.6,8.8Hz,1H),5.25-5.14(m,2H),3.68(t, J ═ 5.8Hz,4H),2.44-2.34(m, 4H). ESI [ M + H ] ═ 421.0

(S) -4- (7- (4- ((1-hydroxyprop-2-yl) amino) piperidin-1-yl) -9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, S25. reacting 4- (7- (4-oxopiperidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]A mixture of diazepine-12-yl) benzonitrile (40mg, 95. mu. mol,1.0eq.) and (2S) -2-aminopropan-1-ol (7.1mg, 95.1. mu. mol,1.0eq.) in MeOH (3.0mL) is stirred at 25 ℃ for 2hr, followed by addition of Ti (i-PrO)₄(5.4mg,19.0umol,5.6uL,0.2eq.) and NaBH₃CN (11.9mg,190.2umol,2.0 eq.). The mixture was stirred at 25 ℃ for 10hr and concentrated. The residue was purified by preparative HPLC (TFA conditions) to give (S) -4- (7- (4- ((1-hydroxyprop-2-yl) amino) piperidin-1-yl) -9H-benzo [ e ] as a white solid]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile (15.8mg,26.7umol, 28% yield, 100% purity, TFA salt). 1H NMR (400MHz, methanol-d 4) δ 9.04(s,1H),7.74-7.57(m,5H),7.51(d, J8.8 Hz,1H),7.25-7.18(m,2H),7.11(dd, J2.2, 8.8Hz,1H),5.16(s,2H),4.00(d, J12.8 Hz,2H),3.82(dd, J3.5, 11.9, 1H),3.64-3.41(m,3H),2.94(t, J12.1 Hz,2H),2.18(d, J11.5 Hz,2H),1.90-1.65(m,2H),1.33(d, J6.6, 3H). ESI [ M + H ]]＝480.2

(S) -4- (7- (4- ((1-hydroxyprop-2-yl) ((S))Methyl) amino) piperidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 104, (S) -4- (7- (4- ((1-hydroxyprop-2-yl) amino) piperidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]A mixture of diazepine-12-yl) benzonitrile (20mg,41.7umol,1.0eq.) and formaldehyde (16.9mg,208.5umol,15.5uL,5.0eq.) in MeOH (2.0mL) was stirred at 30 ℃ for 1hr, followed by addition of NaBH₃CN (5.2mg,83.4umol,2.0eq.) and the mixture was stirred for 1 hr. The mixture was concentrated and the residue was purified by preparative HPLC (TFA conditions) to give (S) -4- (7- (4- ((1-hydroxypropan-2-yl) (methyl) amino) piperidin-1-yl) -9H-benzo [ e ] as a white solid]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile (4.5mg,7.2umol, 17.4% yield, 98% purity, TFA). 1H NMR (400MHz, methanol-d 4) δ 9.04(d, J3.5 Hz,1H),7.76-7.59(m,5H),7.53(d, J8.8 Hz,1H),7.26-7.20(m,2H),7.12(d, J9.3 Hz,1H),5.19(s,2H),4.04(d, J12.3 Hz,2H),3.83-3.74(m,2H),3.63(d, J4.0 Hz,2H),2.92(t, J12.6 Hz,2H),2.84(s,1H),2.76(s,2H),2.34-2.13(m,2H),1.99-1.75(m,2H),1.37 (m,2H), 1.6 (J), 1.27H, 1H, 27H, 1H, 27H). ESI [ M + H ]]＝494.2

Scheme 9

The chemical experiment method comprises the following steps:

4- (7-bromo-11- ((2, 2-dimethoxyethyl) amino) -5H-benzo [ e ] pyrrolo [1,2-a ] [1,4] diazepin-2-yl) benzonitrile, S26. to a solution of 4- (7-bromo-11-chloro-5H-benzo [ e ] pyrrolo [1,2-a ] [1,4] diazepin-2-yl) benzonitrile (2.1g,5.2mmol,1.0eq.) in THF (20mL) and dioxane (40mL) was added 2, 2-dimethoxyethylamine (8.8g,83.8mmol,15eq.) and the mixture was heated in a sealed tube at 100 ℃ for 16 hr. The resulting mixture was concentrated and then partitioned between EtOAc (1000mL) and 0.5M HCl (150 mL). The organic layer was dried and concentrated to give 4- (7-bromo-11- ((2, 2-dimethoxyethyl) amino) -5H-benzo [ e ] pyrrolo [1,2-a ] [1,4] diazepin-2-yl) benzonitrile (1.6g) as a brown solid. 1H NMR (400MHz, DMSO-d6) δ 11.51(s,1H),10.15(s,1H),8.01-7.27(m,9H),5.38(s,2H),4.77(s,1H),3.98-3.90(s,2H),3.57-3.39(s, 6H). ESI [ M + H ] ═ 464.9/466.9

4- (7-bromo-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile, S27. A mixture of 4- (7-bromo-11- ((2, 2-dimethoxyethyl) amino) -5H-benzo [ e ] pyrrolo [1,2-a ] [1,4] diazepine-2-yl) benzonitrile (1.6g,3.4mmol,1.0eq.) in 1M HCl (60mL) and dioxane (60mL) is stirred at 60 ℃ for 20 hr. The reaction mixture was concentrated to give 4- (7-bromo-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile (1.4g, crude) as a gray solid, which was used in the next step without further purification. 1HNMR (400MHz, DMSO-d6) δ ═ 8.30(s,1H),8.01(s,1H),7.93(s,2H),7.86-7.83(m,4H),7.76-7.70(m,2H),7.46(s,1H),5.47(s, 2H). ESI [ M + H ] ═ 401.0/402.9

4- (7- (2-methyl-2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 125. use general procedure C to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] diazepin-12-yl) benzonitrile with 4- (7-bromo-9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile with 2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.99(d, J1.8 Hz,1H),7.78-7.67(m,6H),7.54(d, J8.8 Hz,1H),7.28(s,1H),6.84-6.72(m,2H),5.29(s,2H),4.40-4.24(m,2H),4.20-4.06(m,2H),3.71-3.59(m,2H),3.46(br.s.,2H),2.98(br.s.,3H),2.40(br.s., 2H). ESI [ M + H ] ═ 447.1

Scheme 10

General procedure I

4- (7-bromo-11-chloro-9H-benzo [ e ]]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, S29, to 4- (7-bromo-9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile (1.0g,2.5mmol,1.0eq.) to a solution in THF (20mL) and DMF (30mL) was added NCS (399mg,3mmol,1.2eq.) and the mixture was stirred at 25 ℃ for 16 hr. The reaction mixture was concentrated and passed through column chromatography (SiO)₂Petroleum ether/ethyl acetate/THF 5/1/1 to 1/1/1) to give 4- (7-bromo-11-chloro-9H-benzo [ e) as a gray solid]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile (760mg,1.7mmol, 69.8% yield). ESI [ M + H ]]＝435.9/437.9

Tert-butyl (S) - ((1- (11-chloro-12- (4-cyanophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-7-yl) pyrrolidin-3-yl) methyl) carbamate, S30.

Synthesized using general procedure A using 4- (7-bromo-11-chloro-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and (R) - (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester in place of piperazine-1-carboxylic acid tert-butyl ester. ESI [ M + H ] ═ 556.4

(R) - ((1- (11-chloro-12- (4-cyanophenyl) -9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-7-yl) pyrrolidin-3-yl) methyl) (methyl) carbamic acid tert-butyl ester, S31, to (S) - ((1- (11-chloro-12- (4-cyanophenyl) -9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]T-butyl diazepine-7-yl) pyrrolidin-3-yl) methyl) carbamate (15mg,26.9umol,1.0eq.) and MeI (11.4mg,80.9umol,5.04uL,3.0eq.) to a solution in DMF (2.0mL) was added NaH (2.1mg,53.9umol, 60% purity, 2.0eq.) and the mixture was stirred at 25 ℃ for 20 min. The mixture was then poured into water (10mL) and extracted with EtOAc (30mL × 3). The organic layer was washed with brine (10mL) over MgSO₄Dried, filtered and concentrated to give crude (R) - ((1- (11-chloro-12- (4-cyanophenyl) -9H-benzo [ e) as a brown oil]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]T-butyl diazepine-7-yl) pyrrolidin-3-yl) methyl) (methyl) carbamate (20mg), which was used in the next step without further purification. ESI [ M + H ]]＝570.1

A solution of (S) -4- (11-chloro-7- (3- ((methylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile 173. tert-butyl (R) - ((1- (11-chloro-12- (4-cyanophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methyl) (methyl) carbamate (20mg,35umol,1.0eq.) in TFA (2.0mL) was stirred at 50 ℃ for 5 min. The reaction was concentrated and purified by preparative HPLC (TFA conditions) to give (S) -4- (11-chloro-7- (3- ((methylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile (2.31mg,3.83umol, 10.91% yield, 96.8% purity, TFA salt) as a yellow solid. 1H NMR (400MHz, methanol-d 4) δ 9.03(br.s.,1H),7.87-7.79(m,2H),7.78-7.70(m,2H),7.51(d, J ═ 8.8Hz,1H),7.13(s,1H),6.80(d, J ═ 2.2Hz,1H),6.73(dd, J ═ 2.4,8.8Hz,1H),5.25(br.s.,2H),3.68-3.58(m,1H),3.53(dt, J ═ 3.9,8.9Hz,1H),3.48-3.38(m,1H),3.24-3.10(m,3H),2.82-2.66(m,4H),2.33(dd, 4H), 5.11, 4H, 1H), 8.8.8, 1H, 3.9 (q.9 Hz, 3H). ESI [ M + H ] ═ 470.1

Scheme 11

The chemical experiment method comprises the following steps:

4- (7-bromo-3-methyl-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, S32, to 4- (7-bromo-11-chloro-5H-benzo [ e]Pyrrolo [1,2-a][1,4]To a solution of diazepine-2-yl) benzonitrile (2.1g,5.3mmol,1.0eq.) in toluene/THF (5:2,70mL) was added prop-2-yn-1-amine (5g,91.1mmol,17.2eq.) and the mixture was heated at 120 ℃ for 56hr in a sealed tube. The resulting mixture was concentrated and partitioned between THF/EtOAc (1:1,200mL) and 0.25M ice HCl (100 mL). The separated aqueous layer was extracted with THF/EtOAc (1:1,100 mL. times.3). The combined organic layers were washed with brine (100mL) over anhydrous MgSO₄Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 4- (7-bromo-3-methyl-9H-benzo [ e ] as a gray solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile (1.8g,3.0mmol, 57% yield). 1H NMR (400MHz, chloroform-d) δ 7.63(s,1H),7.63-7.51(m,5H),7.20(d, J8.4 Hz,1H),7.13(d, J1.6 Hz,1H),7.07(s,1H),7.01(s,1H),5.07(d,14.0Hz,1H),4.81(d,14.2Hz,1H),2.38(s, 3H). ESI [ M + H ]]＝415.2/417.2

4- (3-methyl-7- (2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile 201 using general procedure A with 4- (7-bromo-3-methyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, Synthesized using tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate instead of piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.81(s,1H),7.78-7.72(m,4H),7.59(s,1H),7.50(d, J ═ 8.8Hz,1H),7.28(s,1H),6.88(br.s.,1H),6.77(d, J ═ 8.8Hz,1H),5.26(s,2H),4.23-4.17(m,2H),4.15-4.08(m,2H),3.67(s,2H),3.50(t, J ═ 6.8Hz,2H),2.53(s,3H),2.43(t, J ═ 6.8Hz, 2H). ESI [ M + H ] ═ 447.1

Scheme 12

The chemical experiment method comprises the following steps:

4- (7-bromo-11-oxo-10- (2-oxopropyl) -10, 11-dihydro-5H-benzo [ e)]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile, S34, to 4- (7-bromo-11-oxo-10, 11-dihydro-5H-benzo [ e ] at 15 DEG C]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile (2.5g,6.6mmol,1.0eq.), 18-crown-6 (192mg,727umol,0.11eq.) and K₂CO₃(5.0g,36.1mmol,5.4eq.) to a mixture in DMF (40mL) was added 1-chloroprop-2-one (12g,129.7mmol,19.6 eq.). The reaction mixture was heated to 70 ℃ (oil bath) and stirred for 4 days. The reaction mixture was concentrated in vacuo, diluted with EtOAc (100mL), washed with water (10 mL. times.2) and brine (50mL), and washed with Na₂SO₄Drying, followed byConcentration to give 4- (7-bromo-11-oxo-10- (2-oxopropyl) -10, 11-dihydro-5H-benzo [ e ] as a dark brown oil]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile (3.0g, crude), which was used as such without purification. ESI [ M + H ]]＝434.0/436.0

4- (7-bromo-2-methyl-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, S35, from 4- (7-bromo-11-oxo-10- (2-oxopropyl) -10, 11-dihydro-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile (2.5g,5.7mmol,1.0eq.) and NH₄A mixture of OAc (25g,324mmol,56.3eq.) in AcOH (200mL) was stirred at 120 ℃ for 48 hr. The mixture was concentrated and the residue was purified by preparative HPLC (TFA) to give 4- (7-bromo-2-methyl-9H-benzo [ e ] as a brown solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile (450mg,845umol, 14.68% yield, 78% purity), which is used as such. ESI [ M + H ]]＝414.8/416.8

4- (7- (cis-3, 5-dimethylpiperazin-1-yl) -2-methyl-9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 215 using general procedure A with 4- (7-bromo-2-methyl-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and using cis-2, 6-dimethylpiperazine instead of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝7.83-7.69(m,6H),7.62(d,J＝8.8Hz,1H),7.32(dd,J＝2.2,11.9Hz,2H),7.26(dd,J＝2.6,8.8Hz,1H),5.35(s,2H),4.08(d,J＝11.5Hz,2H),3.51(d,J＝6.8Hz,2H),2.82(dd,J＝11.6,13.3Hz,2H),2.49(s,3H),1.42(d,J＝6.4Hz,6H)。ESI[M+H]＝449.2

Scheme 13

The chemical experiment method comprises the following steps:

4- (7-bromo-11-oxo-10- (3-oxobutan-2-yl) -10, 11-dihydro-5H-benzo [ e)]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile, S36, to 4- (7-bromo-11-oxo-10, 11-dihydro-5H-benzo [ e]Pyrrolo [1,2-a][1,4]To a solution of diazepine-2-yl) benzonitrile (1.0g,2.6mmol,1.0eq.) and 3-chlorobutan-2-one (560mg,2.0eq.) in DMF (20mL) was added K₂CO₃(1.8g,13.2mmol,5.0eq.) and 18-C-6(348mg,1.3mmol,0.5 eq.). The mixture was stirred at 70 ℃ for 12hr and poured into ice water (100 mL). The mixture was extracted with ethyl acetate (200mL x 3), washed with brine (30mL x 2), and dried over anhydrous Na₂SO₄Dried, filtered and concentrated to give 4- (7-bromo-11-oxo-10- (3-oxobutan-2-yl) -10, 11-dihydro-5H-benzo [ e ] as a dark brown oil]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile (1.5g, crude). ESI [ M + H ]]＝447.9/449.9

4- (7-bromo-2, 3-dimethyl-9H-benzo [ e ]]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, S37. preparation of 4- (7-bromo-11-oxo-10- (3-oxobutan-2-yl) -10, 11-dihydro-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile (1.5g,3.3mmol,1.0eq.) and NH₄Mixture of OAc (7.7g,100mmol,30.0eq.) in HOAc (50mL) in N₂Heating to 120 ℃ under atmosphere and holding for 16hr and then concentrating under reduced pressure. The residue was poured into ice water (50mL) and extracted with ethyl acetate/THF (1:1,30mL × 5). To be combinedThe organic phase was washed with brine (30 mL. times.2) and anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (TFA conditions) to give 4- (7-bromo-2, 3-dimethyl-9H-benzo [ e ] as a brown oil]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile (700mg,1.3mmol, 38.94% yield, 80% purity). ESI [ M + H ]]＝429.2/431.2

4- (7- (cis-3, 5-dimethylpiperazin-1-yl) -2, 3-dimethyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile 221 using general procedure A instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] - [1, 4-diazepine-12-yl) benzonitrile using cis-2, 6-dimethylpiperazine instead of tert-butyl piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.77-7.66(m,5H),7.52(d, J8.8 Hz,1H),7.35(br.s.,1H),7.28-7.17(m,2H),5.26(s,2H),4.07(d, J13.2 Hz,2H),3.50(br.s.,2H),2.87-2.76(m,2H),2.42(d, J4.4 Hz,6H),1.41(d, J6.2 Hz, 6H). ESI [ M + H ] ═ 463.2

Scheme 14

The chemical experiment method comprises the following steps:

4- (7-bromo-3-methyl-9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]-diazepine-12-yl) benzonitrile, S38. reacting 4- (7-bromo-11-chloro-5H-benzo [ e]-pyrrolo- [1,2-a][1,4]Diazepine-2-yl) benzonitrile (2.0g,5mmol,1.0eq.) and acethydrazide (74 g.)A solution of 6mg,10mmol,2.0eq.) in dioxane (25mL) was stirred at 110 ℃ for 16 hr. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with ice water (20mL) and extracted with hot ethyl acetate/THF (2:1,25mL × 3). The combined organic phases were washed with brine (30mL) and anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give a dark brown solid. The solid was washed with MeOH (10mL) to give 4- (7-bromo-3-methyl-9H-benzo [ e) as a pale yellow solid]Pyrrolo [1,2-a]-[1,2,4]Triazolo- [3,4-c][1,4]-diazepine-12-yl) benzonitrile (1.30g, crude). 1H NMR (400MHz, DMSO-d6) δ 7.97(s,1H),7.80-7.50(m,6H),7.70-7.64(m,1H),7.19(s,1H),5.34-5.13(m,2H),2.58(s, 3H).

4- (7- ((S) -3-aminopyrrolidin-1-yl) -3-methyl-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile 230. Using general procedure A4- (7-bromo-3-methyl-9H-benzo [ e ] pyrrolo- [1,2-a ] [1,2,4] -triazolo- [3,4-c ] [1,4] -diazepine-12-yl) benzonitrile instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] - [1,4] diazepine-12-yl) benzonitrile by replacing piperazine-1-carboxylic acid tert-butyl ester with (S) -pyrrolidin-3-ylcarbamic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.71-7.62(m,5H),7.46(d, J8.8 Hz,1H),7.23(br.s.,1H),6.89(br.s.,1H),6.75(d, J8.8 Hz,1H),5.17(br.s.,2H),4.07(br.s.,1H),3.75-3.60(m,2H),3.54-3.43(m,2H),2.70(br.s.,3H),2.55-2.44(m,1H),2.25-2.16(m, 1H). ESI [ M + H ] ═ 422.1

Scheme 15

The chemical experiment method comprises the following steps:

4- (7-bromo-9H-benzo [ e ]]Pyrrolo [1,2-a]Tetrazolo [5,1-c ]][1,4]Diazepine-12-yl) benzonitrile, S40. reacting 4- (7-bromo-11-chloro-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile (850mg,2.1mmol,1.0eq.) and TMSN₃(271.5mg,2.3mmol,1.1eq.) A mixture in DMF (10mL) was stirred at 10 ℃ for 16hr and then concentrated. MeOH (20mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give 4- (7-bromo-9H-benzo [ e ] as a red solid]Pyrrolo [1,2-a]Tetrazolo [5,1-c ]][1,4]Diazepine-12-yl) benzonitrile (600mg, 62.5% yield, 90% purity). ESI [ M + H ]]＝403.0/405.0

4- (7- (cis-3, 5-dimethylpiperazin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile 242 using general procedure A using 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and cis-2, 6-dimethylpiperazine in place of t-butyl piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.89(d, J8.8 Hz,1H),7.78-7.74(m,2H),7.71-7.68(m,3H),7.40(d, J1.8 Hz,1H),7.34-7.24(m,2H),5.30(s,2H),4.09(d, J11.5 Hz,2H),3.52(d, J7.1 Hz,2H),2.86-2.79(m,2H),1.42(d, J6.6 Hz, 6H). ESI [ M + H ] ═ 437.2

Scheme 16

The chemical experiment method comprises the following steps:

4- (10-amino-7-bromo-11-oxo-10, 11 dihydro-5H-benzo [ e)]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile, S41, to 4- (7-bromo-11-oxo-10, 11-dihydro-5H-benzo [ e ] at 0 deg.C]Pyrrolo [1,2-a][1,4]To a solution of diazepine-2-yl) benzonitrile (1g,2.64mmol,1.0eq.) in DMF (20mL) was added NaH (169mg,4.2mmol, 60% purity, 1.6 eq.). After stirring at 0 ℃ for 1hr, (aminooxy) diphenylphosphine oxide (738mg,3.2mmol,1.2eq.) was added and the mixture was stirred at 20 ℃ for 1 hr. The mixture was poured into ice water (100mL) and extracted with EtOAc (300mL x 3). The organic layer was washed with brine (100mL) over MgSO₄Dried and concentrated in vacuo. MTBE (20mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give 4- (10-amino-7-bromo-11-oxo-10, 11-dihydro-5H-benzo [ e ] as a yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile (1.0g, crude), which was used in the next step without further purification. ESI [ M + H ]]＝393.1/395.1

4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile, S42. A solution of 4- (10-amino-7-bromo-11-oxo-10, 11-dihydro-5H-benzo [ e ] pyrrolo [1,2-a ] [1,4] diazepin-2-yl) benzonitrile (900mg,2.29mmol,1.0eq.) in formamide (10mL) was stirred at 200 ℃ for 1.5hr, after which the mixture was poured into ice water (20mL) and filtered. EtOH (10mL) was added to the filter cake and stirred for 1 hr. The precipitate was collected by filtration to give 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile (600mg) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.34(br.s.,1H),7.93(br.s.,1H),7.78(br.s.,6H),7.40-7.11(m,2H),5.38(br.s., 2H). ESI [ M + H ] ═ 402.1/404.1

4- (7- (2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile 256 using general procedure A with 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, Synthesized by substituting tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate for tert-butyl hexahydropyrazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 8.16(s,1H),7.79-7.64(m,5H),7.62(s,1H),7.21(s,1H),6.80-6.70(m,2H),5.19(s,2H),4.21-4.13(m,2H),4.12-4.04(m,2H),3.63(s,2H),3.47(t, J ═ 6.8Hz,2H),2.39(t, J ═ 6.9Hz, 2H). ESI [ M + H ] ═ 434.1

Scheme 19

The chemical experiment method comprises the following steps:

4- (11-amino-7-bromo-5H-benzo [ e ]]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile, S49, to 4- (7-bromo-11-chloro-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Azadizepine-2-yl) benzonitrile (1.6g,4mmol,1.0eq.) to a solution in MeCN (20mL) and THF (20mL) was added NH₃.H₂O (1.4g,40mmol,10.0eq.) and the mixture was heated at 120 ℃ in a sealed tube for 16 hr. The reaction mixture was concentrated to give 4- (11-amino-7-bromo-5H-benzo [ e ] as a yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile (1.4g, crude), which was used directly in the next step without further purification. ESI [ M + H ]]＝377.1/379.1

4- (7-bromo-3-formyl-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, S50, to 4- (11-amino-7-bromo-5H-benzo [ e]Pyrrolo [1,2-a][1,4]To a solution of the diazepine-2-yl) benzonitrile (1.4g,3.7mmol,1.0eq.) in i-PrOH (10mL) was added Et₃N (413mg,4mmol,1.1eq.) and 2-bromomalondialdehyde (616mg,4mmol,1.0 eq.). The mixture was stirred at 10 ℃ for 0.1hr and then AcOH (267mg,4.4mmol,1.2eq.) was added. The mixture was heated to 90 ℃ and held for 2hr and concentrated. The residue was purified by preparative HPLC (TFA conditions) to give 4- (7-bromo-3-formyl-9H-benzo [ e ] as a yellow solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile (300mg,545umol, 14.68% yield). 1H NMR (400MHz, DMSO-d6) δ 9.71(s, 1H),8.24(s,1H),7.88(s,1H),7.78(s,1H),7.75(s,4H),7.62(d, J ═ 12Hz,1H),7.34(d, J ═ 12Hz,1H),7.29(s,1H),5.35(d, J ═ 12Hz,1H),5.22(d, J ═ 12Hz, 1H). ESI [ M + H ]]＝429.0/431.0

4- (7-bromo-3- (hydroxymethyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, S51, to 4- (7-bromo-3-formyl-9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadizepine-12-yl) benzonitrile (300mg,699umol,1.0eq.) in MeOH (30mL) plus NaBH₄(105mg,2.8mmol,4.0eq.) and the mixture was stirred at 10 ℃ for 16 hr. The reaction mixture was concentrated, diluted with water (30mL) and extracted with EtOAc (30mL x 3). The organic phase was concentrated to give 4- (7-bromo-3- (hydroxymethyl) -9H-benzo [ e ] as a pale yellow solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile (300mg,695.6umol, 99.53% yield), which was used directly in the next step without further purification. ESI [ M + H ]]＝431.1/433.1

4- (7- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -3- (hydroxymethyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile, 274 using general procedure A using 4- (7-bromo-3- (hydroxymethyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile with (R) -N, N-dimethylpyrrolidin-3-amine instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.82(d, J8.8 Hz,1H),7.79-7.75(m,2H),7.74-7.70(m,2H),7.70-7.65(m,2H),7.28(d, J1.8 Hz,1H),6.92(d, J2.2 Hz,1H),6.80(dd, J2.4, 9.0Hz,1H),5.24(d, J7.1 Hz,2H),4.81(d, J14.1 Hz,1H),4.62(d, J14.1 Hz,1H),4.07 (n, J7.2 Hz,1H),3.82(ddd, J3.7, 7, 3, 7, 3, 7, 2,5, 3, 7, 3,5, 3,2, 3,5, 3. ESI [ M + H ] ═ 465.1

Scheme 20

The chemical experiment method comprises the following steps:

4- (7-bromo-3- ((methylamino) methyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, S52, to 4- (7-bromo-3-formyl-9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine-12-yl) benzonitrile (100mg,232umol,1.0eq.) to a solution in MeOH (5.0mL) was added MeNH₂(144mg,4.6mmol,20eq.) and the mixture was stirred at 10 ℃ for 1 hr. Followed by the addition of NaBH₃CN (58.5mg,931.8umol,4.0eq.), the mixture was stirred at 10 ℃ for 16hr and concentrated to give 4- (7-bromo-3- ((methylamino) methyl) -9H-benzo [ e ] as a dark brown solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile (110mg, crude), which is not subjected to further purificationAnd then used in the next step. ESI [ M + H ]]＝444.0/446.0

((7-bromo-12- (4-cyanophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Novel diazepine-3-yl) methyl) (methyl) carbamic acid tert-butyl ester, S53 to 4- (7-bromo-3- ((methylamino) methyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile (110mg,247umol,1.0eq.) to a solution in THF (5mL) was added (Boc)₂O (59mg,272umol,1.1eq.) and Et₃N (50.1mg,495umol,2.0 eq.). The mixture was stirred at 10 ℃ for 1hr and concentrated to dryness by preparative TLC (SiO)₂Ethyl acetate methanol 20:1) to give ((7-bromo-12- (4-cyanophenyl) -9H-benzo [ e) as a yellow solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]T-butyl diazepine-3-yl) methyl) (methyl) carbamate (150mg, crude). ESI [ M + H ]]＝544.1/546.1

4- (7- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -3- ((methylamino) methyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile 276. Using general procedure A tert-butyl ((7-bromo-12- (4-cyanophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-3-yl) methyl) (methyl) carbamate was used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile by using (R) -N, N-dimethylpyrrolidin-3-amine in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.74-7.70(m,2H),7.69-7.64(m,4H),7.30(d, J ═ 8.8Hz,1H),7.17(s,1H),6.95(d, J ═ 2.2Hz,1H),6.83-6.77(m,1H),5.25-5.16(m,2H),4.67-4.60(m,1H),4.54-4.45(m,1H),4.14-4.04(m,1H),3.87-3.76(m,1H),3.75-3.60(m,2H),3.51-3.40(m,1H),2.99(s,6H),2.68(s,3H),2.66-2.56(m, 2H), 2.38-1H (m, 1H). ESI [ M + H ] ═ 478.2

Scheme 21

The chemical experiment method comprises the following steps:

4- (3- (aminomethyl) -7-bromo-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, S55, to 4- (7-bromo-3-formyl-9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Addition of NH to a solution of diazepine-12-yl) benzonitrile (100mg,233umol,1.0eq.) in MeOH (5.0mL)₃H₂O (81mg,2.3mmol,10eq.) and NH₄OAc (35.9mg,465.9umol,2.0 eq.). The mixture was stirred at 80 ℃ for 2hr and subsequently NaBH was added₃CN (29mg,465.9umol,2.0 eq.). The reaction mixture was heated at 80 ℃ for 16hr and concentrated to give crude 4- (3- (aminomethyl) -7-bromo-9H-benzo [ e ] as a dark brown solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile (110mg), which was used directly in the next step without further purification. ESI [ M + H ]]＝430.2/432.0

((7-bromo-12- (4-cyanophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-3-yl) methyl) carbamic acid tert-butyl ester, S56 to 4- (3- (aminomethyl) -7-bromo-9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile (110mg,255umol,1.0eq.) to a solution in THF (5mL) was added (Boc)₂O (61.3mg,281.2umol,1.1eq.) and Et₃N (51.7mg,511.2umol,2.0 eq.). The reaction mixture was stirred at 10 ℃ for 1hr, concentrated and passed through preparative TLC (SiO)₂Dichloromethane methanol 10:1, R_fPurification No. 0.75) to give ((7-bromo-12- (4-cyanophenyl) -9H-benzo [ e) as a yellow solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]T-butyl diazepine-3-yl) methyl) carbamate (120 mg). ESI [ M + H ]]＝530.1/532.1

4- (3- (aminomethyl) -7- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile, 277 using general procedure A with tert-butyl ((7-bromo-12- (4-cyanophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-3-yl) methyl) carbamate in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile by substituting (R) -N, N-dimethylpyrrolidin-3-amine for piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.74-7.68(m,2H),7.68-7.63(m,2H),7.58(s,1H),7.50(s,1H),7.28(d, J ═ 8.4Hz,1H),7.10(s,1H),6.95(s,1H),6.79(d, J ═ 8.8Hz,1H),5.25-5.06(m,2H),4.53(d, J ═ 15.0Hz,1H),4.32(d, J ═ 15.4Hz,1H),4.13-4.04(m,1H),3.81(br.s, 1H),3.72-3.69(m,1H),3.61(br.s, 1H), 3.50H (m, 3.50H), 3.39H, 3.66 (m,2H), 6H), 2H (d, 1H), 1H), 2H, 6.6.6.6H, 1H, 2H. ESI [ M + H ] ═ 464.2

Scheme 22

The chemical experiment method comprises the following steps:

4- (7-bromo-3- (methoxymethyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, S58, to 4- (7-bromo-3- (hydroxymethyl) -9H-benzo [ e ] at 0 deg.C]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile (60mg,139umol,1.0eq.) to a solution in THF (10mL) was added NaH (11mg,278umol,2.0 eq.). After stirring for 0.1hr, MeI (23.7mg,167umol,1.2eq.) was added to the reaction mixture and the mixture was stirred at 10 ℃ for 16 hr. The mixture was washed with saturated NH₄The Cl solution (50mL) was quenched, extracted with EtOAc (30mL × 2) and concentrated. By preparative TLC (SiO)₂Petroleum ether ethyl acetate 1:1, R_f0.30) to give 4- (7-bromo-3- (methoxymethyl) -9H-benzo [ e) as a yellow solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile (40 mg). ESI [ M + H ]]＝445.0/447.0

4- (7- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -3- (methoxymethyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile 278. use of general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] diazepine-12-yl) benzonitrile with 4- (7-bromo-3- (methoxymethyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile, 4] diazepine-12-yl) benzonitrile with (R) -N, N-dimethylpyrrolidin-3-amine instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.80(s,1H),7.77-7.72(m,3H),7.72-7.66(m,3H),7.25(d, J ═ 1.3Hz,1H),6.92(d, J ═ 2.2Hz,1H),6.80(dd, J ═ 2.6,8.8Hz,1H),5.27-5.17(m,2H),4.63(d, J ═ 12.8Hz,1H),4.45(d, J ═ 12.8Hz,1H),4.08(quin, J ═ 7.1Hz,1H),3.87-3.78(m,1H),3.74-3.58(m,2H),3.46(br.s, 1H), 3.42H (m, 3.42H), 3.55H, 2H), 3.55H (m, 2H). ESI [ M + H ] ═ 479.2

Scheme 25

The chemical experiment method comprises the following steps:

methyl 3-Aminopicolinate, S66. to a suspension of 3-Aminopicolinate (100g,724mmol,1.0eq.) in anhydrous MeOH (1.5L) at 15 deg.C was added concentrated H dropwise₂SO₄(460g,4.69mol,6.48eq.) and the mixture was heated to 80 ℃ and stirred for 5 days. The reaction mixture was concentrated to about 500mL and diluted with cold water (2L). Using solid Na at 0 DEG C₂CO₃The resulting mixture was adjusted to about 9 and extracted with DCM/MeOH (10:1,1.0 L.times.5). The combined organic layers were passed over Na₂SO₄Dried, filtered and concentrated to give methyl 3-aminopyralid (60g,394.35mmol, 54.47% yield, 100% purity) as a brown solid.¹H NMR(400MHz,CDCl₃)δ＝8.08-8.06(m,1H),7.24-7.20(m,1H),7.06-7.01(m,1H),5.75(br.s,1H),3.97(s,3H)。ESI[M+H]＝153.1

Methyl 3-amino-6-bromopicolinate, s67. to a solution of methyl 3-aminopyrinate (50g,328mmol,1.0eq.) in MeCN (600mL) at 0 ℃ NBS (60g,337mmol,1.0eq.) was added portionwise and the reaction mixture was stirred at 15 ℃ for 16 hr. The precipitate was collected by filtration to give methyl 3-amino-6-bromo-pyridine-2-carboxylate (48g,187mmol, 56.9% yield, 90% purity) as a light yellow solid, which was used without further purification.¹HNMR(400MHz,CDCl₃)δ＝7.35(d,J＝8.4Hz,1H),6.96(d,J＝8.4Hz,1H),5.83(br.s,1H),3.96(s,3H)。ESI[M+H]＝231.0/233.0

(3-amino-6-bromopyridin-2-yl) methanol, S68 to a solution of methyl 3-amino-6-bromopicolinate (16g,69mmol,1.0eq.) in THF (500mL) and MeOH (50mL) at 0 deg.CAdd NaBH portion by portion₄(10.5g,277mmol,4.0eq.) and the mixture was stirred at 15 ℃ for 16 hr. The mixture was diluted with EtOAc (2L) and 10% NH₄Aqueous Cl (300 mL). The aqueous layer was separated and extracted with EtOAc (200 mL. times.2). The combined organic layers were passed over Na₂SO₄Dried and concentrated to give (3-amino-6-bromo-2-pyridinyl) methanol (13g,57.6mmol, 83.2% yield, 90% purity) as a light yellow solid.¹H NMR(400MHz,DMSO-d₆)δ7.18(d,J＝8.4Hz,1H),6.96(d,J＝8.4Hz,1H),5.36(br.s,1H),5.19(t,J＝5.6Hz,1H),4.43(d,J＝5.6Hz,2H)。ESI[M+H]＝203.0/205.0

1- ((3-amino-6-bromopyridin-2-yl) methyl) -4- (4-cyanophenyl) -1H-pyrrole-2-carboxylic acid methyl ester, S69. at-70 ℃ under N₂To (3-amino-6-bromopyridin-2-yl) methanol (10g,49mmol,1.0eq.) and Et under atmosphere₃N (15g,148.2mmol,3eq.) to a solution in anhydrous DCM (1L) was added MsCl (6.50g,56.7mmol,1.15eq.) dropwise. The mixture was warmed to 15 ℃ and stirred for 30 min. The mixture was then cooled to 0 ℃ and 4- (4-cyanophenyl) -1H-pyrrole-2-carboxylic acid methyl ester (8.5g,37mmol,0.76eq.) and Bu were added sequentially₄NOH (25% in H)₂O, 5.0g,4.8mmol,0.1eq.) and aqueous NaOH (25% in H)₂O, 30g,187mmol,3.8 eq.). The reaction mixture was warmed to 15 ℃ and stirred for a further 16 hr. The mixture was washed with brine (1L) and Na₂SO₄Drying followed by concentration gave methyl 1- ((3-amino-6-bromopyridin-2-yl) methyl) -4- (4-cyanophenyl) -1H-pyrrole-2-carboxylate (13g, crude) as a brown solid which was used directly. ESI [ M + H ]]＝411.0/413.0

4- (2-bromo-6-oxo-6, 11-dihydro-5H-pyrido [3, 2-e)]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile, S70.At 0 ℃ under N₂To 1- [ (3-amino-6-bromo-2-pyridyl) methyl group under an atmosphere]-methyl 4- (4-cyanophenyl) pyrrole-2-carboxylate (22g,24mmol,1.0eq.) to a suspension in anhydrous toluene (2.0L) AlMe was added dropwise₃(2M in toluene, 65mL,5.4 eq.). The reaction mixture was warmed to 15 ℃ and stirred for 16 hr. Addition of cold saturated NH₄Aqueous Cl (500mL) and water (500 mL). The resulting precipitate was collected by filtration (very little product dissolved in the toluene layer). The crude product was washed with THF (1L) and the solid was collected by filtration to give 4- (2-bromo-6-oxo-6, 11-dihydro-5H-pyrido [3, 2-e) as a light yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile (12g,27.5mmol, 57% yield, 86.8% purity), which is used as it is.¹H NMR(400MHz,DMSO-d₆)δ＝10.43(br.s,1H),7.91(br.s,1H),7.77(br.s,4H),7.67-7.65(m,1H),7.56-7.54(m,1H),7.36(br.s,1H),5.37(s,2H)。ESI[M+H]＝379.0。

4- (2-bromo-6-chloro-11H-pyrido [3, 2-e)]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile, S71. reacting 4- (2-bromo-6-oxo-6, 11-dihydro-5H-pyrido [3,2-e]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile (2.0g,4.54mmol,1.0eq.) in POCl₃(100mL) the suspension was heated to 100 ℃ and stirred for 3.5 hr. The reaction mixture was concentrated to give 4- (2-bromo-6-chloro-11H-pyrido [3, 2-e) as a dark yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile (2.0g, crude), which is used as it is.

4- (7-bromo-9H-pyrido [3,2-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, S72. A mixture of 4- (2-bromo-6-chloro-11H-pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepine-8-yl) benzonitrile (1.8g,4.5mmol,1.0eq.) and formhydrazide (1.8g,30mmol,6.6eq.) in anhydrous dioxane (40mL) and anhydrous THF (10mL) is stirred in a sealed tube at 120 ℃ for 16 hr. The mixture was concentrated and the residual solid was washed with 1M HCl (20mL) and EtOAc (20mL), filtered and dried in vacuo to give 4- (7-bromo-9H-pyrido [3,2-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile (1.33g, crude) as a yellow solid which was used as such. ESI [ M + H ] ═ 403.0/405.0

4- (7- (4- (dimethylamino) piperidin-1-yl) -9H-pyrido [3,2-e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 293, using general procedure A with 4- (7-bromo-9H-pyrido [3,2-e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and N, N-dimethylpiperidin-4-amine in place of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝9.07(br.s.,1H),7.87(d,J＝9.0Hz,1H),7.77-7.71(m,2H),7.70-7.64(m,3H),7.27(br.s.,1H),7.02(d,J＝9.0Hz,1H),5.24(s,2H),4.72(d,J＝13.7Hz,2H),3.51(ddd,J＝3.9,8.3,11.9Hz,1H),3.00(t,J＝12.2Hz,2H),2.89(s,6H),2.18(d,J＝11.2Hz,2H),1.70(dq,J＝4.0,12.1Hz,2H)。ESI[M+H]＝451.2

Scheme 26

The chemical experiment method comprises the following steps:

4- (2-bromo-6- ((2, 2-dimethoxyethyl) amino) -11H-pyrido [3,2-e]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile, S73. step 4- (2-bromo-6-chloro-11H-pyrido [3, 2-e)]Pyrrolo [1,2-a][1,4]A mixture of diazepine-8-yl) benzonitrile (2.1g, crude) and 2, 2-dimethoxyethylamine (12g,100mmol,19.07eq.) in anhydrous dioxane (100mL) was heated to 100 ℃ and held for 16hr and then concentrated. The residue was dissolved in EtOAc (200mL) and saturated Na₂CO₃(50mL), 1M HCl (50mL), and brine (50 mL). The organic layer was dried and concentrated to give 4- (2-bromo-6- ((2, 2-dimethoxyethyl) amino) -11H-pyrido [3, 2-e) as a brown solid]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile (2.5g, crude), which is used as it is. ESI [ M + H ]]＝466.0/468.0

4- (7-bromo-9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile, s74. a suspension of 4- (2-bromo-6- ((2, 2-dimethoxyethyl) amino) -11H-pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-8-yl) benzonitrile (700mg,1.50mmol,1.0eq.) in dioxane (25mL) and 1M HCl (25mL) is heated to 60 ℃ and held for 10hr and then concentrated. The residual solids were washed with THF (30mL) to give 4- (7-bromo-9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile (450mg,1.04mmol, 69.36% yield, 93% purity) as a white solid, which was used without further purification.

(R) -4- (7- (3- (dimethylamino) pyrrolidin-1-yl) -9H-imidazo [2,1-c]Pyrido [3,2-e]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 312, using general procedure A with 4- (7-bromo-9H-imidazo [2, 1-c)]Pyrido [3,2-e]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Synthesis of diazepine-12-yl) benzonitrile with (R) -N, N-dimethylpyrrolidin-3-amine in place of tert-butyl piperazine-1-carboxylateAnd (4) obtaining.¹H NMR (400MHz, methanol-d)₄)δ＝8.06-7.99(m,1H),7.93(d,J＝9.0Hz,1H),7.84(s,1H),7.78-7.76(m,3H),7.73-7.68(m,2H),7.36(s,1H),6.77(d,J＝9.0Hz,1H),5.37(s,2H),4.16-4.04(m,2H),3.91-3.83(m,1H),3.82-3.73(m,1H),3.65-3.55(m,1H),3.00(s,6H),2.68-2.56(m,1H),2.41-2.29(m,1H)。ESI[M+H]＝436.1

Scheme 27

The chemical experiment method comprises the following steps:

(E) -2- (2-chloro-5-nitropyridin-4-yl) -N, N-dimethylethylamine, s76. to a solution of 2-chloro-4-methyl-5-nitropyridine (40g,231mmol,1.0eq.) in DMF (200mL) at 20 ℃ DMF-DMA (55g,463mmol,2.0eq.) was added and the mixture was stirred at 90 ℃ for 5 hr. The mixture was then poured into cold water (300mL) and the precipitate was collected by filtration, yielding crude (E) -2- (2-chloro-5-nitro-4-pyridinyl) -N, N-dimethyl-ethylamine (44.3g, crude) as a red solid, which was not further purified.

2-chloro-5-nitroisonicotinaldehyde, S77. (E) -2- (2-chloro-5-nitro-4-pyridinyl) -N, N-dimethyl-ethylamine (44.3g,194.6mmol,1.0eq.) in THF (250mL) and H at 20 deg.C₂NaIO was added in portions to a solution in O (250mL)₄(145g,681mmol,3.5eq.) and the reaction mixture was stirred at 20 ℃ for 16 hr. The mixture was then filtered and the filter cake was washed with EtOAc (100 mL. times.2). The filtrate was extracted with EtOAc (500 mL. times.2). The combined organic layers were washed with brine (300mL) and Na₂SO₄Dried and concentrated to give 2-chloro-5-Nitroisonicotinaldehyde (37.2g, 92% yield, 90% purity). 1H NMR (400MHz, chloroform-d) δ 10.49(br.s.,1H),9.23(br.s.,1H),7.74(br.s., 1H).

(2-chloro-5-nitropyridin-4-yl) methanol, S78. to a solution of 2-chloro-5-nitroisonicotinaldehyde (40g,214mmol,1.0eq.) in MeOH (300mL) at 0 deg.C was added NaBH portionwise₄(12.1g,321.6mmol,1.5 eq.). The mixture was stirred at 0 ℃ for 3hr and passed through saturated NH₄Cl (200mL) was quenched. After removal of MeOH, the aqueous layer was extracted with EtOAc (200mL × 2). The organic layer was washed with brine (200mL) over MgSO₄Dried and concentrated. By column chromatography (SiO)₂Petroleum ether ethyl acetate 20:1 to 10:1) to give (2-chloro-5-nitropyridin-4-yl) methanol as a yellow solid (19.5g,103.4mmol, 48.2% yield). 1H NMR (400MHz, chloroform-d) δ 9.12(br.s.,1H),7.92(br.s.,1H),5.16-5.14(m, J ═ 2.2Hz, 2H).

(5-amino-2-chloropyridin-4-yl) methanol, S79 to a solution of (2-chloro-5-nitropyridin-4-yl) methanol (16g,84.8mmol,1.0eq.) in EtOH (160mL) and THF (160mL) were added Fe (23.6g,424mmol,5.0eq.) and saturated NH₄Cl (80 mL). The mixture was stirred at 90 ℃ for 1hr and filtered. The filtrate was concentrated and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 2:1, Rf ═ 0.12) to give (5-amino-2-chloropyridin-4-yl) methanol (12.9g,74.83mmol, 88.19% yield, 92% purity) as a yellow solid. ESI [ M + H ]]＝158.8

1- ((5-amino-2-chloropyridin-4-yl) methyl) -4- (4-cyanophenyl) -1H-pyrrole-Methyl 2-carboxylate, s80. to a solution of (5-amino-2-chloropyridin-4-yl) methanol (4.0g,25.2mmol,1.0eq.) and TEA (7.6g,75.6mmol,3.0eq.) in DCM (320mL) at-70 ℃ is added MsCl (4.3g,37.8mmol,1.5 eq.). The mixture was slowly warmed to 20 ℃ and stirred for 3 hr. Methyl 4- (4-cyanophenyl) -1H-pyrrole-2-carboxylate (4.5g,20.1mmol,0.8eq.) was then added at 0 ℃, followed by aqueous NaOH (25%, 6.00eq.) and tetrabutylammonium hydroxide (2.62g,2.52mmol,0.1 eq.). After addition, the mixture was stirred at 15 ℃ for 16 hr. The resulting mixture was then diluted with water (500mL) and extracted with DCM (100mL × 2). The combined organic layers were dried over anhydrous MgSO₄Dried, filtered and concentrated to give methyl 1- ((5-amino-2-chloropyridin-4-yl) methyl) -4- (4-cyanophenyl) -1H-pyrrole-2-carboxylate (2.2g,4.4mmol, 17.6% yield, 74% purity) as a yellow solid. 1H NMR (400MHz, chloroform-d) δ ═ 7.86(s,1H),7.64-7.62(m,2H),7.58-7.56(m,2H),7.34-7.33(m,1H),7.21(br.s.,1H),6.71(br.s.,1H),5.45(br.s.,2H),3.86-3.85(m, 3H). ESI [ M + H ]]＝367.0

4- (3-chloro-10-oxo-10, 11-dihydro-5H-pyrido [3, 4-e)]Pyrrolo [1,2-a][1,4]Azadizepine-8-yl) benzonitrile, S81, to a solution of methyl 1- ((5-amino-2-chloropyridin-4-yl) methyl) -4- (4-cyanophenyl) -1H-pyrrole-2-carboxylate (2.3g,6.2mmol,1.0eq.) in toluene (25mL) was added AlMe₃(2M,15.6mL,5.0eq.) and the mixture was stirred at 20 ℃ for 16 hr. The mixture was poured into cold water (100mL) and extracted with EtOAc (200mL × 2). The organic layer was washed with brine (100mL) over MgSO₄Dried and concentrated. The resulting solid was washed with EtOH (20 mL). After filtration, the filter cake was collected to give 4- (3-chloro-10-oxo-10, 11-dihydro-5H-pyrido [3, 4-e) as a yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile (1.82g,4.73mmol, 75.44% yield, 87% purity). ESI [ M + H ]]＝334.9

4- (3-chloro-10-thione-10, 11 dihydro-5H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepin-8-yl) benzonitrile, S82, to a solution of 4- (3-chloro-10-oxo-10, 11-dihydro-5H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepin-8-yl) benzonitrile (1.8g,5.4mmol,1.0eq.) in THF (20mL) was added the Lawson's reagent (2.6g,6.5mmol,1.2eq.) and the mixture was stirred at 70 ℃ for 1 hr. The mixture was concentrated and the residue was washed with MeOH (20 mL). After filtration, the filter cake was collected and concentrated to give crude 4- (3-chloro-10-thione-10, 11-dihydro-5H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepine-8-yl) benzonitrile (1.39g, crude) as a yellow solid.

4- (3-chloro-10- (methylthio) -5H-pyrido [3, 4-e)]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile, S83, to 4- (3-chloro-10-thione-10, 11-dihydro-5H-pyrido [3,4-e ] at 0 deg.C]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile (1.4g,3.9mmol,1.0eq.) and K₂CO₃(3.8g,27.7mmol,7.0eq.) to a suspension in DMF (20mL) was added MeI (1.1g,7.9mmol,2.0 eq.). The mixture was stirred at 20 ℃ for 1hr and filtered. The filtrate was concentrated to give 4- (3-chloro-10- (methylthio) -5H-pyrido [3, 4-e) as a yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile (1.3g, crude).

4- (7-chloro-9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, S84. A mixture of 4- (3-chloro-10- (methylthio) -5H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepine-8-yl) benzonitrile (535mg,8.9mmol,2.5eq.) and formhydrazide (3.0g) in n-BuOH (20mL) is stirred at 130 ℃ for 16hr and concentrated. The residue was washed with 1N HCl (20mL) and EtOH (10 mL). After filtration, the filter cake was collected to give 4- (7-chloro-9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile (600mg, 33.3% yield, 71% purity) as a yellow solid. ESI [ M + H ] ═ 358.9

4- (7- (4- (dimethylamino) piperidin-1-yl) -9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile 321. Using general procedure A4- (7-chloro-9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and N, n-dimethylpiperidin-4-amine instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.15(br.s.,1H),8.42(s,1H),7.76-7.58(m,5H),7.26(br.s.,1H),7.13(s,1H),5.22(s,2H),4.66(d, J ═ 13.7Hz,2H),3.51(ddd, J ═ 3.9,8.3,11.9Hz,1H),3.01(t, J ═ 12.5Hz,2H),2.92-2.80(m,6H),2.16(d, J ═ 11.5Hz,2H),1.70(dq, J ═ 4.0,12.1Hz, 2H). ESI [ M + H ] ═ 451.2

Scheme 28

The chemical experiment method comprises the following steps:

4- (3, 10-dichloro-5H-pyrido [3,4-e ]]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile, S85. general reaction of 4- (3-chloro-10-oxo-10, 11-dihydro-5H-pyrido [3,4-e]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile (500mg,1.49mmol,1.0eq.) in POCl₃(30mL) of the solution was stirred at 90 ℃ for 1hr and concentrated to give 4- (3, 10-dichloro-5H-pyrido [3,4-e ] as a dark brown oil]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile (550mg, crude, HCl).

4- (3-chloro-10- ((2, 2-dimethoxyethyl) amino) -5H-pyrido [3,4-e]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile, S86, to 4- (3, 10-dichloro-5H-pyrido [3,4-e]Pyrrolo [1,2-a][1,4]A solution of diazepine-8-yl) benzonitrile (550mg,1.41mmol,1.0eq., HCl) in THF (10mL) and dioxane (10mL) was adjusted to pH 9 with TEA, followed by addition of 2, 2-dimethoxyethylamine (1.48g,14.1mmol,1.53mL,10.0eq.) and stirring of the mixture at 120 ℃ under a sealed tube for 16 hr. After completion of the reaction, the mixture was poured into 0.5M HCl (50mL) and extracted with hot EtOAc/THF 1/1(50mL × 3). The organic layer was washed with brine (50mL) over MgSO₄Dried and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 1:1, Rf ═ 0.53) to give 4- (3-chloro-10- ((2, 2-dimethoxyethyl) amino) -5H-pyrido [3,4-e ] as a yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile (130mg,150umol, 10.6% yield, 48.8% purity). ESI [ M + H ]]＝422.1

4- (7-chloro-9H-imidazo [2,1-c ] pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile, S87. A solution of 4- (3-chloro-10- ((2, 2-dimethoxyethyl) amino) -5H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepin-8-yl) benzonitrile (130mg,150umol,1.0eq.) in dioxane (6.0mL) and 1M HCl (6.0mL) is stirred at 80 ℃ for 16 hr. After completion of the reaction, the mixture was concentrated. The residual solid was washed with THF (5mL) and filtered. The filter cake was collected to yield the crude product 4- (7-chloro-9H-imidazo [2,1-c ] pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile (70mg, crude, HCl) as a black solid, without further purification. ESI [ M + H ] ═ 358.1

4- (7- (2, 6-diazaspiro [3.4] oct-6-yl) -9H-imidazo [2,1-c ] pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 323 using general procedure A using 4- (7-chloro-9H-imidazo [2,1-c ] pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and 2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.40(s,1H),8.08(m,1H),7.80-7.68(d, J9.9 Hz,6H),7.34(d, J1.8 Hz,1H),7.33(d, J1.1 Hz,1H),5.11(s,2H),4.00-3.92(m,2H),3.91-3.83(m,2H),3.73(s,2H),3.54(t, J6.9 Hz,2H),2.33(t, J6.9 Hz, 2H). ESI [ M + H ] ═ 434.1

Scheme 29

The chemical experiment method comprises the following steps:

(4, 5-difluoro-2-nitrophenyl) methanol, S90. at 0 ℃ over a period of 30min under N₂To a solution of 4, 5-difluoro-2-nitrobenzoic acid (8.0g,39.39mmol,1.0eq.) in THF (80mL) was added BH dropwise₃-Me₂Solution of S (10M,11.82mL,3.0 eq.). The reaction mixture was heated to 70 ℃ over a period of 30min and stirred at 70 ℃ for 3 hr. The reaction was slowly quenched through ice water and then extracted with ethyl acetate (50mL × 3). The combined organic phases were washed with brine (10mL x 2) and over Na₂SO₄Dried, filtered and concentrated to give (4, 5-difluoro-2-nitrophenyl) methanol (7.2g, crude) as a yellow solid. TLC R_f0.6 (petroleum ether/ethyl)Ethyl acetate 3/1).

4- (2-fluoro-5- (hydroxymethyl) -4-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester, s91. a mixture of (4, 5-difluoro-2-nitrophenyl) methanol (7.6g,40.3mmol,1.00eq.) and piperazine-1-carboxylic acid tert-butyl ester (9.0g,48.4mmol,1.2eq.) in DMSO (80mL) was heated to 90 ℃ and held for 3hr and poured into ice water (100 mL). The aqueous phase was extracted with ethyl acetate (200mL x 3). The combined organic phases were washed with brine (20mL x 2) and anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give tert-butyl 4- (2-fluoro-5- (hydroxymethyl) -4-nitrophenyl) piperazine-1-carboxylate (11.26g, crude) as a yellow solid. TLC R_f0.35 (3/1 petroleum ether/ethyl acetate). 1H NMR (400MHz, chloroform-d) δ 7.85(d, J13.2 Hz,1H),7.09(d, J8.4 Hz,1H),4.89(br.s.,2H),3.61-3.49(m,4H),3.31-3.14(m,4H),1.42(s, 9H).

4- (5- ((4- (4-cyanophenyl) -2- (methoxycarbonyl) -1H-pyrrol-1-yl) methyl) -2-fluoro-4-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester, s92. at 30 ℃ under N₂To a mixture of tert-butyl 4- (2-fluoro-5- (hydroxymethyl) -4-nitrophenyl) piperazine-1-carboxylate (863mg,2.43mmol,1.1eq.) and methyl 4- (4-cyanophenyl) -1H-pyrrole-2-carboxylate (500mg,2.21mmol,1.0eq.) in Tol. (10mL) was added 2- (tributyl-phosphinylidene) acetonitrile (1.07g,4.42mmol,2.0eq.) in one portion. The mixture was stirred at 30 ℃ for 30min, then heated to 100 ℃ and stirred for 11.5 hr. The mixture was concentrated and diluted with ice water (50 mL). The aqueous phase was extracted with ethyl acetate (50mL x 3). The combined organic phases were washed with brine (10mL x 2) and anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give 4- (5- ((4- (4-cyanophenyl) -2- (methoxylphenyl) -2) as a yellow solidAlkylcarbonyl) -1H-pyrrol-1-yl) methyl) -2-fluoro-4-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester (600mg,1.0mmol, 45.76% yield, 95% purity). TLC R_f0.3 (3/1 petroleum ether/ethyl acetate). 1H NMR (400MHz, chloroform-d) δ 7.96(d, J13.2 Hz,1H),7.69-7.57(m,4H),7.39(s,1H),7.29(s,2H),5.99(s,2H),3.79(s,3H),3.53-3.42(m,4H),3.02(br.s.,4H),1.44(s, 9H). ESI [ M + H ]]＝564.5

4- (4-amino-5- ((4- (4-cyanophenyl) -2- (methoxycarbonyl) -1H-pyrrol-1-yl) methyl) -2-fluorophenyl) piperazine-1-carboxylic acid tert-butyl ester, s93. at 30 ℃ in N₂To a mixture of tert-butyl 4- (5- ((4- (4-cyanophenyl) -2- (methoxycarbonyl) -1H-pyrrol-1-yl) methyl) -2-fluoro-4-nitrophenyl) piperazine-1-carboxylate (620mg,1.1mmol,1.0eq.) in AcOH (10mL) was added Zn (719mg,11.0mmol,10.0eq.) in one portion. The mixture was stirred at 30 ℃ for 1hr, filtered and concentrated. The residue was diluted with ice water (20mL) and extracted with ethyl acetate (15mL × 3). The combined organic phases were washed with brine (5mL x 2) and dried over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give tert-butyl 4- (4-amino-5- ((4- (4-cyanophenyl) -2- (methoxycarbonyl) -1H-pyrrol-1-yl) methyl) -2-fluorophenyl) piperazine-1-carboxylate (580mg, crude) as a yellow solid. TLC R_f0.26 (3/1 petroleum ether/ethyl acetate). ESI [ M + H ]]＝533.9

4- (8-fluoro-11-oxo-7- (piperazin-1-yl) -10, 11-dihydro-5H-benzo [ e)]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile, S94, at 0 ℃ over a period of 30min₂To a solution of tert-butyl 4- (4-amino-5- ((4- (4-cyanophenyl) -2- (methoxycarbonyl) -1H-pyrrol-1-yl) methyl) -2-fluorophenyl) piperazine-1-carboxylate (300mg,562umol,1.0eq.) in toluene (20mL) was added a dropwiselMe₃Solution (2M,1.41mL,5.0 eq.). The reaction mixture was warmed to 30 ℃ and stirred for 3 hr. The reaction was slowly quenched through ice water (30mL) and extracted with DCM (30mL × 3). The combined organic phases were washed with saturated brine (5mL _ 2) and dried over anhydrous Na₂SO₄Dried, filtered and concentrated to give crude 4- (8-fluoro-11-oxo-7- (piperazin-1-yl) -10, 11-dihydro-5H-benzo [ e) as a yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-2-yl) benzonitrile (140mg, crude). TLC R_f0.46 (3/1 petroleum ether/ethyl acetate). ESI [ M + H ]]＝402.1

4- (2- (4-cyanophenyl) -8-fluoro-11-oxo-10, 11-dihydro-5H-benzo [ e)]Pyrrolo [1,2-a][1,4]Novel forms of t-butyl diazepine-7-yl piperazine-1-carboxylate, S95, to 4- (8-fluoro-11-oxo-7- (piperazin-1-yl) -10, 11-dihydro-5H-benzo [ e ]]Pyrrolo [1,2-a][1,4]Azadizepine-2-yl) benzonitrile (150mg,373umol,1.0eq.) in MeOH (5.0mL) was added Boc in one portion₂O (97mg,448umol,1.2 eq.). The mixture was stirred at 30 ℃ for 2hr and concentrated under reduced pressure to give 4- (2- (4-cyanophenyl) -8-fluoro-11-oxo-10, 11-dihydro-5H-benzo [ e ] as a yellow solid]Pyrrolo [1,2-a][1,4]T-butyl diazepine-7-yl) piperazine-1-carboxylate (200mg, crude). TLC R_f0.53 (3/1 petroleum ether/ethyl acetate). ESI [ M + H ]]＝502.2

4- (2- (4-cyanophenyl) -8-fluoro-11-thione-10, 11-dihydro-5H-benzo [ e)]Pyrrolo [1,2-a][1,4]Novel general formula (I) novel forms of]Pyrrolo [1,2-a][1,4]A solution of t-butyl diazepine-7-yl) piperazine-1-carboxylate (200mg,398umol,1.0eq.) and Lawson's reagent (193mg,478umol,1.2eq.) in THF (10.0mL) was stirred at 80 ℃ for 16hr and concentrated. Tong (Chinese character of 'tong')The residue was purified by preparative TLC (DCM/methanol ═ 15/1) to give 4- (2- (4-cyanophenyl) -8-fluoro-11-thione-10, 11-dihydro-5H-benzo [ e ] as a white solid]Pyrrolo [1,2-a][1,4]T-butyl diazepine-7-yl) piperazine-1-carboxylate (80mg,123umol, 31% yield, 80% purity). TLC R_f0.33 (dichloromethane/methanol 20/1).

4- (2- (4-cyanophenyl) -8-fluoro-11- (methylthio) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]Novel forms of t-butyl diazepine-7-yl piperazine-1-carboxylate, S97, novel forms of 4- (2- (4-cyanophenyl) -8-fluoro-11-thione-10, 11-dihydro-5H-benzo [ e ]]Pyrrolo [1,2-a][1,4]T-butyl diazepine-7-yl piperazine-1-carboxylate (80mg,154umol,1.0eq.) and K₂CO₃(42.7mg,309umol,2.0eq.) to a mixture in MeCN (3.0mL) MeI (109mg,772umol,5.0eq.) was added. The mixture was stirred at 28 ℃ for 16hr and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/ethyl acetate ═ 2/1) to give 4- (2- (4-cyanophenyl) -8-fluoro-11- (methylthio) -5H-benzo [ e ] as an orange oil]Pyrrolo [1,2-a][1,4]T-butyl diazepine-7-yl) piperazine-1-carboxylate (75mg,112umol, 73% yield, 80% purity). TLC R_f0.23 (3/1 petroleum ether/ethyl acetate).

4- (12- (4-cyanophenyl) -6-fluoro-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Novel t-butyl diazepine-7-yl piperazine-1-carboxylate, S98, prepared by reacting formylhydrazine (18mg,300umol,2.0eq.) and 4- (2- (4-cyanophenyl) -8-fluoro-11- (methylthio) -5H-benzo [ e ]]Pyrrolo [1,2-a][1,4]A mixture of tert-butyl diazepine-7-yl) piperazine-1-carboxylate (80mg,150umol,1.0eq.) in n-BuOH (2.0mL) was stirred at 130 ℃ for 16hr and concentrated under reduced pressure to give 4- (12- (4-cyanophenyl) -6-fluoro-9H-benzo [ e ]]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-7-yl) piperazine-1-carboxylic acid tert-butyl ester (50mg, crude) without further purification. TLC R_f0.05 (3/1 petroleum ether/ethyl acetate).

4- (6-fluoro-7- (piperazin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile 325. tert-butyl 4- (12- (4-cyanophenyl) -6-fluoro-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-7-yl) piperazine-1-carboxylate (80mg,152umol,1.0eq.) was dissolved in HCl/EtOAc (4M,3.0mL) and the mixture was stirred at 28 ℃ for 0.5 hr. The mixture was concentrated and the residue was purified by preparative HPLC to give 4- (6-fluoro-7- (piperazin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile (30mg,70umol, 46.3% yield, 100% purity). 1HNMR (400MHz, methanol-d 4) δ 9.07(s,1H),7.77-7.65(m,4H),7.65-7.58(m,2H),7.41(d, J ═ 8.8Hz,1H),7.26(s,1H),5.25(s,2H),3.50-3.39(m, 8H). ESI [ M + H ] ═ 426.1

Scheme 30

Chemical experimental method

Methyl 3-amino-5-fluoropyridinecarboxylate, S100. 2-bromo-5-fluoropyridin-3-amine (22g,115.18mmol,1.00eq.), Et₃N (23.3g,230mmol,2.0eq.) and Pd (dppf) Cl₂(4.2g,5.7mmol,0.05eq.) A mixture in MeOH (1L) was degassed and stirred at 80 deg.C under CO (2MPa) for 50 hr. The mixture was concentrated and ice water (300mL) was added. The aqueous phase was extracted with ethyl acetate (200mL x 3). The phases were washed with brine (50mL) and anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography to give methyl 3-amino-5-fluoropicolinate (15g,74.3mmol, 64.5% yield) as a yellow solid. 1H NMR (400MHz, chloroform-d) δ 7.92(d, J2.0 Hz,1H),6.74(dd, J2.3, 9.8Hz,1H),5.96(br.s.,2H),3.98(s, 3H). ESI [ M + H ]]＝171.1

Methyl 3-amino-6-bromo-5-fluoropicolinate, s101. to a solution of methyl 3-amino-5-fluoropicolinate (15g,88mmol,1.0eq.) in MeCN (500mL) was added NBS (15.7g,88.4mmol,1.0eq.) and the mixture was stirred at 15 ℃ for 14 hr. The mixture was concentrated and the residue partitioned between EtOAc (500mL) and ice water (100 mL). The combined organic phases were washed with brine (50mL) and anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give methyl 3-amino-6-bromo-5-fluoropicolinate (18g,62mmol, 70.27% yield) as a white solid. 1H NMR (400MHz, chloroform-d) δ 6.79(d, J8.4 Hz,1H),5.98(br.s.,2H),3.95(s, 3H). ESI [ M + H ]]＝249.2/251.2

(3-amino-6-bromo-5-fluoropyridin-2-yl) methanol, S102. to a solution of methyl 3-amino-6-bromo-5-fluoropicolinate (13.8g,55.5mmol,1.0eq.) in THF (200mL) was added an aqueous LiOH solution (11.6g,277mmol,5.00eq.,1M in H₂O) and the mixture was stirred at 15 ℃ for 2 hr. The solution was adjusted to pH 2 with 4M HCl and then concentrated. The residue was partitioned between EtOAc (300mL) and ice-water (100 mL). The organic phase was washed with brine (20mL) and anhydrous Na₂SO₄Dried, filtered and concentrated to give 3-amino-6-bromo-5-fluoropicolinic acid (13g, crude) as a yellow solid, which was used in the next step without further purification.

To a solution of 3-amino-6-bromo-5-fluoropicolinic acid (11.0g,46.8mmol,1.0eq.) in THF (20mL) was added BH₃THF (1M,300mL,6.4eq.) and the mixture was heated to 70 ℃ and held for 16 hr. The mixture was cooled to 0 ℃, slowly quenched with MeOH (400mL) and then concentrated in vacuo. MeOH (30mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give (3-amino-6-bromo-5-fluoropyridin-2-yl) methanol (8.0g,36.19mmol, 77.31% yield) as a white solid. ESI [ M + H ]]＝221.2/223.2

Methanesulfonic acid (3-amino-6-bromo-5-fluoropyridin-2-yl) methyl ester, S103. at-70 ℃ under N₂Methanesulfonyl chloride (3.26g,28.5mmol,1.05eq.) was added dropwise to a solution of (3-amino-6-bromo-5-fluoropyridin-2-yl) methanol (6g,27.12mmol,1.0eq.) and TEA (5.49g,54.24mmol,2.0eq.) in DCM (200 mL). After addition, the mixture was warmed to 15 ℃ and stirred for 30 min. The solution was used directly in the next step.

Methyl 1- ((3-amino-6-bromo-5-fluoropyridin-2-yl) methyl) -4- (4-cyanophenyl) -1H-pyrrole-2-carboxylate, S104 methyl 4- (4-cyanophenyl) -1H-pyrrole-2-carboxylate (4.9g,21.8mmol,0.80eq.) Bu was added to the above solution at 0 ℃₄NOH (2.6g,2.7mmol,0.1eq.) and NaOH (10.4g,163.7mmol,6.0 eq.25%, w%). The mixture was stirred at 15 ℃ for 3.5hr and then diluted with ice water (100 mL). The organic layer was washed with brine (100mL x 2) and over anhydrous MgSO₄Dried, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give methyl 1- ((3-amino-6-bromo-5-fluoropyridin-2-yl) methyl) -4- (4-cyanophenyl) -1H-pyrrole-2-carboxylate (3g,4.9mmol) as a yellow solid. 1H NMR (400MHz, chloroform-d) δ 7.56-7.52(m,2H),7.49(s,1H),7.47-7.45(m,1H),7.19(s,2H),6.67(d, J8.8 Hz,1H),5.52 (c, H)s,2H),3.83(s,3H)。ESI[M+H]＝429.1/431.1

4- (2-bromo-3-fluoro-6-oxo-6, 11-dihydro-5H-pyrido [3, 2-e)]Pyrrolo [1,2-a][1,4]Azadizepine-8-yl) benzonitrile, S105. to a suspension of methyl 1- ((3-amino-6-bromo-5-fluoropyridin-2-yl) methyl) -4- (4-cyanophenyl) -1H-pyrrole-2-carboxylate (2.80g,6.52mmol,1.0eq.) in toluene (50mL) at 0 deg.C is added Me₃Al (2M in toluene, 16.30mL,5.0eq.) and the mixture was stirred at 15 ℃ for 12 hr. The mixture was poured into ice water (100mL) and extracted with hot EtOAc/THF (1:1,100mL 4). Subjecting the organic layer to anhydrous Na₂SO₄Dried, filtered and concentrated. THF (20mL) was added to the residue and stirred at 0 ℃ for 1 hr. The precipitate was collected by filtration to give 4- (2-bromo-3-fluoro-6-oxo-6, 11-dihydro-5H-pyrido [3, 2-e) as a white solid]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile (1.0g,2.11mmol, 32.44% yield). ESI [ M + H ]]＝397.1/399.1

4- (2-bromo-6-chloro-3-fluoro-11H-pyrido [3, 2-e)]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile, S106. preparation of 4- (2-bromo-3-fluoro-6-oxo-6, 11-dihydro-5H-pyrido [3,2-e]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile (550mg,1.38mmol,1.0eq.) in POCl₃The solution in (30mL) was stirred at 90 ℃ for 2 hr. The solution was concentrated under reduced pressure to give crude 4- (2-bromo-6-chloro-3-fluoro-11H-pyrido [3, 2-e) as a dark brown oil]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile (575.00mg, crude), which was used in the next step without further purification.

4- (7-bromo-6-fluoro-9H-pyrido [3, 2-e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, S107, to 4- (2-bromo-6-chloro-3-fluoro-11H-pyrido [3,2-e]Pyrrolo [1,2-a][1,4]Diazepine-8-yl) benzonitrile (575mg,1.38mmol,1.0eq.) to a solution in dioxane (50mL) was added TEA to adjust pH 7. Then formylhydrazine (1.7g,28.9mmol,21.0eq.) was added and the mixture was heated to 120 ℃ in a sealed tube and held for 10 hr. The mixture was concentrated to dryness and the residue was dissolved in hot EtOAc/THF (1:1,200 mL). The solution was washed with 1M ice HCl (10mL), saturated NaHCO₃Aqueous solution (10mL) and brine (10 mL). Passing the organic phase over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. EtOH (5mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give 4- (7-bromo-6-fluoro-9H-pyrido [3, 2-e) as a white solid]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile (450mg, crude). 1H NMR (400MHz, DMSO-d6) δ 9.21(s,1H),8.45(d, J8.4 Hz,1H),7.94(br.s, 1H),7.76(s,4H),7.31(s,1H),5.43(br.s, 2H). ESI [ M + H ]]＝421.2/423.2

(S) -4- (7- (3- (dimethylamino) pyrrolidin-1-yl) -6-fluoro-9H-pyrido [3,2-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile 328. Using general procedure A4- (7-bromo-6-fluoro-9H-pyrido [3,2-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile by using (S) -N, N-dimethylpyrrolidin-3-amine in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.04(br.s.,1H),7.87(d, J12.3 Hz,1H),7.76-7.60(m,5H),7.26(br.s.,1H),5.23(s,2H),4.24-4.12(m,1H),4.09-3.97(m,2H),3.96-3.87(m,1H),3.78(d, J9.3 Hz,1H),3.01(s,6H),2.56(d, J6.2 Hz,1H),2.29(dd, J8.6, 12.6Hz, 1H). ESI [ M + H ] ═ 455.2

Scheme 31

The chemical experiment method comprises the following steps:

4- (4-fluorophenyl) -1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, s108. to 4-bromo-1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (59.8g,196.6mmol,1.0eq.) and (4-fluorophenyl) boronic acid (41g,294mmol,1.5eq.) in dioxane (1.8L) and H₂Boc was added to the mixture in O (180mL)₂O(64.3g,294.9mmol,1.50eq.)、Na₂CO₃(41.68g,393.24mmol,2.00eq.) and Pd (dppf) Cl₂(7.1g,9.8mmol,0.05 eq.). The mixture was stirred at 100 ℃ for 12hr and then concentrated. The residue was partitioned between ethyl acetate/THF (700mL/100mL) and water (500 mL). The organic layer was washed with brine (400mL) over anhydrous MgSO₄Dried, filtered and concentrated to provide 4- (4-fluorophenyl) -1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (75g, crude, black solid). ESI [ M + H ]]＝320.1

4- (4-fluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester, s109. a solution of 4- (4-fluorophenyl) -1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (75g,234mmol,1.0eq.) in TFA (500mL) was stirred at 50 ℃ for 1hr and then concentrated in vacuo. MeOH (250mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give 4- (4-fluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester as a gray solid (25g,112mmol, 47.8% yield, 98.6% purity). 1HNMR (400MHz, methanol-d 4) δ 7.55(dd, J8.8, 5.6Hz,2H),7.30(d, J1.2 Hz,1H),7.15(d, J1.6 Hz,1H),7.06(t, J8.8 Hz,2H),3.86(s, 3H). ESI [ M + H ] ═ 220.1

Methyl 1- (5-bromo-2-nitrobenzyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate, s110. to a solution of (5-bromo-2-nitrophenyl) methanol (30g,129mmol,1.0eq.) and TEA (19g,193mmol,1.50eq.) in DCM (600mL) at 0 ℃ was added MsCl (16g,142mmol,1.1eq.) and the mixture was stirred at 20 ℃ for 30 min. Subsequently 4- (4-fluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester (24g,110mmol,0.95eq.) was added at 0 ℃, followed by NaOH (25% aq., 5.00eq.) and tetrabutylammonium hydroxide (12.0g,11.6mmol,0.10 eq.). The mixture was stirred at 20 ℃ for 16hr and then poured into cold water (800mL) and extracted with DCM (300mL × 3). The organic layer was washed with MgSO₄Dried and concentrated in vacuo. EtOH/MeOH (220mL,10/1) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to afford methyl 1- (5-bromo-2-nitrobenzyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (48.6g,107.45mmol, 92.57% yield, 95.78% purity) as a yellow solid. 1H NMR (400MHz, chloroform-d) δ 8.05(d, J8.8 Hz,1H),7.53(d, J5.6 Hz,1H),7.52-7.50(m,2H),7.33(d, J2.0 Hz,1H),7.19(d, J2.0 Hz,1H),7.10(t, J8.4 Hz,2H),6.77(s,1H),5.95(s,2H),3.78(s, 3H). ESI [ M + H ]]＝435.0

1- (2-amino-5-bromobenzyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester, S111. to a solution of 1- (5-bromo-2-nitrobenzyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester (47.60g,109.87mmol,1.0eq.) in THF (480mL) and EtOH (480mL) were added Fe (30.68g,549.35mmol,5.0eq.) and saturated NH₄Aqueous Cl (240 mL). The mixture was stirred at 90 ℃ for 30min and concentrated in vacuo. The residue was dissolved in hot THF (2L)In (1). After filtration, the filtrate was concentrated to give methyl 1- (2-amino-5-bromobenzyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (66g, crude) as a yellow solid. TLC R_f0.25 (petroleum ether: ethyl acetate: 5: 1).

7-bromo-2- (4-fluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]To a suspension of methyl 1- (2-amino-5-bromobenzyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (65g,101.55mmol,1.0eq.) in toluene (650mL) was added AlMe-11 (10H) -one, S112₃(2M,253.88mL,5.0eq.) and the mixture was stirred at 20 ℃ for 16 hr. The mixture was quenched by 1M ice HCl (2L) and extracted with ethyl acetate/THF (2/1,1000mL x 3). The organic layer was washed with brine (1L) over MgSO₄Dried and concentrated in vacuo. EtOH/MeOH (220mL) was added to the residue and filtered. The filter cake was collected and dried to afford 7-bromo-2- (4-fluorophenyl) -5H-benzo [ e ] as a yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one (28g,67.89mmol, 66.85% yield, 90% purity). ESI [ M + H ]]＝370.9/372.9

7-bromo-11-chloro-2- (4-fluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine, S113, preparation of 7-bromo-2- (4-fluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]-diazepine-11 (10H) -one (2.00g,5.39mmol,1.0eq.) in POCl₃(50mL) of the solution was stirred at 90 ℃ for 1hr and then concentrated to give 7-bromo-11-chloro-2- (4-fluorophenyl) -5H-benzo [ e ] as a dark brown oil]Pyrrolo [1,2-a][1,4]Diazepine (2.3g, crude).

7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine, S114. preparation of 7-bromo-11-chloro-2- (4-fluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]A solution of diazepine (2.30g,5.90mmol,1.0eq.) in THF (20mL) and dioxane (20.00mL) was adjusted to pH 9 with TEA. Formyl hydrazine (5.45g,90mmol,20.0eq.) was then added to the solution and the mixture was stirred in a sealed tube at 120 ℃ for 16 hr. The reaction was concentrated in vacuo and purified by column chromatography (SiO)₂Petroleum ether/ethyl acetate 10:1 to 3:1) to give 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e) as a yellow solid]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine (2.3g,3.4 mmol). 1H NMR (400MHz, DMSO-d6) δ 9.22(s,1H),7.95(s,1H),7.80(d, J ═ 8.4Hz,1H),7.69(d, J ═ 8.8Hz,1H),7.61(t, J ═ 6.0Hz,2H),7.53(s,1H),7.17(t, J ═ 8.4Hz,2H),7.11(s,1H),5.29(s, 2H).

(S) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-7-yl) -N, N-dimethylpyrrolidin-3-amine 338 using general procedure A substituting 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] -pyrrolo [1,2-a ] - [1,2,4] triazolo [3,4-c ] [1,4] diazepin for 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] - [1,4] diazepine-12-yl) benzonitrile with (S) -N, N-dimethylpyrrolidin-3-amine instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.06(s,1H),7.61-7.49(m,3H),7.43(s,1H),7.13(s,1H),7.06(t, J ═ 8.6Hz,2H),6.89(br.s.,1H),6.79(d, J ═ 8.4Hz,1H),5.17(s,2H),4.17-4.01(m,1H),3.87-3.75(m,1H),3.72-3.56(m,2H),3.44(q, J ═ 8.3Hz,1H),2.99(s,6H),2.60(br.s.,1H),2.40-2.22(m, 1H). ESI [ M + H ] ═ 429.2

Scheme 32

The chemical experiment method comprises the following steps:

7-bromo-N- (2, 2-dimethoxyethyl) -2- (4-fluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]Azadipine-11-amine, S115, to 7-bromo-11-chloro-2- (4-fluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]To a solution of diazepine (3.0g,8.0mmol,1.0eq.) in THF (30mL) and dioxane (30mL) was added 2, 2-dimethoxyethylamine (8.5g,80.8mmol,10.0eq.) and the mixture was stirred in a sealed tube at 130 ℃ for 16 hr. The mixture was poured into 1N ice HCl solution (300mL) and extracted with ethyl acetate (300mL x 3). The combined organic phases were washed with brine (400mL) and over anhydrous Na₂SO₄Dried, filtered and concentrated to give 7-bromo-N- (2, 2-dimethoxyethyl) -2- (4-fluorophenyl) -5H-benzo [ e ] as a dark brown solid]Pyrrolo [1,2-a][1,4]The diazepine-11-amine (3.70g, crude), which is used without any purification. ESI [ M + H ]]＝458.1/460.1

7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine, S116, preparation of 7-bromo-N- (2, 2-dimethoxyethyl) -2- (4-fluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]A solution of diazepine-11-amine (3.7g,8.0mmol,1.0eq.) in dioxane (50mL) and 1M HCl (50mL) was stirred at 70 ℃ for 16hr and then concentrated. The residual solid was washed with methanol (30mL) and filtered, yielding 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] as a dark brown solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine (2.5g,6.3mmol, 78.6% yield), which was used directly without any purification.¹H NMR(400MHz,DMSO-d₆)δ＝8.22(s,1H),7.97(s,1H),7.84(d,J＝5.6Hz,2H),7.66(d,J＝8.0Hz,2H),7.59-7.55(m,2H),7.21-7.18(m,3H),5.38(s,2H)。ESI[M+H]＝394.1/396.1

12- (4-fluorophenyl) -7- (2, 6-diazaspiro [3.4]]Oct-6-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine, S376 using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Novel diazepine-12-yl) benzonitrile in combination with 2, 6-diazaspiro [3.4]Octane-2-carboxylic acid tert-butyl ester was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, chloroform-d) δ 7.42(dd, J5.5, 8.6Hz,2H),7.30(s,1H),7.24-7.18(m,2H),7.05-6.92(m,4H),6.57-6.46(m,2H),4.93(br.s.,2H),3.70-3.54(m,4H),3.50(s,2H),3.34(t, J6.6 Hz,2H),2.24(t, J6.6 Hz, 2H). ESI [ M + H ]]＝426.1

General procedure J is as follows:

2- (6- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) -2, 6-diazaspiro [3.4]Oct-2-yl) ethanol, S369, to 12- (4-fluorophenyl) -7- (2, 6-diazaspiro [3.4]]Oct-6-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine (16mg,37umol,1.0eq.) and 2-bromoethanol (14.1mg,112.8umol,8.0uL,3.0eq.) in CH₃Adding Na to CN (3.0mL)₂CO₃(7.9mg,75.2umol,2.0eq.) and the mixture was stirred at 60 ℃ for 16 hr. The mixture was concentrated and the residue was purified by neutral preparative HPLC to give 2- (6- (12- (4-fluorophenyl) -9H-benzo [ e) as a white solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) -2, 6-diazaspiro [3.4]Oct-2-yl) ethanol (2.4mg,4.7umol, 12.6% yield).¹H NMR (400MHz, methanol-d)₄)δ＝7.56-7.48(m,3H),7.32(d,J＝8.4Hz,1H),7.26(s,1H),7.17(s,1H),7.02(t,J＝8.8Hz,2H),6.89(d,J＝0.9Hz,1H),6.70(s,1H),6.62(d,J＝8.8Hz,1H),5.01(s,2H),3.58(t,J＝5.7Hz,2H),3.47(s,2H),3.42-3.32(m,6H),2.69(t,J＝5.7Hz,2H),2.22(t,J＝6.6Hz,2H)。ESI[M+H]＝470.3

Scheme 33

The chemical experiment method comprises the following steps:

7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Pyrrolo [1,2-a]Tetrazolo [5,1-c ]][1,4]Azadipine, S118, was reacted at 20 ℃ with 7-bromo-11-chloro-2- (4-fluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]Azepine (2.1g, crude) to a solution in anhydrous DMF (10mL) was added TMSN dropwise₃(1.86g,16.17mmol,3.0 eq.). The reaction mixture was stirred at 20 ℃ for 16hr and poured into ice water (50 mL). The resulting mixture was extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with brine (30mL) over MgSO₄Dried and concentrated. The residual solid was washed with MeOH (20mL) and dried to give 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] as a gray solid]Pyrrolo [1,2-a]Tetrazolo [5,1-c ]][1,4]Diazepine (1.6g, crude), which is used without further purification. ESI [ M + H ]]＝396.0/398.0

7- (cis-3, 5-dimethylpiperazin-1-yl) -12- (4-fluorophenyl) -9H-benzo [ e]Pyrrolo [1,2-a]Tetrazolo [5,1-c ]][1,4]Diazepine, 395, utilizing general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Pyrrolo [1,2-a]Tetrazolo [5,1-c ]][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and using cis-2, 6-dimethylpiperazine instead of tert-butyl piperazine-1-carboxylate.¹HNMR (400MHz, methanol-d)₄)δ＝7.88(d,J＝9.3Hz,1H),7.56(dd,J＝5.5,8.2Hz,2H),7.49(s,1H),7.31(br.s.,1H),7.28-7.20(m,2H),7.07(t,J＝8.6Hz,2H),5.26(s,2H),4.08(d,J＝13.2Hz,2H),3.53(br.s.,2H),2.82(t,J＝12.3Hz,2H),1.42(d,J＝6.6Hz,6H)。ESI[M+H]＝430.2

Scheme 34

The chemical experiment method comprises the following steps:

10-amino-7-bromo-2- (4-fluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one, S119, to 7-bromo-2- (4-fluorophenyl) -5H-benzo [ e ] at 0 deg.C]Pyrrolo [1,2-a][1,4]To a solution of diazepine-11 (10H) -one (1.0g,2.69mmol,1.0eq.) in DMF (20mL) was added NaH (161.64mg,4.04mmol, 60% purity, 1.5 eq.). After stirring for 1hr, (aminooxy) diphenylphosphine oxide (753.88mg,3.23mmol,1.2eq.) was added. The reaction mixture was stirred at 30 ℃ for 1hr, and then passed through saturated NH₄The Cl solution (100mL) was quenched. The resulting mixture was extracted with EtOAc (30 mL. times.3). The combined organic layers were washed with brine (30mL) over MgSO₄Dried and concentrated. The residual solid was washed with TBME (20mL) and dried to give 10-amino-7-bromo-2- (4-fluorophenyl) -5H-benzo [ e ] as a yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one (700mg,1.81mmol, 67.29% yield). ESI [ M + H ]]＝386.1/388.1

7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazole compoundsAnd [5,1-c ]][1,4]Diazepine, S120, preparation of 10-amino-7-bromo-2- (4-fluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]A mixture of diazepine-11 (10H) -one (700mg,1.8mmol,1.0eq.) in formamide (10mL) was stirred at 200 ℃ for 2hr and then poured into cold water (20 mL). The resulting precipitate was collected by filtration and purified by column chromatography on silica gel (petroleum ether/ethyl acetate ═ 20:1 to 2:1) to give 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] as a yellow solid]Pyrrolo [1,2-a][1,2,4]Triazolo [5,1-c][1,4]Diazepine (240mg,607.24umol, 33.55% yield). TLC R_f0.7 (petroleum ether/EtOAc 2/1). ESI [ M + H ]]＝394.9/396.9

1- (12- (4-fluorophenyl) -9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [5,1-c][1,4]Diazepine-7-yl) -N, N-dimethylpiperidin-4-amine, 428, using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [5,1-c][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and N, N-dimethylpiperidin-4-amine in place of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝8.19(s,1H),7.72(d,J＝9.3Hz,1H),7.54(dd,J＝53,8.4Hz,2H),7.41(s,1H),7.20-7.01(m,5H),5.17(s,2H),4.04(d,J＝13.2Hz,2H),3.47-3.35(m,1H),2.96-2.90(m,2H),2.89(s,6H),2.18(d,J＝11.5Hz,2H),1.82(dq,J＝3.7,12.1Hz,2H)。ESI[M+H]＝443.2

Scheme 35

The chemical experiment method comprises the following steps:

1- ((3-amino-6-bromopyridin-2-yl) methyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester, S121. at-70 ℃ under N₂To (3-amino-6-bromopyridin-2-yl) methanol (8.0g,39.40mmol,1.0eq.) and Et under atmosphere₃N (12.00g,118.59mmol,16.44mL,3.01eq.) to a mixture of anhydrous DCM (1.60L) and anhydrous THF (160mL) was added dropwise MsCl (6.0g,52.40mmol,4.05mL,1.33 eq.). The mixture was slowly warmed to 20 ℃ and stirred for 30 min. The mixture was then cooled again to 0 ℃ and 4- (4-fluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester (5.5g,25.09mmol,0.64eq.) was added, followed by Bu₄NOH (5.0g,4.82mmol,6.25mL, 25% in H)₂0.12eq in O, NaOH solution (25% in H)₂O, 30g,187.54mmol,4.76 eq.). The reaction mixture was slowly warmed to 25 ℃ and stirred for an additional 15.5 hr. The mixture was washed with water (1L) and brine (1L), over Na₂SO₄Dried and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/THF ═ 30/1 to 5/1) to give methyl 1- ((3-amino-6-bromopyridin-2-yl) methyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (3.3g,6.94mmol, 17.61% yield, 90% purity) as a yellow solid. TLC R_f0.35 (5/1 in petroleum ether/THF).¹H NMR(400MHz,DMSO-d₆)δ＝7.64-7.60(m,2H),7.55(br.s,1H),7.27(br.s,1H),7.17-7.14(m,3H),6.99-6.97(m,1H),5.56(s,2H),5.43(s,2H),3.71(s,3H)。ESI[M+H]＝404.0/406.0

2-bromo-8- (4-fluorophenyl) -5H-pyrido [3,2-e]Pyrrolo [1,2-a][1,4]Diazepine-6 (11H) -one, S122. at 0 ℃ under N₂To a suspension of methyl 1- ((3-amino-6-bromopyridin-2-yl) methyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (3.3g,8.16mmol,1.0eq.) in dry toluene (150mL) under an atmosphere was added AlMe dropwise₃(2M in toluene, 20mL,4.9 eq.). The reaction mixture was warmed to 25 ℃ and stirred for 16 hours. Pouring the mixture into cold NH₄Aqueous Cl (200mL) and extracted with hot EtOAc/THF (4:1,100 mL. times.3). The combined organic layers were washed with brine (100mL)Washing with Na₂SO₄Dried and concentrated. The residual solid was washed with EtOH (10 mL. times.2) and dried, yielding 2-bromo-8- (4-fluorophenyl) -5H-pyrido [3,2-e as a pale yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-6 (11H) -one (1.80g,4.05mmol, 49.68% yield, 83.82% purity).¹H NMR(400MHz,DMSO-d₆)δ＝10.35(s,1H),7.69-7.64(m,2H),7.59-7.54(m,3H),7.19-7.14(m,3H),5.34(s,2H)。ESI[M+H]＝372.0/374.0

2-bromo-6-chloro-8- (4-fluorophenyl) -11H-pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepine, S123.

At 25 ℃ under N₂To 2-bromo-8- (4-fluorophenyl) -5H-pyrido [3,2-e under atmosphere]Pyrrolo [1,2-a][1,4]To a suspension of diazepine-6 (11H) -one (600mg,1.61mmol,1.0eq.) in anhydrous dioxane (20mL) was added dropwise POCl₃(1.0g,6.52mmol,600uL,4.0 eq.). The mixture was stirred at 85 ℃ for 4 hours and then concentrated to dryness. The crude product was used without purification.

2-bromo-N- (2, 2-dimethoxyethyl) -8- (4-fluorophenyl) -11H-pyrido [3,2-e]Pyrrolo [1,2-a][1,4]Diazepine-6-amine, S124. at 0 ℃ under N₂To 2-bromo-6-chloro-8- (4-fluorophenyl) -11H-pyrido [3,2-e under atmosphere]Pyrrolo [1,2-a][1,4]Diazepine (600mg,1.6mmol,1.0eq.) to a solution in anhydrous dioxane (50mL) was added dropwise 2, 2-dimethoxyethylamine (7g,66mmol,7.2mL,41 eq.). The mixture was stirred at 100 ℃ for 8 hours and concentrated. The residue was purified by column chromatography on silica gel using petrol/THF 40:1 to 10:1 to give 2-bromo-N- (2, 2-dimethoxyethyl) -8- (4-fluorophenyl) -11H-pyrido [3,2-e as a light yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-6-amine (600mg,1.09mmol, 67.6% yield, 83.4% purity), which is notFurther purifying and directly using. TLC R_fPetroleum ether/THF 2/1 ═ 0.6. ESI [ M + H ]]＝459.1/461.1

7-bromo-12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepine, S125. A mixture of 2-bromo-N- (2, 2-dimethoxyethyl) -8- (4-fluorophenyl) -11H-pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-6-amine (700mg,1.27mmol,1.00eq.) in dioxane (30mL) and 1M HCl (30mL) is heated to 70 ℃ and held for 16hr and then concentrated. The residual solids were washed with THF (10mL × 2) and dried in vacuo to give 7-bromo-12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepine (500mg, crude) as a pale yellow solid, which was used without further purification. ESI [ M + H ] ═ 395.0/397.0

12- (4-fluorophenyl) -7- (2, 6-diazaspiro [3.4]]Oct-6-yl) -9H-imidazo [2,1-c]Pyrido [3,2-e]Pyrrolo [1,2-a][1,4]Diazepine, 440, using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-imidazo [2,1-c]Pyrido [3,2-e]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Novel diazepine-12-yl) benzonitrile in combination with 2, 6-diazaspiro [3.4]Octane-2-carboxylic acid tert-butyl ester was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.01(s,1H),7.88(d,J＝8.8Hz,1H),7.78(s,1H),7.64(s,1H),7.59(t,J＝6.2Hz,2H),7.24(s,1H),7.10(t,J＝8.1Hz,2H),6.68(d,J＝9.0Hz,1H),5.32(s,2H),4.23-4.15(m,2H),4.13-4.05(m,2H),3.85(br.s.,2H),3.70-3.56(m,2H),2.40(t,J＝6.7Hz,2H)。ESI[M+H]＝427.1

Scheme 36

The chemical experiment method comprises the following steps:

1- ((5-amino-2-chloropyridin-4-yl) methyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester, S127. at-78 ℃ under N₂To a solution of (5-amino-2-chloropyridin-4-yl) methanol (4.0g,25mmol,1.0eq.) and TEA (7.6g,75.6mmol,10.4mL,3.0eq.) in DCM (400mL) was added methanesulfonyl chloride (3.4g,30.2mmol,2.3mL,1.2 eq.). The mixture was warmed to 26 ℃ and at 26 ℃ under N₂Stirring for 1 hr. To the solution was added 4- (4-fluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester (4.4g,20.1mmol,0.8eq.) NaOH (25%, 6.00eq.) and TBAOH (2.62g,2.52mmol,3.28mL, 25% purity, 0.10eq.) at 0 ℃. The mixture was stirred at 26 ℃ for 16hr, diluted with water (500mL) and extracted with DCM (500mL × 2). The combined organic layers were dried over anhydrous MgSO₄Dried, filtered and concentrated to yield a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 5/1 to 1/1) to give methyl 1- ((5-amino-2-chloropyridin-4-yl) methyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (1.9g,5.28mmol, 20.94% yield) as a yellow solid. TLC, Rf 0.22 (petroleum ether/ethyl acetate 1/1). ESI [ M + H ]]＝360.0

3-chloro-8- (4-fluorophenyl) -5H-pyrido [3,4-e]Pyrrolo [1,2-a][1,4]Diazepine-10 (11H) -one, S128. at 0 ℃ under N₂To a solution of methyl 1- ((5-amino-2-chloropyridin-4-yl) methyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (1.8g,5.2mmol,1.0eq.) in toluene (100mL) was added AlMe dropwise₃(2M,12.85mL,5.0 eq.). The mixture was then stirred at 20 ℃ for 16hr, quenched with ice water (200mL) and washed with hot EtOAc/THF (1/1,200 m)L × 2) extraction. The combined organic layers were washed with brine (100mL) and Na₂SO₄Dried and concentrated. The residual solid was washed with MeOH (20 mL). After filtration, the filter cake was collected to give 3-chloro-8- (4-fluorophenyl) -5H-pyrido [3,4-e as a yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-10 (11H) -one (1.60g, crude). 1H NMR (400MHz, methanol-d 4) δ 8.13(s,1H),7.49-7.39(m,3H),7.28(d, J ═ 1.8Hz,1H),7.14(d, J ═ 1.8Hz,1H),6.96(t, J ═ 8.8Hz,2H),5.16(s, 2H). ESI [ M + H ]]＝327.9

3, 10-dichloro-8- (4-fluorophenyl) -5H-pyrido [3,4-e]Pyrrolo [1,2-a][1,4]Diazepine, S129. preparation of 3-chloro-8- (4-fluorophenyl) -5H-pyrido [3,4-e]Pyrrolo [1,2-a][1,4]Diazepine-10 (11H) -one (300mg,806umol,1.0eq.) in POCl₃(5mL) the solution was stirred at 90 ℃ for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with THF (5mL), adjusted to pH 7-8 with TEA and concentrated under reduced pressure to give crude 3, 10-dichloro-8- (4-fluorophenyl) -5H-pyrido [3,4-e]Pyrrolo [1,2-a][1,4]The diazepine (310mg) without further purification.

3-chloro-N- (2, 2-dimethoxyethyl) -8- (4-fluorophenyl) -5H-pyrido [3,4-e]Pyrrolo [1,2-a][1,4]Diazepine-10-amine, S130, preparation of 3, 10-dichloro-8- (4-fluorophenyl) -5H-pyrido [3,4-e]Pyrrolo [1,2-a][1,4]A solution of diazepine (310mg,793umol,1.0eq.) and 2, 2-dimethoxyethylamine (834mg,7.94mmol,860uL,10eq.) in THF (10mL)/1, 4-dioxane (10mL) was stirred at 130 ℃ for 16hr in a sealed tube. The reaction mixture was concentrated under reduced pressure, diluted with THF/EtOAc (50mL/50mL) and washed with 1M HCl (20 mL). The combined organic layers were washed with brine, over Na₂SO₄Dried, filtered and concentrated under reduced pressure to give crude 3-chloro-N- (2, 2-dimethoxyethyl) -8- (black brown oil4-fluorophenyl) -5H-pyrido [3,4-e]Pyrrolo [1,2-a][1,4]The diazepine-10-amine (360.00mg, crude) without further purification.

7-chloro-12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepine, S131. A solution of 3-chloro-N- (2, 2-dimethoxyethyl) -8- (4-fluorophenyl) -5H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepin-10-amine (360mg,867umol,1.0eq.) in dioxane (10mL) and 1M HCl (10mL) is stirred at 70 ℃ for 16hr and concentrated under reduced pressure. The residual solids were washed with THF (5mL) and filtered to yield crude 7-chloro-12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepine (250mg, crude) as a dark brown solid without further purification. ESI [ M + H ] ═ 350.9

(R) -2- ((((R) -1- (12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methyl) amino) propan-1-ol, 442 using general procedure A substituting 7-chloro-12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepine for 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and (R) -2- (((S) -pyrrolidin-3-ylmethyl) amino) propan-1-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.43(s,1H),8.09(br.s.,1H),7.78(br.s.,1H),7.65-7.53(m,3H),7.24(br.s.,1H),7.10(t, J ═ 8.0Hz,2H),6.76(s,1H),5.33(s,2H),3.94-3.79(m,2H),3.72(br.s.,1H),3.65-3.50(m,2H),3.41(br.s.,2H),3.26-3.16(m,2H),2.81-2.67(m,1H),2.36(br.s.,1H),2.02-1.86(m,1H),1.35 (J ═ 6H), 7.6H (J ═ 6H). ESI [ M + H ] ═ 473.1

Scheme 37

The chemical experiment method comprises the following steps:

3-chloro-8- (4-fluorophenyl) -5H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepine-10 (11H) -thione, S132 to a solution of 3-chloro-8- (4-fluorophenyl) -5H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepine-10 (11H) -one (1.3g,3.9mmol,1.0eq.) in THF (30mL) was added the Lawson reagent (2.1g,5.2mmol,1.3eq.) and the mixture was stirred at 70 ℃ for 1 hr. The mixture was concentrated and the residual solid was washed with methanol (10mL) to give 3-chloro-8- (4-fluorophenyl) -5H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepine-10 (11H) -thione (1.0g,2.9mmol, 73.5% yield) as a yellow solid which was used without any purification. ESI [ M + H ] ═ 344.1

3-chloro-8- (4-fluorophenyl) -10- (methylthio) -5H-pyrido [3,4-e]Pyrrolo [1,2-a][1,4]Azadipine, S133, toward 3-chloro-8- (4-fluorophenyl) -5H-pyrido [3,4-e]Pyrrolo [1,2-a][1,4]Addition of K to a solution of diazepine-10 (11H) -thione (1.0g,2.9mmol,1.0eq.) in DMF (8.0mL)₂CO₃(1.2g,8.7mmol,3.0eq.) and methyl iodide (2.0g,14mmol,905uL,5.0 eq.). The mixture was stirred at 26 ℃ for 1hr and filtered. The filtrate was concentrated under reduced pressure to give 3-chloro-8- (4-fluorophenyl) -10- (methylthio) -5H-pyrido [3,4-e as a yellow solid]Pyrrolo [1,2-a][1,4]Diazepine (1.0g,2.8mmol, 96% yield), which was used directly without any purification. ESI [ M + H ]]＝358.1

7-chloro-12- (4-fluorophenyl) -9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine, S134 to a solution of 3-chloro-8- (4-fluorophenyl) -10- (methylthio) -5H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepine (1.0g,2.8mmol,1.0eq.) in n-BuOH (30mL) is added formhydrazide (837mg,14mmol,5.0eq.) and the mixture is stirred at 120 ℃ for 16 hr. The mixture was concentrated and the residual solids were washed with 1N HCl (20mL) to give 7-chloro-12- (4-fluorophenyl) -9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine (650mg,1.85mmol, 66.23% yield) as a yellow solid. ESI [ M + H ] ═ 352.2

(S) -1- (1- (12- (4-fluorophenyl) -9H-pyrido [3, 4-e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Azadipine-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine, 443, using general procedure C with 7-chloro-12- (4-fluorophenyl) -9H-pyrido [3,4-e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]The diazepine-12-yl) benzonitrile and the replacement of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate with tert-butyl (R) - (pyrrolidin-3-ylmethyl) carbamate.¹H NMR (400MHz, methanol-d)₄)δ＝9.04(br.s.,1H),8.35(br.s.,1H),7.61-7.51(m,2H),7.42(s,1H),7.17(br.s.,1H),7.06(t,J＝8.6Hz,2H),6.76(s,1H),5.18(br.s.,2H),3.94-3.82(m,1H),3.69(d,J＝6.7Hz,1H),3.58-3.47(m,1H),3.37-3.32(m,2H),2.96(s,6H),2.90-2.76(m,1H),2.70(s,1H),2.34(br.s.,1H),1.96-1.83(m,1H)。ESI[M+H]＝444.2

Scheme 38

Chemical experimental method

4- (2, 4-difluorophenyl) -1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, S137. at 25 ℃ under N₂To 4-bromo-1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (34g,111mmol,1.0eq.) and (2, 4-difluorophenyl) boronic acid (26g,164mmol,1.47eq.) and Boc under an atmosphere₂O (38g,174mmol,40mL,1.56eq.) and Na₂CO₃(24g,226mmol,2.0eq.) in dioxane (1.0L) and H₂Pd (dppf) Cl was added to a mixture in O (100mL)₂(4g,5.4mmol,0.05 eq.). The mixture was stirred at 100 ℃ for 16hr and concentrated. The residue was diluted with EtOAc/THF (400mL/100mL) and washed with brine (400 mL). The aqueous layer was separated and extracted with EtOAc (150 mL. times.2). The combined organic layers were passed over Na₂SO₄Dried and concentrated to give a mixture of 4- (2, 4-difluorophenyl) -1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (40g crude) as a dark brown oil, which was used directly. ESI [ M + H ]]＝338.0

Methyl 4- (2, 4-difluorophenyl) -1H-pyrrole-2-carboxylate, s138 to a solution of 4- (2, 4-difluorophenyl) -1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (40g, crude) in DCM (50mL) was added TFA (100mL) dropwise. The reaction mixture was stirred at 25 ℃ for 1.0hr and concentrated. MeOH (50mL) was added to the residue and stirred for 1.0 hr. The solid was collected by filtration to give methyl 4- (2, 4-difluorophenyl) -1H-pyrrole-2-carboxylate (15g,56.91mmol, 56.41% yield over all 2 steps) as a dark brown solid, which was used directly.¹H NMR(400MHz,CDCl₃)δ＝9.21,(br.s,1H),7.54-7.48,(m,1H),7.38(s,1H),7.22(s,1H),6.92-6.85(m,2H),3.90(s,3H)。ESI[M+H]＝238.0

1- (5-bromo-2-nitrobenzyl) -4- (2, 4-difluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester, S139. at 0 ℃ in N₂To (5-bromo-2-nitrophenyl) methanol (9.0g,38.7mmol,1.0eq.) and Et under atmosphere₃N (6.0g,59.2mmol,8.20mL,1.5eq.) to a solution in anhydrous DCM (300mL) was added dropwise MsCl (5.2g,45.5mmol,3.5mL,1.2 eq.). The reaction mixture was stirred at 0 ℃ for 1.0hr, followed by the addition of methyl 4- (2, 4-difluorophenyl) -1H-pyrrole-2-carboxylate (9.0g,37.9mmol,1.0eq.) followed by Bu₄NOH (25% in H)₂O, 4.0g,3.8mmol,0.1eq.) and aqueous NaOH (25%, 35g,218.9mmol,5.7 eq.). The reaction mixture was warmed to 25 ℃ and stirred for a further 16 hr. The mixture was washed with brine (200mL) and Na₂SO₄Dried and concentrated. The residual solid was washed with EtOAc/petroleum ether (1:1,50mL × 2), filtered and dried to give methyl 1- (5-bromo-2-nitrobenzyl) -4- (2, 4-difluorophenyl) -1H-pyrrole-2-carboxylate (14.50g, crude) as a yellow solid, which was used directly. ESI [ M + H ]]＝450.9/452.9

1- (2-amino-5-bromobenzyl) -4- (2, 4-difluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester, S140.

Methyl 1- (5-bromo-2-nitrobenzyl) -4- (2, 4-difluorophenyl) -1H-pyrrole-2-carboxylate (14.5g,32.1mmol,1.0eq.), Fe (9.0g,161mmol,5.0eq.), and NH₄Cl (5.0g,93.5mmol,3.27mL,2.9eq.) in THF (100mL), EtOH (100mL) and H₂The mixture in O (50mL) was stirred at 100 ℃ for 2.5hr and then concentrated. The residue was dissolved with hot THF (2L), filtered and the filtrate was concentrated to give methyl 1- (2-amino-5-bromobenzyl) -4- (2, 4-difluorophenyl) -1H-pyrrole-2-carboxylate (13g, crude) as a yellow solid, which was used directly. ESI [ M + H ]]＝420.9/422.9

7-bromo-2- (2, 4-difluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one, S141. at 0 ℃ under N₂To a suspension of methyl 1- (2-amino-5-bromobenzyl) -4- (2, 4-difluorophenyl) -1H-pyrrole-2-carboxylate (13g,30.8mmol,1.0eq.) in dry toluene (150mL) under an atmosphere was added AlMe dropwise₃(2M in toluene, 75mL,4.8 eq.). The reaction mixture was stirred at 25 ℃ for 16hr and then poured slowly into cold 0.5M HCl (100 mL). The aqueous layer was separated and extracted with EtOAc/THF (8:1,100 mL. times.3). The combined organic layers were washed with brine (150mL), Na₂SO₄Dried and concentrated. The residual solid was washed with petroleum ether/EtOAc (3:1,50 mL. times.2) and dried in vacuo to give 7-bromo-2- (2, 4-difluorophenyl) -5H-benzo [ e ] as a pale yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -ketone (7.5g, crude), which was used without further purification. ESI [ M + H ]]＝388.9/390.9

7-bromo-11-chloro-2- (2, 4-difluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine, S142, prepared by reacting 7-bromo-2- (2, 4-difluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one (1.5g,3.8mmol,1.0eq.) in POCl₃The solution in (50mL) was heated to 90 ℃ and held for 6hr and then concentrated in vacuo to give the crude product, which was used without purification.

7-bromo-12- (2, 4-difluorophenyl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine, S143, to 7-bromo-11-chloro-2- (2, 4-difluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]To a mixture of diazepine (1.6g,3.9mmol,1.0eq.) in anhydrous dioxane (50mL) was added formylhydrazine (2.4g,39.9mmol,10.1eq.) and the reaction mixture was stirred at 110 ℃ for 16 hr. The mixture was then cooled to 25 ℃ and poured into ice-cold water (1)50mL), extracted with hot EtOAc/THF (4:1,100 mL. times.4). The combined organic layers were washed with brine (100mL) and Na₂SO₄Dried and concentrated. The residual solid was washed with EtOAc (50mL × 2) and dried in vacuo to give 7-bromo-12- (2, 4-difluorophenyl) -9H-benzo [ e ] as an off-white solid]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine (1.0g, crude), which is used as such. ESI [ M + H ]]＝412.9/414.9

(S) -1- (12- (2, 4-difluorophenyl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-7-yl) -N, N-dimethylpyrrolidin-3-amine, 449 using general procedure A with 7-bromo-12- (2, 4-difluorophenyl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (S) -N, N-dimethylpyrrolidin-3-amine in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.97(s,1H),7.68-7.60(m,1H),7.51-7.46(m,2H),7.15(s,1H),6.99-6.90(m,2H),6.88(d,J＝2.6Hz,1H),6.76(dd,J＝2.4,8.6Hz,1H),5.16(s,2H),3.91(br.s.,1H),3.79-3.72(m,1H),3.65(dt,J＝3.1,9.0Hz,1H),3.55(dd,J＝6.6,10.1Hz,1H),3.46-3.37(m,1H),2.88(s,6H),2.73-2.65(m,1H),2.26(dd,J＝7.9,12.8Hz,1H)。ESI[M+H]＝447.1

Scheme 39

The chemical experiment method comprises the following steps:

10-amino-7-bromo-2- (2, 4-difluorophenyl) -5H-benzo [ e]Azole compoundsAnd [1,2-a ]][1,4]Diazepine-11 (10H) -one, S144, to 7-bromo-2- (2, 4-difluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]To a solution of diazepine-11 (10H) -one (1.0g,2.5mmol,1.0eq.) in anhydrous DMF (15mL) was added NaH (260mg,6.50mmol, 60% purity, 2.53eq.) and the mixture was stirred at 0 ℃ for 30 min. Subsequently, (aminooxy) diphenylphosphine oxide (797.1mg,3.4mmol,1.3eq.) was added in portions and the reaction mixture was stirred at 25 ℃ for a further 2.5 hr. The mixture was taken up in an ice-cold saturated aqueous solution NH₄Cl (50mL) was quenched and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried and concentrated. The residue was purified by column chromatography on silica gel using petrol/EtOAc (10:1 to 1:1) to give 10-amino-7-bromo-2- (2, 4-difluorophenyl) -5H-benzo [ e ] as an off-white solid]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one (600mg,1.34mmol, 52.14% yield, 90.2% purity). TLC R_f0.55 (petroleum ether/EtOAc 1/1). ESI [ M + H ]]＝404.0/406.0

7-bromo-12- (2, 4-difluorophenyl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [5,1-c][1,4]Diazepine, S145. reacting 10-amino-7-bromo-2- (2, 4-difluorophenyl) -5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one (250mg,618umol,1.0eq.) and ZnCl₂(250mg,1.8mmol,85.9uL,2.9eq.) in NH₂The mixture in CHO (5.0mL) was stirred at 200 ℃ for 1hr and then the mixture was poured into water (50 mL). The resulting precipitate was collected by filtration and subsequently purified by preparative TLC (petroleum ether/EtOAc ═ 2:1) to give 7-bromo-12- (2, 4-difluorophenyl) -9H-benzo [ e ] as a light yellow solid]Pyrrolo [1,2-a][1,2,4]Triazolo [5,1-c][1,4]Diazepine (125mg,453umol, 36% yield, 75% purity), which was used as such. ESI [ M + H ]]＝413.0/415.0

(S)-1- (12- (2, 4-difluorophenyl) -9H-benzo [ e [ ]]Pyrrolo [1,2-a][1,2,4]Triazolo [5,1-c][1,4]Diazepine-7-yl) -N-methylpyrrolidin-3-amine, 451, using general procedure A with 7-bromo-12- (2, 4-difluorophenyl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [5,1-c][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and tert-butyl (S) -methyl (pyrrolidin-3-yl) carbamate in place of piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝8.16(s,1H),7.73(d,J＝8.8Hz,1H),7.70-7.60(m,1H),7.50(s,1H),7.17(s,1H),7.03-6.92(m,2H),6.89-6.78(m,2H),5.25-5.17(m,2H),4.05-3.94(m,1H),3.75-3.56(m,3H),3.46(dt,J＝5.7,9.0Hz,1H),2.86-2.74(m,3H),2.55(dt,J＝6.7,14.4Hz,1H),2.28(dt,J＝5.3,13.3Hz,1H)。ESI[M+H]＝433.1

Scheme 40

The chemical experiment method comprises the following steps:

4-phenyl-1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, S147. 4-bromo-1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (44g,144mmol,1.0eq.), phenylboronic acid (26.4g,217mmol,1.5eq.), Na₂CO₃(30.6g,289mmol,12mL,2.0eq.) and (Boc)₂O(47.3g,217mmol,49.8mL,1.5eq.)、Pd(dppf)Cl₂(5.3g,7.2mmol,0.05eq.) in dioxane/H₂The suspension in O (1.5L,10:1) was degassed and then in N₂Heating to 80-100 deg.C for 12 hr. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (1.0L) and brine (200 mL). Subjecting the organic layer to anhydrous Na₂SO₄Dried, filtered and concentrated to give crude 1-tert-butyl 4-phenyl-1H-pyrrole-1, 2-dicarboxylate 2 as an off-white solid-methyl ester (43.00g, crude), which was used in the next step without further purification. ESI [ M + H ]]＝302.2

4-phenyl-1H-pyrrole-2-carboxylic acid methyl ester, s148. a solution of 4-phenyl-1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (43g,142.7mmol,1.0eq.) in TFA (300mL) was stirred at 50 ℃ for 2hr and then concentrated under reduced pressure. MeOH (200mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give methyl 4-phenyl-1H-pyrrole-2-carboxylate (20g, crude) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ＝7.60(d,J＝7.4Hz,2H),7.49(dd,J＝1.6,2.7Hz,1H),7.30(t,J＝7.6Hz,2H),7.19-7.11(m,2H),3.77(s,3H)。ESI[M+H]＝202.2

1- (5-bromo-2-nitrobenzyl) -4-phenyl-1H-pyrrole-2-carboxylic acid methyl ester, s149. to a solution of (5-bromo-2-nitrophenyl) methanol (12.0g,51.7mmol,1.00eq.) and TEA (10.4g,103.4mmol,14.3mL,2.0eq.) in DCM (300mL) at 0 ℃ was added MsCl (6.5g,56.8mmol,4.4mL,1.1eq.) and the mixture was stirred at 0 ℃ for 0.5 hr. Subsequently to the solution was added 4-phenyl-1H-pyrrole-2-carboxylic acid methyl ester (10.4g,51.7mmol,1.0eq) followed by tetrabutylammonium hydroxide (5.37g,5.2mmol,6.7mL, 25% w%, 0.10eq.) and NaOH solution (25%, 5.0eq.) at 0 ℃. The mixture was stirred at 20 ℃ for 11hr and then diluted with ice water (200mL) and DCM (800 mL). Separating the organic layer over anhydrous Na₂SO₄Dried, filtered and concentrated. EtOH (50mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give methyl 1- (5-bromo-2-nitrobenzyl) -4-phenyl-1H-pyrrole-2-carboxylate (20g) as an off white solid.¹H NMR (400MHz, chloroform-d) δ 8.01(d, J8.8 Hz,1H),7.54(d, J7.5 Hz,3H),7.41-7.34(m,3H),7.25(s,1H),7.22(d, J1.8 Hz,1H),6.73(s,1H),5.92(s,2H),3.75(s,3H)

1- (2-amino-5-bromobenzyl) -4-phenyl-1H-pyrrole-2-carboxylic acid methyl ester, S150. 1- (5-bromo-2-nitrobenzyl) -4-phenyl-1H-pyrrole-2-carboxylic acid methyl ester (17g,40.9mmol,1.0eq.), Fe (11.43g,204.70mmol,5.00eq.) and NH₄Cl (10.9g,204.7mmol,7.1mL,5.0eq.) in EtOH (80mL), H₂The suspension in O (40mL) and THF (80mL) was heated to 80 ℃ and held for 5 hr. The mixture was concentrated to dryness and to the residue was added hot THF (2L). The mixture was filtered and the filtrate was concentrated. EtOH (100mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give methyl 1- (2-amino-5-bromobenzyl) -4-phenyl-1H-pyrrole-2-carboxylate (13.00g) as a yellow solid. ESI [ M + H ]]＝385.1/387.1

7-bromo-2-phenyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]To a suspension of methyl 1- (2-amino-5-bromobenzyl) -4-phenyl-1H-pyrrole-2-carboxylate (13g,33.74mmol,1.0eq.) in toluene (150mL) at 0 deg.C was added Me-11 (10H) -one, S151₃Al (2M in toluene, 85mL,5.0eq.) and the mixture was stirred at 30 ℃ for 10 hr. The mixture was poured into 1M ice HCl (300mL) and extracted with hot EtOAc/THF (1:1,300mL 4). Subjecting the organic layer to anhydrous Na₂SO₄Dried, filtered and concentrated. MeOH (50mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give 7-bromo-2-phenyl-5H-benzo [ e ] as a white solid]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one (10 g).¹H NMR(400MHz,DMSO-d₆)δ＝10.29(s,1H),7.73(s,1H),7.63-7.52(m,4H),7.39(t,J＝7.5Hz,2H),7.26-7.17(m,3H),5.27(s,2H)

7-bromo-11-chloro-2-phenyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine, S152. reacting 7-bromo-2-phenyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one (1.0g,2.83mmol,1.0eq.) in POCl₃The solution in (50mL) was stirred at 90 ℃ for 2 hr. The solution was concentrated under reduced pressure to give 7-bromo-11-chloro-2-phenyl-5H-benzo [ e ] as a black oil]Pyrrolo [1,2-a][1,4]Diazepine (1.2g, crude), which was used in the next step without further purification.

7-bromo-12-phenyl-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine, S153, substituted 7-bromo-11-chloro-2-phenyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]A solution of diazepine (670mg,1.75mmol,1.0eq.) and formhydrazide (525mg,8.75mmol,5.0eq.) in dioxane (20mL) was stirred in a sealed tube at 130 ℃ for 12 hours. The mixture was concentrated and the residue partitioned between hot EtOAc/THF (1:1,200mL) and HCl (3M,50 mL). The organic phase was washed with brine (15mL) and anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. MeOH (10mL) was added to the residue and stirred for 1 hr. The precipitate was collected by filtration to give 7-bromo-12-phenyl-9H-benzo [ e ] as a white solid]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine (500mg,1.19mmol, 68.16% yield).¹H NMR(400MHz,DMSO-d₆)δ＝9.21(s,1H),7.94(br.s.,1H),7.78(d,J＝8.2Hz,1H),7.67(d,J＝8.6Hz,1H),7.59-7.52(m,3H),7.33(t,J＝7.0Hz,2H),7.16(t,J＝7.2Hz,1H),7.11(s,1H),5.28(s,2H)。

(R) -1- ((1- (12-phenyl-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methyl) piperidin-4-ol, 459 using general procedure A substituting 7-bromo-12-phenyl-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin for 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, and, Synthesized with (S) -1- (pyrrolidin-3-ylmethyl) piperidin-4-ol instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.14(br.s.,1H),7.59-7.39(m,4H),7.32(t, J ═ 7.5Hz,2H),7.24-7.12(m,2H),6.74(br.s.,1H),6.65(d, J ═ 8.4Hz,1H),5.08(s,2H),4.11(br.s.,1H),3.84(br.s.,1H),3.76-3.58(m,2H),3.54-3.42(m,2H),3.42-3.32(m,2H),3.17-3.02(m,2H),2.93-2.76(m,1H),2.33(d, J ═ 5.3, 1H), 2.15H (m,1H), 13-11H, 13H, 1H), 13-3.9H (d, 1H). ESI [ M + H ] ═ 481.2

Scheme 41

The chemical experiment method comprises the following steps:

7-bromo-N- (2, 2-dimethoxyethyl) -2-phenyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Azadipine-11-amine, S154, to 7-bromo-11-chloro-2-phenyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]To a solution of diazepine (1.05g,2.83mmol,1.0eq.) in dioxane (30mL) and THF (30mL) was added TEA (1.4g,14.1mmol,1.9mL,5.0eq.) and 2, 2-dimethoxyethylamine (5.9g,56.6mmol,6.1mL,20.0 eq.). The mixture was stirred in a sealed tube at 130 ℃ for 16hr and concentrated. The residue was diluted with the solvents EtOAc (300mL) and THF (100mL), 0.5MHCl (100mL), saturated NaHCO₃(100mL) and brine (100mL) over Na₂SO₄Dried, filtered and concentrated to give crude 7-bromo-N- (2, 2-dimethoxyethyl) -2-phenyl-5H-benzo [ e ] as a dark brown oil]Pyrrolo [1,2-a][1,4]Diazepine-11-amine (1.25g, crude). ESI [ M + H ]]＝440.0/442.0

7-bromo-12-phenyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine, S155. A mixture of 7-bromo-N- (2, 2-dimethoxyethyl) -2-phenyl-5H-benzo [ e ] pyrrolo [1,2-a ] [1,4] diazepine-11-amine (1.25g,2.84mmol,1.0eq.) in dioxane (20mL) and 1M HCl (20mL) is stirred at 80 ℃ for 16 hr. After completion of the reaction, the mixture was concentrated and THF (15mL) and ethanol (1mL) were added to the residue. After stirring for 1hr, the precipitate was collected by filtration to give 7-bromo-12-phenyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine (1.5g, crude) as a dark brown solid. ESI [ M + H ] ═ 376.0/378.0

12-phenyl-7- (2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine, 462. synthesized using general procedure A using 7-bromo-12-phenyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate in place of tert-butyl piperazine-1-carboxylate. 1HNMR (400MHz, methanol-d 4) δ 7.56-7.48(m,3H),7.38-7.25(m,4H),7.17(s,1H),7.15-7.08(m,1H),6.93(s,1H),6.73(br.s.,1H),6.65(d, J ═ 6.8Hz,1H),5.04(s,2H),3.86-3.69(m,2H),3.54(s,2H),3.49-3.34(m,4H),2.35-2.24(m, 2H). ESI [ M + H ] ═ 408.1

Amine synthesis

The chemical experiment method comprises the following steps:

6-oxa-3-azabicyclo [3.1.0]Hexane-3-carboxylic acid tert-butyl ester, m2. to a solution of 2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester (100g,590.9mmol,1.0eq.) in DCM (1.2L) at 0 ℃ m-CPBA (180g,886.43mmol, 85% purity, 1.50eq.) was added portionwise and the mixture was stirred at 25 ℃ for 16 hr. The mixture was treated with 10% NaHSO₃Aqueous solution (600 mL. times.2), saturated NaHCO₃The aqueous solution (600 mL. times.2) and brine (600mL) were washed with Na₂SO₄Dried and concentrated to give 6-oxa-3-azabicyclo [3.1.0 ] as a yellow oil]Hexane-3-carboxylic acid tert-butyl ester (220g, crude). 1H NMR (400MHz, chloroform-d) δ 3.75(d, J12.8 Hz,1H),3.67(d, J12.8 Hz,1H),3.60(d, J3.3 Hz,2H),3.24(dd, J5.0, 12.7Hz,2H),1.43-1.31(m,9H)

Trans-3- (benzylamino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M3, 6-oxa-3-azabicyclo [3.1.0 ] at 25 deg.C]Hexane-3-carboxylic acid tert-butyl ester (135g,728.8mmol,1.0eq.) in EtOH (1.3L) was added BnNH portionwise₂(160g,1.49mol,163.27mL,2.05 eq.). The reaction mixture was heated to reflux (oil bath 95 ℃) and held for 16hr and then concentrated. To the residue was added EtOAc/petroleum ether (1:1,400mL) and stirred for 1.0 hr. The precipitate was collected by filtration to give trans-3- (benzylamino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (137g,421.7mmol, 57.8% yield, 90% purity) as a white solid. 1H NMR (400MHz, chloroform-d) δ 7.37-7.18(m,5H),4.09(d, J4.0 Hz,1H),3.88-3.73(m,2H),3.73-3.56(m,2H),3.31-3.07(m,3H),1.48-1.37(m,9H)

General procedure K

(3S,4S) -3- (benzylamino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M4. trans-3- (benzylamino)) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (151g,516.4mmol,1.0eq.) in MeCN (4.20L) and H₂To the suspension in O (280.00mL) was added (2S) -2-hydroxy-2-phenyl-acetic acid (85.6g,562.9mmol,1.1 eq.). The mixture was heated to 85 ℃ and held for 2hr and the solids slowly dissolved. The solution was cooled to 20 ℃ and held for 11hr and the precipitate was collected by filtration. The filter cake was removed from MeCN/H₂O (3L,20:1) was recrystallized again to give another crop of solid. Adding solids to K₂CO₃Aqueous (3%, 1.0L) and extracted with EtOAc (500mL x 3). Subjecting the organic layer to Na₂SO₄Dried and concentrated to give (3S,4S) -3- (benzylamino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as a white solid (50g,168mmol, 32.7% yield, 98.7% purity).By SFC, ee% ═ 97.5%.

(3S,4S) -3- (dimethylamino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester M5. to a solution of (3S,4S) -3- (benzylamino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (30g,102mmol,1.0eq.) and HCHO (102.7g,1.0mol,94.2mL,10eq.) in MeOH (1.0L) was added Pd (OH)₂(2.8g,10.2mmol, 50% purity, 0.1eq.) and the mixture was heated to 50 ℃ under 50psi of hydrogen and held for 5 hr. The mixture was filtered and concentrated to give (3S,4S) -3- (dimethylamino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil (23.5g,102mmol, 99.4% yield). 1H NMR (400MHz, chloroform-d) δ 4.23-4.20(m,1H),3.75-3.50(m,2H),3.26-3.14(m,2H),2.75(m,1H),2.29(s,6H),1.42(s,9H)

(3S,4S) -4- (dimethylamino) pyrrolidin-3-ol, M6. A solution of tert-butyl (3S,4S) -3- (dimethylamino) -4-hydroxypyrrolidine-1-carboxylate (23.5g,102mmol,1.0eq.) in HCl/MeOH (4M,200mL) was stirred at 40 deg.C for 2 hr. The mixture was concentrated to dryness. Then 100mL of MeOH was added to the residue and the solution was added to the basic resin. The mixture was stirred for 1 hour and the pH of the solution was adjusted to 7-8. The mixture was filtered and the filtrate was concentrated. To the residue was added 100mL THF and the suspension was stirred overnight. The solid was collected by filtration to give (3S,4S) -4- (dimethylamino) pyrrolidin-3-ol (13g,99mmol, 97.8% yield) as a yellow solid. 1H NMR (400MHz, chloroform-d) δ 4.35(br.s.,3H),3.41-3.44(m,1H),3.29-3.32(m,1H),3.13-3.18(m,2H),2.85(m,1H),2.27(s,6H)

General procedure L

(3S,4S) -3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester M7. addition of Pd (OH) to a solution of (3S,4S) -3- (benzylamino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (20g,68.4mmol,1.0eq) in AcOH (300mL)₂(5.0g,3.56mmol, 10% purity, 0.05eq.) and the mixture was heated at 50 ℃ at 50psi H₂Stirring for 1 hr. The mixture was filtered and the filtrate was concentrated to give (3S,4S) -3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (17.9g,68.3mmol, 100% yield, AcOH salt) as a yellow oil. ESI [ M + H ]]＝203.1

(3S,4S) -3- (((benzyloxy) carbonyl) amino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M8. to (3S,4S) -3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (29.0g,110.5mmol,1.0eq., AcOH salt) in THF (290mL) and H at 0 deg.C₂To a solution in O (290mL) was added K ₂CO₃(45.8g,331mmol,3.0eq.) and CbzCl (24.5g,143.7mmol,20.4mL,1.3 eq.). The reaction was stirred at 25 ℃ for 1hr and extracted with EtOAc (500mL × 3). The organic layer was washed with brine (500mL) over MgSO₄Dried and concentrated. By column chromatography (SiO)₂The residue was purified with petroleum ether/ethyl acetate 10:1 to 1:1) to give (3S,4S) -3- (((benzyloxy) carbonyl) amino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil (18.3g,54.4mmol, 49.2% yield). 1H NMR (400MHz, methanol-d 4) δ 7.32-7.26(m,5H),5.06(s,2H),4.08(s,1H),4.07-3.89(s,1H),3.65-3.61(s,1H),3.50-3.48(s,1H),3.29-3.22(m,2H),1.43(s, 9H). ESI [ M + H ]]＝336.9

(3S,4R) -3- (((benzyloxy) carbonyl) amino) -4- ((4-nitrobenzoyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester, M9. at 0 ℃ under N₂To (3S,4S) -3- (((benzyloxy) carbonyl) amino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (8.0g,23.7mmol,1.0eq.), 4-nitrobenzoic acid (5.9g,35.6mmol,1.5eq.) and PPh₃(11.2g,42.8mmol,1.8eq.) to a solution in toluene (200mL) was added DEAD (7.4g,42.8mmol,7.7mL,1.8eq.) all at once. After stirring for 10min, the mixture was heated to 80 ℃ and held for 16 hr. The solution was concentrated and purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 3:1) to give (3S,4R) -3- (((benzyloxy) carbonyl) amino) -4- ((4-nitrobenzoyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow solid (14g, crude). ESI [ M + H ]]＝486.2

(3S,4R) -3- (((benzyloxy) carbonyl) amino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M10. to a solution of (3S,4R) -3- (((benzyloxy) carbonyl) amino) -4- ((4-nitrobenzoyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester (6.0g,12.3mmol,1.0eq.) in MeOH (20mL) was added in one portionAddition of K₂CO₃(2.0g,14.8mmol,1.2eq.) and the mixture was stirred at 20 ℃ for 10 min. The mixture was filtered and the filtrate was adjusted to pH 3 with 1M HCl. The filtrate was concentrated and purified by column chromatography to give (3S,4R) -3- (((benzyloxy) carbonyl) amino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil (4.1g, crude).

(3S,4R) -3- (dimethylamino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M11. to a solution of (3S,4R) -3- (benzyloxycarbonylamino) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (3.6g,10.7mmol,1.0eq.) and formaldehyde (6.4g,214mmol,5.9mL,20eq.) in MeOH (30mL) was added Pd (OH)₂(20.5g,14.6mmol, 10% purity, 1.3eq.) and the mixture was brought to 50psi H₂Stirring at 20 deg.C for 16 hr. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (DCM: MeOH ═ 20:1) to give (3S,4R) -3- (dimethylamino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil (2.0g, crude). 1H NMR (400MHz, methanol-d 4) δ 4.22(br.s.,1H),3.65-3.54(m,1H),3.48-3.37(m,2H),3.27-3.16(m,1H),2.61-2.45(m,1H),2.29(d, J2.4 Hz,6H),1.56-1.36(m, 9H). ESI [ M + H ]]＝231.1

(3R,4S) -4- (dimethylamino) pyrrolidin-3-ol, M12. A solution of tert-butyl (3S,4R) -3- (dimethylamino) -4-hydroxypyrrolidine-1-carboxylate (1g,4.3mmol,1.0eq.) in HCl/MeOH (4M,20mL) was stirred at 20 ℃ for 30 min. The solution was concentrated to give (3R,4S) -4- (dimethylamino) pyrrolidin-3-ol (600mg, HCl salt) as a yellow oil. 1H NMR (400MHz, methanol-d 4) δ 4.70(br.s.,1H),4.13-4.01(m,1H),3.88(t, J ═ 10.2Hz,1H),3.57-3.43(m,3H),3.11-2.90(m, 6H). ESI [ M + H ] ═ 131.1

The chemical experiment method comprises the following steps:

cis-2-benzyltetrahydro-2H-pyrrolo [3,4-d]Isooxazole-5 (3H) -carboxylic acid tert-butyl ester, M13. to a solution of 2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester (70.6g,417.6mmol,1.0eq.) in toluene (2.1L) and EtOH (700mL) was added (HCHO)_n(62.8g,697mmol,1.6eq.), N-benzylhydroxylamine (100g,626mmol,1.5eq., HCl salt) and TEA (63.4g,626mmol,86mL,1.5 eq.). The mixture was stirred at 80 ℃ for 24hr and then concentrated under reduced pressure. The residue was diluted with hexane/EtOAc (1.5L/1.5L), filtered and the filtrate was concentrated under reduced pressure to give cis-2-benzyltetrahydro-2H-pyrrolo [3,4-d ] as a yellow oil]Tert-butyl isoxazole-5 (3H) -carboxylate (230g, crude), which was used in the next step without further purification. ESI [ M + H ]]＝305.1

Cis-3- ((benzylamino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M14.

cis-2-benzyltetrahydro-2H-pyrrolo [3, 4-d)]Tert-butyl isoxazole-5 (3H) -carboxylate (229g,752mmol,1.0eq.) was dissolved in AcOH (2.5L). The solution was heated to 70 ℃ and then Zn powder (245g,3.7mol,5.0eq.) was added portionwise with vigorous stirring, after which 30min another batch of Zn powder (80g) was added. The mixture was stirred at 70 ℃ for 1.5hr, diluted with water (1.5L) and extracted with DCM (2L x 3). The combined organic layers were dried over MgSO₄Dried, filtered and concentrated under reduced pressure. By column chromatography (SiO)₂DCM: MeOH ═ 1/0 to 10:1) purification of the residue yielded cis-3- ((benzylamino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as a pale orange solid (107g,272mmol, 36.2% yield78% purity). 1H NMR (400MHz, chloroform-d) δ 7.31-7.17(m,5H),4.40-4.32(m,1H),3.78-3.67(m,2H),3.46-3.35(m,2H),3.34-3.09(m,2H),2.99-2.84(m,2H),2.20(br.s.,1H),1.48-1.31(s, 9H). ESI [ M + H ]]＝307.0

Cis-3- (aminomethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M15. to a solution of cis-3- ((benzylamino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (20g,65.2mmol,1.0eq.) in MeOH (500mL) was added Pd (OH)₂(13.9g,99mmol,1.5eq.) and the mixture was heated at 70 ℃ at 50psi H₂Stirring for 36 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude cis-3- (aminomethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (11g, crude) as a colorless oil, which was used in the next step without further purification. ESI [ M + H ]]＝217.1

Cis-3- ((((benzyloxy) carbonyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M16. cis-3- (aminomethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (11g,50.8mmol,1.0eq.) in H₂To a solution of O (50mL) and THF (50mL) was added K₂CO₃(14g,101.7mmol,2.0eq.) and CbzCl (10.4g,61mmol,8.6mL,1.2 eq.). The reaction was stirred at 20 ℃ for 12hr, and then concentrated under reduced pressure. The residue is washed with H₂O (50mL) was diluted and extracted with DCM (50mL × 3). The combined organic layers were concentrated and purified by column chromatography (SiO)₂Dichloromethane/ethyl acetate 10/1 to 1/1 to DCM/methanol 20/1) to give cis-3- ((((benzyloxy) carbonyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (10g) as a white solid.

(3S,4S) -3- ((((benzyloxy) carbonyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester and (3R,4R) -3- (((((benzyloxy) carbonyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M16A and M169B. separation of cis-3- ((((benzyloxy) carbonyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester by SFC, this gave (3S,4S) -3- (benzyloxycarbonylaminomethyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (4.0g,10.7mmol, 21% yield, 93.7% purity) as a white solid (see below).By SFC, ee% ═ 100%) and (3R,4R) -3- (benzyloxycarbonylaminomethyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as white solid (4.0g,10.10mmol, 19.8% yield, 88% purity) ((4.0 g,10.10mmol, 19.8% purity)By SFC, ee% ═ 99.5%).

General procedure M

(3R,4R) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M17. tert-butyl (3R,4R) -3- (benzyloxycarbonylaminomethyl) -4-hydroxy-pyrrolidine-1-carboxylate (2.0g,5.71mmol,1.0eq.), HCHO (4.5g,57.1mmol,4.14mL,10eq.) and Pd (OH)₂(1.6g,5.7mmol, 50% purity, 1.0eq.) in MeOH (50mL) in a mixture of 50psi H₂Stirring at 50 deg.C for 50 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. By column chromatography (SiO)₂DCM/MeOH ═ 100/1 to 20:1) the residue was purified to give (3R,4R) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as a white solid (1.2g,4.9mmol, 86% yield). 1H NMR (400MHz, chloroform-d) δ 4.43(d, J5.5 Hz,1H),3.72-3.57(m,1H),3.50-3.38(m,1H),3.35-3.20(m,1H), 3.16.16-3.00(m,1H),2.81(q,J＝11.6Hz,1H),2.45-2.27(m,8H),1.44(s,9H)。ESI[M+H]＝245.0

(3R,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol, M18. A solution of tert-butyl (3R,4R) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidine-1-carboxylate (1.2g,4.9mmol,1.0eq.) in HCl/MeOH (4M,20mL) was stirred at 45 ℃ for 1 hr. The reaction mixture was concentrated under reduced pressure. The residue is washed with H₂Diluted with O (10mL) and basified with basic resin. The mixture was filtered and the filtrate was lyophilized, yielding (3R,4S) -4- [ (dimethylamino) methyl group as a pale yellow solid]Pyrrolidin-3-ol (700mg, crude). 1H NMR (400MHz, methanol-d 4) δ 4.46(t, J3.1 Hz,1H),3.53(dd, J8.6, 11.3Hz,1H),3.39-3.31(m,2H),3.28(br.s.,1H),3.14-3.03(m,2H),2.90(dd, J6.7, 12.9Hz,1H),2.63(s, 6H). ESI [ M + H ]]＝145.0

General procedure N

(3R,4S) -3- (((((benzyloxy) carbonyl) amino) methyl) -4- ((4-nitrobenzoyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester, M19. at 25 ℃ under N₂To a solution of (3R,4R) -3- (benzyloxycarbonylaminomethyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0g,2.8mmol,1.0eq.) in toluene (20mL) was added 4-nitrobenzoic acid (714mg,4.2mmol,1.5eq.) and PPh₃(1.5g,5.7mmol,2.0 eq.). DEAD (992mg,5.7mmol,1.0mL,2.0eq.) was then added at 0 ℃ and N₂The mixture was then heated to 80 ℃ and held for 16 hr. The reaction mixture was concentrated and purified by column chromatography (SiO)₂Petroleum ether/ethyl acetate 20/1 to 3:1) purificationThe residue was taken up as yellow oil (3R,4S) -3- (((((benzyloxy) carbonyl) amino) methyl) -4- ((4-nitrobenzoyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester (2.2g, crude). ESI [ M + H ]]＝500.1

(3R,4S) -3- ((((benzyloxy) carbonyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M20. to a solution of (3R,4S) -3- (((((benzyloxy) carbonyl) amino) methyl) -4- ((4-nitrobenzoyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester (2.2g,4.4mmol,1.0eq.) in MeOH (30mL) was added K₂CO₃(1.2g,8.8mmol,2.0eq.) and the mixture was stirred at 25 ℃ for 30 min. The mixture was concentrated in vacuo. The residue was dissolved in water (30mL) and extracted with DCM (20mL × 3). The organic layer was purified over MgSO₄Dried and concentrated. By column chromatography (SiO)₂Petroleum ether/ethyl acetate 20/1 to 1:1) to give (3R,4S) -3- (benzyloxycarbonylaminomethyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil (900mg, crude).¹H NMR (400MHz, methanol-d)₄)δ＝7.38-7.29(m,4H),7.27(d,J＝4.9Hz,1H),5.06(s,2H),4.08-3.99(m,1H),3.57-3.46(m,2H),3.21-3.10(m,3H),3.07-2.98(m,1H),2.23(dd,J＝4.0,7.1Hz,1H),1.43(s,9H)。ESI[M+H]＝351.2

(3R,4S) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M21. to a solution of (3R,4S) -3- (benzyloxycarbonylaminomethyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (900mg,2.5mmol,1.0eq.) in MeOH (50mL) was added Pd (OH)₂(0.5g) and the mixture was brought to 50psi H₂Stirring at 60 deg.C for 16 hr. After filtration, the filtrate was concentrated. The residue was acidified by cold 0.5M HCl (30mL) and extracted with EtOAC (10mL × 2). The aqueous phase is saturated with K₂CO₃Solutions ofAdjusted to pH 11 and extracted with DCM (50mL × 4). The organic layer was purified over MgSO₄Dried and concentrated to give (3R,4S) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil (250mg, crude), which was used in the next step without further purification.¹H NMR (400MHz, methanol-d)₄)δ＝4.07-3.97(m,1H),3.60(dd,J＝5.3,10.1Hz,1H),3.52(dd,J＝6.0,11.2Hz,1H),3.19-3.05(m,2H),2.46-2.33(m,1H),2.31-2.18(m,8H),1.44(s,9H)。ESI[M+H]＝245.1

(3S,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol, M22. Van. (3R,4S) -3- [ (dimethylamino) methyl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (250mg,1.02mmol,1.0eq.) to a solution in MeOH (5.0mL) HCl/MeOH (4M,10mL) was added and the mixture was stirred at 25 ℃ for 30 min. The reaction was concentrated in vacuo. The residue was dissolved in MeOH (10mL) and basified to pH 7-8 by anion exchange resin. After filtration, the filtrate was concentrated to give (3S,4S) -4- [ (dimethylamino) methyl group as a yellow oil]Pyrrolidin-3-ol (150mg, crude), which was used in the next step without further purification.¹H NMR (400MHz, methanol-d)₄)δ＝4.23(td,J＝2.6,5.0Hz,1H),3.54(dd,J＝7.1,11.9Hz,1H),3.33(dd,J＝4.9,12.3Hz,1H),3.15(dd,J＝2.6,12.3Hz,1H),3.06(dd,J＝4.9,11.9Hz,1H),2.51-2.41(m,2H),2.40-2.35(m,1H),2.33(s,6H)。ESI[M+H]＝145.1

General procedure O

Trans-3-hydroxy-4- (((4-methoxybenzyl) (methyl) amino) methyl) Pyrrolidine-1-carboxylic acid tert-butyl ester, m24. to a solution of trans-3- (aminomethyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (2.0g,9.2mmol,1.0eq.) in MeOH (40mL) were added AcOH (666mg,11mmol,1.2eq.) and 4-methoxybenzaldehyde (1.5g,11mmol,1.2 eq.). The mixture was stirred at 26 ℃ for 0.5h and subsequently NaBH was added₃CN (1.4g,23.1mmol,2.5eq), after which HCHO (3.7g,46.2mmol,5.0eq) was added after 1.0 hr. The mixture was stirred at 26 ℃ for 16 hours and concentrated under reduced pressure. The residue was purified by acidic preparative HPLC to give trans-3-hydroxy-4- (((4-methoxybenzyl) (methyl) amino) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil (3.0g,8.5mmol, 92.5% yield). ESI [ M + H ]]＝351.1

Trans-3-hydroxy-4- ((methylamino) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester, M25 to a solution of trans-3-hydroxy-4- (((4-methoxybenzyl) (methyl) amino) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.8g,5.1mmol,1.0eq) in MeOH (25mL) was added Pd (OH)₂(72.1mg,513umol,0.1eq.) and the mixture was heated at 26 ℃ at 50psi H₂Stirred for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give trans-3-hydroxy-4- ((methylamino) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.1g,4.7mmol, 92.9% yield) as a yellow oil, which was used directly without any purification. ESI [ M + H ]]＝231.1

Trans-3- ((((benzyloxy) carbonyl) (methyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M26. to trans-3-hydroxy-4- ((methylamino) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.1g,4.7mmol,1.0eq) in THF (15mL) and H at 0 deg.C₂To a solution in O (15mL) was added K₂CO₃(1.3g,9.5mmol,2.0 eq.) and CbzCl (1.2g,7.1mmol,1.5 eq.). Mixing the mixture with 2Stirring at 6 deg.C for 16hr and concentrating under reduced pressure. The residue was purified by basic preparative HPLC to give trans-3- ((((benzyloxy) carbonyl) (methyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil (800mg,2.2mmol, 45.9% yield). ESI [ M + H ]]＝365.1

Benzyl ((trans-4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamate, M27. tert-butyl trans-3- ((((benzyloxy) carbonyl) (methyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylate (400mg,1.1mmol,1.0eq) was dissolved in HCl/MeOH (4M,10mL) and the mixture was stirred at 26 ℃ for 1 hour. The mixture was concentrated under reduced pressure and then dissolved in MeOH (15 mL). The pH was adjusted to 8-9 by basic resin and the mixture was filtered. The filtrate was concentrated to give benzyl ((trans-4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamate (120mg,454umol, 41.2% yield) as a yellow oil. [ M + H ] ═ 264.9

General procedure P

(S) -3- (4-hydroxypiperidine-1-carbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester, M29. to a solution of (3S) -1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (1.0g,4.6mmol,1.0eq.) and piperidin-4-ol (1.4g,13.9mmol,3.0eq) in DCM (20mL) was added HATU (2.3g,6.0mmol,1.3eq) and DIEA (1.5g,11.6mmol,2.0mL,2.5 eq). The mixture was stirred at 20 ℃ for 1 hour and diluted with DCM (100 mL). The organic layer was washed with brine (20mL) and anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to give (S) -3- (4-hydroxypiperidine-1-carbonyl) pyrrolidine-1-carboxylic acid as a yellow oilTert-butyl ester (1.2g, crude), which was used in the next step without further purification.¹HNMR (400MHz, chloroform-d) δ — 3.69-3.62(m,1H),3.48-3.31(m,1H),3.20(br.s.,1H),2.90(d, J ═ 7.1Hz,1H),2.71(d, J ═ 5.3Hz,2H),2.28(br.s.,2H),2.13(br.s.,2H),1.92-1.79(m,3H),1.52(d, J ═ 8.8Hz,3H),1.46-1.35(m, 9H). ESI [ M + H ]]＝299.0

(R) -3- ((4-hydroxypiperidin-1-yl) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester, M30. to a solution of (S) -3- (4-hydroxypiperidin-1-carbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.2g,4.0mmol,1.0eq.) in THF (30mL) at 0 deg.C, LiAlH was added₄(183mg,4.8mmol,1.2 eq.). The mixture was stirred at 20 ℃ for 1 hour and MgSO with saturated aqueous solution₄(20mL) quenched and filtered. The filtrate was concentrated and purified by silica gel chromatography (DCM: MeOH ═ 10:1) to give tert-butyl (R) -3- ((4-hydroxypiperidin-1-yl) methyl) pyrrolidine-1-carboxylate (600mg, crude) as a yellow oil. ESI [ M + H ]]＝285.2

(S) -1- (pyrrolidin-3-ylmethyl) piperidin-4-ol, M31. a solution of (R) -tert-butyl 3- ((4-hydroxypiperidin-1-yl) methyl) pyrrolidine-1-carboxylate (600mg,2.1mmol,1.0eq.) in HCl/MeOH (4M,10mL) was stirred at 20 ℃ for 0.5h and then concentrated under reduced pressure. The residue was diluted with MeOH (20mL), basified to pH 7-8 by basic resin and filtered. The filtrate was concentrated to give (S) -1- (pyrrolidin-3-ylmethyl) piperidin-4-ol (400mg, crude) as a pale yellow oil, which was used in the next step without further purification. ESI [ M + H ] ═ 184.9

General procedure Q

Benzyl 3- ((3- ((tert-butoxycarbonyl) amino) propyl) carbamoyl) pyrrolidine-1-carboxylate, M33. tert-butyl N- (3-aminopropyl) carbamate (418mg,2.4mmol,2.0eq) was added in one portion at 20 ℃ to a mixture of 1-benzyloxycarbonylpyrrolidine-3-carboxylic acid (300mg,1.2mmol,1.0eq), DIEA (466mg,3.6mmol,3.0eq) and HATU (686mg,1.8mmol,1.5eq) in DCM (20 mL). The mixture was stirred at 20 ℃ for 0.5 hour and then poured into ice water (50 mL). The aqueous layer was extracted with ethyl acetate (20mL x 3). The combined organic phases were washed with brine (10mL x 2) and anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. By preparative TLC (SiO)₂Ethyl acetate) to yield benzyl 3- ((3- ((tert-butoxycarbonyl) amino) propyl) carbamoyl) pyrrolidine-1-carboxylate (450mg,654umol, 54.5% yield, 59% purity) as a colorless oil. ESI [ M + H ]]＝406.1

Benzyl 3- (((3- ((tert-butoxycarbonyl) amino) propyl) amino) methyl) pyrrolidine-1-carboxylate, M34. to a solution of benzyl 3- ((3- ((tert-butoxycarbonyl) amino) propyl) carbamoyl) pyrrolidine-1-carboxylate (400mg,986umol,1.0eq) in THF (5mL) was added BH₃THF (1M,9.8mL,10eq.) and the reaction mixture was warmed to 70 ℃ and held for 1 hr. The reaction was slowly quenched with methanol (100mL) and concentrated under reduced pressure at 40 ℃ to give crude 3- [ [3- (tert-butoxycarbonylamino) propylamino ] amino as a colorless oil]Methyl radical]Benzyl pyrrolidine-1-carboxylate (400mg, crude). ESI [ M + H ]]＝392.1

Benzyl 3- (((tert-butoxycarbonyl) (3- ((tert-butoxycarbonyl) amino) propyl) amino) methyl) pyrrolidine-1-carboxylate, M35 to a solution of benzyl 3- [ [3- (tert-butoxycarbonylamino) propylamino ] methyl ] pyrrolidine-1-carboxylate (400mg,1.0mmol,1.0eq) and tert-butylbutoxycarbonyl carbonate (1.3g,6.1mmol,6.0eq) in MeOH (50mL) was added TEA (309mg,3.0mmol,3.0eq) in one portion, and the mixture was stirred at 20 ℃ for 10 hours. The mixture was concentrated and purified by preparative HPLC (neutral conditions) to give benzyl 3- (((tert-butoxycarbonyl) (3- ((tert-butoxycarbonyl) amino) propyl) amino) methyl) pyrrolidine-1-carboxylate (200mg,227umol, 22.3% yield, 56% purity) as a colorless oil. ESI [ M + H ] ═ 492.4

(3- ((tert-butoxycarbonyl) amino) propyl) (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester, M36. to a solution of 3- (((tert-butoxycarbonyl) (3- ((tert-butoxycarbonyl) amino) propyl) amino) methyl) pyrrolidine-1-carboxylic acid benzyl ester (100mg,203umol,1.0eq.) in EtOAc (30mL) was added Pd/C (100mg,203umol,1.0eq) and the mixture was left to stand at 20 ℃ at 50psi H₂Stirring for 1 hr. The mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl (3- ((tert-butoxycarbonyl) amino) propyl) (pyrrolidin-3-ylmethyl) carbamate (70mg, crude) as a colorless oil. ESI [ M + H ]]＝358.2

Amine synthesis

(3R,4R) -4- (dimethylamino) pyrrolidin-3-ol, m37. synthesized using general procedure K with (2R) -2-hydroxy-2-phenyl-acetic acid instead of (2S) -2-hydroxy-2-phenyl-acetic acid. ESI [ M + H ] ═ 130.8

(3S,4R) -4- (dimethylamino) pyrrolidin-3-ol, m38. synthesized using general procedure L replacing (3S4S) -3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester with (3R,4R) -3-amino-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester. 1HNMR (400MHz, methanol-d 4) δ 4.60(br.s.,1H),3.81-3.63(m,2H),3.48-3.37(m,3H),2.82(s, 6H). ESI [ M + H ] ═ 130.8

(3S,4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol, M39. was synthesized using general procedure M replacing (3R,4R) -3- ((((benzyloxy) carbonyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester with (3S,4S) -3- ((((benzyloxy) carbonyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 4.44(t, J3.3 Hz,1H),3.50(dd, J8.6, 11.3Hz,1H),3.40-3.31(m,2H),3.27(s,1H),3.08(t, J11.3 Hz,1H),2.96(dd, J6.8, 12.7Hz,1H),2.83-2.75(m,1H),2.54(s, 6H). ESI [ M + H ] ═ 145.0

(3R,4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol, m40. was synthesized using general procedure N replacing tert-butyl (3R,4R) -3- ((((benzyloxy) carbonyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylate with tert-butyl (3S,4S) -3- ((((benzyloxy) carbonyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 4.29-4.19(m,1H),3.55(dd, J6.8, 11.7Hz,1H),3.34(dd, J4.9, 12.3Hz,1H),3.15(dd, J3.1, 12.3Hz,1H),3.06(dd, J4.9, 11.9Hz,1H),2.54-2.39(m,3H),2.39-2.28(s, 6H). ESI [ M + H ] ═ 145.0

(((3R,4R) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamic acid benzyl ester, M41.

Synthesized using general procedure O replacing trans-3- (aminomethyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester with (3S,4R) -3- (aminomethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, chloroform-d) δ 7.38-7.26(m,5H),5.16-5.04(m,2H),4.16-3.91(m,1H),3.35(d, J ═ 7.5Hz,1H),3.17(br.s.,2H),3.00-2.73(m,4H),2.25(br.s.,1H),2.11(br.s., 2H). ESI [ M + H ] ═ 265.1

(((3S,4S) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamic acid benzyl ester, M42.

Synthesized using general procedure O replacing trans-3- (aminomethyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester with (3R,4S) -3- (aminomethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester. ESI [ M + H ] ═ 265.1

(((3R,4S) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamic acid benzyl ester, M43.

Synthesized using general procedure O replacing trans-3- (aminomethyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester with (3S,4S) -3- (aminomethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester. ESI [ M + H ] ═ 265.1

(R) -2- (((R) -pyrrolidin-3-ylmethyl) amino) propan-1-ol, M44. synthesized using general procedure P with (3R) -1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid instead of (3S) -1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid and (R) -2-aminopropan-1-ol instead of piperidin-4-ol. ESI [ M + H ] ═ 159.1

(R) -2- (((S) -pyrrolidin-3-ylmethyl) amino) propan-1-ol, M45. synthesized using general procedure P with (R) -2-aminopropan-1-ol instead of piperidin-4-ol.¹H NMR (400MHz, methanol-d)₄)δ＝3.84(dd,J＝3.7,12.1Hz,1H),3.67-3.54(m,2H),3.52-3.37(m,2H),3.34(s,1H),3.28-3.20(m,2H),3.11(dd,J＝9.0,11.7Hz,1H),2.85-2.73(m,1H),2.35(dd,J＝4.6,13.0Hz,1H),1.85(qd,J＝8.7,13.2Hz,1H),1.35(d,J＝6.6Hz,3H)。ESI[M+H]＝159.1

(S) -2- (((R) -pyrrolidin-3-ylmethyl) amino) propan-1-ol, M46. synthesized using general procedure P with (R) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid instead of (S) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid and (S) -2-aminopropan-1-ol instead of piperidin-4-ol. ESI [ M + H ] ═ 159.1

(S) -2- (((S) -pyrrolidin-3-ylmethyl) amino) propan-1-ol, M47. synthesized using general procedure P with (S) -2-aminopropan-1-ol instead of piperidin-4-ol. ESI [ M + H ] ═ 159.1

(R) -3-methyl-2- (((R) -pyrrolidin-3-ylmethyl) amino) butan-1-ol, M48. synthesized using general procedure P with (R) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid instead of (S) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid and (R) -2-amino-3-methylbutan-1-ol instead of piperidin-4-ol. ESI [ M + H ] ═ 187.1

(R) -3-methyl-2- (((S) -pyrrolidin-3-ylmethyl) amino) butan-1-ol, M49. synthesized using general procedure P with (R) -2-amino-3-methylbutan-1-ol instead of piperidin-4-ol. ESI [ M + H ] ═ 187.1

(S) -3-methyl-2- (((R) -pyrrolidin-3-ylmethyl) amino) butan-1-ol, M50. synthesized using general procedure P with (R) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid instead of (S) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid and (S) -2-amino-3-methylbutan-1-ol instead of piperidin-4-ol. ESI [ M + H ] ═ 187.1

(S) -3-methyl-2- (((S) -pyrrolidin-3-ylmethyl) amino) butan-1-ol, m51. synthesized using general procedure P with (S) -2-amino-3-methylbutan-1-ol instead of piperidin-4-ol. ESI [ M + H ] ═ 187.1

(1R,4R) -4- (((R) -pyrrolidin-3-ylmethyl) amino) cyclohexanol, M52. synthesized using general procedure P with (R) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid instead of (S) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid and (1R,4R) -4-aminocyclohexanol instead of piperidin-4-ol. 1H NMR (400MHz, methanol-d 4) δ 3.52-3.46(m,2H),3.43-3.42(m,1H),3.32-3.22(m,1H),2.96-2.90(m,3H),2.88-2.86(m,1H),2.54-2.52(m,1H),2.02-2.01(m,1H),1.98-1.96(m,4H),1.73-1.71(m,1H),1.31-1.26(m, 4H). ESI [ M + H ] ═ 199.1

(1S,4r) -4- (((S) -pyrrolidin-3-ylmethyl) amino) cyclohexanol, M53. synthesized using general procedure P with (1r,4r) -4-aminocyclohexanol instead of piperidin-4-ol. 1H NMR (400MHz, methanol-d 4) δ 3.56-3.51(m,2H),3.07-3.01(m,4H),2.66-2.62(m,1H),2.31-2.28(m,1H),2.13-2.02(m,4H),1.80-1.77(m,1H),1.44-1.28(m, 6H). ESI [ M + H ] ═ 199.1

(R) -2-methyl-2- ((pyrrolidin-3-ylmethyl) amino) propan-1-ol, M54. synthesized using general procedure P with (R) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid instead of (S) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid and 2-amino-2-methylpropan-1-ol instead of piperidin-4-ol. 1H NMR (400MHz, methanol-d 4) δ 3.57-3.53(m,3H),3.41-3.38(m,1H),3.09-3.02(m,3H),2.93(s,1H),2.67-2.64(m,1H),2.32-2.31(m,1H),1.82-.177(m,1H),1.30(s, 6H). ESI [ M + H ] ═ 173.2

(S) -2-methyl-2- ((pyrrolidin-3-ylmethyl) amino) propan-1-ol, m55. synthesized using general procedure P with 2-amino-2-methylpropan-1-ol instead of piperidin-4-ol. 1H NMR (400MHz, methanol-d 4) δ 3.46-3.41(m,3H),3.33-3.30(m,1H),3.22(m,1H),2.97-2.96(m,1H),2.88-2.86(m,2H),2.54-2.50(m,1H),2.25-2.23(m,1H),1.76-1.71(m,1H),1.19(s, 6H). ESI [ M + H ] ═ 173.2

(R) -1- (pyrrolidin-3-ylmethyl) piperidin-4-ol, M56. synthesized using general procedure P with (R) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid instead of (S) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid. ESI [ M + H ] ═ 185.1

Tert-butyl (3- ((tert-butoxycarbonyl) (methyl) amino) propyl) (pyrrolidin-3-ylmethyl) carbamate, m57. synthesized using general procedure Q replacing tert-butyl N- (3-aminopropyl) carbamate with tert-butyl (3-aminopropyl) (methyl) carbamate. ESI [ M + H ] ═ 372.2

Tert-butyl (3- (dimethylamino) propyl) (pyrrolidin-3-ylmethyl) carbamate, M58.

Synthesized using general procedure Q substituting N, N-dimethylpropane-1, 3-diamine for N- (3-aminopropyl) carbamic acid tert-butyl ester. ESI [ M + H ] ═ 286.1

4- (pyrrolidin-3-ylmethyl) piperazine-1-carboxylic acid tert-butyl ester, m59. synthesized using general procedure Q with piperazine-1-carboxylic acid tert-butyl ester instead of N- (3-aminopropyl) carbamic acid tert-butyl ester. ESI [ M + H ] ═ 270.0

Tert-butyl (2- ((tert-butoxycarbonyl) amino) ethyl) (pyrrolidin-3-ylmethyl) carbamate, m60. synthesized using general procedure Q replacing tert-butyl N- (3-aminopropyl) carbamate with tert-butyl (2-aminoethyl) carbamate. ESI [ M + H ] ═ 344.1

Tert-butyl (2- ((tert-butoxycarbonyl) amino) ethyl) (pyrrolidin-3-ylmethyl) carbamate, m61. was synthesized using general procedure Q replacing tert-butyl N- (3-aminopropyl) carbamate with tert-butyl (2-aminoethyl) (methyl) carbamate. ESI [ M + H ] ═ 358.1

Tert-butyl (2- (dimethylamino) ethyl) (pyrrolidin-3-ylmethyl) carbamate, M62.

N for Q using the general procedure¹,N¹-dimethylethane-1, 2-diamine was synthesized instead of N- (3-aminopropyl) carbamic acid tert-butyl ester. ESI [ M + H ]]＝272.1

Tert-butyl (2- ((tert-butoxycarbonyl) amino) propyl) (pyrrolidin-3-ylmethyl) carbamate, m63. was synthesized using general procedure Q replacing tert-butyl N- (3-aminopropyl) carbamate with tert-butyl (1-aminopropyl-2-yl) carbamate. ESI [ M + H ] ═ 358.1

Tert-butyl (2-hydroxyethyl) (pyrrolidin-3-ylmethyl) carbamate, m64. was synthesized using general procedure Q replacing tert-butyl N- (3-aminopropyl) carbamate with 2-aminoethanol. ESI [ M + H ] ═ 245.1

Tert-butyl (3-hydroxypropyl) (pyrrolidin-3-ylmethyl) carbamate, m65. was synthesized using general procedure Q replacing tert-butyl N- (3-aminopropyl) carbamate with 3-aminopropan-1-ol. ESI [ M + H ] ═ 259.1

4- (7- (3- (dimethylamino) piperidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 2, using general procedure A with N, N-dimethylpiperidin-3-amine instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝9.13(br.s.,1H),7.85-7.64(m,5H),7.61(d,J＝8.8Hz,1H),7.33(d,J＝2.3Hz,1H),7.28(br.s.,1H),7.24-7.18(m,1H),5.26(s,2H),3.90(d,J＝11.8Hz,1H),3.63(d,J＝12.5Hz,1H),3.48(br.s.,1H),3.11(t,J＝9.5Hz,2H),3.01(d,J＝3.8Hz,6H),2.18(br.s.,1H),2.01(d,J＝9.3Hz,1H),1.93-1.80(m,2H)。ESI[M+H]＝450.2

4- (7- (trans-pyrrolo [3, 2-b)]Pyrrol-1 (2H) -yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 3, using general procedure A with trans-pyrrolo [3,2-b]Pyrrole-1 (2H) -carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝9.06(br.s.,1H),7.77-7.70(m,2H),7.70-7.61(m,3H),7.54(d,J＝8.8Hz,1H),7.25(s,1H),6.95(d,J＝2.2Hz,1H),6.89-6.83(m,1H),5.22(s,2H),4.34-4.19(m,1H),4.13-3.97(m,2H),3.90-3.76(m,2H),3.69(dt,J＝5.5,11.1Hz,1H),2.79-2.67(m,1H),2.39-2.25(m,1H),2.23-2.10(m,1H),2.08-1.97(m,1H)。ESI[M+H]＝434.2

(R) -4- (7- (3- (methylamino) pyrrolidin-1-yl) -9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 4. synthesized using general procedure A with tert-butyl (R) -methyl (pyrrolidin-3-yl) carbamate instead of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝9.06(s,1H),7.83-7.60(m,5H),7.57(d,J＝8.8Hz,1H),7.26(d,J＝1.5Hz,1H),6.94(d,J＝2.3Hz,1H),6.83(dd,J＝2.6,8.9Hz,1H),5.24(s,2H),4.03(br.s.,1H),3.77-3.60(m,3H),3.53-3.46(m,1H),2.83(s,3H),2.65-2.51(m,1H),2.30(d,J＝5.3Hz,1H)。ESI[M+H]＝422.2

(S) -4- (7- (3- (methylamino) pyrrolidin-1-yl) -9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 5, using general procedure A with tert-butyl (S) -methyl (pyrrolidin-3-yl) carbamate instead of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝9.06(s,1H),7.83-7.60(m,5H),7.57(d,J＝8.8Hz,1H),7.26(d,J＝1.5Hz,1H),6.94(d,J＝2.3Hz,1H),6.83(dd,J＝2.6,8.9Hz,1H),5.24(s,2H),4.03(br.s.,1H),3.77-3.60(m,3H),3.53-3.46(m,1H),2.83(s,3H),2.65-2.51(m,1H),2.30(d,J＝5.3Hz,1H)。ESI[M+H]＝422.2

4- (7- (3- ((methylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 18, using general procedure A with tert-butyl methyl (pyrrolidin-3-ylmethyl) carbamate in place of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝9.17(br.s.,1H),7.73-7.60(m,5H),7.47(d,J＝7.5Hz,1H),7.26(br.s.,1H),6.78(br.s.,1H),6.68(d,J＝7.5Hz,1H),5.14(br.s.,2H),3.59(br.s.,1H),3.55-3.46(m,1H),3.42(br.s.,1H),3.15(br.s.,3H),2.77(s,3H),2.75-2.66(m,1H),2.32(d,J＝6.2Hz,1H),1.88(dd,J＝8.4,11.5Hz,1H)。ESI[M+H]＝436.2

(S) -4- (7- (3- (dimethylamino) piperidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 20, using general procedure C, with tert-butyl (S) -piperidin-3-ylcarbamate instead of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate.¹H NMR (400MHz, methanol-d)₄)δ＝9.06(br.s.,1H),7.80-7.64(m,4H),7.62(s,1H),7.58(d,J＝8.8Hz,1H),7.31(d,J＝2.6Hz,1H),7.25(s,1H),7.19(dd,J＝2.6,8.8Hz,1H),5.23(s,2H),3.88(d,J＝11.9Hz,1H),3.66-3.56(m,1H),3.45(t,J＝9.0Hz,1H),3.35(br.s.,1H),3.13-3.05(m,1H),3.04-2.86(m,6H),2.24-2.12(m,1H),1.99(d,J＝11.5Hz,1H),1.92-1.77(m,2H)。ESI[M+H]＝450.2

4- (7- (trans-3- (dimethylamino) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 57, using general procedure A in place of tert-butyl piperazine-1-carboxylate with trans-4- (dimethylamino) pyrrolidin-3-ol.¹H NMR (400MHz, methanol-d)₄)δ＝9.07(s,1H),7.75-7.69(m,2H),7.68-7.60(m,3H),7.54(d,J＝8.8Hz,1H),7.23(s,1H),6.89(d,J＝2.2Hz,1H),6.79(dd,J＝2.4,8.6Hz,1H),5.20(s,2H),4.72(q,J＝6.6Hz,1H),3.96-3.82(m,3H),3.59(dd,J＝6.8,9.5Hz,1H),3.28-3.22(m,1H),3.14-2.99(m,6H)。ESI[M+H]＝452.2

4- (7- ((3S,4S) -3- (dimethylamino) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 58, using general procedure A with (3S,4S) -4- (dimethylamino) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝9.07(br.s.,1H),7.75-7.58(m,5H),7.53(d,J＝8.8Hz,1H),7.22(br.s.,1H),6.88(br.s.,1H),6.78(d,J＝8.4Hz,1H),5.18(br.s.,2H),4.73(d,J＝6.6Hz,1H),3.99-3.79(m,3H),3.60(t,J＝7.7Hz,1H),3.27(br.s.,1H),3.08(br.s.,6H)。ESI[M+H]＝452.2

4- (7- (cis-3-hydroxy-4- ((methylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, 73. synthesized using general procedure A with cis-4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.02(br.s.,1H),7.77-7.60(m,5H),7.50(d, J ═ 8.8Hz,1H),7.23(s,1H),6.79(d, J ═ 2.2Hz,1H),6.70(dd, J ═ 2.6,8.8Hz,1H),5.18(s,2H),4.57(br.s.,1H),3.72-3.56(m,2H),3.49-3.38(m,2H),3.23(dd, J ═ 5.7,12.8Hz,1H),3.00(d, J ═ 11.9Hz,1H),2.78(s,3H),2.71 (br.71, 1H). ESI [ M + H ] ═ 452.1

4- (7- (trans-3- ((dimethylamino) methyl) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, 74. synthesized using general procedure A with trans-4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of tert-butyl piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 9.15(br.s.,1H),7.67-7.51(m,5H),7.42(d, J ═ 8.4Hz,1H),7.19(br.s.,1H),6.71(br.s.,1H),6.61(d, J ═ 7.9Hz,1H),5.10(br.s.,2H),4.28-4.15(m,1H),3.74-3.58(m,2H),3.38-3.25(m,2H),3.20-3.07(m,2H),2.97-2.86(m,6H),2.69-2.60(m, 1H). ESI [ M + H ] ═ 466.2

4- (7- (cis-3- ((dimethylamino) methyl) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, 75. synthesized using general procedure A using cis-4- ((dimethylamino) methyl) pyrrolidin-3-ol instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.10(s,1H),7.79-7.59(m,5H),7.49(d, J ═ 8.8Hz,1H),7.24(br.s, 1H),6.79(d, J ═ 1.8Hz,1H),6.69(d, J ═ 8.4Hz,1H),5.17(s,2H),4.57(br.s, 1H),3.74-3.53(m,4H),3.44(d, J ═ 10.6Hz,1H),3.24(br.s, 1H),2.98(s,6H),2.86(br.s, 1H). ESI [ M + H ] ═ 466.2

4- (7- (cis-3-amino-4-fluoropyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, 76 using general procedure A with tert-butyl (cis-4-fluoropyrrolidin-3-yl) carbamate instead of tert-butyl piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 9.06(br.s.,1H),7.77-7.70(m,2H),7.69-7.61(m,3H),7.55(d, J ═ 8.8Hz,1H),7.24(s,1H),6.89(d, J ═ 2.6Hz,1H),6.77(dd, J ═ 2.2,8.8Hz,1H),5.21(s,2H),4.25-4.11(m,1H),3.91(t, J ═ 8.8Hz,1H),3.87-3.81(m,1H),3.77(s,1H),3.51(t, J ═ 9.3Hz,1H),3.41-3.32(m, 1H). ESI [ M + H ] ═ 426.1

4- (7- ((3S,4S) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, 81.

Synthesized using general procedure a substituting (3S,4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol for piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.02(s,1H),7.74-7.60(m,5H),7.48(d, J ═ 8.6Hz,1H),7.22(s,1H),6.78(d, J ═ 2.3Hz,1H),6.69(dd, J ═ 2.3,8.6Hz,1H),5.16(s,2H),4.57(br.s.,1H),3.72-3.54(m,3H),3.44(d, J ═ 10.2Hz,1H),3.34(br.s.,1H),3.28-3.22(m,1H),2.99(s,6H),2.91-2.81(m, 1H). ESI [ M + H ] ═ 466.2

4- (7- ((3R,4R) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, 82.

Synthesized using general procedure a substituting (3R,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol for piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.01(br.s.,1H),7.74-7.60(m,5H),7.48(d, J ═ 8.6Hz,1H),7.21(s,1H),6.78(d, J ═ 2.3Hz,1H),6.69(dd, J ═ 2.3,9.0Hz,1H),5.16(s,2H),4.57(br.s.,1H),3.73-3.55(m,3H),3.44(d, J ═ 10.6Hz,1H),3.34(br.s.,1H),3.29-3.22(m,1H),2.99(s,6H),2.90-2.82(m, 1H). ESI [ M + H ] ═ 466.2

4- (7- ((3R,4S) -3- (dimethylamino) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, 83 using general procedure A to replace piperazine-1-carboxylic acid tert-butyl ester with (3S,4R) -4- (dimethylamino) pyrrolidin-3-ol. 1H NMR (400MHz, methanol-d 4) δ 9.05(s,1H),7.74-7.67(m,2H),7.67-7.60(m,3H),7.52(d, J ═ 8.8Hz,1H),7.25(br.s.,1H),6.86(d, J ═ 1.8Hz,1H),6.74(d, J ═ 7.1Hz,1H),5.19(s,2H),4.68(br.s.,1H),3.99-3.86(m,2H),3.69(dd, J ═ 3.3,11.2Hz,1H),3.61-3.47(m,2H),3.13-2.90(m, 6H). ESI [ M + H ] ═ 452.2

4- (7- ((R) -3- ((((R) -1-hydroxypropan-2-yl) amino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, 85. synthesized using general procedure A with (R) -2- (((S) -pyrrolidin-3-ylmethyl) amino) propan-1-ol in place of tert-butyl piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ is 9.01(s,1H),7.76-7.67(m,2H),7.67-7.57(m,3H),7.46(d, J ═ 8.8Hz,1H),7.21(d, J ═ 1.3Hz,1H),6.77(d, J ═ 2.2Hz,1H),6.68(dd, J ═ 2.2,8.8Hz,1H),5.14(s,2H),3.83(dd, J ═ 3.7,12.1Hz,1H),3.65-3.55(m,2H),3.51(dt, J ═ 4.0,8.8Hz,1H),3.45-3.35(m,2H),3.23-3.14(m, 3.14H), 3.7 (m, 3.73H), 3.7, 3.8H, 1H, 3.7 (d, 1H),3.7, 3.8H, 1H, 3.7H, 1H, 3.7H, 3. ESI [ M + H ] ═ 480.2

4- (7- ((S) -3- ((((S) -1-hydroxypropan-2-yl) amino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, 86.

Synthesized using general procedure a with (S) -2- (((R) -pyrrolidin-3-ylmethyl) amino) propan-1-ol instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.04(br.s.,1H),7.75-7.57(m,5H),7.47(d, J ═ 8.8Hz,1H),7.22(br.s.,1H),6.78(d, J ═ 2.2Hz,1H),6.68(dd, J ═ 2.2,8.8Hz,1H),5.15(s,2H),3.83(dd, J ═ 3.5,11.9Hz,1H),3.59(dd, J ═ 5.7,11.9Hz,2H),3.55-3.47(m,1H),3.41(d, J ═ 8.4Hz,2H),3.23-3.13(m,3H),2.80-2.66(m,1H), 1.35H, 6.85(d, 1H),3.7, 3.6H, 1H),3.7, 6.6.7H, 1H, 3.6.6H, 1H, 3.7, 3.6H, 3.7H, 1H, and 1H. ESI [ M + H ] ═ 480.2

4- (7- ((3R,4S) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, 108.

Synthesized using general procedure a substituting (3S,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol for piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.97(s,1H),7.67-7.73(m,2H),7.57-7.67(m,3H),7.44(d,J＝8.4Hz,1H),7.18(d,J＝1.3Hz,1H),6.77(d,J＝2.2Hz,1H),6.66(dd,J＝8.8,2.2Hz,1H),5.13(s,2H),4.26(q,J＝6.0Hz,1H),3.62-3.76(m,2H),3.20(ddd,J＝16.3,9.9,6.4Hz,2H),2.98-3.07(m,1H),2.86-2.96(m,1H),2.70(s,6H),2.54-2.63ppm(m,1H)。ESI[M+H]＝466.1

4- (7- ((3S,4R) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, 109.

Synthesized using general procedure a with (3R,4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.97(s,1H),7.74-7.68(m,2H),7.67-7.57(m,3H),7.45(d,J＝8.8Hz,1H),7.18(d,J＝1.3Hz,1H),6.77(d,J＝2.2Hz,1H),6.66(dd,J＝2.4,8.6Hz,1H),5.13(s,2H),4.25(q,J＝6.2Hz,1H),3.74-3.62(m,2H),3.27-3.14(m,2H),3.08-2.95(m,1H),2.94-2.83(m,1H),2.68(s,6H),2.63-2.53(m,1H)。ESI[M+H]＝466.1

(S) -4- (7- (3- ((4-hydroxypiperidin-1-yl) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, 110. synthesized using general procedure A with (R) -1- (pyrrolidin-3-ylmethyl) piperidin-4-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.00(s,1H),7.78-7.60(m,5H),7.49(d, J8.6 Hz,1H),7.22(s,1H),6.81(d, J2.2 Hz,1H),6.74-6.68(m,1H),5.18(s,2H),4.11(br.s, 1H),3.85(br.s, 1H),3.74-3.61(m,2H),3.57-3.41(m,3H),3.17-3.06(m,3H),2.88(d, J7.9 Hz,1H),2.36(br.s, 1H),2.17(d, J13.9, 1H), 2.86(d, 1H), 1H, 13.08 (d, 1H), 1H, 13.77H, 1H, 13H, 1H). ESI [ M + H ] ═ 506.2

(R) -4- (7- (3- ((4-hydroxypiperidin-1-yl) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, 111. synthesized using general procedure A with (S) -1- (pyrrolidin-3-ylmethyl) piperidin-4-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.10(br.s.,1H),7.73-7.61(m,5H),7.48(d, J ═ 8.8Hz,1H),7.28-7.21(m,1H),6.78(d, J ═ 2.2Hz,1H),6.69(dd, J ═ 2.6,8.8Hz,1H),5.17(s,2H),4.10(br.s.,1H),3.90-3.76(m,1H),3.65(t, J ═ 8.2Hz,2H),3.56-3.34(m,4H),3.19-3.03(m,2H),2.85(td, J ═ 7.6,14.8, 1H),2.34 (br.13.13H), 1H),7.07 (d, 1H). ESI [ M + H ] ═ 506.2

4- (7- (3- (dimethylamino) piperidin-1-yl) -9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 112. Using general procedure C4- (7-bromo-9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile and tert-butyl piperidin-3-ylcarbamate is used in place of (azetidin-3-ylmethyl) (methyl) carbamate Tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.07(br.s.,1H),7.84-7.67(m,6H),7.63(d, J ═ 8.8Hz,1H),7.38-7.30(m,2H),7.23(dd, J ═ 2.9,9.0Hz,1H),5.36(s,2H),3.99(d, J ═ 12.3Hz,1H),3.70(s,1H),3.50-3.40(m,1H),3.25(s,1H),3.06(d, J ═ 10.1Hz,1H),2.98(s,6H),2.18(br.s.,1H),1.99(dd, J ═ 4.4,8.8, 1H),1.90 (m,1H), 1.79(m, 2H). ESI [ M + H ] ═ 449.2

4- (7- (trans-pyrrolo [3,2-b ] pyrrol-1 (2H) -yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 113. Using general procedure A4- (7-bromo-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, trans-pyrrolo [3,2-b ] pyrrole-1 (2H) -carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.05(br.s.,1H),7.89-7.69(m,6H),7.61(d, J8.5 Hz,1H),7.34(br.s.,1H),6.99(br.s.,1H),6.96-6.88(m,1H),5.36(s,2H),4.68-4.49(m,1H),4.30(d, J7.5 Hz,1H),4.14-4.00(m,1H),3.92-3.82(m,1H),3.74(d, J5.3 Hz,1H),3.45(d, J7.8 Hz,1H),2.77(d, J5.5, 1H), 2.37H, 1H),2.7, 10H, 1H, 7.06 (d, J, 1H), 2.7.7H, 10H, 1H, 7. ESI [ M + H ] ═ 433.2

(R) -4- (7- (3- (methylamino) pyrrolidin-1-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 114. use of general procedure A with 4- (7-bromo-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and (R) -methyl (pyrrolidin-3-yl) carbamic acid tert-butyl ester in place of piperazin-1, 2-a ] [1,2,4] diazepin-12-yl) benzonitrile Tert-butyl formate. 1H NMR (400MHz, methanol-d 4) δ 8.06(s,1H),7.84-7.71(M,6H),7.62(d, J8.8 Hz,1H),7.34(s,1H),6.95(d, J2.5 Hz,1H),6.91-6.85(M,1H),5.36(s,2H),4.10-4.00(M,1H),3.82-3.58(M,3H),3.51(d, J6.0 Hz,1H),2.83(s,3H),2.62-2.53(M,1H),2.32(d, J5.8 Hz,1H) ESI [ M + H ] ═ 421.2 (M + H) ], 421.2 (M,1H)

(S) -4- (7- (3- (methylamino) pyrrolidin-1-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 115. Using general procedure A4- (7-bromo-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and (S) -methyl (pyrrolidin-3-yl) carbamic acid tert-butyl ester instead of piperazin-1, 2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile Tert-butyl formate. 1H NMR (400MHz, methanol-d 4) δ 8.06(s,1H),7.84-7.71(M,6H),7.62(d, J8.8 Hz,1H),7.34(s,1H),6.95(d, J2.5 Hz,1H),6.91-6.85(M,1H),5.36(s,2H),4.10-4.00(M,1H),3.82-3.58(M,3H),3.51(d, J6.0 Hz,1H),2.83(s,3H),2.62-2.53(M,1H),2.32(d, J5.8 Hz,1H) ESI [ M + H ] ═ 421.2 (M + H) ], 421.2 (M,1H)

4- (7- (3- (aminomethyl) azetidin-1-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 118. Using general procedure A, 4- (7-bromo-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, and tert-butyl (azetidin-3-ylmethyl) carbamate is used in place of tert-butyl piperazine-1-carboxylate And (4) obtaining. 1H NMR (400MHz, methanol-d 4) δ 8.01(br.s.,1H),7.85-7.63(m,6H),7.55(d, J ═ 8.4Hz,1H),7.32(br.s.,1H),6.71(br.s.,1H),6.64(d, J ═ 8.4Hz,1H),5.29(br.s.,2H),4.14(t, J ═ 7.5Hz,2H),3.86-3.74(m,2H),3.31-3.26(m,2H),3.07(br.s., 1H). ESI [ M + H ] ═ 407.1

4- (7- (3- ((methylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile, 122. Using general procedure A4- (7-bromo-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, methyl (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester in place of piperazine-1-carboxylic acid tert-butyl ester And (3) synthesizing the ester. 1H NMR (400MHz, methanol-d 4) δ 8.01(br.s.,1H),7.84-7.66(m,6H),7.55(d, J ═ 8.8Hz,1H),7.31(s,1H),6.82(br.s.,1H),6.76(d, J ═ 8.8Hz,1H),5.30(s,2H),3.64(br.s.,1H),3.55(br.s.,1H),3.44(d, J ═ 7.9Hz,1H),3.18(d, J ═ 7.1Hz,3H),2.78(s,3H),2.75(br.s.,1H),2.35(d, J ═ 6.2Hz,1H), 1.98-1H), 1.83(m, 1H). ESI [ M + H ] ═ 435.2

(S) -4- (7- (3- (dimethylamino) piperidin-1-yl) -9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 123. use of general procedure C with 4- (7-bromo-9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile and in place of (S) -piperidin-3-ylcarbamic acid tert-butyl ester (azetidin-3- Tert-butyl methyl) (methyl) carbamate. 1H NMR (400MHz, methanol-d 4) δ 8.06(s,1H),7.85-7.68(m,6H),7.63(d, J ═ 8.8Hz,1H),7.38-7.29(m,2H),7.23(dd, J ═ 2.6,8.8Hz,1H),5.35(s,2H),3.99(d, J ═ 11.9Hz,1H),3.76-3.63(m,1H),3.45(d, J ═ 3.1Hz,1H),3.25(br.s.,1H),3.13-3.03(m,1H),2.98(s,6H),2.27-2.13(m,1H),2.06-1.93(m,1H),1.89-1.78(m, 2H). ESI [ M + H ] ═ 449.2

4- (7- (3-aminopyrrolidin-1-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile, 124 using general procedure A with 4- (7-bromo-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, pyrrolidine-3-ylcarbamic acid tert-butyl ester was used instead of piperazine-1-carboxylic acid tert-butyl ester for synthesis. 1HNMR (400MHz, methanol-d 4) δ is 8.02(d, J is 1.8Hz,1H),7.85-7.66(m,6H),7.58(d, J is 9.3Hz,1H),7.32(s,1H),6.90(d, J is 2.6Hz,1H),6.83(dd, J is 2.6,8.8Hz,1H),5.33(s,2H),4.09(br.s.,1H),3.79-3.61(m,2H),3.52(dd, J is 3.7,10.8Hz,2H),2.58-2.43(m,1H),2.24(dd, J is 4.6,8.6, 1H). ESI [ M + H ] ═ 407.1

4- (7- ((3S,4S) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile 128. Using general procedure A4- (7-bromo-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, Synthesized with (3S,4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.98(d, J2.2 Hz,1H),7.80-7.64(m,6H),7.53(d, J9.3 Hz,1H),7.28(d, J1.3 Hz,1H),6.80(d, J2.6 Hz,1H),6.74(dd, J2.6, 8.8Hz,1H),5.29(s,2H),4.57(br.s.,1H),3.70-3.55(m,4H),3.44(d, J10.6 Hz,2H),2.97(s,6H),2.86(br.s., 1H). ESI [ M + H ] ═ 465.1

4- (7- ((3R,4R) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile 129. Using general procedure A4- (7-bromo-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, Synthesized with (3R,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.98(s,1H),7.79-7.66(m,6H),7.53(d, J ═ 8.8Hz,1H),7.29(s,1H),6.80(d, J ═ 2.2Hz,1H),6.74(dd, J ═ 2.6,9.3Hz,1H),5.29(s,2H),4.56(br.s.,1H),3.71-3.53(m,4H),3.44(d, J ═ 10.6Hz,2H),2.97(s,6H),2.86(br.s., 1H). ESI [ M + H ] ═ 465.1

4- (7- ((3R,4R) -3- (dimethylamino) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile 130 using general procedure A using 4- (7-bromo-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, Synthesized by substituting (3R,4R) -4- (dimethylamino) pyrrolidin-3-ol for piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.01(d, J ═ 2.0Hz,1H),7.81-7.67(m,6H),7.59(d, J ═ 9.0Hz,1H),7.30(d, J ═ 1.6Hz,1H),6.92(d, J ═ 2.3Hz,1H),6.85(dd, J ═ 2.5,9.0Hz,1H),5.32(s,2H),4.72(q, J ═ 6.8Hz,1H),4.00-3.82(m,3H),3.60(dd, J ═ 7.2,10.2Hz,1H),3.33(br.s.,1H),3.15-2.96(m, 6H). ESI [ M + H ] ═ 451.1

4- (7- ((3S,4S) -3- (dimethylamino) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 131, using general procedure A with 4- (7-bromo-9H-benzo [ e]Imidazo [2, 1-c)]Azole compoundsAnd [1,2-a ]][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (3S,4S) -4- (dimethylamino) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝7.99(d,J＝1.8Hz,1H),7.79-7.66(m,6H),7.59(d,J＝9.0Hz,1H),7.29(d,J＝1.6Hz,1H),6.92(d,J＝2.5Hz,1H),6.84(dd,J＝2.5,9.0Hz,1H),5.31(s,2H),4.72(q,J＝7.0Hz,1H),4.00-3.82(m,3H),3.60(dd,J＝7.1,10.1Hz,1H),3.33(br.s.,1H),3.06(s,6H)。ESI[M+H]＝451.1

4- (7- ((3S,4R) -3- (dimethylamino) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 133, using general procedure A with 4- (7-bromo-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (3R,4S) -4- (dimethylamino) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝7.99(br.s.,1H),7.79-7.66(m,6H),7.58(d,J＝7.6Hz,1H),7.29(br.s.,1H),6.88(s,1H),6.82(d,J＝8.8Hz,1H),5.31(s,2H),4.70(br.s.,1H),3.95(br.s.,2H),3.77-3.69(m,1H),3.63-3.52(m,2H),3.03(d,J＝16.0Hz,6H)。ESI[M+H]＝451.1

4- (7- ((3R,4S) -3- (dimethylamino) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile, 134.

General procedure A was used with 4- (7-bromo-9H-benzo [ e ]]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzeneAnd [ e ]]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (3S,4R) -4- (dimethylamino) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.02(br.s.,1H),7.82-7.67(m,6H),7.59(d,J＝8.8Hz,1H),7.31(br.s.,1H),6.88(s,1H),6.82(d,J＝8.8Hz,1H),5.32(s,2H),4.70(br.s.,1H),3.95(br.s.,2H),3.73(dd,J＝3.1,11.0Hz,1H),3.63-3.51(m,2H),3.03(br.s.,6H)。ESI[M+H]＝451.1

4- (7- ((S) -3- ((((R) -1-hydroxypropan-2-yl) amino) methyl) pyrrolidin-1-yl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 135, using general procedure A with 4- (7-bromo-9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (R) -2- (((R) -pyrrolidin-3-ylmethyl) amino) propan-1-ol in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝7.98(d,J＝2.0Hz,1H),7.81-7.68(m,6H),7.54(d,J＝9.0Hz,1H),7.29(d,J＝1.6Hz,1H),6.82(d,J＝2.3Hz,1H),6.76(dd,J＝2.5,9.0Hz,1H),5.29(s,2H),3.84(dd,J＝3.8,12.0Hz,1H),3.70-3.51(m,3H),3.50-3.37(m,2H),3.26-3.14(m,3H),2.81-2.64(m,1H),2.36(s,1H),1.92(dd,J＝8.6,12.3Hz,1H),1.35(d,J＝6.8Hz,3H)。ESI[M+H]＝479.2

4- (7- ((R) -3- ((((R) -1-hydroxypropan-2-yl) amino) methyl) pyrrolidin-1-yl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 136, using general procedure A with 4- (7-bromo-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (R) -2- (((S) -pyrrolidin-3-ylmethyl) amino) propan-1-ol in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝7.96(br.s.,1H),7.77-7.65(m,6H),7.52(d,J＝8.8Hz,1H),7.27(br.s.,1H),6.84-6.71(m,2H),5.27(s,2H),3.83(dd,J＝4.0,11.9Hz,1H),3.69-3.50(m,3H),3.47-3.36(m,2H),3.23-3.14(m,3H),2.79-2.69(m,1H),2.36(br.s.,1H),1.99-1.84(m,1H),1.33(d,J＝6.6Hz,3H)。ESI[M+H]＝479.2

4- (7- ((3S,4R) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 137, using general procedure A with 4- (7-bromo-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and using (3R,4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝7.99(br.s.,1H),7.79-7.66(m,6H),7.55(d,J＝9.0Hz,1H),7.30(br.s.,1H),6.82(d,J＝2.3Hz,1H),6.75(dd,J＝2.3,8.6Hz,1H),5.29(s,2H),4.30(q,J＝6.7Hz,1H),3.82-3.71(m,2H),3.46-3.34(m,2H),3.27-3.18(m,2H),2.99(s,6H),2.78-2.65(m,1H)。ESI[M+H]＝465.1

4- (7- ((3R,4S) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidin-1-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 138, using general procedure A with 4- (7-bromo-9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrileSynthesized with (3S,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.00(br.s.,1H),7.83-7.66(m,6H),7.54(d,J＝8.8Hz,1H),7.30(br.s.,1H),6.81(d,J＝2.4Hz,1H),6.74(dd,J＝2.4,8.8Hz,1H),5.29(s,2H),4.29(q,J＝6.6Hz,1H),3.80-3.69(m,2H),3.44-3.33(m,2H),3.26-3.19(m,2H),3.02-2.90(m,6H),2.75-2.61(m,1H)。ESI[M+H]＝465.2

(S) -4- (7- (3- (((1-hydroxy-2-methylpropan-2-yl) amino) methyl) pyrrolidin-1-yl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 141, using general procedure A with 4- (7-bromo-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (R) -2-methyl-2- ((pyrrolidin-3-ylmethyl) amino) propan-1-ol in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝7.96(br.s.,1H),7.72(dd,J＝7.4,19.1Hz,6H),7.53(d,J＝8.8Hz,1H),7.27(br.s.,1H),6.81(br.s.,1H),6.76(d,J＝9.0Hz,1H),5.28(s,2H),3.72-3.61(m,1H),3.57(s,3H),3.50-3.41(m,1H),3.26-3.18(m,1H),3.16-3.08(m,2H),2.76-2.64(m,1H),2.38(d,J＝6.6Hz,1H),1.99-1.89(m,1H),1.40-1.27(m,6H)。ESI[M+H]＝493.3

(S) -4- (7- (3- ((4-hydroxypiperidin-1-yl) methyl) pyrrolidin-1-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 142, using general procedure A with 4- (7-bromo-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]The use of (R) -1-, (R) -12-yl) benzonitrilePyrrolidin-3-ylmethyl) piperidin-4-ol was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.02(br.s.,1H),7.83-7.66(m,6H),7.54(d,J＝8.8Hz,1H),7.31(br.s.,1H),6.82(s,1H),6.76(d,J＝8.8Hz,1H),5.30(s,2H),4.11(br.s.,1H),3.84(br.s.,1H),3.69(t,J＝8.2Hz,2H),3.61-3.37(m,4H),3.18(br.s.,1H),3.09(br.s.,1H),2.89(d,J＝6.2Hz,1H),2.36(br.s.,1H),2.21-1.99(m,2H),1.99-1.67(m,4H)。ESI[M+H]＝505.3

(R) -4- (7- (3- ((4-hydroxypiperidin-1-yl) methyl) pyrrolidin-1-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 143, using general procedure A with 4- (7-bromo-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (S) -1- (pyrrolidin-3-ylmethyl) piperidin-4-ol in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.01(d,J＝2.2Hz,1H),7.78(d,J＝1.8Hz,1H),7.76-7.67(m,5H),7.53(d,J＝8.8Hz,1H),7.30(d,J＝1.8Hz,1H),6.81(d,J＝2.6Hz,1H),6.75(dd,J＝2.6,8.8Hz,1H),5.29(s,2H),4.10(br.s.,1H),3.73-3.62(m,2H),3.58-3.49(m,1H),3.48-3.38(m,2H),3.32(br.s.,3H),3.22-3.01(m,2H),2.94-2.79(m,1H),2.35(br.s.,1H),2.15(d,J＝11.0Hz,1H),2.03(d,J＝11.5Hz,1H),1.97-1.84(m,2H),1.77(d,J＝11.0Hz,1H)。ESI[M+H]＝505.2

4- (7- (2, 6-diazaspiro [3.4]]Oct-6-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 146, using general procedure A with 4- (7-bromo-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Azole compoundsAnd [1,2-a ]][1,2,4]Triazolo [3,4-c][1,4]Novel diazepine-12-yl) benzonitrile in combination with 2, 6-diazaspiro [3.4]Octane-2-carboxylic acid tert-butyl ester was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝7.98(br.s.,1H),7.83-7.63(m,6H),7.54(d,J＝8.8Hz,1H),7.29(br.s.,1H),6.83(d,J＝2.6Hz,1H),6.76(dd,J＝2.2,8.8Hz,1H),5.29(s,2H),4.25-4.04(m,4H),3.65(s,2H),3.48(t,J＝6.8Hz,2H),2.40(t,J＝7.1Hz,2H)。ESI[M+H]＝433.2

4- (7- (2, 6-diazaspiro [3.5]]Non-2-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 149, using general procedure A with 4- (7-bromo-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Novel diazepine-12-yl) benzonitrile in combination with 2, 6-diazaspiro [3.5]Nonane-6-carboxylic acid tert-butyl ester was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.05(br.s.,1H),7.86-7.69(m,6H),7.58(d,J＝8.8Hz,1H),7.35(br.s.,1H),6.74(s,1H),6.67(d,J＝8.8Hz,1H),5.33(s,2H),3.90(d,J＝7.8Hz,2H),3.80(d,J＝7.5Hz,2H),3.44(s,2H),3.18(br.s.,2H),2.02(d,J＝5.3Hz,2H),1.90(br.s.,2H)。ESI[M+H]＝447.2

4- (7- (2, 6-diazaspiro [3.4]]Oct-2-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 152, using general procedure A with 4- (7-bromo-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile (S12) in combination with 2, 6-diazaspiro [3.4]Synthesis of octane-6-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl esterAnd (4) obtaining.¹H NMR (400MHz, methanol-d)₄)δ＝8.05(s,1H),7.85-7.70(m,6H),7.59(d,J＝8.8Hz,1H),7.34(s,1H),6.76(s,1H),6.70(d,J＝8.5Hz,1H),5.33(s,2H),4.09-3.99(m,4H),3.56(s,2H),3.42(t,J＝7.3Hz,2H),2.39(t,J＝7.3Hz,2H)。ESI[M+H]＝433.2

4- (7- ((1R,5S,6S) -6-amino-3-azabicyclo [ 3.1.0)]Hex-3-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 153 using general procedure A with 4- (7-bromo-9H-benzo [ e ]]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Novel diazepine-12-yl) benzonitrile in combination with (1R,5S,6S) -3-azabicyclo [3.1.0]Tert-butyl hex-6-ylcarbamate was synthesized instead of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝8.02(br.s.,1H),7.86-7.65(m,6H),7.55(d,J＝8.8Hz,1H),7.32(br.s.,1H),6.87(br.s.,1H),6.80(d,J＝8.8Hz,1H),5.31(s,2H),3.78(d,J＝9.3Hz,2H),3.44(d,J＝9.3Hz,2H),2.53(br.s.,1H),2.21(br.s.,2H)。ESI[M+H]＝419.2

4- (7- (pyrrolo [3, 4-c))]Pyrrol-2 (1H) -yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 154, using general procedure A with 4- (7-bromo-9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile in combination with pyrrolo [3,4-c]Pyrrole-2 (1H) -carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.02(br.s.,1H),7.83-7.68(m,6H),7.58(d,J＝8.8Hz,1H),7.31(br.s.,1H),6.96(br.s.,1H),6.89(d,J＝8.8Hz,1H),5.32(s,2H),3.64(d,J＝4.9Hz,2H),3.53(br.s.,4H),3.29-3.20(m,4H)。ESI[M+H]＝433.1

4- (7- (3- (methylamino) pyrrolidin-1-yl) -9H-benzo [ e ]]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 155, using general procedure A with 4- (7-bromo-9H-benzo [ e ]]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and tert-butyl methyl (pyrrolidin-3-yl) carbamate in place of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝8.04(br.s.,1H),7.85-7.65(m,6H),7.60(d,J＝8.8Hz,1H),7.33(br.s.,1H),6.92(br.s.,1H),6.85(d,J＝8.8Hz,1H),5.34(s,2H),4.01(br.s.,1H),3.80-3.71(m,1H),3.65(d,J＝4.0Hz,2H),3.54-3.43(m,1H),2.81(s,3H),2.64-2.49(m,1H),2.37-2.24(m,1H)。ESI[M+H]＝421.1

(R) -4- (7- (3- (dimethylamino) pyrrolidin-1-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 156, using general procedure A with 4- (7-bromo-9H-benzo [ e ]]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (R) -N, N-dimethylpyrrolidin-3-amine in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.01(d,J＝1.8Hz,1H),7.81-7.69(m,6H),7.61(d,J＝8.8Hz,1H),7.31(d,J＝1.5Hz,1H),6.94(d,J＝2.3Hz,1H),6.88(dd,J＝2.5,8.8Hz,1H),5.34(s,2H),4.16-4.06(m,1H),3.86(dd,J＝7.7,10.7Hz,1H),3.78-3.70(m,1H),3.66(dd,J＝6.4,10.7Hz,1H),3.54-3.44(m,1H),3.02(s,6H),2.71-2.59(m,1H),2.35(dd,J＝8.2,13.2Hz,1H)。ESI[M+H]＝435.2

4- (7- (2, 6-diazaspiro [3.3 ]]Hept-2-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 157, using general procedure A with 4- (7-bromo-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Novel diazepine-12-yl) benzonitrile in combination with 2, 6-diazaspiro [3.3]Tert-butyl heptane-2-carboxylate was synthesized instead of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝8.03(br.s.,1H),7.84-7.65(m,6H),7.55(d,J＝8.8Hz,1H),7.32(br.s.,1H),6.73(br.s.,1H),6.65(d,J＝8.8Hz,1H),5.30(s,2H),4.33(s,4H),4.18(s,4H)。ESI[M+H]＝419.2

(S) -4- (7- (3- (dimethylamino) pyrrolidin-1-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 158, using general procedure A with 4- (7-bromo-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (S) -N, N-dimethylpyrrolidin-3-amine in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.01(d,J＝1.8Hz,1H),7.81-7.69(m,6H),7.61(d,J＝8.8Hz,1H),7.31(d,J＝1.5Hz,1H),6.94(d,J＝2.3Hz,1H),6.88(dd,J＝2.5,8.8Hz,1H),5.34(s,2H),4.16-4.06(m,1H),3.86(dd,J＝7.7,10.7Hz,1H),3.78-3.70(m,1H),3.66(dd,J＝6.4,10.7Hz,1H),3.54-3.44(m,1H),3.02(s,6H),2.71-2.59(m,1H),2.35(dd,J＝8.2,13.2Hz,1H)。ESI[M+H]＝435.2

(S) -4- (7- (3-Aminopyrrolidin-1-yl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 159, using general procedure A with 4- (7-bromo-9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (S) -pyrrolidin-3-ylcarbamic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.03(d,J＝2.0Hz,1H),7.84-7.69(m,6H),7.61(d,J＝9.0Hz,1H),7.33(d,J＝1.5Hz,1H),6.92(d,J＝2.5Hz,1H),6.85(dd,J＝2.6,8.9Hz,1H),5.35(s,2H),4.16-4.07(m,1H),3.81-3.63(m,2H),3.59-3.49(m,2H),2.61-2.48(m,1H),2.26(dd,J＝4.4,8.7Hz,1H)。ESI[M+H]＝407.1

(R) -4- (7- (3-Aminopyrrolidin-1-yl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 161, using general procedure A with 4- (7-bromo-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (R) -pyrrolidin-3-ylcarbamic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.03(d,J＝2.0Hz,1H),7.84-7.69(m,6H),7.61(d,J＝9.0Hz,1H),7.33(d,J＝1.5Hz,1H),6.92(d,J＝2.5Hz,1H),6.85(dd,J＝2.6,8.9Hz,1H),5.35(s,2H),4.16-4.07(m,1H),3.81-3.63(m,2H),3.59-3.49(m,2H),2.61-2.48(m,1H),2.26(dd,J＝4.4,8.7Hz,1H)。ESI[M+H]＝407.1

4- (11-chloro-7- (piperazin-1-yl)) -9H-benzo [ e ]]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 164 using general procedure A with 4- (7-bromo-11-chloro-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile.¹H NMR (400MHz, methanol-d)₄)δ＝9.09(s,1H),7.84-7.71(m,4H),7.63(d,J＝8.8Hz,1H),7.34(d,J＝2.6Hz,1H),7.21(dd,J＝2.9,9.0Hz,1H),7.15(s,1H),5.31(s,2H),3.61-3.52(m,4H),3.46-3.37(m,4H)。ESI[M+H]＝442.1

(R) -4- (11-chloro-7- (3- (methylamino) pyrrolidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 166, using general procedure A with 4- (7-bromo-11-chloro-9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and tert-butyl (R) -methyl (pyrrolidin-3-yl) carbamate in place of piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝9.06(br.s.,1H),7.87-7.79(m,2H),7.78-7.72(m,2H),7.56(d,J＝8.6Hz,1H),7.14(s,1H),6.92(d,J＝2.4Hz,1H),6.82(dd,J＝2.4,8.8Hz,1H),5.28(br.s.,2H),4.00(br.s.,1H),3.79-3.58(m,3H),3.52-3.41(m,1H),2.86-2.74(m,3H),2.55(dt,J＝6.7,14.3Hz,1H),2.34-2.19(m,1H)。ESI[M+H]＝456.1

(S) -4- (11-chloro-7- (3- (methylamino) pyrrolidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 167. Using general procedure A with 4- (7-bromo-11-chloro-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile instead of 4- (7-bromo-9H-benzo [ e ]]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and tert-butyl (S) -methyl (pyrrolidin-3-yl) carbamate in place of piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝9.04(br.s.,1H),7.84-7.76(m,2H),7.75-7.68(m,2H),7.54(d,J＝8.8Hz,1H),7.12(s,1H),6.90(d,J＝2.6Hz,1H),6.80(dd,J＝2.6,8.8Hz,1H),5.26(br.s.,2H),4.04-3.93(m,1H),3.76-3.55(m,3H),3.45(dt,J＝5.7,9.0Hz,1H),2.85-2.73(m,3H),2.61-2.46(m,1H),2.27(dt,J＝5.4,13.4Hz,1H)。ESI[M+H]＝456.1

4- (11-chloro-7- (2-methyl-2, 6-diazaspiro [3.4]]Oct-6-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 168, using general procedure C with 4- (7-bromo-11-chloro-9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Novel diazepine-12-yl) benzonitrile in combination with 2, 6-diazaspiro [3.4]Octane-2-carboxylic acid tert-butyl ester was synthesized instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝9.03(s,1H),7.83-7.75(m,2H),7.75-7.66(m,2H),7.51(d,J＝8.8Hz,1H),7.11(s,1H),6.80(d,J＝3.5Hz,1H),6.72(t,J＝6.6Hz,1H),5.24(br.s.,2H),4.40-4.25(m,2H),4.22-4.07(m,2H),3.70-3.58(m,2H),3.45(td,J＝6.7,13.1Hz,2H),2.98(d,J＝5.1Hz,3H),2.44-2.33(m,2H)。ESI[M+H]＝482.1

(S) -4- (7- (3- (aminomethyl) pyrrolidin-1-yl) -11-chloro-9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 169, using general procedure A with 4- (7-bromo-11-chloro-9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (R) - (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝9.04(br.s.,1H),7.86-7.79(m,2H),7.78-7.71(m,2H),7.51(d,J＝8.8Hz,1H),7.13(s,1H),6.80(d,J＝2.2Hz,1H),6.73(dd,J＝2.5,8.7Hz,1H),5.32-5.18(m,2H),3.66-3.50(m,2H),3.47-3.38(m,1H),3.22-3.01(m,3H),2.68(td,J＝7.4,14.9Hz,1H),2.32(dt,J＝6.9,11.5Hz,1H),1.88(qd,J＝8.3,12.4Hz,1H)。ESI[M+H]＝456.1

(S) -4- (11-chloro-7- (3- ((dimethylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 170, using general procedure C with 4- (7-bromo-11-chloro-9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]The diazepine-12-yl) benzonitrile and the replacement of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate with tert-butyl (R) - (pyrrolidin-3-ylmethyl) carbamate.¹H NMR (400MHz, methanol-d)₄)δ＝9.03(s,1H),7.82-7.69(m,4H),7.49(d,J＝8.8Hz,1H),7.09(s,1H),6.78(d,J＝2.4Hz,1H),6.71(dd,J＝2.4,8.8Hz,1H),5.30-5.17(m,2H),3.72-3.61(m,1H),3.52(dt,J＝3.1,8.8Hz,1H),3.46-3.36(m,1H),3.34(s,2H),3.20-3.11(m,1H),2.97(s,6H),2.91-2.80(m,1H),2.40-2.29(m,1H),1.88(qd,J＝8.8,12.3Hz,1H)。ESI[M+H]＝484.1

(R) -4- (7- (3- (aminomethyl) pyrrolidin-1-yl) -11-chloro-9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, 171, using general procedure a with 4- (7-bromo-11-chloro-9H-benzo [ e)]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and tert-butyl (S) - (pyrrolidin-3-ylmethyl) carbamate in place of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝9.04(br.s.,1H),7.84-7.78(m,2H),7.77-7.70(m,2H),7.51(d,J＝8.8Hz,1H),7.13(s,1H),6.79(d,J＝2.2Hz,1H),6.72(dd,J＝2.4,8.8Hz,1H),5.24(br.s.,2H),3.65-3.49(m,2H),3.47-3.39(m,1H),3.22-3.02(m,3H),2.74-2.61(m,1H),2.32(dt,J＝6.9,11.5Hz,1H),1.88(qd,J＝8.3,12.5Hz,1H)。ESI[M+H]＝456.1

4- (7- (cis-pyrrolo [3, 2-b)]Pyrrol-1 (2H) -yl) -3-methyl-9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 184, using general procedure A with 4- (7-bromo-3-methyl-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile with cis-hexahydro-pyrrolo [3,2-b]Pyrrole-1 (2H) -carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝7.78(d,J＝8.8Hz,1H),7.76-7.67(m,4H),7.56(s,1H),7.52(d,J＝8.8Hz,1H),7.26(br.s.,1H),6.99(br.s.,1H),6.86(d,J＝9.3Hz,1H),5.33-5.21(m,2H),4.66-4.48(m,2H),3.72-3.56(m,2H),3.44(d,J＝4.4Hz,1H),3.25(br.s.,1H),2.51(d,J＝3.1Hz,3H),2.47-2.34(m,2H),2.17(d,J＝16.8Hz,2H)。ESI[M+H]＝447.2

(R) -4- (3-methyl-7- (3- (methylamino) pyrrolidin-1-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo[1,2-a][1,4]Diazepine-12-yl) benzonitrile, 186, using general procedure A with 4- (7-bromo-3-methyl-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and tert-butyl (R) -methyl (pyrrolidin-3-yl) carbamate in place of piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝7.81(s,1H),7.74(q,J＝8.2Hz,4H),7.59(br.s.,1H),7.53(d,J＝8.8Hz,1H),7.29(br.s.,1H),6.97(br.s.,1H),6.84(d,J＝8.8Hz,1H),5.28(br.s.,2H),4.03(br.s.,1H),3.82-3.60(m,3H),3.51(br.s.,1H),2.83(s,3H),2.63-2.48(m,4H),2.32(d,J＝5.8Hz,1H)。ESI[M+H]＝435.2

(S) -4- (3-methyl-7- (3- (methylamino) pyrrolidin-1-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 187, using general procedure A with 4- (7-bromo-3-methyl-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and tert-butyl (S) -methyl (pyrrolidin-3-yl) carbamate in place of piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝7.81(s,1H),7.74(q,J＝8.2Hz,4H),7.59(br.s.,1H),7.53(d,J＝8.8Hz,1H),7.29(br.s.,1H),6.97(br.s.,1H),6.84(d,J＝8.8Hz,1H),5.28(br.s.,2H),4.03(br.s.,1H),3.82-3.60(m,3H),3.51(br.s.,1H),2.83(s,3H),2.63-2.48(m,4H),2.32(d,J＝5.8Hz,1H)。ESI[M+H]＝435.2

4- (3-methyl-7- (3- ((methylamino) methyl) azetidin-1-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 190, using generalProcedure A with 4- (7-bromo-3-methyl-9H-benzo [ e ]]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate in place of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝7.80(d,J＝1.3Hz,1H),7.78-7.68(m,4H),7.59(s,1H),7.49(d,J＝8.8Hz,1H),7.28(d,J＝1.3Hz,1H),6.76(d,J＝2.3Hz,1H),6.63(dd,J＝2.3,8.8Hz,1H),5.25(d,J＝4.8Hz,2H),4.19(dt,J＝4.0,7.8Hz,2H),3.87-3.76(m,2H),3.39(d,J＝7.3Hz,2H),3.22-3.08(m,1H),2.77(s,3H),2.52(s,3H)。ESI[M+H]＝435.2

(S) -4- (7- (3- (aminomethyl) pyrrolidin-1-yl) -3-methyl-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 196, using general procedure A with 4- (7-bromo-3-methyl-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (R) - (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝7.78(s,1H),7.76-7.66(m,4H),7.56(s,1H),7.46(d,J＝8.8Hz,1H),7.26(s,1H),6.84(br.s.,1H),6.73(d,J＝8.8Hz,1H),5.28-5.18(m,2H),3.67-3.51(m,2H),3.44(d,J＝7.9Hz,1H),3.24-3.14(m,1H),3.14-3.03(m,2H),2.69(td,J＝7.1,14.4Hz,1H),2.50(s,3H),2.33(d,J＝6.2Hz,1H),1.95-1.82(m,1H)。ESI[M+H]＝435.2

(S) -4- (7- (3- ((dimethylamino) methyl) pyrrolidin-1-yl) -3-methyl-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzenesCarbonitrile, 197. Using general procedure C with 4- (7-bromo-3-methyl-9H-benzo [ e ]]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]The diazepine-12-yl) benzonitrile and the replacement of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate with tert-butyl (R) - (pyrrolidin-3-ylmethyl) carbamate.¹H NMR (400MHz, methanol-d)₄)δ＝7.76(s,1H),7.70(q,J＝8.4Hz,4H),7.55(s,1H),7.45(d,J＝8.8Hz,1H),7.24(s,1H),6.83(d,J＝2.6Hz,1H),6.72(dd,J＝2.4,9.0Hz,1H),5.27-5.17(m,2H),3.73-3.61(m,1H),3.59-3.50(m,1H),3.48-3.38(m,1H),3.37-3.30(m,2H),3.16(dt,J＝4.2,8.5Hz,1H),2.96(s,6H),2.90-2.80(m,1H),2.55-2.44(m,3H),2.41-2.29(m,1H),1.94-1.81(m,1H)。ESI[M+H]＝463.2

(R) -4- (7- (3- ((dimethylamino) methyl) pyrrolidin-1-yl) -3-methyl-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-12-yl) benzonitrile, 198, using general procedure C with 4- (7-bromo-3-methyl-9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]The diazepine-12-yl) benzonitrile and replacement of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate with tert-butyl (S) - (pyrrolidin-3-ylmethyl) carbamate.¹H NMR (400MHz, methanol-d)₄)δ＝7.77(s,1H),7.72(q,J＝7.9Hz,4H),7.56(s,1H),7.47(d,J＝8.8Hz,1H),7.26(s,1H),6.85(br.s.,1H),6.73(d,J＝8.8Hz,1H),5.23(s,2H),3.73-3.62(m,1H),3.56(br.s.,1H),3.45(d,J＝8.4Hz,1H),3.34(br.s.,2H),3.17(br.s.,1H),2.97(s,6H),2.92-2.82(m,1H),2.50(s,3H),2.35(br.s.,1H),1.96-1.83(m,1H)。ESI[M+H]＝463.2

4- (3-methyl-7- (2, 6-diazaspiro [3.4] oct-2-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 203. Using general procedure A4- (7-bromo-3-methyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo- [1,2-a ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, Synthesized using tert-butyl 2, 6-diazaspiro [3.4] octane-6-carboxylate instead of piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.80(s,1H),7.74(q, J8.4 Hz,4H),7.59(s,1H),7.50(d, J8.8 Hz,1H),7.29(s,1H),6.79(d, J2.5 Hz,1H),6.66(dd, J2.4, 8.7Hz,1H),5.25(d, J2.8 Hz,2H),4.10-3.97(m,4H),3.56(s,2H),3.42(t, J7.3 Hz,2H),2.52(s,3H),2.38(t, J7.3 Hz, 2H). ESI [ M + H ] ═ 447.2

4- (7- (pyrrolo [3,4-c ] pyrrol-2 (1H) -yl) -3-methyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 204 using general procedure A with 4- (7-bromo-3-methyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo- [1,2-a ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, Synthesized using tert-butyl piperazolo [3,4-c ] pyrrole-2 (1H) -carboxylate instead of piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.76(s,1H),7.72(q, J8.1 Hz,4H),7.54(s,1H),7.49(d, J8.8 Hz,1H),7.25(s,1H),6.98(br.s.,1H),6.86(d, J8.8 Hz,1H),5.24(s,2H),3.64(d, J4.9 Hz,2H),3.52(br.s, 4H),3.29-3.21(m,4H),2.50(s, 3H). ESI [ M + H ] ═ 447.2

(R) -4- (7- (3- (dimethylamino) pyrrolidin-1-yl) -2-methyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile 218. Using general procedure A4- (7-bromo-2-methyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, (R) -N, N-dimethylpyrrolidin-3-amine was used instead of piperazine-1-carboxylic acid tert-butyl ester for synthesis. 1H NMR (400MHz, methanol-d 4) δ 7.81-7.68(m,6H),7.57(d, J8.8 Hz,1H),7.29(d, J1.8 Hz,1H),6.92(d, J2.4 Hz,1H),6.85(dd, J2.5, 8.9Hz,1H),5.32(s,2H),4.10(quin, J7.2 Hz,1H),3.84(dd, J7.6, 10.7Hz,1H),3.74-3.60(m,2H),3.51-3.41(m,1H),3.00(s,6H),2.68-2.57(m,1H),2.49(s,3H),2.40-2.27(m, 1H). ESI [ M + H ] ═ 449.2

4- (2, 3-dimethyl-7- (3- ((methylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile, 220. Using general procedure A4- (7-bromo-2, 3-dimethyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] - [1,4] diazepine-12-yl) benzonitrile, with tert-butyl methyl (pyrrolidin-3-ylmethyl) carbamate being used instead of tert-butyl piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.75-7.67(m,5H),7.41(d, J8.8 Hz,1H),7.21(d, J1.3 Hz,1H),6.81(d, J2.6 Hz,1H),6.71(dd, J2.4, 9.0Hz,1H),5.20(s,2H),3.66-3.50(m,2H),3.48-3.37(m,1H),3.18-3.13(m,3H),2.75(s,3H),2.74-2.67(m,1H),2.41(d, J7.1 Hz,6H),2.32(dd, J5.1, 11.2, 1H),1.88(dd, 8, 12H), 1H). ESI [ M + H ] ═ 463.2

4- (2, 3-dimethyl-7- (2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 222. Using general procedure A, 4- (7-bromo-2, 3-dimethyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, Synthesized using tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate instead of piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.76-7.66(m,5H),7.41(d, J8.8 Hz,1H),7.21(d, J1.8 Hz,1H),6.83(d, J2.2 Hz,1H),6.71(dd, J2.6, 8.8Hz,1H),5.26-5.15(m,2H),4.20-4.03(m,4H),3.66-3.60(m,2H),3.46(t, J7.1 Hz,2H),2.45-2.35(m, 8H). ESI [ M + H ] ═ 461.2

4- (7- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -2, 3-dimethyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile 223 utilizing general procedure A using 4- (7-bromo-2, 3-dimethyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile with (R) -N, N-dimethylpyrrolidin-3-amine instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.79-7.65(m,5H),7.46(d, J8.8 Hz,1H),7.23(s,1H),6.94(br.s, 1H),6.81(d, J8.4 Hz,1H),5.30-5.17(m,2H),4.09(t, J6.8 Hz,1H),3.87-3.77(m,1H),3.74-3.58(m,2H),3.46(d, J6 Hz,1H),2.98(s,6H),2.60(br.s, 1H),2.42(d, J6.2, 6H),2.34(dd, 7.9, 13.13H, 1H). ESI [ M + H ] ═ 463.2

4- (3-methyl-7- (3- ((methylamino) methyl) azetidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile 225 using general procedure A with 4- (7-bromo-3-methyl-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile by using tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate in place of tert-butyl piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.74-7.62(m,5H),7.44(d, J8.8 Hz,1H),7.25(d, J17.6 Hz,1H),6.72(br.s.,1H),6.59(d, J8.4 Hz,1H),5.16(br.s.,2H),4.15(d, J3.1 Hz,2H),3.78(d, J4.9 Hz,2H),3.37(d, J7.1 Hz,2H),3.12(d, J5.7 Hz,1H),2.77-2.64(m, 6H). ESI [ M + H ] ═ 436.2

4- (3-methyl-7- (3- ((methylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile 226 use general procedure A with 4- (7-bromo-3-methyl-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, with tert-butyl methyl (pyrrolidin-3-ylmethyl) carbamate being used instead of tert-butyl piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.72-7.68(m,2H),7.64(d, J7.5 Hz,3H),7.41(d, J8.8 Hz,1H),7.19(br.s.,1H),6.81(d, J2.6 Hz,1H),6.68(dd, J2.4, 9.0Hz,1H),5.12(s,2H),3.64-3.48(m,2H),3.41(d, J7.5 Hz,1H),3.21-3.10(m,3H),2.77-2.70(m,4H),2.67(s,3H),2.31(dd, J4.4, 11.5, 1H), 1.93-1H (m, 82H). ESI [ M + H ] ═ 450.2

4- (3-methyl-7- (2-methyl-2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile 227, using general procedure C to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile with 4- (7-bromo-3-methyl-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, using tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate instead of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate. 1H NMR (400MHz, methanol-d 4) δ 7.74-7.62(m,5H),7.43(d, J8.8 Hz,1H),7.20(s,1H),6.83(br.s.,1H),6.70(d, J6.2 Hz,1H),5.14(s,2H),4.40-4.27(m,2H),4.19-4.09(m,2H),3.70-3.59(m,2H),3.51-3.41(m,2H),2.99(d, J4.4 Hz,3H),2.68(s,3H),2.44-2.34(m, 2H). ESI [ M + H ] ═ 462.2

4- (7- ((S) -3- ((dimethylamino) methyl) pyrrolidin-1-yl) -3-methyl-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile 228. Using general procedure C substituting 4- (7-bromo-3-methyl-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile for 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile by replacing tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate with tert-butyl (R) - (pyrrolidin-3-ylmethyl) carbamate. 1H NMR (400MHz, methanol-d 4) δ 7.74-7.61(m,5H),7.41(d, J8.8 Hz,1H),7.17(s,1H),6.83(d, J2.2 Hz,1H),6.70(dd, J2.6, 8.8Hz,1H),5.12(s,2H),3.70-3.61(m,1H),3.54(br.s.,1H),3.49-3.39(m,1H),3.33(br.s.,2H),3.20-3.12(m,1H),2.97(s,6H),2.91-2.80(m,1H),2.66(s,3H),2.34(d, J4.0, 1H),1.94 (m, 83H), 1H). ESI [ M + H ] ═ 464.2

4- (7- ((R) -3- ((dimethylamino) methyl) pyrrolidin-1-yl) -3-methyl-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile 229. Using general procedure C replacing 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile with 4- (7-bromo-3-methyl-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile by replacing tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate with tert-butyl (S) - (pyrrolidin-3-ylmethyl) carbamate. 1H NMR (400MHz, methanol-d 4) δ 7.73-7.65(m,5H),7.44(d, J8.8 Hz,1H),7.26(br.s, 1H),6.84(d, J2.2 Hz,1H),6.71(dd, J2.2, 8.8Hz,1H),5.17(d, J3.5 Hz,2H),3.71-3.62(m,1H),3.54(d, J4.4 Hz,1H),3.48-3.39(m,1H),3.20-3.11(m,1H),3.01-2.92(m,8H),2.91-2.81(m,1H),2.72(br.s, 3H), 2.40-1H, 1H), 1.83-1H, 3.72 (br.s, 3H). ESI [ M + H ] ═ 464.2

4- (7- (trans-pyrrolo [3,2-b ] pyrrol-1 (2H) -yl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile 232 using general procedure A instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile using general procedure A, trans-pyrrolo [3,2-b ] pyrrole-1 (2H) -carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.83(d, J8.8 Hz,1H),7.78-7.64(m,5H),7.37(d, J1.8 Hz,1H),6.97-6.88(m,2H),5.28(s,2H),4.28(d, J7.5 Hz,1H),4.09-3.96(m,2H),3.84(d, J9.7 Hz,2H),3.75-3.65(m,1H),2.76(d, J5.3 Hz,1H),2.37-2.29(m,1H),2.17(d, J11.0 Hz,1H),2.08-2.00(m, 1H). ESI [ M + H ] ═ 435.1

4- (7- (3- (dimethylamino) azetidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepine-12-yl) benzonitrile 235. this was synthesized using general procedure A using 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and N, N-dimethylazetidin-3-amine in place of t-butyl piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.85(d, J8.8 Hz,1H),7.78-7.73(m,2H),7.73-7.66(m,3H),7.38(d, J1.8 Hz,1H),6.81(d, J2.2 Hz,1H),6.76(dd, J2.4, 8.8Hz,1H),5.27(s,2H),4.40-4.24(m,3H),4.16(dd, J4.0, 9.0Hz,2H),2.98(s, 6H). ESI [ M + H ] ═ 423.1

4- (7- (3- ((methylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile 239 use general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1, 1-c ] [1,4] diazepin-12-yl) benzonitrile with 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile and to replace piperazine-1-carboxylic acid tert-butyl ester with methyl (pyrrolidin-3-ylmethyl) carbamate tert-butyl ester And (3) synthesizing the ester. 1H NMR (400MHz, methanol-d 4) δ 7.75(s,3H),7.70(d, J4.9 Hz,3H),7.36(s,1H),6.84-6.74(m,2H),5.24(s,2H),3.64(br.s.,1H),3.60-3.51(m,1H),3.46(d, J8.4 Hz,1H),3.24-3.14(m,3H),2.78(s,3H),2.75-2.65(m,1H),2.35(d, J7.5 Hz,1H),1.91(dd, J8.4, 12.3Hz, 1H). ESI [ M + H ] ═ 437.2

4- (7- (2-methyl-2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-C ] [1,4] diazepin-12-yl) benzonitrile 240 using general procedure C using 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-C ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile, using 2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.81-7.72(m,3H),7.71-7.65(m,3H),7.35(d, J ═ 1.3Hz,1H),6.83-6.74(m,2H),5.24(s,2H),4.31(br.s.,1H),4.18(br.s.,1H),3.77-3.60(m,4H),3.48(br.s.,2H),3.00(s,3H),2.41(t, J ═ 6.6Hz, 2H). ESI [ M + H ] ═ 449.2

(S) -4- (7- (3- ((dimethylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-C ] [1,4] diazepin-12-yl) benzonitrile, 241. Using general procedure C4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-C ] [1,4] diazepin-12-yl) benzonitrile is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile, and (R) - (pyrrolidine-3-ylmethyl) carbamic acid tert-butyl ester is used in place of (nitrogen) Heterocyclic but-3-ylmethyl) (methyl) carbamic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.83-7.71(m,3H),7.71-7.64(m,3H),7.35(d, J ═ 0.9Hz,1H),6.83-6.73(m,2H),5.23(s,2H),3.68(t, J ═ 8.4Hz,1H),3.56(d, J ═ 6.2Hz,1H),3.46(d, J ═ 8.4Hz,1H),3.34(d, J ═ 7.1Hz,2H),3.18(t, J ═ 8.6Hz,1H),2.98(s,6H),2.88(br.s.,1H),2.36(d, J ═ 5.7Hz,1H),1.90 (ddd, 8, 11H), 1H). ESI [ M + H ] ═ 451.2

4- (7- (2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile 244. Using general procedure A4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] - [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and 2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-substituted for piperazine-1-methyl [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile Tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.86-7.60(m,6H),7.37(br.s.,1H),6.84-6.76(m,2H),5.26(s,2H),4.23-4.15(m,2H),4.14-4.06(m,2H),3.66(br.s.,2H),3.49(d, J7.1 Hz,2H),2.49-2.33(m, 2H). ESI [ M + H ] ═ 435.2

4- (7- (2, 7-diazaspiro [3.5] non-2-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile 245 using general procedure A instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and 2, 7-diazaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester using 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and general procedure A And (3) synthesizing the ester. 1H NMR (400MHz, methanol-d 4) δ 7.80-7.72(m,3H),7.71-7.64(m,3H),7.37-7.33(m,1H),6.71-6.62(m,2H),5.23(s,2H),3.81(s,4H),3.25-3.10(m,4H),2.12-2.05(m, 4H). ESI [ M + H ] ═ 449.2

4- (7- (trans-pyrrolo [3,2-b ] pyrrol-1 (2H) -yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile 249 use of general procedure A with 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, and, Trans-pyrrolo [3,2-b ] pyrrole-1 (2H) -carboxylic acid tert-butyl ester was used instead of piperazine-1-carboxylic acid tert-butyl ester for synthesis. 1H NMR (400MHz, methanol-d 4) δ 8.16(s,1H),7.75-7.70(m,3H),7.68-7.63(m,2H),7.60(d, J ═ 1.5Hz,1H),7.20(d, J ═ 1.3Hz,1H),6.93-6.82(m,2H),5.21(s,2H),4.33-4.21(m,1H),4.13-3.93(m,2H),3.87-3.75(m,2H),3.66(dt, J ═ 5.5,11.0Hz,1H),2.79-2.67(m,1H),2.38-2.26(m,1H),2.22-1.95(m, 2H). ESI [ M + H ] ═ 434.2

4- (7- (3- ((methylamino) methyl) azetidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepine-12-yl) benzonitrile, 250 using general procedure A using 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, Synthesized with tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate instead of piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 8.14(s,1H),7.76-7.55(m,6H),7.19(s,1H),6.69-6.53(m,2H),5.21-5.11(m,2H),4.12(t, J ═ 7.7Hz,2H),3.75(dd, J ═ 5.3,7.5Hz,2H),3.36(d, J ═ 7.3Hz,2H),3.15-3.01(m,1H),2.79-2.66(m, 3H). ESI [ M + H ] ═ 422.2

4- (7- (2-methyl-2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepin-12-yl) benzonitrile 253 use general procedure C to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepin-12-yl) benzonitrile with 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile, Synthesized by substituting tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate for tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate. 1H NMR (400MHz, methanol-d 4) δ 8.16(s,1H),7.81-7.58(m,6H),7.20(s,1H),6.80-6.69(m,2H),5.19(s,2H),4.42-4.25(m,2H),4.22-4.06(m,2H),3.64(d, J ═ 19.8Hz,2H),3.52-3.41(m,2H),3.06-2.94(m,3H),2.47-2.33(m, 2H). ESI [ M + H ] ═ 448.2

(S) -4- (7- (3- ((dimethylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepine-12-yl) benzonitrile 254. Using general procedure C Using 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine-12-yl) benzonitrile, (R) - (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester was used instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester for synthesis. 1H NMR (400MHz, methanol-d 4) δ 8.20(br.s.,1H),7.78-7.57(m,6H),7.24(br.s.,1H),6.80-6.68(m,2H),5.18(s,2H),3.65(t, J ═ 8.4Hz,1H),3.59-3.51(m,1H),3.49-3.39(m,1H),3.34(s,2H),3.16(t, J ═ 8.6Hz,1H),2.98(s,6H),2.91-2.78(m,1H),2.41-2.28(m,1H),1.95-1.81(m, 1H). ESI [ M + H ] ═ 450.2

(R) -4- (7- (3- ((dimethylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepine-12-yl) benzonitrile 255 use general procedure C to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepine-12-yl) benzonitrile with 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine-12-yl) benzonitrile, (S) - (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester was used instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester for synthesis. 1H NMR (400MHz, methanol-d 4) δ 8.22(br.s.,1H),7.84-7.47(m,6H),7.24(br.s.,1H),6.83-6.55(m,2H),5.14(s,2H),3.69-3.59(m,1H),3.58-3.47(m,1H),3.46-3.36(m,2H),3.20-3.10(m,1H),3.09-3.02(m,1H),3.00-2.76(m,6H),2.73-2.61(m,1H),2.46-2.26(m,1H),1.96-1.78(m, 1H). ESI [ M + H ] ═ 450.2

4- (7- (2, 6-diazaspiro [3.4] oct-2-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile 258 using general procedure A with 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, Synthesized using tert-butyl 2, 6-diazaspiro [3.4] octane-6-carboxylate instead of piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 8.15(s,1H),7.75-7.62(m,5H),7.59(s,1H),7.19(s,1H),6.69-6.60(m,2H),5.17(s,2H),4.01-3.92(m,4H),3.51(s,2H),3.37(t, J7.5 Hz,2H),2.34(t, J7.3 Hz, 2H). ESI [ M + H ] ═ 434.1

(R) -4- (7- (3- (dimethylamino) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepine-12-yl) benzonitrile 259 use general procedure C to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepine-12-yl) benzonitrile with 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine-12-yl) benzonitrile, (R) -pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester was used instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester for the synthesis. 1H NMR (400MHz, methanol-d 4) δ 8.18(br.s.,1H),7.79-7.56(m,6H),7.22(br.s.,1H),6.88-6.79(m,2H),5.21(s,2H),4.09(td, J ═ 7.2,13.9Hz,1H),3.80(dd, J ═ 7.5,10.6Hz,1H),3.74-3.57(m,2H),3.50-3.39(m,1H),3.06-2.94(m,6H),2.67-2.55(m,1H),2.38-2.23(m, 1H). ESI [ M + H ] ═ 436.2

(S) -4- (7- (3- (dimethylamino) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepine-12-yl) benzonitrile 260 using general procedure C using 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine-12-yl) benzonitrile, (S) -pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester was used instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester for synthesis. 1H NMR (400MHz, methanol-d 4) δ 8.17(s,1H),7.75-7.63(m,5H),7.60(s,1H),7.20(br.s.,1H),6.92-6.77(m,2H),5.20(s,2H),4.07(quin, J ═ 7.1Hz,1H),3.79(dd, J ═ 7.4,10.7Hz,1H),3.73-3.55(m,2H),3.49-3.39(m,1H),3.04-2.89(m,6H),2.65-2.52(m,1H),2.37-2.21(m, 1H). ESI [ M + H ] ═ 436.2

(S) -4- (7- (3- ((methylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepine-12-yl) benzonitrile 262 use general procedure I to replace 4- (7-bromo-11-chloro-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepine-12-yl) benzonitrile with 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile. 1HNMR (400MHz, methanol-d 4) δ is 8.13(s,1H),7.76-7.62(m,5H),7.60(d, J ═ 1.3Hz,1H),7.18(d, J ═ 1.8Hz,1H),6.74-6.61(m,2H),5.14(s,2H),3.53(t, J ═ 8.4Hz,1H),3.44(dd, J ═ 3.3,8.6Hz,1H),3.40-3.33(m,1H),3.10-3.01(m,1H),2.69(d, J ═ 7.1Hz,2H),2.60-2.50(m,1H),2.44(s,3H),2.29-2.17(m,1H),1.78(dd, 8, 1H), 1H, 12.12 (dd, 1H). ESI [ M + H ] ═ 436.1

(R) -4- (7- (3- ((methylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepine-12-yl) benzonitrile 263. Using general procedure I4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepine-12-yl) benzonitrile is used in place of 4- (7-bromo-11-chloro-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, by substituting tert-butyl (S) - (pyrrolidin-3-ylmethyl) carbamate for tert-butyl (R) - (pyrrolidin-3-ylmethyl) carbamate. 1H NMR (400MHz, methanol-d 4) δ 8.13(s,1H),7.76-7.57(m,6H),7.18(d, J ═ 1.8Hz,1H),6.73-6.64(m,2H),5.14(s,2H),3.53(s,1H),3.45(d, J ═ 3.1Hz,1H),3.35(d, J ═ 8.4Hz,1H),3.06(t, J ═ 8.6Hz,1H),2.70(d, J ═ 7.1Hz,2H),2.61-2.50(m,1H),2.45(s,3H),2.23(dd, J ═ 3.7,11.7Hz,1H),1.78(dd, J ═ 8.4, 12.12, 1H). ESI [ M + H ] ═ 436.2

4- (3- (hydroxymethyl) -7- (3- ((methylamino) methyl) pyrrolidin-1-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile 272. Using general procedure A4- (7-bromo-3- (hydroxymethyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and methyl (pyrrolidin-3-yl) benzonitrile is used Methyl) carbamic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.78(br.s.,1H),7.74(d, J8.8 Hz,4H),7.71-7.67(m,2H),7.28(s,1H),6.84(br.s.,1H),6.72(d, J ═ 8.8Hz,1H),5.28-5.17(m,2H),4.80(br.s.,1H),4.65(d, J ═ 14.1Hz,1H),3.62(br.s.,1H),3.55(br.s.,1H),3.44(q, J ═ 7.9Hz,1H),3.25-3.09(m,3H),2.83-2.68(m,4H),2.34(d, 1H), 6.85H, 1H), 1H (d, 1H), 1H, 85H). ESI [ M + H ] ═ 465.2

4- (3- (hydroxymethyl) -7- (2, 6-diazaspiro [3.5] non-2-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 273. Using general procedure A4- (7-bromo-3- (hydroxymethyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, Synthesized using tert-butyl 2, 6-diazaspiro [3.5] nonane-6-carboxylate instead of piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.77(d, J7.9 Hz,3H),7.75-7.71(m,2H),7.70-7.66(m,2H),7.28(d, J0.9 Hz,1H),6.72(d, J2.6 Hz,1H),6.60(dd, J2.2, 8.8Hz,1H),5.26-5.17(m,2H),4.79(s,1H),4.62(d, J14.1 Hz,1H),3.86(dd, J3.1, 7.5Hz,2H),3.76(dd, J4.4, 7.5Hz,2H),3.39(s,2H), 3.13.13 (t, 3.5Hz, 7.5H), 7.85H, br, H, 1H, 3.7.7.5 Hz, 3.85H, 1H, 1H, 1H, 1H. ESI [ M + H ] ═ 477.2

(R) -4- (7- (3- (dimethylamino) pyrrolidin-1-yl) -9H-pyrido [3,2-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile 291 using general procedure A substituting 4- (7-bromo-9H-pyrido [3,2-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile for 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile instead of tert-butyl (R) -N, N-dimethylpyrrolidin-3-aminopiperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 9.06(s,1H),7.89(d, J8.8 Hz,1H),7.76-7.70(m,2H),7.68-7.66(m,3H),7.27(d, J1.3 Hz,1H),6.71(d, J9.0 Hz,1H),5.25(s,2H),4.13-4.03(m,2H),3.89-3.80(m,1H),3.79-3.70(m,1H),3.62-3.52(m,1H),3.01(s,6H),2.68-2.57(m,1H),2.38-2.26(m, 1H). ESI [ M + H ] ═ 437.2

(S) -4- (7- (3- (dimethylamino) pyrrolidin-1-yl) -9H-pyrido [3,2-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile 292 general procedure A was used to replace 4- (7-bromo-9H-pyrrolo [3,2-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile with 4- (7-bromo-9H-pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile with (S) -N, N-dimethylpyrrolidin-3-amine instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.07(s,1H),7.91(d, J9.0 Hz,1H),7.78-7.72(m,2H),7.71-7.65(m,3H),7.28(d, J1.5 Hz,1H),6.73(d, J8.8 Hz,1H),5.27(s,2H),4.16-4.01(m,2H),3.85(t, J8.0 Hz,1H),3.75-3.74(m,1H),3.63-3.53(m,1H),3.01(s,6H),2.66-2.62(m,1H),2.37-2.27(m, 1H). ESI [ M + H ] ═ 437.2

4- (7- (3- ((methylamino) methyl) azetidin-1-yl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile 295. Using general procedure A with 4- (7-bromo-9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, Synthesized with tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate instead of piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.96(s,1H),7.86(d, J9.3 Hz,1H),7.79(s,1H),7.76-7.73(m,2H),7.72-7.67(m,3H),7.30(s,1H),6.56(d, J8.8 Hz,1H),5.30(s,2H),4.29(t, J8.4 Hz,2H),3.91(dd, J5.3, 8.8Hz,2H),3.36(d, J7.5 Hz,2H),3.18-3.06(m,1H),2.79-2.70(m, 3H). ESI [ M + H ] ═ 422.2

4- (7- (3- ((methylamino) methyl) pyrrolidin-1-yl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile 296 use of general procedure A with 4- (7-bromo-9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile, Synthesized with tert-butyl methyl (pyrrolidin-3-ylmethyl) carbamate instead of piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.95(br.s.,1H),7.84(d, J8.8 Hz,1H),7.80-7.67(m,6H),7.31(br.s.,1H),6.66(d, J9.3 Hz,1H),5.29(s,2H),3.91-3.82(m,1H),3.73(br.s.,1H),3.60-3.50(m,1H),3.42-3.33(m,1H),3.17(dd, J ═ 2.9,7.3Hz,2H),2.77(s,3H),2.75-2.67(m,1H),2.33(dd, J ═ 4.6,11.2, 1H),1.97 (m, 82H). ESI [ M + H ] ═ 436.2

4- (7- (2-methyl-2, 6-diazaspiro [3.4] oct-6-yl) -9H-imidazo [2,1-C ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile, 297. use general procedure C using 4- (7-bromo-9H-imidazo [2,1-C ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile and 2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.73-7.60(m,5H),7.56(s,1H),7.52(d, J ═ 1.8Hz,1H),7.21(s,1H),7.03(d, J ═ 1.8Hz,1H),6.54(d, J ═ 8.8Hz,1H),5.10(s,2H),3.64(s,2H),3.51(t, J ═ 6.8Hz,2H),3.42-3.36(m,4H),2.44(s,3H),2.24-2.17(m, 2H). ESI [ M + H ] ═ 448.1

4- (7- ((3S,4S) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidin-1-yl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 298. Using general procedure A4- (7-bromo-9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile with (3S,4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.00(s,1H),7.87(d, J9.0 Hz,1H),7.82(d, J1.2 Hz,1H),7.79-7.73(m,3H),7.72-7.67(m,2H),7.34(s,1H),6.67(d, J9.0 Hz,1H),5.33(s,2H),4.56(br.s.,1H),3.90(br.s.,1H),3.81-3.65(m,2H),3.58(dd, J8.0, 13.1Hz,1H),3.44-3.32(m,2H),2.99(s,6H),2.86(d, J3.9, 1H). ESI [ M + H ] ═ 466.2

4- (7- ((3R,4R) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidin-1-yl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 299 use of general procedure A with 4- (7-bromo-9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile with (3R,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.01(br.s.,1H),7.90-7.80(m,2H),7.80-7.71(m,3H),7.71-7.65(m,2H),7.35(br.s, 1H),6.66(d, J ═ 9.0Hz,1H),5.38-5.25(m,2H),4.55(br.s, 1H),3.89(br.s, 1H),3.80-3.62(m,2H),3.57(dd, J ═ 7.9,13.0Hz,1H),3.44-3.30(m,2H),3.05-2.92(m,6H),2.89-2.75(m, 1H). ESI [ M + H ] ═ 466.1

4- (7- ((3R,4R) -3- (dimethylamino) -4-hydroxypyrrolidin-1-yl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile, 300. use of general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile by using (3R,4R) -4- (dimethylamino) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.03(br.s.,1H),7.92(d, J9.3 Hz,1H),7.83(s,1H),7.80-7.72(m,3H),7.71-7.66(m,2H),7.36(br.s.,1H),6.75(d, J9.3 Hz,1H),5.36(s,2H),4.72(q, J7.4 Hz,1H),4.19(dd, J8.2, 11.2Hz,1H),4.09(dd, J7.9, 10.6Hz,1H),3.85(q, J7.6 Hz,1H),3.72(dd, J9, 1H),3.5 (dd, J), 8.6Hz,1H), 3.5 (dd, 7.9, 1H),3.5 (dd, 8.6H, 8.05H), 8.6H, 1H). ESI [ M + H ] ═ 452.1

4- (7- ((3S,4S) -3- (dimethylamino) -4-hydroxypyrrolidin-1-yl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 301. use of general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile with 4- (7-bromo-9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile by using (3S,4S) -4- (dimethylamino) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.02(s,1H),7.92(d, J9.3 Hz,1H),7.83(s,1H),7.79-7.66(m,5H),7.35(s,1H),6.75(d, J9.3 Hz,1H),5.36(s,2H),4.72(d, J7.1 Hz,1H),4.23-4.14(m,1H),4.09(d, J3.1 Hz,1H),3.85(d, J7.5 Hz, ddh), 3.72 (J7.9, 11.5Hz,1H),3.39(dd, J7.1, 10.6Hz,1H),3.05(s, 6H). ESI [ M + H ] ═ 452.1

4- (7- ((3S,4R) -3- (dimethylamino) -4-hydroxypyrrolidin-1-yl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 302. Using general procedure A4- (7-bromo-9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile by using (3R,4S) -4- (dimethylamino) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.05(br.s.,1H),7.94(d, J9.0 Hz,1H),7.88-7.67(m,6H),7.37(s,1H),6.76(d, J8.8 Hz,1H),5.38(s,2H),4.69(br.s.,1H),4.23(br.s.,1H),3.94(br.s.,1H),3.88-3.73(m,2H),3.66(t, J9.9 Hz,1H),3.11-2.92(m, 6H). ESI [ M + H ] ═ 452.1

4- (7- ((3R,4S) -3- (dimethylamino) -4-hydroxypyrrolidin-1-yl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 303. use of general procedure A with 4- (7-bromo-9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile by using (3S,4R) -4- (dimethylamino) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.04(br.s.,1H),7.93(d, J8.8 Hz,1H),7.85(s,1H),7.82-7.66(m,5H),7.37(s,1H),6.76(d, J8 Hz,1H),5.37(s,2H),4.69(br.s, 1H),4.23(br.s, 1H),4.01-3.90(m,1H),3.85-3.71(m,2H),3.66(t, J9.9 Hz,1H),3.03(br.s, 6H). ESI [ M + H ] ═ 452.1

4- (7- ((3S,4R) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidin-1-yl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 306. Using general procedure A4- (7-bromo-9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile with (3R,4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.00(br.s.,1H),7.87(d, J9.0 Hz,1H),7.81(s,1H),7.78-7.66(m,5H),7.34(br.s.,1H),6.67(d, J9.0 Hz,1H),5.32(s,2H),4.29(q, J6.7 Hz,1H),4.04-3.89(m,2H),3.45-3.32(m,4H),3.05-2.95(m,6H),2.77-2.65(m, 1H). ESI [ M + H ] ═ 466.2

4- (7- ((3R,4S) -3- ((dimethylamino) methyl) -4-hydroxypyrrolidin-1-yl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 307. use of general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile with (3S,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.98(br.s.,1H),7.86(d, J9.0 Hz,1H),7.80(s,1H),7.77-7.67(m,5H),7.32(s,1H),6.66(d, J9.0 Hz,1H),5.31(s,2H),4.27(q, J6 Hz,1H),4.03-3.89(m,2H),3.45-3.33(m,4H),2.98(s,6H),2.74-2.63(m, 1H). ESI [ M + H ] ═ 466.2

(S) -4- (7- (3- ((4-hydroxypiperidin-1-yl) methyl) pyrrolidin-1-yl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 308 use general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile with (R) -1- (pyrrolidin-3-ylmethyl) piperidin-4-ol instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.04(s,1H),7.94-7.84(m,3H),7.81(s,1H),7.79-7.75(m,2H),7.74-7.68(m,1H),7.37(s,1H),6.68(d, J ═ 8.8Hz,1H),5.34(s,2H),4.12(br.s.,1H),3.95(br.s.,1H),3.85(t, J ═ 10.1Hz,1H),3.79-3.62(m,2H),3.60-3.43(m,3H),3.34(br.s.,2H),3.09(t, J ═ 12.6, 1H),2.96-2.79(m,1H), 2.01-2H, 1H, 71H, 1H, 2H, 2.7.7H, 1H, 2H. ESI [ M + H ] ═ 506.2

4- (7- (2, 6-diazaspiro [3.4] oct-6-yl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 310. Using general procedure A4- (7-bromo-9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, Synthesized using tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate instead of piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 8.04(d, J1.8 Hz,1H),7.89(d, J9.0 Hz,1H),7.87-7.79(m,2H),7.79-7.74(m,2H),7.73-7.68(m,2H),7.38(s,1H),6.69(d, J9.0 Hz,1H),5.35(s,2H),4.24-4.16(m,2H),4.13-4.05(m,2H),3.88-3.81(m,2H),3.63(t, J6.7 Hz,2H),2.40(t, J6.9 Hz, 2H). ESI [ M + H ] ═ 434.2

4- (7- (2, 6-diazaspiro [3.4] oct-2-yl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 311, using general procedure A using 4- (7-bromo-9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, Synthesized using tert-butyl 2, 6-diazaspiro [3.4] octane-6-carboxylate instead of piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 8.03(d, J2.2 Hz,1H),7.89(d, J8.8 Hz,1H),7.85-7.78(m,2H),7.77-7.73(m,2H),7.73-7.67(m,2H),7.35(d, J1.8 Hz,1H),6.60(d, J8.8 Hz,1H),5.34(s,2H),4.20-4.14(m,2H),4.14-4.10(m,2H),3.53(s,2H),3.38(t, J7.3 Hz,2H),2.35(t, J7.3 Hz, 2H). ESI [ M + H ] ═ 434.2

4- (7- (trans-pyrrolo [3,2-b ] pyrrol-1 (2H) -yl) -9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, 314. Using general procedure A4- (7-chloro-9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1, 4-diazepine-12-yl) benzonitrile using trans-pyrrolo [3,2-b ] pyrrole-1 (2H) -carboxylic acid tert-butyl ester in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.09(s,1H),8.43(s,1H),7.77-7.59(m,5H),7.25(s,1H),6.81(s,1H),5.24(s,2H),4.27-4.12(m,1H),4.07-3.88(m,3H),3.85-3.66(m,2H),2.79(d, J6.6 Hz,1H),2.42-2.26(m,1H),2.23-2.10(m,1H),2.02(quin, J10.5 Hz, 1H). ESI [ M + H ] ═ 435.1

4- (7- (3- ((methylamino) methyl) azetidin-1-yl) -9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile 315 using general procedure A with 4- (7-chloro-9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile by using tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate in place of tert-butyl piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 9.16(br.s.,1H),8.36(s,1H),7.73-7.55(m,5H),7.25(s,1H),6.74-6.63(m,1H),5.30-5.19(m,2H),4.37-4.27(m,2H),3.95(dd, J ═ 5.3,8.8Hz,2H),3.37(d, J ═ 7.5Hz,2H),3.24-3.09(m,1H),2.79-2.71(m, 3H). ESI [ M + H ] ═ 423.1

(S) -4- (7- (3- ((dimethylamino) methyl) pyrrolidin-1-yl) -9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile 317. Using general procedure C4- (7-chloro-9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine-12-yl) benzonitrile and replacement of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate with tert-butyl (R) - (pyrrolidin-3-ylmethyl) carbamate. 1H NMR (400MHz, methanol-d 4) δ 9.09(s,1H),8.35(br.s.,1H),7.78-7.56(m,5H),7.30(s,1H),6.78(s,1H),5.21(br.s.,2H),3.88(dd, J ═ 7.7,10.1Hz,1H),3.70(t, J ═ 7.8Hz,1H),3.60-3.45(m,1H),3.32(d, J ═ 7.1Hz,2H),3.25(d, J ═ 10.6Hz,1H),3.02-2.90(m,6H),2.88-2.75(m,1H),2.34(td, J ═ 2.8,6.0, 1H),1.79 (m, 79H). ESI [ M + H ] ═ 451.2

4- (7- (2, 6-diazaspiro [3.4] oct-6-yl) -9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile 318 use of general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile with 4- (7-chloro-9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, Synthesized using tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate instead of piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 9.19(br.s.,1H),8.38(s,1H),7.77-7.60(m,5H),7.27(br.s.,1H),6.78(s,1H),5.24(s,2H),4.24-4.01(m,4H),3.82(s,2H),3.60(t, J6.9 Hz,2H),2.47-2.32(m, 2H). ESI [ M + H ] ═ 435.1

(R) -4- (7- (3- (dimethylamino) pyrrolidin-1-yl) -9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile 319 using general procedure A using 4- (7-chloro-9H-pyrido [3,4-e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile with (R) -N, N-dimethylpyrrolidin-3-amine instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.16(br.s.,1H),8.42(s,1H),7.80-7.56(m,5H),7.27(br.s.,1H),6.87-6.74(m,1H),5.23(s,2H),4.05(d, J ═ 7.3Hz,2H),3.87-3.67(m,2H),3.63-3.50(m,1H),3.02-2.89(m,6H),2.62(d, J ═ 12.6Hz,1H),2.38-2.24(m, 1H). ESI [ M + H ] ═ 437.1

4- (7- (2-methyl-2, 6-diazaspiro [3.4] oct-6-yl) -9H-imidazo [2,1-C ] pyrido [3,4-e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile 322 using general procedure C instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile and 2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.43(s,1H),8.09(d, J ═ 1.3Hz,1H),7.84-7.66(m,6H),7.35(s,1H),6.77(br.s.,1H),5.36(s,2H),4.44-4.26(m,2H),4.21-4.07(m,2H),3.92-3.76(m,2H),3.67-3.55(m,2H),2.98(br.s.,3H),2.42(br.s., 2H). ESI [ M + H ] ═ 448.2

1- (1- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-7-yl) azetidin-3-yl) -N-methylmethylamine, 330, use of general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzazepine, Synthesized with tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate instead of piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 9.14(br.s.,1H),7.58-7.43(m,4H),7.15(br.s.,1H),7.04(t, J ═ 8.8Hz,2H),6.67(d, J ═ 2.6Hz,1H),6.57(dd, J ═ 2.4,8.6Hz,1H),5.14(s,2H),4.12(t, J ═ 7.7, 2H),3.75(dd, J ═ 5.3,7.9Hz,2H),3.35(d, J ═ 7.5Hz,2H),3.15-3.04(m,1H),2.74(s, 3H). ESI [ M + H ] ═ 415.1

12- (4-fluorophenyl) -7- (2-methyl-2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine, 332 using general procedure C to replace the 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine and 2 with a 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine-12-yl) benzazepine, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.14(br.s.,1H),7.57-7.46(m,4H),7.16(br.s.,1H),7.05(t, J ═ 8.8Hz,2H),6.80(d, J ═ 4.9Hz,1H),6.74-6.67(m,1H),5.17(s,2H),4.39-4.27(m,2H),4.18-4.08(m,2H),3.68-3.58(m,2H),3.44(td, J ═ 6.8,13.3Hz,2H),2.98(d, J ═ 5.3Hz,3H),2.43-2.34(m, 2H). ESI [ M + H ] ═ 441.2

(S) -1- (1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine, 333 using general procedure C replacing 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine-12-yl) benzonitrile and replacement of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate with tert-butyl (R) - (pyrrolidin-3-ylmethyl) carbamate. 1H NMR (400MHz, methanol-d 4) δ 9.06(br.s.,1H),7.55(dd, J5.3, 8.8Hz,2H),7.48(d, J8.8 Hz,1H),7.43(s,1H),7.13(br.s.,1H),7.06(t, J8 Hz,2H),6.79(s,1H),6.70(d, J8.8 Hz,1H),5.14(s,2H),3.64(d, J7.9 Hz,1H),3.53(d, J5.7 Hz,1H),3.43(d, J8.4 Hz,1H),3.34(s,2H), 3.19-3.11H), 3.19H, 3.11H, 3H, 3.6H, 1H, 3.6 (d, J8.4 Hz,1H),3.34(s,2H), 3.19H, 3.11H, 3.6H, 12H, 1H, 3.6H, 12J (dd, 12H, 1. ESI [ M + H ] ═ 443.1

(R) - (1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methylamine, 334 use general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and with tert-butyl (S) - (pyrrolidin-3-ylmethyl) carbamate The alkyl ester was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.06(s,1H),7.54(dd, J53, 8.4Hz,2H),7.50-7.39(m,2H),7.12(d, J1.3 Hz,1H),7.05(t, J8.8 Hz,2H),6.77(d, J2.6 Hz,1H),6.68(dd, J2.6, 8.8Hz,1H),5.13(s,2H),3.63-3.46(m,2H),3.40(d, J8.8 Hz,1H),3.20-2.99(m,3H),2.74-2.60(m,1H),2.31(dd, J4.4, 11.5, 1H), 1.95-1H). ESI [ M + H ] ═ 415.1

(R) -1- (1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine, 335. use general procedure C to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine-12-yl) benzonitrile and replacement of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate with tert-butyl (S) - (pyrrolidin-3-ylmethyl) carbamate. 1H NMR (400MHz, methanol-d 4) δ 9.15(br.s.,1H),7.59-7.48(m,2H),7.41(s,2H),7.14(br.s.,1H),7.04(t, J ═ 8.6Hz,2H),6.75(s,1H),6.66(d, J ═ 7.1Hz,1H),5.09(s,2H),3.66-3.57(m,1H),3.50(d, J ═ 2.6Hz,1H),3.39(d, J ═ 8.4Hz,1H),3.31(s,2H),3.12(t, J ═ 8.6Hz,1H),2.96(s,6H),2.89-2.76(m,1H),2.39 (m,2H), 2.86(m,1H), 8.26, 8H), 3.26 (ddh, 8H). ESI [ M + H ] ═ 443.1

12- (4-fluorophenyl) -7- (2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine, 336. Using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and with 2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 9.08(s,1H),7.58-7.41(m,4H),7.14(s,1H),7.06(t, J ═ 8.7Hz,2H),6.80(d, J ═ 2.2Hz,1H),6.70(dd, J ═ 2.4,8.8Hz,1H),5.21-5.12(m,2H),4.22-4.14(m,2H),4.13-4.04(m,2H),3.62(s,2H),3.45(t, J ═ 6.8Hz,2H),2.43-2.35(m, 2H). ESI [ M + H ] ═ 427.2

1- (1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) azetidin-3-yl) -N-methylmethylamine, 341 using general procedure A substituting 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine for 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate for piperazine Tert-butyl-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.93(d, J1.8 Hz,1H),7.66(d, J1.8 Hz,1H),7.59-7.47(m,4H),7.14(d, J1.8 Hz,1H),7.07(t, J8.8 Hz,2H),6.69(d, J2.2 Hz,1H),6.62(dd, J2.6, 8.8Hz,1H),5.26-5.20(m,2H),4.14(t, J7.7 Hz,2H),3.77(dd, J5.1, 7.7Hz,2H),3.36(d, J7.5, 2H),3.15-3.04(m, 3.74H), 3.36(d, J, 7.5Hz, 2H). ESI [ M + H ] ═ 414.2

1- (1- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmethylamine, 342. Using general procedure A instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine and instead of piperazine-1-butyl methyl (pyrrolidin-3-ylmethyl) carbamate, 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzazepine Tert-butyl formate. 1H NMR (400MHz, methanol-d 4) δ 7.99(br.s.,1H),7.72(br.s.,1H),7.60-7.51(m,4H),7.19(br.s.,1H),7.09(t, J ═ 8.7Hz,2H),6.81(d, J ═ 2.4Hz,1H),6.75(dd, J ═ 2.5,8.9Hz,1H),5.27(s,2H),3.67-3.60(m,1H),3.55(dt, J ═ 3.6,8.9Hz,1H),3.48-3.41(m,1H),3.22-3.12(m,3H),2.82-2.69(m,4H),2.40-2.29(m,1H), 1H, 8.90 (m,1H), 3.12 (q, 3H). ESI [ M + H ] ═ 428.1

12- (4-fluorophenyl) -7- (2-methyl-2, 6-diazaspiro [3.4]]Oct-6-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine, 344 using general procedure C with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile, use of 2, 6-diazaspiro [3.4]Octane-2-carboxylic acid tert-butyl ester was synthesized instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝7.55-7.46(m,3H),7.32(d,J＝8.8Hz,1H),7.26(s,1H),7.16(s,1H),7.01(t,J＝8.6Hz,2H),6.87(d,J＝1.8Hz,1H),6.69(br.s.,1H),6.62(d,J＝8.8Hz,1H),5.01(br.s.,2H),4.61(br.s.,1H),3.45(s,2H),3.35(br.s.,5H),2.40(s,3H),2.21(t,J＝6.6Hz,2H)。ESI[M+H]＝440.1

(S) -1- (1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine, 345 using general procedure C with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]The diazepine-12-yl) benzonitrile and the replacement of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate with tert-butyl (R) - (pyrrolidin-3-ylmethyl) carbamate.¹H NMR (400MHz, methanol-d)₄)δ＝8.00(br.s.,1H),7.74(br.s.,1H),7.63-7.48(m,4H),7.20(br.s.,1H),7.09(t,J＝8.8Hz,2H),6.85-6.72(m,2H),5.28(s,2H),3.73-3.63(m,1H),3.56(dt,J＝3.1,8.8Hz,1H),3.49-3.39(m,1H),3.34(s,2H),3.22-3.12(m,1H),2.97(s,6H),2.92-2.80(m,1H),2.35(ddd,J＝3.3,6.1,9.2Hz,1H),1.89(qd,J＝8.7,12.3Hz,1H)。ESI[M+H]＝442.2

(R) -1- (1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine, 346 using general procedure C with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]The diazepine-12-yl) benzonitrile and replacement of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate with tert-butyl (S) - (pyrrolidin-3-ylmethyl) carbamate.¹H NMR (400MHz, methanol-d)₄)δ＝8.00(br.s.,1H),7.74(br.s.,1H),7.62-7.49(m,4H),7.19(br.s.,1H),7.09(t,J＝8.6Hz,2H),6.82(d,J＝2.2Hz,1H),6.76(dd,J＝2.6,8.8Hz,1H),5.28(s,2H),3.67(t,J＝8.6Hz,1H),3.56(dt,J＝3.1,8.8Hz,1H),3.49-3.39(m,1H),3.33(d,J＝7.5Hz,2H),3.21-3.12(m,1H),2.97(s,6H),2.92-2.80(m,1H),2.36(dd,J＝3.3,12.1Hz,1H),1.95-1.81(m,1H)。ESI[M+H]＝442.2

(S) -1- (1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) -N-methylmethanamine, 347 using general procedure I with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-11-chloro-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile.¹H NMR (400MHz, methanol-d)₄)δ＝7.98(d,J＝2.2Hz,1H),7.72(d,J＝1.8Hz,1H),7.60-7.48(m,4H),7.18(d,J＝1.8Hz,1H),7.07(t,J＝8.8Hz,2H),6.79(d,J＝2.6Hz,1H),6.73(dd,J＝2.4,9.0Hz,1H),5.25(s,2H),3.61(dd,J＝7.5,9.7Hz,1H),3.53(dt,J＝3.7,8.9Hz,1H),3.47-3.38(m,1H),3.21-3.07(m,3H),2.82-2.65(m,4H),2.39-2.24(m,1H),1.88(qd,J＝8.4,12.3Hz,1H)。ESI[M+H]＝428.1

(R) -1- (1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmethylamine 348 use general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzazepine and tert-butyl (S) - (pyrrolidin-3-ylmethyl) carbamate Esters were synthesized instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.78(s,1H),7.59-7.51(m,2H),7.46(d, J ═ 10.6Hz,3H),7.12-7.00(m,3H),6.78(br.s.,1H),6.72(d, J ═ 8.8Hz,1H),5.16(s,2H),3.61(br.s.,1H),3.53(br.s.,1H),3.42(d, J ═ 8.4Hz,1H),3.17(br.s.,3H),2.84-2.66(m,4H),2.32(br.s.,1H),1.97-1.81(m, 1H). ESI [ M + H ] ═ 428.1

(3S,4S) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-ol, 349 using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and using (3S,4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d 4) δ 7.98(s,1H),7.71(s,1H),7.62-7.50(m,4H),7.18(s,1H),7.08(t, J ═ 8.8Hz,2H),6.80(d, J ═ 2.2Hz,1H),6.74(dd, J ═ 2.4,9.0Hz,1H),5.26(s,2H),4.58(br.s.,1H),3.73-3.63(m,2H),3.58(dd, J ═ 7.9,13.2Hz,1H),3.45(d, J ═ 11.0Hz,1H),3.33(d, J ═ 6.2, 1H),3.29-3.24(m,1H), 2H (s, 6.86H), 7.5 (d, 6.5H). ESI [ M + H ]]＝458.1

(3R,4R) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol 350 use general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzazepine and use of (3R,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.99(s,1H),7.72(s,1H),7.63-7.50(m,4H),7.19(s,1H),7.08(t, J ═ 8.8Hz,2H),6.80(d, J ═ 2.2Hz,1H),6.74(dd, J ═ 2.2,8.8Hz,1H),5.27(s,2H),4.58(br.s, 1H),3.72-3.63(m,2H),3.58(dd, J ═ 7.9,13.2Hz,1H),3.45(d, J ═ 10.6Hz,1H),3.33(d, J ═ 5.7, 1H),3.29-3.24(m,1H), 2H (98, 6H), 6H, 1H),3.33(d, J ═ 5.7, 1H). ESI [ M + H ] ═ 458.1

(3R,4R) -4- (dimethylamino) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol 351. Using general procedure A using 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and using (3R,4R) -4- (dimethylamino) pyrrolidin-3-ol instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.98(s,1H),7.70(s,1H),7.61-7.52(m,4H),7.18(s,1H),7.09(t, J ═ 8.8Hz,2H),6.91(d, J ═ 2.3Hz,1H),6.84(dd, J ═ 2.5,8.8Hz,1H),5.28(s,2H),4.72(q, J ═ 7.0Hz,1H),4.00-3.80(m,3H),3.60(dd, J ═ 7.2,10.2Hz,1H),3.33(br.s.,1H),3.06(s, 6H). ESI [ M + H ] ═ 444.2

(3S,4S) -4- (dimethylamino) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol 352 use of general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzazepine and use of (3S,4S) -4- (dimethylamino) pyrrolidin-3-ol instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.00(d, J1.5 Hz,1H),7.72(d, J1.8 Hz,1H),7.62-7.52(m,4H),7.19(s,1H),7.08(t, J8.7 Hz,2H),6.91(d, J2.2 Hz,1H),6.83(dd, J2.3, 8.9Hz,1H),5.29(s,2H),4.77-4.68(m,1H),3.98-3.82(m, ddh), 3.61(m, ddl), J7.3, 9.9Hz,1H),3.36-3.31(m,1H),3.06(s, 6H). ESI [ M + H ] ═ 444.2

(3S,4R) -4- (dimethylamino) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol 353 general procedure A was used to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzazepine and to use (3S,4R) -4- (dimethylamino) pyrrolidin-3-ol instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.01(br.s.,1H),7.73(br.s.,1H),7.63-7.52(m,4H),7.20(br.s.,1H),7.09(t, J ═ 8.8Hz,2H),6.88(br.s.,1H),6.82(d, J ═ 8.8Hz,1H),5.29(s,2H),4.70(br.s.,1H),3.95(d, J ═ 3.5Hz,2H),3.72(dd, J ═ 3.1,11.0Hz,1H),3.64-3.52(m,2H),3.03(br.s., 6H). ESI [ M + H ] ═ 444.1

(R) -2- ((((S) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methyl) amino) propan-1-ol, 354 ] use of general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzazepine and (R) -2- (((R) -pyrrolidin-3-ylmethyl) amino) propan-1-ol instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.98(d, J1.8 Hz,1H),7.71(d, J2.0 Hz,1H),7.61-7.49(m,4H),7.18(d, J1.5 Hz,1H),7.08(t, J8.7 Hz,2H),6.81(d, J2.2 Hz,1H),6.75(dd, J2.4, 8.8, 1H),5.33-5.20(m,2H),3.89-3.77(m,1H),3.71-3.50(m,3H),3.48-3.34(m,2H),3.25-3.08(m,3H),2.75 (J7, 3.86, 14.8H), 1.8H, 1H), 1.8-7H, 14.86 (t, 1H), 1H, 11.86 (H), 1H), 1H, 8H, 1H, and 1H. ESI [ M + H ] ═ 472.2

(R) -2- ((((R) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methyl) amino) propan-1-ol, 355 use general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) benzazepine and (R) -2- (((S) -pyrrolidin-3-ylmethyl) amino) propan-1-ol instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.98(s,1H),7.71(s,1H),7.62-7.50(m,4H),7.18(s,1H),7.09(t, J ═ 8.8Hz,2H),6.81(d, J ═ 2.3Hz,1H),6.75(dd, J ═ 2.3,9.0Hz,1H),5.26(s,2H),3.84(dd, J ═ 3.7,11.9Hz,1H),3.68-3.52(m,3H),3.49-3.37(m,2H),3.27-3.16(m,3H),2.76(td, J ═ 7.3,14.8, 1H),2.37(dd, 4, 3.7, 1H),1.35(d, 1H), 1.7.3, 1H, and d, 3H. ESI [ M + H ] ═ 472.2

(3R,4S) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 356 utilizing general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzazepine and to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] diazepin-12-yl) benzazepine with (, 4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.00(d, J1.8 Hz,1H),7.75(s,1H),7.62-7.53(m,4H),7.19(s,1H),7.09(t, J8.6 Hz,2H),6.82(s,2H),5.28(s,2H),4.34-4.26(m,1H),3.81-3.73(m,2H),3.44-3.35(m,2H),3.28-3.16(m,2H),3.00(br.s.,6H),2.78-2.66(m, 1H). ESI [ M + H ] ═ 458.1

(3S,4R) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol 357, using general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzazepine and (3S,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.00(s,1H),7.74(d, J ═ 1.3Hz,1H),7.62-7.53(m,4H),7.19(s,1H),7.09(t, J ═ 8.6Hz,2H),6.82(s,1H),6.76(d, J ═ 8.8Hz,1H),5.28(s,2H),4.30(q, J ═ 6.6Hz,1H),3.81-3.72(m,2H),3.45-3.33(m,2H),3.28-3.19(m,2H),2.99(s,6H),2.77-2.67(m, 1H). ESI [ M + H ] ═ 458.1

(R) -2- ((((R) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methyl) amino) -3-methylbutan-1-ol 358. Using general procedure A7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin for 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and (R) -3-methyl-2- (((S) -pyrrolidin-3-ylmethyl) amino) butan-1-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.93(br.s.,1H),7.66(br.s.,1H),7.60-7.48(m,4H),7.15(br.s.,1H),7.08(t, J ═ 8.6Hz,2H),6.81(br.s.,1H),6.75(d, J ═ 8.8Hz,1H),5.24(s,2H),3.91(dd, J ═ 3.5,12.1Hz,1H),3.76(dd, J ═ 6.6,12.1Hz,1H),3.70-3.62(m,1H),3.54(d, J ═ 4.9Hz,1H),3.49-3.39(m,2H), 3.25-3.25 (H), 3.9H, 1H), 1H (m,1H), 6.5 (d, 1H), 1H),3.9, 1H, 3.9 (d, 1H, 6H), 3.5 (d, 6.5H, 1H), 6H, 1H, 6H, 1H, 6H, 1H, 3H) in that respect ESI [ M + H ] ═ 500.3

(S) -2- ((((R) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methyl) amino) -3-methylbutan-1-ol 359 ] use general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin, 4] diazepine-12-yl) benzonitrile and (S) -3-methyl-2- (((S) -pyrrolidin-3-ylmethyl) amino) butan-1-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.98(br.s.,1H),7.71(s,1H),7.64-7.50(m,4H),7.19(s,1H),7.09(t, J ═ 8.4Hz,2H),6.84(br.s.,1H),6.75(d, J ═ 8.6Hz,1H),5.28(br.s.,2H),3.91(d, J ═ 12.1Hz,1H),3.78(dd, J ═ 6.8,11.9Hz,1H),3.69(t, J ═ 8.4Hz,1H),3.54(br.s.,1H),3.49-3.35(m,2H),3.29-3.19(m,2H), 13.88 (H), 1H, 3.23.8-3.1H, 1H, 3.1H, 13.8, 2H, 1. ESI [ M + H ] ═ 500.2

(S) -2- (((1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methyl) amino) -2-methylpropan-1-ol, 360. Using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and with (R) -2-methyl-2- ((pyrrolidin-3-ylmethyl) amino) propan-1-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.95(br.s.,1H),7.67(br.s.,1H),7.62-7.49(m,4H),7.16(br.s.,1H),7.08(t, J ═ 8.6Hz,2H),6.81(br.s.,1H),6.75(d, J ═ 8.8Hz,1H),5.25(s,2H),3.71-3.62(m,1H),3.57(s,2H),3.49-3.39(m,1H),3.25-3.18(m,2H),3.17-3.08(m,2H),2.74-2.64(m,1H),2.38(d, J ═ 6.6, 1H),1.94 (ddl, 1H), 2.35H, 1H, 2H), and 7.16 (dd.6 Hz, 1H). ESI [ M + H ] ═ 486.2

(S) -1- ((1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) methyl) piperidin-4-ol, 361 using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (R) -1- (pyrrolidin-3-ylmethyl) piperidin-4-ol in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.01(d,J＝2.2Hz,1H),7.74(d,J＝1.8Hz,1H),7.63(s,1H),7.61-7.51(m,3H),7.20(s,1H),7.09(t,J＝8.8Hz,2H),6.85(d,J＝2.2Hz,1H),6.76(dd,J＝2.2,8.8Hz,1H),5.29(s,2H),4.11(br.s.,1H),3.91-3.80(m,1H),3.77-3.63(m,2H),3.60-3.39(m,3H),3.33(br.s.,2H),3.25-3.17(m,1H),3.11(t,J＝12.3Hz,1H),2.90(td,J＝7.6,14.8Hz,1H),2.36(br.s.,1H),2.21-2.05(m,2H),1.99-1.74(m,3H)。ESI[M+H]＝498.2

(R) -1- ((1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methyl) piperidin-4-ol 362 use general procedure A in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and (S) -1- (pyrrolidin-3-ylmethyl) with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzazepine Piperidin-4-ol was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.98(d, J1.8 Hz,1H),7.72(d, J2.2 Hz,1H),7.60-7.50(m,4H),7.18(d, J1.3 Hz,1H),7.07(t, J8.6 Hz,2H),6.80(d, J2.2 Hz,1H),6.74(dd, J2.4, 9.0Hz,1H),5.26(s,2H),4.10(br.s.,1H),3.83(br.s.,1H),3.68(t, J8.6 Hz,2H),3.57-3.49(m,1H), 3.48-3.37H, 3.35H), 3.31H, 3.01 (br.3H., 3.31H), 3.31H., 3.31H), 3.71H, 3.7H., 3.3.3H., 3.3H., 3.3.3H., 3.3H, 3H., 3.3H, 3H., 3H., 3.01, 2H., 3H., 3.7, 2H., 3.7, 1H., 3H. ESI [ M + H ] ═ 498.2

(3R,4S) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-7-yl) -4- ((methylamino) methyl) pyrrolidin-3-ol, 363 using general procedure G with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile.¹H NMR (400MHz, methanol-d)₄)δ＝7.97(d,J＝1.8Hz,1H),7.71(d,J＝1.8Hz,1H),7.61-7.49(m,4H),7.17(d,J＝1.8Hz,1H),7.07(t,J＝8.8Hz,2H),6.80(d,J＝2.6Hz,1H),6.73(dd,J＝2.6,8.8Hz,1H),5.26(s,2H),4.30(q,J＝6.3Hz,1H),3.78-3.65(m,2H),3.26-3.09(m,4H),2.76(s,3H),2.64-2.52(m,1H)。ESI[M+H]＝444.1

(3S,4R) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) -4- ((methylamino) methyl) pyrrolidin-3-ol, 364. Using general procedure G, 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin was used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and (((3S,4S) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamic acid benzyl ester instead of benzyl (((3R,4R) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamic acid. 1HNMR (400MHz, methanol-d 4) δ 7.98(d, J ═ 1.8Hz,1H),7.72(d, J ═ 1.8Hz,1H),7.60-7.51(m,4H),7.17(d, J ═ 1.8Hz,1H),7.08(t, J ═ 8.6Hz,2H),6.80(d, J ═ 2.2Hz,1H),6.73(dd, J ═ 2.2,8.8Hz,1H),5.26(s,2H),4.30(q, J ═ 6.5Hz,1H),3.77-3.66(m,2H),3.26-3.12(m,4H),2.75(s,3H),2.61-2.54(m, 1H). ESI [ M + H ] ═ 444.1

(3R,4S) -4- (aminomethyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol 365 use general procedure G to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzazepine and to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] diazepin-12-yl) benzonitrile with (((3R,4R) -4-hydroxypyrrolidin-3-yl) methyl) carbamic acid benzyl ester instead of benzyl (((3R,4R) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamate. 1H NMR (400MHz, methanol-d 4) δ 7.93(br.s.,1H),7.65(br.s.,1H),7.62-7.46(m,4H),7.15(br.s.,1H),7.08(t, J ═ 8.7Hz,2H),6.82(br.s.,1H),6.74(d, J ═ 9.0Hz,1H),5.25(s,2H),4.32(d, J ═ 6.0Hz,1H),3.73(dd, J ═ 7.3,17.0Hz,2H),3.48(s,2H),3.09(dd, J ═ 12.3,19.8Hz,2H),2.54(d, J ═ 6.6, 1H). ESI [ M + H ] ═ 430.1

(3S,4R) -4- (aminomethyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol 366 using general procedure G instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and using (((3S,4S) -4-hydroxypyrrolidin-3-yl) methyl) carbamic acid benzyl ester instead of benzyl (((3R,4R) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamate. 1H NMR (400MHz, methanol-d 4) δ 7.99(s,1H),7.73(s,1H),7.64-7.50(m,4H),7.19(s,1H),7.09(t, J ═ 8.4Hz,2H),6.82(br.s.,1H),6.75(d, J ═ 9.0Hz,1H),5.28(s,2H),4.32(d, J ═ 6.1Hz,1H),3.78-3.66(m,2H),3.28-2.99(m,4H),2.59-2.49(m, 1H). ESI [ M + H ] ═ 430.1

7- (2-Ethyl-2, 6-diazaspiro [3.4] oct-6-yl) -12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepine, 367, use general procedure C to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] diazepine with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepine and 2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester for (azetidine) benzazepine, 367 -3-ylmethyl) (methyl) carbamic acid tert-butyl ester and acetaldehyde instead of formaldehyde. 1H NMR (400MHz, methanol-d 4) δ 7.58-7.48(m,3H),7.35(d, J8.6 Hz,1H),7.27(s,1H),7.17(s,1H),7.03(t, J8.1 Hz,2H),6.89(s,1H),6.72(br.s.,1H),6.64(d, J8.8 Hz,1H),5.04(s,2H),3.48(s,2H),3.40-3.33(m,6H),2.61(d, J7.0 Hz,2H),2.24(t, J6.5 Hz,2H),1.02(t, J6.7 Hz, 3H). ESI [ M + H ] ═ 454.1

12- (4-fluorophenyl) -7- (2-isopropyl-2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepine, 368 using general procedure C instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] diazepine and 2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester instead of (azetidine) azetidine -3-ylmethyl) (methyl) carbamic acid tert-butyl ester and propan-2-one instead of formaldehyde. 1H NMR (400MHz, methanol-d 4) δ 7.56-7.47(m,3H),7.35(d, J8.8 Hz,1H),7.27(s,1H),7.17(s,1H),7.03(t, J8.1 Hz,2H),6.89(s,1H),6.71(br.s.,1H),6.64(d, J8.8 Hz,1H),5.03(s,2H),3.48(br.s.,6H),3.39(t, J6.5 Hz,2H),2.70(br.s.,1H),2.25(t, J6.3 Hz,2H),1.04(d, J5.7 Hz, 6H). ESI [ M + H ] ═ 468.2

(R) -2- (6- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) -2, 6-diazaspiro [3.4] oct-2-yl) propan-1-ol 370 using general procedure C to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl ] diazepin-e ] azepine, Synthesized with tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate instead of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate and 1-hydroxypropan-2-one instead of formaldehyde. SFC was isolated using general procedure E, using 2- (6- (12- (4-fluorophenyl) -9H-benzo [ E ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) -2, 6-diazaspiro [3.4] oct-2-yl) propan-1-ol in place of 4- (7- (2- ((dimethylamino) methyl) morpholinyl) -9H-benzo [ E ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile. 1H NMR (400MHz, methanol-d 4) δ 7.54-7.46(m,3H),7.32(d, J8.8 Hz,1H),7.26(d, J1.8 Hz,1H),7.15(d, J1.1 Hz,1H),7.01(t, J8.8 Hz,2H),6.87(d, J1.8 Hz,1H),6.69(d, J2.4 Hz,1H),6.61(dd, J2.6, 8.8Hz,1H),5.00(s,2H),3.48-3.36(m,10H),2.55(br.s, 1H),2.27-2.16(m,2H),0.98(d, 6.4, 3H). ESI [ M + H ] ═ 484.2

(S) -2- (6- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) -2, 6-diazaspiro [3.4] oct-2-yl) propan-1-ol, 371 use general procedure C to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepin-12-yl) diazepin-e, Synthesized with tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate instead of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate and 1-hydroxypropan-2-one instead of formaldehyde. SFC was isolated using general procedure E, using 2- (6- (12- (4-fluorophenyl) -9H-benzo [ E ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) -2, 6-diazaspiro [3.4] oct-2-yl) propan-1-ol in place of 4- (7- (2- ((dimethylamino) methyl) morpholinyl) -9H-benzo [ E ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile. 1H NMR (400MHz, methanol-d 4) δ 7.55-7.48(m,3H),7.32(d, J8.6 Hz,1H),7.26(d, J1.8 Hz,1H),7.16(s,1H),7.01(t, J8.8 Hz,2H),6.87(d, J1.5 Hz,1H),6.69(d, J2.4 Hz,1H),6.61(dd, J2.4, 8.8Hz,1H),5.03-4.98(m,2H),3.47-3.42(m,2H),3.38-3.31(m,8H),2.45(d, J6.0, 1H),2.21(t, J6.96H), 7.96H (d, 3H), 3.96H). ESI [ M + H ] ═ 484.1

7- (2-cyclopentyl-2, 6-diazaspiro [3.4] oct-6-yl) -12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepine, 375 use of general procedure C instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] diazepine for 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepine and tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate for (azetidine [1,2-a ] [1,4] diazepine-12-yl) benzazepine -3-ylmethyl) (methyl) carbamic acid tert-butyl ester and cyclopentanone instead of formaldehyde. 1H NMR (400MHz, methanol-d 4) δ 7.59-7.47(m,3H),7.37-7.24(m,2H),7.17(s,1H),7.02(t, J ═ 8.6Hz,2H),6.89(s,1H),6.68(br.s.,1H),6.61(d, J ═ 8.6Hz,1H),5.00(s,2H),3.43(s,2H),3.28(br.s.,6H),2.85(d, J ═ 5.7Hz,1H),2.20(t, J ═ 6.5Hz,2H),1.80-1.49(m,6H),1.32(d, J ═ 5.3Hz, 2H). ESI [ M + H ] ═ 494.2

12- (4-fluorophenyl) -7- (2, 6-diazaspiro [3.4]]Oct-6-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine, 376 using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Novel diazepine-12-yl) benzonitrile in combination with 2, 6-diazaspiro [3.4]Octane-2-carboxylic acid tert-butyl ester was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, chloroform-d) δ 7.42(dd, J5.5, 8.6Hz,2H),7.30(s,1H),7.24-7.18(m, 2)H),7.05-6.92(m,4H),6.57-6.46(m,2H),4.93(br.s.,2H),3.70-3.54(m,4H),3.50(s,2H),3.34(t,J＝6.6Hz,2H),2.24(t,J＝6.6Hz,2H)。ESI[M+H]＝426.1

12- (4-fluorophenyl) -7- (2, 6-diazaspiro [3.5]]Non-2-yl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine, 377 using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Novel diazepine-12-yl) benzonitrile in combination with 2, 6-diazaspiro [3.5]Nonane-6-carboxylic acid tert-butyl ester was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝7.99(d,J＝2.2Hz,1H),7.73(d,J＝2.2Hz,1H),7.61-7.49(m,4H),7.18(d,J＝1.8Hz,1H),7.08(t,J＝8.6Hz,2H),6.70(d,J＝2.6Hz,1H),6.63(dd,J＝2.6,8.8Hz,1H),5.26(s,2H),3.86(d,J＝7.5Hz,2H),3.76(d,J＝7.5Hz,2H),3.40(s,2H),3.14(t,J＝5.5Hz,2H),2.04-1.93(m,2H),1.86(d,J＝4.9Hz,2H)。ESI[M+H]＝440.2

12- (4-fluorophenyl) -7- (2, 6-diazaspiro [3.4] oct-2-yl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine, 378 Using general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine and tert-butyl 2, 6-diazaspiro [3.4] octane-6-carboxylate for tert-butyl piperazine-1-carboxylate with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzazepine To synthesize. 1H NMR (400MHz, methanol-d 4) δ 8.01(d, J2.0 Hz,1H),7.79-7.72(m,1H),7.63-7.50(m,4H),7.20(d, J1.5 Hz,1H),7.09(t, J8.8 Hz,2H),6.74(d, J2.4 Hz,1H),6.66(dd, J2.4, 8.8Hz,1H),5.34-5.20(m,2H),4.08-3.94(m,4H),3.58-3.49(m,2H),3.43-3.34(m,2H),2.36(t, J7.4 Hz, 2H). ESI [ M + H ] ═ 426.2

(R) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) -N, N-dimethylpyrrolidin-3-amine, 379 using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile by using (R) -N, N-dimethylpyrrolidin-3-amine in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.02(br.s.,1H),7.75(br.s.,1H),7.65-7.49(m,4H),7.21(s,1H),7.09(t,J＝8.6Hz,2H),6.91(d,J＝2.2Hz,1H),6.84(dd,J＝2.2,8.8Hz,1H),5.30(s,2H),4.09(quin,J＝7.3Hz,1H),3.83(dd,J＝7.5,10.6Hz,1H),3.74-3.58(m,2H),3.52-3.41(m,1H),2.99(s,6H),2.67-2.54(m,1H),2.41-2.24(m,1H)。ESI[M+H]＝428.2

(S) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) -N, N-dimethylpyrrolidin-3-amine, 380 using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile by using (S) -N, N-dimethylpyrrolidin-3-amine in place of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝8.02(d,J＝2.2Hz,1H),7.75(d,J＝2.2Hz,1H),7.63-7.51(m,4H),7.21(d,J＝1.3Hz,1H),7.08(t,J＝8.6Hz,2H),6.92(d,J＝2.2Hz,1H),6.84(dd,J＝2.4,9.0Hz,1H),5.30(s,2H),4.09(quin,J＝7.2Hz,1H),3.83(dd,J＝7.5,10.6Hz,1H),3.75-3.60(m,2H),3.51-3.40(m,1H),2.99(s,6H),2.67-2.56(m,1H),2.42-2.29(m,1H)。ESI[M+H]＝428.2

1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) -N, N-dimethylpiperidin-4-amine, 381 using general procedure C replacing 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-C ] pyrrolo [1,2-a ] [1,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) diazepin and replacing (azetidin-3-ylmethyl) (methyl) with tert-butyl piperidin-4-ylcarbamate Tert-butyl carbamate. 1H NMR (400MHz, methanol-d 4) δ 8.01(d, J1.8 Hz,1H),7.74(s,1H),7.60-7.52(m,4H),7.25(d, J2.2 Hz,1H),7.21-7.14(m,2H),7.08(t, J8.8 Hz,2H),5.29(s,2H),4.08(d, J13.2 Hz,2H),3.42(t, J12.1 Hz,1H),2.99-2.92(m,2H),2.90-2.87(m,6H),2.18(d, J11.5 Hz,2H),1.88-1.74(m, 2H). ESI [ M + H ] ═ 442.2

1- (1- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepin-7-yl) azetidin-3-yl) -N-methylmethylamine 386 use of general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepin and tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate for piperazine Tert-butyl-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.79(d, J8.8 Hz,1H),7.57(dd, J5.3, 8.8Hz,2H),7.49(d, J1.8 Hz,1H),7.24(d, J1.8 Hz,1H),7.08(t, J8 Hz,2H),6.69(d, J2.2 Hz,1H),6.65(dd, J2.5, 8.7Hz,1H),5.23(s,2H),4.17(t, J7.8 Hz,2H),3.80(dd, J5.3, 7.7, 2H),3.39(d, J7.3, 2H), 12.12H, 12H, 7.7, 2H),3.7 (d, J, 3.3, 12H), 7.7, 12H, 7H, 3.7, 12H, 7H, 1H). ESI [ M + H ] ═ 416.1

1- (1- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmethylamine 388. Using general procedure A replacement of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine for 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and methyl (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester for piperazine-1 Tert-butyl formate. 1H NMR (400MHz, methanol-d 4) δ 7.78(d, J8.8 Hz,1H),7.57(dd, J5.4, 8.7Hz,2H),7.49(d, J1.8 Hz,1H),7.23(d, J1.5 Hz,1H),7.07(t, J8.8 Hz,2H),6.81-6.72(m,2H),5.19(s,2H),3.67-3.61(m,2H),3.56-3.46(m,1H),3.23-3.13(m,3H),2.82-2.69(m,4H),2.41-2.29(m,1H),1.91(m, 1H). ESI [ M + H ] ═ 430.2

(R) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepin-7-yl) piperidin-3-amine, 389 synthesized using general procedure A using 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepine in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and (R) -piperidin-3-ylcarbamic acid tert-butyl ester in place of piperazine-1-carboxylic acid tert-butyl ester. 1HNMR (400MHz, methanol-d 4) δ 7.84(d, J8.8 Hz,1H),7.55(dd, J5.3, 8.4Hz,2H),7.48(d, J1.8 Hz,1H),7.26-7.21(m,2H),7.18(dd, J2.6, 8.8Hz,1H),7.05(t, J8.8 Hz,2H),5.23(s,2H),3.67(dd, J2.9, 12.6Hz,1H),3.52-3.41(m,2H),3.27-3.19(m,2H),2.13-2.03(m,1H),2.01-1.91(m,1H),1.86-1.69(m, 2H). ESI [ M + H ] ═ 416.2

(S) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepin-7-yl) piperidin-3-amine 390. this was synthesized using general procedure A using 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepine in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and using (S) -piperidin-3-ylcarbamic acid tert-butyl ester in place of piperazine-1-carboxylic acid tert-butyl ester. 1HNMR (400MHz, methanol-d 4) δ 7.83(d, J9.3 Hz,1H),7.55(dd, J5.3, 8.8Hz,2H),7.49(d, J1.8 Hz,1H),7.23(s,2H),7.18(dd, J2.4, 9.0Hz,1H),7.06(t, J8.6 Hz,2H),5.26-5.19(m,2H),3.69(d, J10.1 Hz,1H),3.54-3.44(m,1H),3.40(br.s.,1H),3.25-3.14(m,2H),2.05(dd, J4.2, 8.2, 1H),1.94(dd, 8.6H), 7.79(d, 8.6, 8H, 1H), 8.79 (dd, 8.6Hz, 8H, 1H). ESI [ M + H ] ═ 416.2

12- (4-fluorophenyl) -7- (2-methyl-2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-C ] [1,4] diazepine, 392 using general procedure C instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] tetrazolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine-12-yl) benzazepine, and tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate instead of (azetidine [1,2-a ] [1,2,4] diazaspiro [ e ] benzazepine -3-ylmethyl) (methyl) carbamic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.78(d, J8.4 Hz,1H),7.56(dd, J5.3, 8.4Hz,2H),7.49(s,1H),7.22(s,1H),7.06(t, J8.8 Hz,2H),6.83-6.72(m,2H),5.20(s,2H),3.65(br.s.,2H),3.52-3.44(m,2H),3.34(br.s.,4H),2.99(s,3H),2.40(t, J6.8 Hz, 2H). ESI [ M + H ] ═ 442.2

(S) -1- (1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-C ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine, 393 using general procedure C instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzamide, (S) - (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester was used instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester for synthesis. 1H NMR (400MHz, methanol-d 4) δ 7.78(d, J8.8 Hz,1H),7.60-7.53(m,2H),7.49(s,1H),7.22(d, J1.8 Hz,1H),7.06(t, J8.6 Hz,2H),6.81-6.74(m,2H),5.21(s,2H),3.71-3.64(m,1H),3.57(s,1H),3.50-3.42(m,1H),3.34(br.s.,3H),3.20-3.08(m,1H),2.97(s,6H),2.90-2.80(m,1H),1.92-1.76(m, 1H). ESI [ M + H ] ═ 444.2

(R) -1- (1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-C ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine 394 use general procedure C instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzazepine, (R) - (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester was used instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester for synthesis. 1H NMR (400MHz, methanol-d 4) δ 7.77(d, J8.8 Hz,1H),7.56(dd, J5.5, 8.6Hz,2H),7.49(d, J1.3 Hz,1H),7.22(d, J1.8 Hz,1H),7.06(t, J8 Hz,2H),6.81-6.73(m,2H),5.20(s,2H),3.71-3.63(m,1H),3.59-3.52(m,1H),3.49-3.39(m,1H),3.33(s,3H),3.21-3.12(m,1H),2.97(s,6H),2.91-2.81(m,1H), 1.95-1H (m,1H), 1.83(m, 1H). ESI [ M + H ] ═ 444.2

12- (4-fluorophenyl) -7- (2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepine, 398 using general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester and to replace piperazine-1-carboxylic acid tert-butyl ester with 2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester To synthesize. 1H NMR (400MHz, methanol-d 4) δ 7.80(d, J8.6 Hz,1H),7.58(dd, J5.3, 8.8Hz,2H),7.51(d, J1.8 Hz,1H),7.24(d, J1.8 Hz,1H),7.08(t, J8 Hz,2H),6.84-6.76(m,2H),5.22(s,2H),4.24-4.16(m,2H),4.14-4.05(m,2H),3.66(s,2H),3.50(t, J6.8 Hz,2H),2.41(t, J6.9 Hz, 2H). ESI [ M + H ] ═ 428.1

12- (4-fluorophenyl) -7- (2, 7-diazaspiro [3.5] non-7-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepine, 402 using general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester and to replace piperazine-1-carboxylic acid tert-butyl ester with 2, 7-diazaspiro [ e ] nonane-2-carboxylic acid tert-butyl ester To synthesize. 1H NMR (400MHz, methanol-d 4) δ 7.73(d, J9.3 Hz,1H),7.51(dd, J5.3, 8.8Hz,2H),7.44(d, J1.3 Hz,1H),7.16(dd, J2.0, 12.1Hz,2H),7.08(dd, J2.6, 8.8Hz,1H),7.03(t, J8.8 Hz,2H),5.13(s,2H),3.90(s,4H),3.34-3.29(m,4H),2.06-1.93(m, 4H). ESI [ M + H ] ═ 442.2

12- (4-fluorophenyl) -7- (2, 6-diazaspiro [3.4] oct-2-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepine, 403. Using general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzazepine and to replace tert-butyl piperazine-1-carboxylate with tert-butyl 2, 6-diazaspiro [3.4] octane-6-carboxylate To synthesize. 1H NMR (400MHz, methanol-d 4) δ 7.79(d, J8.8 Hz,1H),7.60-7.54(m,2H),7.49(d, J1.8 Hz,1H),7.23(d, J1.8 Hz,1H),7.08(t, J8.7 Hz,2H),6.71(d, J2.2 Hz,1H),6.67(dd, J2.5, 8.7, 1H),5.20(s,2H),4.05-3.99(m,4H),3.55(s,2H),3.40(t, J7.4 Hz,2H),2.38(t, J7.4, 2H). ESI [ M + H ] ═ 428.1

(R) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepin-7-yl) -N, N-dimethylpyrrolidin-3-amine 406. Using general procedure A, 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-c ] [1,4] diazepine is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and (R) -N, n-dimethylpyrrolidin-3-amine was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.81(d, J8.8 Hz,1H),7.55(dd, J5.3, 8.8Hz,2H),7.48(d, J1.8 Hz,1H),7.22(d, J1.8 Hz,1H),7.06(t, J8.6 Hz,2H),6.90-6.82(m,2H),5.21(s,2H),4.08(quin, J7.2 Hz,1H),3.83(dd, J7.5, 10.6Hz,1H),3.70(dt, J3.5, 9.3Hz,1H),3.63(dd, J6.4, 10.8, 3.42H), 3.42H (1.42, 2H), 3.55H, 2m, 2H. ESI [ M + H ] ═ 430.2

(S) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-C ] [1,4] diazepin-7-yl) -N, N-dimethylpyrrolidin-3-amine, 407. Using general procedure C instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine and instead of (azetidin-12-yl) benzonitrile with (S) -pyrrolidin-3-ylcarbamic acid tert-butyl ester, 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] tetrazolo [5,1-C ] [1,4] diazepine derivative -3-ylmethyl) (methyl) carbamic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.84(d, J8.8 Hz,1H),7.57(dd, J5.3, 8.8Hz,2H),7.50(d, J1.8 Hz,1H),7.24(d, J1.8 Hz,1H),7.08(t, J8.6 Hz,2H),6.94-6.84(m,2H),5.24(s,2H),4.05(d, J6.2 Hz,1H),3.84(dd, J7.5, 10.6Hz,1H),3.76-3.68(m,1H),3.62(dd, J6.2, 10.6, 1H), 3.54-3.42H), 3.63, 1H (m,1H), 18.62 (dd, J6.2, 10.6, 1H), 3.54-3.42H (m,2H), 2H, 1H, 18H, 26H, 1H, and d. ESI [ M + H ] ═ 430.2

(R) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) -N-methylpyrrolidin-3-amine, 409. use of general procedure I to replace 4- (7-bromo-11-chloro-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and (R) -pyrrolidin-3-yl -tert-butyl ylcarbamate instead of (R) - (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.14(s,1H),7.72(d, J8.8 Hz,1H),7.55(dd, J5.3, 8.8Hz,2H),7.41(d, J1.8 Hz,1H),7.10-7.00(m,3H),6.88-6.77(m,2H),5.18(s,2H),4.04-3.94(m,1H),3.74-3.59(m,3H),3.45(dt, J5.7, 9.0Hz,1H),2.80(s,3H),2.61-2.48(m,1H),2.34-2.22(m, 1H). ESI [ M + H ] ═ 415.1

(S) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) -N-methylpyrrolidin-3-amine, 410 use of general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and with (S) -methyl (pyrrolidin-3-yl) amino Tert-butyl benzoate was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.14(s,1H),7.71(d, J8.6 Hz,1H),7.53(dd, J5.3, 8.6Hz,2H),7.39(s,1H),7.10-7.00(m,3H),6.84-6.76(m,2H),5.23-5.12(m,2H),4.04-3.92(m,1H),3.74-3.55(m,3H),3.44(dt, J5.7, 9.2Hz,1H),2.83-2.74(m,3H),2.53(dt, J6, 14.3Hz,1H),2.26 (J, J5.3, 13.3Hz, 1H). ESI [ M + H ] ═ 415.1

12- (4-fluorophenyl) -7- (2-methyl-2, 6-diazaspiro [3.4] oct-6-yl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepine, 412 using general procedure C to replace the 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepine and 2 with a 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine-12-yl) benzazepine, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.19(br.s.,1H),7.68(d, J8.4 Hz,1H),7.55(dd, J53, 8.4Hz,2H),7.41(s,1H),7.12(br.s.,1H),7.06(t, J8.6 Hz,2H),6.80-6.70(m,2H),5.16(s,2H),4.40-4.27(m,2H),4.21-4.08(m,2H),3.70-3.60(m,2H),3.51-3.40(m,2H),2.99(d, J5.3 Hz,3H),2.44-2.34(m, 2H). ESI [ M + H ] ═ 441.1

(S) -1- (1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine, 413 using general procedure C replacing 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine-12-yl) benzonitrile and replacement of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate with tert-butyl (R) - (pyrrolidin-3-ylmethyl) carbamate. 1H NMR (400MHz, methanol-d 4) δ 8.18(br.s.,1H),7.68(d, J8.6 Hz,1H),7.55(dd, J5.4, 8.5Hz,2H),7.40(s,1H),7.15-7.00(m,3H),6.77-6.66(m,2H),5.22-5.08(m,2H),3.71-3.60(m,1H),3.54(dt, J3.1, 8.8Hz,1H),3.47-3.38(m,1H),3.33(s,2H),3.15(t, J8.6 Hz,1H),2.97(s,6H),2.85(td, J7.5, 15.4, 1H),2.15 (t, J) 8.6Hz,1H), 2.85 (q, 1H, 2.6H, 1H, 8.8H, 1H, 2.85 (q, 12H, 1H). ESI [ M + H ] ═ 443.2

(R) -1- (1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine, 414 using general procedure C replacing 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepine-12-yl) benzonitrile and (S) - (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.22(br.s.,1H),7.67(d, J9.0 Hz,1H),7.54(dd, J5.4, 8.3Hz,2H),7.39(s,1H),7.22-6.98(m,3H),6.75-6.64(m,2H),5.19-5.07(m,2H),3.64(t, J8.5 Hz,1H),3.57-3.49(m,1H),3.47-3.36(m,1H),3.33(s,2H),3.14(t, J8.5 Hz,1H),2.97(s,6H),2.85(tt, J8.0, 15.4, 1H), 2.14 (t, J ═ 8.5Hz,1H),2.97(s,6H),2.85(tt, J, 8.0,15.4, 1H), 2.29.87 (d, 1H), 1H, 8.87 (d, 8.87). ESI [ M + H ] ═ 443.2

(3S,4S) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 415 use general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and with (3S,4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.13(s,1H),7.67(d, J8.8 Hz,1H),7.54(dd, J5.5, 8.6Hz,2H),7.39(s,1H),7.10-7.00(m,3H),6.74-6.67(m,2H),5.14(s,2H),4.57(br.s, 1H),3.72-3.52(m,3H),3.44(d, J10.6 Hz,1H),3.32(d, J5.7 Hz,2H),2.97(br.s, 6H),2.84(dd, J5.3, 13.2, 1H). ESI [ M + H ] ═ 459.2

(3R,4R) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 416 use general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and with (3R,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.12(s,1H),7.68(d, J8.8 Hz,1H),7.54(dd, J55, 8.6Hz,2H),7.39(d, J1.8 Hz,1H),7.11-6.99(m,3H),6.76-6.65(m,2H),5.15(s,2H),4.56(d, J1.8 Hz,1H),3.74-3.53(m,3H),3.48-3.40(m,1H),3.36-3.30(m,2H),2.97(d, J3.1 Hz,6H),2.88-2.80(m, 1H). ESI [ M + H ] ═ 459.1

(3R,4R) -4- (dimethylamino) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-ol 417 using general procedure A substituting 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin for 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and with (3S,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.16(s,1H),7.72(d, J8.6 Hz,1H),7.54(dd, J5.5, 8.6Hz,2H),7.40(d, J1.6 Hz,1H),7.11-7.01(m,3H),6.86-6.76(m,2H),5.16(s,2H),4.70(q, J7.0 Hz,1H),3.96-3.81(m,3H),3.58(dd, J6.7, 9.8Hz,1H),3.28(d, J7.0 Hz,1H),3.07(br.s, 6H). ESI [ M + H ] ═ 445.1

(3S,4S) -4- (dimethylamino) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 418 use general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and with (3R,4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.14(s,1H),7.72(d, J8.4 Hz,1H),7.53(dd, J5.5, 8.6Hz,2H),7.39(d, J1.8 Hz,1H),7.09-7.01(m,3H),6.84-6.76(m,2H),5.16(s,2H),4.69(q, J6.9 Hz,1H),3.94-3.80(m,4H),3.57(dd, J6.6, 9.7Hz,1H),3.05(br.s., 6H). ESI [ M + H ] ═ 445.2

(R) -2- ((((S) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methyl) amino) propan-1-ol, 419 using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepine in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [ 3), 4-c ] [1,4] diazepine-12-yl) benzonitrile and (R) -2- (((R) -pyrrolidin-3-ylmethyl) amino) propan-1-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.15(s,1H),7.67(d, J9.4 Hz,1H),7.54(dd, J5.1, 8.6Hz,2H),7.39(s,1H),7.12-7.00(m,3H),6.75-6.67(m,2H),5.13(s,2H),3.84(dd, J3.7, 11.9Hz,1H),3.67-3.57(m,2H),3.57-3.48(m,1H),3.45-3.37(m,2H),3.26-3.15(m,3H),2.74(td, J7.3, 14.8, 1H),2.40-2.30(m,1H),1.91 (m,1H),1.35(d, 1H), 1.6H, 1H, 3.35(d, 1H), 1H). ESI [ M + H ] ═ 473.2

(R) -2- ((((R) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methyl) amino) propan-1-ol, 420. use of general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepine for 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [ 3], 4-c ] [1,4] diazepine-12-yl) benzonitrile and (R) -2- (((S) -pyrrolidin-3-ylmethyl) amino) propan-1-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.15(s,1H),7.66(d, J8.8 Hz,1H),7.54(dd, J5.3, 8.4Hz,2H),7.39(s,1H),7.11-7.00(m,3H),6.75-6.67(m,2H),5.12(s,2H),3.84(dd, J3.5, 11.9Hz,1H),3.67-3.57(m,2H),3.52(dt, J3.7, 8.7Hz,1H),3.46-3.35(m,2H),3.26-3.12(m,3H),2.74(td, J7.3, 14.6, 1H),2.42 (m,2H), 6.85H, 1H, 6H, 1H, 6H, 1H, 6H, 1H, 6H, 1. ESI [ M + H ] ═ 473.1

(3R,4S) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 421. use general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and with (3R,4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.17(s,1H),7.68(d, J8.4 Hz,1H),7.59-7.50(m,2H),7.40(s,1H),7.11-7.01(m,3H),6.75-6.67(m,2H),5.14(s,2H),4.28(q, J6.6 Hz,1H),3.74(t, J8.4 Hz,2H),3.46-3.33(m,2H),3.28-3.15(m,2H),2.99(br.s.,6H),2.76-2.64(m, 1H). ESI [ M + H ] ═ 459.3

(3S,4R) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 422 use general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and with (3S,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.14(br.s.,1H),7.67(d, J8.8 Hz,1H),7.53(dd, J5.3, 8.8Hz,2H),7.39(s,1H),7.05(q, J8.7 Hz,3H),6.75-6.67(m,2H),5.14(s,2H),4.28(q, J6.6 Hz,1H),3.77-3.69(m,2H),3.42-3.32(m,2H),3.26-3.16(m,2H),2.98(br.s.,6H),2.73-2.65(m, 1H). ESI [ M + H ] ═ 459.3

(S) -2- (((1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methyl) amino) -2-methylpropan-1-ol, 425. Using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and (R) -2-methyl-2- ((pyrrolidin-3-ylmethyl) amino) propan-1-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1HNMR (400MHz, methanol-d 4) δ 8.17(br.s.,1H),7.67(d, J8.8 Hz,1H),7.54(dd, J5.4, 8.5Hz,2H),7.39(s,1H),7.17-6.99(m,3H),6.76-6.67(m,2H),5.13(s,2H),3.68-3.59(m,1H),3.58-3.48(m,3H),3.46-3.37(m,1H),3.19(dd, J6.8, 9.5Hz,1H),3.15-3.07(m,2H),2.72-2.62(m,1H),2.35(dd, J4.7, 11.8, 1H), 1.15-3.85H), 1.6-6.7, 1H, 7, 6.6.85H, 7H, 6.6.6H, 1H, and 85H). ESI [ M + H ] ═ 487.3

(R) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepin-7-yl) -N, N-dimethylpyrrolidin-3-amine 426. Using general procedure C instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-C ] [1,4] diazepin and (R) -pyrrolidin-3-ylaminopyrrole [1,2-a ] [1,2,4] triazolo [3,4-C ] [1,4] diazepin-12-yl) benzonitrile Tert-butyl formate was synthesized instead of tert-butyl (azetidin-3-ylmethyl) (methyl) carbamate. 1H NMR (400MHz, methanol-d 4) δ 8.15(s,1H),7.72(d, J8.8 Hz,1H),7.54(dd, J5.5, 8.6Hz,2H),7.40(d, J1.3 Hz,1H),7.11-7.01(m,3H),6.86-6.78(m,2H),5.17(s,2H),4.13-4.03(m,1H),3.80(dd, J7.5, 10.6Hz,1H),3.72-3.59(m,2H),3.48-3.39(m,1H),2.99(s,6H),2.67-2.55(m,1H),2.38-2.27(m, 1H). ESI [ M + H ] ═ 429.1

(S) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) -N, N-dimethylpyrrolidin-3-amine, 427 utilizing general procedure A substituting 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin for 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and ((S) -N, n-dimethylpyrrolidin-3-amine was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.13(s,1H),7.71(d, J8.8 Hz,1H),7.53(dd, J5.3, 8.8Hz,2H),7.39(s,1H),7.09-7.00(m,3H),6.85-6.78(m,2H),5.16(s,2H),4.06(t, J6.4 Hz,1H),3.83-3.75(m,1H),3.72-3.64(m,1H),3.61(dd, J6.2, 10.1Hz,1H),3.48-3.39(m,1H),2.98(s,6H),2.61(d, J19.8, 1H), 2.36H, 24.36H, 1H). ESI [ M + H ] ═ 429.2

(3S,4S) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 429 use general procedure A to replace the 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,2-a ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepine-12-yl) benzonitrile and with (3S,4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.00(d, J ═ 2.2Hz,1H),7.86(d, J ═ 9.3Hz,1H),7.76(d, J ═ 1.8Hz,1H),7.62(d, J ═ 1.3Hz,1H),7.57(dd, J ═ 5.3,8.8Hz,2H),7.23(d, J ═ 1.8Hz,1H),7.08(t, J ═ 8.8Hz,2H),6.66(d, J ═ 8.8Hz,1H),5.29(s,2H),4.55(br.s.,1H),3.89(br.s.,1H),3.78-3.62(m,2H),3.56(dd, 2H), 7.9.8H, 3.9, 3.78H), 3.89 (dd.9, 2H), 3.8H, 1H), 3.9.8H, 1H, 3.89 (m-3.8H). ESI [ M + H ] ═ 459.1

(3R,4R) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 430. Using general procedure A, 7-bromo-12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and with (3R,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.00(d, J1.8 Hz,1H),7.86(d, J9.3 Hz,1H),7.76(d, J1.8 Hz,1H),7.62(d, J1.3 Hz,1H),7.57(dd, J5.3, 8.8Hz,2H),7.24(d, J1.8 Hz,1H),7.07(t, J8.8 Hz,2H),6.65(d, J9.3 Hz,1H),5.29(s,2H),4.55(br.s, 1H),3.97-3.83(m,1H),3.78-3.62(m,2H),3.56(dd, 2H), 7.92 (dd, 3.8H), 3.78H), 3.43H (1H), 3.78-3H), 3.78-3.8H, 1H, 3H, 1H, 3.8H, 1H, 3H, 1H, and 3H. ESI [ M + H ] ═ 4591

(3R,4R) -4- (dimethylamino) -1- (12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 431 using general procedure A replacing the 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and (3R,4R) -4- (dimethylamino) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.01(s,1H),7.92(d, J8.8 Hz,1H),7.77(s,1H),7.63(s,1H),7.57(dd, J5.3, 8.8Hz,2H),7.23(s,1H),7.08(t, J8.8 Hz,2H),6.75(d, J9.3 Hz,1H),5.33(s,2H),4.72(q, J7.2 Hz,1H),4.19(dd, J8.2, 11.2Hz,1H),4.09(dd, J7.9, 10.6, 1H),3.85(q, J7.8, 3.3H), 3.9, 7.6, 1H), 3.7H, 7.6, 7H, 7.9, 7.6, 1H, 7.6, 7H, 7.5H, 7.05H, 7H, 7.6H, 7H, 7.7H, 7H, and 7.05H. ESI [ M + H ] ═ 445.1

(3R,4S) -4- (dimethylamino) -1- (12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 432. Using general procedure A, a 7-bromo-12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin is used instead of a 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and (3R,4S) -4- (dimethylamino) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ is 8.01(d, J is 1.8Hz,1H),7.91(d, J is 9.3Hz,1H),7.77(d, J is 1.8Hz,1H),7.63(d, J is 1.3Hz,1H),7.57(dd, J is 5.3,8.8Hz,2H),7.25(d, J is 1.3Hz,1H),7.08(t, J is 8.8Hz,2H),6.74(d, J is 8.8Hz,1H),5.33(s,2H),4.68(br.s, 1H),4.22(br.s, 1H),3.98-3.89(m,1H),3.84 (m, 3.84, 3.65, 3.15H), 3.15H (d, 9H, 15H), 1H, 15H, 1H). ESI [ M + H ] ═ 445.1

(3S,4R) -4- (dimethylamino) -1- (12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 433 using general procedure A substituting 7-bromo-12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin for 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and (3S,4R) -4- (dimethylamino) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.00(d, J1.8 Hz,1H),7.91(d, J9.3 Hz,1H),7.76(d, J2.2 Hz,1H),7.63(d, J1.8 Hz,1H),7.57(dd, J5.3, 8.8Hz,2H),7.23(d, J1.8 Hz,1H),7.08(t, J8.8 Hz,2H),6.74(d, J8.8 Hz,1H),5.32(s,2H),4.68(br.s, 1H),4.22(br.s, 1H),4.00-3.88(m,1H),3.82 (m, 3.82, 3.65, 3H), 9.02 (H), 3.9H, 9H, 1H). ESI [ M + H ] ═ 445.1

(R) -2- ((((R) -1- (12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methyl) amino) propan-1-ol 434. Using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepine in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and (R) -2- (((S) -pyrrolidin-3-ylmethyl) amino) propan-1-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.00(d, J1.8 Hz,1H),7.86(d, J8.8 Hz,1H),7.77(d, J2.2 Hz,1H),7.63-7.53(m,3H),7.23(d, J1.3 Hz,1H),7.08(t, J8.6 Hz,2H),6.65(d, J9.3 Hz,1H),5.29(s,2H),3.95-3.78(m,2H),3.73(br.s.,1H),3.63-3.47(m,2H),3.44-3.32(m,2H),3.21(d, J7.5, 2H),7.73 (J, 3.3H), 3.9, 3.3H, 3, 3.3, 14H), 3.3.7, 3H, 3,14, 3H, 3H, 3,14, 3, etc. ESI [ M + H ] ═ 473.1

(3R,4S) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 435. Using general procedure A substituting 7-bromo-12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin for 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and with (3R,4R) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.97(br.s.,1H),7.87(d, J8.8 Hz,1H),7.73(br.s.,1H),7.64-7.53(m,3H),7.22(br.s.,1H),7.09(t, J ═ 8.2Hz,2H),6.66(d, J ═ 8.8Hz,1H),5.29(s,2H),4.29(d, J ═ 6.6Hz,1H),3.97(d, J ═ 8.4Hz,2H),3.45-3.32(m,4H),2.99(s,6H),2.79-2.62(m, 1H). ESI [ M + H ] ═ 459.3

(3S,4R) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 436. Using general procedure A substituting 7-bromo-12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin for 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and ((3S,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.98(br.s.,1H),7.86(d, J ═ 9.3Hz,1H),7.74(br.s.,1H),7.62 to 7.53(m,3H),7.21(s,1H),7.08(t, J ═ 8.8Hz,2H),6.66(d, J ═ 9.3Hz,1H),5.29(s,2H),4.27(q, J ═ 6.6Hz,1H),4.02 to 3.89(m,2H),3.42 to 3.31(m,4H),2.98(s,6H),2.73 to 2.64(m, 1H). ESI [ M + H ] ═ 459.2

(S) -2- ((((R) -1- (12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methyl) amino) propan-1-ol, 437 ] using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepin in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and (S) -2- (((S) -pyrrolidin-3-ylmethyl) amino) propan-1-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.01(d, J1.3 Hz,1H),7.86(d, J8.8 Hz,1H),7.78(d, J1.3 Hz,1H),7.66-7.53(m,3H),7.25(s,1H),7.09(t, J8.6 Hz,2H),6.66(d, J8.8 Hz,1H),5.30(s,2H),3.95-3.80(m,2H),3.74(br.s.,1H),3.67-3.50(m,2H),3.46-3.33(m,2H),3.27-3.18(m,2H),2.74 (J, 7.2,14.8, 1H),3.18 (m,2H),2.74 (d, J, 1H), 14.8, 1H), 1.18 (d, 1H),1.9, 1H), 1H, 9, 1H, and 1H). ESI [ M + H ] ═ 473.1

12- (4-fluorophenyl) -7- (2-methyl-2, 6-diazaspiro [3.4] oct-6-yl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepine, 441 using general procedure A with a 7-bromo-12- (4-fluorophenyl) -9H-imidazo [2,1-c ] pyrido [3,2-e ] pyrrolo [1,2-a ] [1,4] diazepine in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile and with 2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester instead of (azetidin-3-ylmethyl) (methyl) carbamic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.02(s,1H),7.89(d, J9.0 Hz,1H),7.78(s,1H),7.64(s,1H),7.59(t, J6.3 Hz,2H),7.24(s,1H),7.10(t, J8.3 Hz,2H),6.68(d, J8.8 Hz,1H),5.32(s,2H),4.42-4.27(m,1H),4.22-4.05(m,3H),3.93-3.80(m,2H),3.64(d, J6.3 Hz,2H),3.00(br.s.,3H),2.41(d, J6.1, 2H). ESI [ M + H ] ═ 441.1

Scheme 42:

the chemical experiment method comprises the following steps: general procedure R is as follows.

2- (((1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) methyl) amino) -2-methylpropanoic acid methyl ester, S157. preparation of 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine (40mg,101umol,1.0eq), methyl 2-methyl-2- ((pyrrolidin-3-ylmethyl) amino) propionate (60mg,304umol,3.0eq), CuI (80mg,420umol,4.1eq), L-proline (16mg,139umol,1.37eq), and K₃PO₄A mixture of (96mg,452.5umol,4.4eq) in DMSO (1.5mL) at 90 ℃ under N₂Stirring under atmosphere for 12 hr. The solution was used in the next step without work-up.

2- (((1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) methyl) amino) -2-methylpropionic acid, 479 preparation of 2- (((1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]A mixture of diazepine-7-yl) pyrrolidin-3-yl) methyl) amino) -2-methylpropanoic acid methyl ester (52mg,101umol,1.0eq) in DMSO (1.5mL) was diluted with THF (1.5mL) and NaOH (20mg,506umol,5.0eq) was subsequently added to H₂Solution in O (500 uL). The mixture was stirred at 50 ℃ for 5 hr. The pH of the mixture was adjusted to 6-7 by TFA. It was then filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (TFA conditions) to give 2- (((1- (12- (4-fluorobenzene) 1) as a white solidRadical) -9H-benzo [ e ]]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) methyl) amino) -2-methylpropanoic acid (21mg,34umol, 33.8% yield, 98.4% purity, TFA).¹H NMR (400MHz, methanol-d)₄)δ＝8.00(d,J＝1.3Hz,1H),7.74(d,J＝1.8Hz,1H),7.66-7.49(m,4H),7.20(s,1H),7.09(t,J＝8.6Hz,2H),6.81(br.s.,1H),6.76(d,J＝9.3Hz,1H),5.28(s,2H),3.72-3.61(m,1H),3.54(dd,J＝4.0,8.4Hz,1H),3.50-3.38(m,1H),3.28-3.13(m,3H),2.75(td,J＝7.1,14.1Hz,1H),2.38(dd,J＝4.9,11.5Hz,1H),2.03-1.90(m,1H),1.63(s,6H)。ESI[M+H]＝500.2

Scheme 43:

the chemical experiment method comprises the following steps: the general procedure S is as follows.

2,2, 2-trifluoro-N- ((trans) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) -4- (hydroxymethyl) pyrrolidin-3-yl) acetamide, S158, to 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]To a solution of diazepine (70mg,177umol,1.0eq) in DMSO (3.0mL) was added 2,2, 2-trifluoro-N- ((trans) -4- (hydroxymethyl) pyrrolidin-3-yl) acetamide (289.6mg,887.8umol,5.0eq, TFA), CuI (101mg,532.7umol,3.0eq), L-proline (10.2mg,88.8umol,0.5eq), and K-proline (K-E)₃PO₄(188.4mg,887.8umol,5.0eq) and the mixture was heated at 90 ℃ under N₂Stirring under atmosphere for 16 hr. The mixture was poured into water (50mL) and the aqueous phase was extracted with DCM (50 mL. times.3). The combined organic phases were dried, filtered and concentrated. By preparative HPLC (column: Boston Green ODS150 x 305 u; mobile phase: [ water (0.1% TFA) -ACN](ii) a B%: 1% -40%, 15min) to give 2,2, 2-trifluoro-N- ((trans) -1- (12- (4-fluorophenyl) -9H-benzo [ e) as a yellow solid]Imidazo [2 ]2,1-c]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) -4- (hydroxymethyl) pyrrolidin-3-yl) acetamide (60mg, crude).

((trans) -4-amino-1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) methanol, 489 to 2,2, 2-trifluoro-N- ((trans) -1- (12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Addition of K to a solution of diazepine-7-yl) -4- (hydroxymethyl) pyrrolidin-3-yl) acetamide (60mg,114umol,1.0eq) in MeOH (5.0mL)₂CO₃(47.3mg,342.5umol,3.0eq) and the mixture was stirred at 60 ℃ for 16 hr. The mixture was concentrated and purified by acidic preparative HPLC (column: Boston Green ODS150 x 305 u; mobile phase: [ water (0.1% TFA) -ACN](ii) a B%: 1% -40%, 15min) to give ((trans) -4-amino-1- (12- (4-fluorophenyl) -9H-benzo [ e) as a yellow solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) methanol (40.7mg,92umol, 80.6% yield, 97% purity).¹H NMR (400MHz, methanol-d)₄)δ＝8.01(d,J＝2.2Hz,1H),7.74(d,J＝2.2Hz,1H),7.64-7.50(m,4H),7.19(d,J＝1.8Hz,1H),7.07(t,J＝8.7Hz,2H),6.88(d,J＝2.4Hz,1H),6.80(dd,J＝2.5,8.9Hz,1H),5.29(s,2H),3.97-3.89(m,1H),3.83-3.70(m,3H),3.64(dd,J＝7.3,10.8Hz,1H),3.51(dd,J＝4.3,10.9Hz,1H),3.27-3.22(m,1H),2.71-2.60(m,1H)。ESI[M+H]＝430.1

Scheme 44:

the chemical experiment method comprises the following steps: the general procedure T is as follows.

((cis) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) methyl) (methyl) carbamic acid benzyl ester, S159. preparation of 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine (300mg,761umol,1.0eq), (((cis) -4-fluoropyrrolidin-3-yl) methyl) (methyl) carbamic acid benzyl ester (810mg,3mmol,4.0eq), CuI (144.9mg,760.9umol,1.0eq), K₃PO₄A mixture of (484.6mg,2.3mmol,3.0eq) and L-proline (26.3mg,228.3umol,0.3eq) in DMSO (5.0mL) at 100 ℃ in N₂Stirring under atmosphere for 12 hr. The mixture was diluted with THF (20mL) and TMT (5mL), stirred at 60 ℃ for 30min and then filtered. The filtrate was concentrated in vacuo. By preparative HPLC (column: Boston Green ODS150 x 305 u; mobile phase: [ water (0.1% TFA) -ACN](ii) a B%: 45% -75%, 10min) to give (((cis) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e) as a yellow solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) methyl) (methyl) carbamic acid benzyl ester (110mg,170umol, 22.4% yield, 90% purity).¹H NMR (400MHz, chloroform-d) δ 7.55(s,1H),7.40-7.22(m,11H),6.99-6.95(m,2H),6.54-6.50(m,2H),5.14-5.11(m,2H),4.94(s,2H),3.72-3.23(m,7H),3.04(s,3H),3.00-2.68(m, 1H). ESI [ M + H ]]＝580.3

1- ((3S,4S) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmelamine, 466.

1- ((3R,4R) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmelamine, 474.

To (((cis) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Benzyl diazepine-7-yl) pyrrolidin-3-yl) methyl) (methyl) carbamate(500mg,862umol,1.0eq) to a solution in DCM (5.0mL) and ACN (5.0mL) TMSI (345mg,1.7mmol,234.8uL,2.0eq) was added dropwise followed by stirring at 35 ℃ for 0.5hr and concentration. The residue was purified by acidic preparative HPLC to give 1- (cis-4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) -N-methylmethanamine (476) (300 mg). The cis-compound 476 was subsequently separated by SFC, yielding two homochiral compounds. 1- ((3S,4S) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e) is obtained as a white solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) -N-methyl methylamine (466) (100mg,177umol, 20.6% yield, 99.4% purity, TFA, ee% ═ 100%), which was randomly assigned as the left peak in SFC.¹H NMR (400MHz, methanol-d)₄)δ＝δ＝8.01(d,J＝2.2Hz,1H),7.74(d,J＝1.8Hz,1H),7.62-7.51(m,4H),7.19(d,J＝1.8Hz,1H),7.08(t,J＝8.6Hz,2H),6.83(d,J＝2.6Hz,1H),6.77(dd,J＝2.6,8.8Hz,1H),5.53-5.33(m,1H),5.28(s,2H),3.87-3.81(m,1H),3.80-3.71(m,2H),3.71-3.66(m,1H),3.44(dd,J＝7.7,13.0Hz,1H),3.26(br.s.,1H),2.88(d,J＝15.0Hz,1H),2.80(s,3H)。ESI[M+H]＝446.2

1- ((3R,4R) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-7-yl) pyrrolidin-3-yl) -N-methylmethanamine (474) (3.41mg,6.97umol, 3.67% yield, 91% purity, ee% ═ 96.6%) was obtained as a yellow solid, which was randomly assigned as the right peak in SFC. 1H NMR (400MHz, methanol-d 4) δ 7.56-7.49(m,3H),7.37(d, J8.8 Hz,1H),7.27(s,1H),7.18(s,1H),7.03(t, J8.7 Hz,2H),6.90(s,1H),6.74(s,1H),6.66(dd, J2.2, 8.8Hz,1H),5.44-5.26(m,1H),5.05(s,2H),3.78-3.56(m,3H),3.24-3.13(m,1H),3.04(dd, J7.4, 12.0Hz,1H),2.87(br dd, J7.1, 11.9, 1H),2.76 (1H), 2.57H, 52H), 2.52H (m, 2H). ESI [ M + H ] ═ 446.1

Scheme 45:

the chemical experiment method comprises the following steps: general procedure U is as follows.

1- ((cis) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine, 477 reacting 1- ((cis) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ]]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]A mixture of diazepine-7-yl) pyrrolidin-3-yl) -N-methylmethanamine (5.0mg,11.2umol,1.0eq) and formaldehyde (9.1mg,112umol,8.3uL,10eq) in MeOH (3.0mL) was stirred at 25 ℃ for 10min, followed by addition of NaBH₃CN (2.1mg,33.6umol,3.0eq) and stirred at 25 ℃ for 5 min. The mixture was concentrated and purified by preparative HPLC (column: Boston Green ODS150 x 305 u; mobile phase: [ water (0.1% TFA) -ACN](ii) a B%: 17% -47%, 10min) to yield the product 1- ((cis) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e) as a yellow solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine (1.0mg,1.7umol, 15.2% yield, 95% purity, TFA). 1H NMR (400MHz, methanol-d 4) δ 8.03(s,1H),7.77(s,1H),7.63-7.53(m,4H),7.21(s,1H),7.10(t, J ═ 8.6Hz,2H),6.85(s,1H),6.80(d, J ═ 8.8Hz,1H),5.56-5.37(m,1H),5.30(s,2H),3.89-3.82(m,1H),3.80(d, J ═ 11.0Hz,1H),3.73(d, J ═ 11.8Hz,1H),3.63(dd, J ═ 7.0,13.6Hz,1H),3.43(dd, J, 6.8,13.4, 1H),3.37 (dd, 7.0,13.6Hz,1H),3.43(dd, J, 13.8, 13.4, 1H), 3.37H, 3.08(m, 7H), 7.08H). ESI [ M + H ]]＝460.2

Scheme 46:

the chemical experiment method comprises the following steps: general procedure V is as follows.

Azetidin-1-yl((trans) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) -4-hydroxypyrrolidin-3-yl) methanone, S160. preparation of 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine (100mg,253umol,1.0eq), azetidin-1-yl ((trans) -4-hydroxypyrrolidin-3-yl) methanone (86.4mg,507umol,2.0eq), CuI (144.9mg,760.9umol,3.0eq), K₃PO₄A mixture of (26.9mg,126.8umol,0.5eq) and L-proline (87.6mg,760.9umol,3.0eq) in DMSO (5.0mL) at 100 ℃ in N₂Stirring for 2 hr. The mixture was diluted with THF (20mL) and TMT (2mL) and stirred at 60 ℃ for 30 min. The mixture was filtered and the filtrate was concentrated. By preparative HPLC (column: Boston Green ODS150 x 305 u; mobile phase: [ water (0.1% TFA) -ACN](ii) a B%: 23% -53%, 10min) to yield azetidin-1-yl ((trans) -1- (12- (4-fluorophenyl) -9H-benzo [ e) as a white solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) -4-hydroxypyrrolidin-3-yl methanone (40mg,82umol, 32.6% yield). ESI [ M + H ]]＝484.3

Trans-4- (azetidin-1-ylmethyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-ol, S161 azetidin-1-yl ((trans) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) -4-hydroxypyrrolidin-3-yl methanone (70mg,144umol,1.0eq) in BH₃A solution in THF (1M,20mL,138eq) was stirred at 65 ℃ for 30 min. The mixture was quenched with methanol (100mL) at 0 ℃ and then concentrated. The residue was dissolved in ethanol (50mL) and stirred at 80 ℃ for 10 hr. The mixture was concentrated and purified by preparative HPLC (column: Boston Green ODS150 x 305 u; mobile phase: [ water (0.1% TFA) -ACN](ii) a B%: 15% -45%, 10min) to give (trans) -4- (azetidin-1-ylmethyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e) as a yellow solid]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-ol (45mg,77 u)mol, 53% yield, 100% purity, TFA).¹H NMR (400MHz, methanol-d)₄)δ＝7.98(d,J＝1.6Hz,1H),7.71(d,J＝2.4Hz,1H),7.58-7.52(m,4H),7.17(d,J＝1.6Hz,1H),7.10-7.05(m,2H),6.78(d,J＝2.4Hz,1H),6.75-6.65(m,1H),5.26(s,2H),4.30-4.14(m,5H),3.73-3.67(m,2H),3.41-3.38(m,2H),3.24-3.16(m,2H),2.65–2.43(m,3H)。ESI[M+H]＝470.1

(3R,4S) -4- (azetidin-1-ylmethyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 468

(3S,4R) -4- (azetidin-1-ylmethyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 469

Racemic compound S161 was separated by SFC.

The left peak was randomly assigned to (3R,4S) -4- (azetidin-1-ylmethyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol (17mg,29umol, 30% yield, 100% purity, TFA, ee% ═ 99.78%) which was obtained as a yellow solid. 1H NMR (400MHz, methanol-d 4) δ 8.01(d, J ═ 2.0Hz,1H),7.74(d, J ═ 2.0Hz,1H),7.62-7.52(m,4H),7.20(d, J ═ 1.5Hz,1H),7.09(t, J ═ 8.7Hz,2H),6.81(d, J ═ 2.4Hz,1H),6.74(dd, J ═ 2.6,8.8, 1H),5.28(s,2H),4.40-4.09(m,5H),3.77-3.66(m,2H),3.46-3.35(m,2H),3.28-3.15(m,2H),2.70-2.56(m,1H), 2.53-2H (m, 2H). ESI [ M + H ] ═ 470.1

The right peak was randomly assigned to (3S,4R) -4- (azetidin-1-ylmethyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol (21mg,36umol, 37.9% yield, 97% purity, TFA, ee% ═ 94.62%) which was obtained as a yellow solid. 1H NMR (400MHz, methanol-d 4) δ 8.01(d, J ═ 2.0Hz,1H),7.74(d, J ═ 2.0Hz,1H),7.62-7.53(m,4H),7.20(d, J ═ 1.8Hz,1H),7.10(t, J ═ 8.8Hz,2H),6.81(d, J ═ 2.6Hz,1H),6.74(dd, J ═ 2.5,8.9, 1H),5.28(s,2H),4.40-4.09(m,5H),3.72(ddd, J ═ 7.4,9.6,16.9Hz,2H),3.47-3.36(m,2H),3.27-3.15(m,2H), 2H (br, 9, 3.54H), 3.54H (m,2H), 3.9H, 1H, and 1H. ESI [ M + H ] ═ 470.2

Scheme 47:

the chemical experiment method comprises the following steps:

4- (4-fluorophenyl) -1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, S162. to methyl 4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (5.5g,25mmol,1.0eq) and (Boc)₂DMAP (306mg,2.5mmol,0.1eq) was added in one portion to a mixture of O (6.5g,30.1mmol,6.9mL,1.2eq) in THF (200 mL). The mixture was stirred at 20 ℃ for 1hr and then concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 5:1) to give 4- (4-fluorophenyl) -1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a yellow oil (17g,47.9mmol, 95.5% yield, 90% purity).¹H NMR (400MHz, chloroform-d) δ 7.50-7.49(m,1H),7.45-7.42(m,2H),7.06-7.04(m,3H),3.86(s,3H),1.58(s, 9H).

1- (4- (4-fluorophenyl) -1H-pyrrol-2-yl) pent-4-en-1-one, S163. to a solution of 4- (4-fluorophenyl) -1H-pyrrole-1, 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (4.7g,14.8mmol,1.0eq) in THF (90mL) was added CuCN (799mg,8.9mmol,1.9mL,0.6eq) and the mixture was cooled to-78 deg.C, then under N₂Bromine (vinyl) magnesium (1M,89.2mmol,89.2mL,6.0eq) was added dropwise. Stirring the reaction mixture at-78 deg.C for 1hr, and heating to room temperatureStirring at 0 deg.C for 1 hr. The mixture was passed over saturated NH at 0 deg.C₄The Cl solution (100mL) was quenched and extracted with EtOAc (100 mL. times.3). The combined organic phases were dried and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate 10:1 to give 1- (4- (4-fluorophenyl) -1H-pyrrol-2-yl) pent-4-en-1-one (1.5g,4.3mmol, crude) as a yellow solid. ESI [ M + H ]]＝243.9

1- (1- (5-bromo-2-nitrobenzyl) -4- (4-fluorophenyl) -1H-pyrrol-2-yl) pent-4-en-1-one, S164. to a mixture of (5-bromo-2-nitrophenyl) methanol (1.9g,8.3mmol,1.5eq) and TEA (648mg,6.4mmol,888uL,1.2eq) in DCM (20mL) at 0 deg.C was added MsCl (1.2g,10.6mmol,826uL,2.0 eq). The mixture was warmed to 10 ℃ and stirred for 2 hr. Subsequently, 1- [4- (4-fluorophenyl) -1H-pyrrol-2-yl ] pent-4-en-1-one (1.3g,5.3mmol,1.0eq), 25% NaOH solution (4.2g,26.7mmol,5.0eq) and tetrabutylammonium hydroxide (25%, 138mg,534umol,173.31uL,0.1eq) were added to the mixture and stirred at 10 ℃ for 16 hr. The mixture was diluted with water (50mL) and extracted with DCM (30 mL. times.3). The combined organic phases were dried, filtered and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate ═ 20:1 to give the product 1- [1- [ (5-bromo-2-nitro-phenyl) methyl ] -4- (4-fluorophenyl) pyrrol-2-yl ] pent-4-en-1-one (1.4g, crude) as a yellow oil. ESI [ M + H ] ═ 457.0/459.0

1- (1- (2-amino-5-bromobenzyl) -4- (4-fluorophenyl) -1H-pyrrol-2-yl) pent-4-en-1-one, S165. to 1- (1- (5-bromo-2-nitrobenzyl) -4- (4-fluorophenyl) -1H-pyrrol-2-yl) pent-4-en-1-one (700mg,1.5mmol,1.0eq) in THF (10mL), EtOH (10mL) and H₂To a solution in O (3mL) were added Fe (256mg,4.5mmol,3.0eq) and NH₄Cl (122mg,2.3mmol,80.2uL,1.5eq) and the mixture was stirred at 90 ℃ for 1 hr.It was then filtered and the aqueous layer extracted with EtOAc/THF (1:1,20 mL. times.3). The combined organic layers were washed with saturated NaHCO₃Washed (20mL), dried, filtered and concentrated. By preparative HPLC (column: Phenomenex luna C18250 mm 10 um; mobile phase: [ water (10mM NH) ], HPLC₄HCO3)-ACN](ii) a B%: 45% -75%, 20min) to yield 1- (1- (2-amino-5-bromobenzyl) -4- (4-fluorophenyl) -1H-pyrrol-2-yl) pent-4-en-1-one (220mg,514umol, 33.6% yield) as a white solid.¹HNMR (400MHz, chloroform-d) δ 7.42-7.39(m,2H),7.25-7.21(m,2H),7.10-7.02(m,4H),6.56-6.54(m,1H),5.90-5.83(m,1H),5.45(s,2H),5.09-4.98(m,2H),2.97-2.93(m,2H),2.49-2.44(m, 2H). ESI [ M + H ]]＝427.1/429.1

4- (1- (2-amino-5-bromobenzyl) -4- (4-fluorophenyl) -1H-pyrrol-2-yl) -4-oxobutyraldehyde, s166. to 1- (1- (2-amino-5-bromobenzyl) -4- (4-fluorophenyl) -1H-pyrrol-2-yl) pent-4-en-1-one (220mg,514umol,1.0eq) in dioxane (30mL) and H₂NaIO was added to a solution in O (8mL)₄(440mg,2mmol,114uL,4.0eq)、OsO₄(2.6mg, 10.3. mu. mol,0.53uL,0.02eq) and 2, 6-lutidine (110mg,1.0mmol,119.9uL,2.0 eq). The mixture was stirred at 10 ℃ for 16 hr. The mixture was diluted with water (20mL) and then extracted with DCM (50 mL. times.2). The combined organic phases were dried, filtered and concentrated to give 4- (1- (2-amino-5-bromobenzyl) -4- (4-fluorophenyl) -1H-pyrrol-2-yl) -4-oxobutyraldehyde (250mg, crude) as a dark brown solid, which was used directly in the next step without further purification.

7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Dipyrrolo [1,2-a:2',1' -c][1,4]Azepine, S167. 4- (1- (2-amino-5-bromobenzyl) -4- (4-fluorophenyl) -1H-pyrrol-2-yl) -4-oxobutyraldehyde (150mg,349umol,1.0eq) was dissolved inACN (5.0mL), then AcONa (28.6mg,349.4umol,1.0eq), AcOH (20.9mg,349.4umol,19.9uL,1.0eq), and ammonium formate (22mg,349umol,1.0eq) were added to the mixture. The mixture was stirred at 65 ℃ for 16hr, followed by filtration and concentration of the filtrate. By preparative HPLC (column: Daiso 250 x 50mm,10 um; mobile phase: [ water (0.1% TFA) -ACN](ii) a B%: 55% -85%, 20min) to give 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] as a dark brown solid]Dipyrrolo [1,2-a:2',1' -c][1,4]Diazepine (80mg,203umol, 58.2% yield).¹H NMR (400MHz, chloroform-d) δ 7.57-7.52(m,2H),7.44(dd, J5.3, 8.8Hz,2H),7.29(d, J8.4 Hz,1H),7.12-7.07(m,1H),7.05-6.97(m,3H),6.57(d, J1.8 Hz,1H),6.52(dd, J1.8, 3.5Hz,1H),6.45(t, J3.1 Hz,1H),5.03(s, 2H).

Scheme 48:

the chemical experiment method comprises the following steps:

1- (5-bromo-2-nitrophenyl) ethanol, S169. to a solution of 1- (5-bromo-2-nitrophenyl) ethanone (4.9g,20.4mmol,1.0eq) in MeOH (100mL) at 0 deg.C was added NaBH portionwise₄(1.5g,40mmol,2.0 eq). The mixture was warmed to 15 ℃ and stirred for 2 hr. The reaction mixture was quenched with water (50mL) and then concentrated to remove MeOH. The aqueous phase was extracted with DCM (50 mL. times.3). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated to give 1- (5-bromo-2-nitrophenyl) ethanol (4.9g, 90% purity) as a yellow solid, which was used in the next step without purification.¹HNMR (400MHz, chloroform-d) δ is 8.00(d, J is 2.4Hz,1H),7.81(d, J is 8.4Hz,1H),7.61(dd, J is 2.4,8.4Hz,2H),5.29(q, J is 6.4Hz,1H),1.44(d, J is 6.4Hz, 3H).

Methyl 1- (1- (5-bromo-2-nitrophenyl) ethyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate, S170. methyl 4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (2.2g,10mmol,1.0eq), 1- (5-bromo-2-nitrophenyl) ethanol (2.99g,12mmol,1.2eq) and PPh₃A mixture of (4.7g,18mmol,1.8eq) in THF (20mL) was degassed and N was used₂Purge 3 times, and then add DEAD (3.15g,18mmol,3.3mL,1.8eq) dropwise to the solution. The mixture was heated at 70 ℃ under N₂Stir under atmosphere for 1hr and then concentrate. By column chromatography (SiO)₂Petroleum ether/ethyl acetate 100:1 to 50:1) to give methyl 1- (1- (5-bromo-2-nitrophenyl) ethyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (1.05g,2.1mmol, 21% yield, 90% purity) as a pale red solid.¹H NMR (400MHz, chloroform-d) δ 7.79(d, J8.8 Hz,1H),7.49-7.40(m,4H),7.17(d, J1.8 Hz,1H),7.02(t, J8.6 Hz,2H),6.96(d, J1.8 Hz,1H),6.72(q, J6.8 Hz,1H),3.60(s,3H),1.91(d, J7.1 Hz, 3H). ESI [ M + H ]]＝447.0/449.0

Methyl 1- (1- (2-amino-5-bromophenyl) ethyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate, S170A. to methyl 1- (1- (5-bromo-2-nitrophenyl) ethyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (1.0g,2.2mmol,1.0eq) in H₂To a mixture of O (2.0mL), THF (6.0mL) and MeOH (6.0mL) were added Fe (1.25g,22.4mmol,10.0eq) and NH₄Cl (5.0g,93.5mmol,3.3mL,41.7 eq). The mixture was stirred at 80 ℃ for 1hr, then the filtrate was filtered and concentrated to give methyl 1- (1- (2-amino-5-bromophenyl) ethyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (1.1g, crude) as a light yellow solid, which was used in the next step without purification.

7-bromo-2- (4-fluorophenyl) -5-methyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]To a mixture of methyl 1- (1- (2-amino-5-bromophenyl) ethyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (1.1g,2.6mmol,1.0eq) in toluene (30mL) was added dropwise AlMe-11 (10H) -one, S171₃(2M,6.6mL,13.2mmol,5.0eq) and the mixture was stirred at 15 ℃ for 12 hr. The mixture was quenched by cooled 1N HCl (30mL) and extracted with ethyl acetate/THF (2:1,100 mL. times.3). The organic layer was washed with brine (50mL) over MgSO₄Dried and concentrated to give 7-bromo-2- (4-fluorophenyl) -5-methyl-5H-benzo [ e ] as a pale yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one (1.05g, crude), which was used in the next step without purification. ESI [ M + H ]]＝385.0/387.0

7-bromo-11-chloro-2- (4-fluorophenyl) -5-methyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine, S172, preparation of 7-bromo-2- (4-fluorophenyl) -5-methyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one (300mg,778umol,1.0eq) in POCl₃(30mL) the mixture was stirred at 70 ℃ for 2 hr. The reaction mixture was concentrated to give 7-bromo-11-chloro-2- (4-fluorophenyl) -5-methyl-5H-benzo [ e ] as a yellow oil]Pyrrolo [1,2-a][1,4]Diazepine (1.50g, crude), which was used in the next step without purification.

7-bromo-N- (2, 2-dimethoxyethyl) -2- (4-fluorophenyl) -5-methyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Azadipine-11-amine, S173, to 7-bromo-11-chloro-2- (4-fluorophenyl) -5-methyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]To a mixture of diazepine (1.5g,3.7mmol,1.0eq) in THF (5mL) and dioxane (5mL) was added Et₃N until pH 9.2, 2-Dimethoxyethylamine (2.3g,22.3mmol,2.4mL,6.0eq) was then added and the mixture was mixedThe mixture was stirred at 120 ℃ for 12 hr. The reaction mixture was concentrated and the residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate 10/1 to 6/1) to give 7-bromo-N- (2, 2-dimethoxyethyl) -2- (4-fluorophenyl) -5-methyl-5H-benzo [ e ] as a pale yellow oil]Pyrrolo [1,2-a][1,4]Diazepine-11-amine (305mg,368umol, 9.9% yield, 57% purity). ESI [ M + H ]]＝472.2/474.2

7-bromo-12- (4-fluorophenyl) -9-methyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine, S174. A mixture of 7-bromo-N- (2, 2-dimethoxyethyl) -2- (4-fluorophenyl) -5-methyl-5H-benzo [ e ] pyrrolo [1,2-a ] [1,4] diazepine-11-amine (305mg,645umol,1.0eq) in 1M HCl (5mL) and dioxane (5mL) is stirred at 80 ℃ for 12hr and then concentrated. The residual solids were washed with THF (2 mL. times.2) and dried to yield 7-bromo-12- (4-fluorophenyl) -9-methyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine (150mg, crude) as a brown solid. ESI [ M + H ] ═ 407.9/409.9

Scheme 49:

the chemical experiment method comprises the following steps:

scheme 50:

the chemical experiment method comprises the following steps:

3- (4-fluorophenyl) methyl propiolate, S181At-70 ℃ under N₂To a solution of 1-ethynyl-4-fluorobenzene (22.5g,187.3mmol,21.4mL,1.0eq) in anhydrous THF (400mL) under atmosphere was added n-BuLi (2.5M,88mL,1.17eq) dropwise. After stirring at-70 ℃ for 1hr, methyl chloroformate (20g,211mmol,16mL,1.13eq) was added dropwise and the mixture was stirred at-70 ℃ for 0.5hr, followed by warming to 15 ℃ and holding for 1.5 hr. The mixture was cooled to-5 ℃ with saturated NH₄Aqueous Cl (200mL) was quenched and extracted with EtOAc (100 mL. times.3). The combined organic layers were passed over Na₂SO₄Dried and concentrated to dryness. The residual solid was washed with EtOAc/petroleum ether (1:80,100 mL. times.2) and filtered. The filter cake was dried in vacuo to give methyl 3- (4-fluorophenyl) propiolate as a white solid (23g,122mmol, 65.5% yield, 95% purity). 1HNMR (400MHz, chloroform-d) d ═ 7.60(dd, J ═ 5.6,8.4Hz,2H),7.09(t, J ═ 8.6Hz,2H),3.85(s,3H)

3- (4-fluorophenyl) -1H-pyrrole-2, 4-dicarboxylic acid dimethyl ester, S182. in N₂Atmosphere down Cu₂To a mixture of O (915mg,6.4mmol,654uL,0.06eq), 1, 10-phenanthroline (2.3g,12.8mmol,0.12eq) and methyl 3- (4-fluorophenyl) propiolate (19g,106mmol,1.0eq) in dioxane (300mL) was added dropwise methyl 2-isocyanoacetate (13g,131mmol,11.9mL,1.2 eq). The mixture was stirred at 100 ℃ for 16hr, filtered and the filtrate was concentrated. The residual solid was washed with petroleum ether/EtOAc (1:1,150mL) and then dried to give dimethyl 3- (4-fluorophenyl) -1H-pyrrole-2, 4-dicarboxylate (25g,63mmol, 59.5% yield, 70.4% purity) as a light brown solid. 1H NMR (400MHz, chloroform-d) d 7.59(d, J3.5 Hz,1H),7.35-7.28(m,2H),7.07(t, J8.8 Hz,2H),3.70(s,3H),3.69(s, 3H). ESI [ M + H ]]＝277.9

Dimethyl 3- (4-fluorophenyl) -5-iodo-1H-pyrrole-2, 4-dicarboxylate s182a to a solution of dimethyl 3- (4-fluorophenyl) -1H-pyrrole-2, 4-dicarboxylate (5.0g,18mmol,1.0eq.) in AcOH (200mL) was added AcONa (8.9g,108mmol,6.0eq.) and the mixture was heated to 80 ℃. A solution of ICl (8.8g,54mmol,2.7mL,3.0eq.) in AcOH (200mL) was then added and the mixture was stirred at 80 ℃ for 16 hr. The mixture was cooled and sodium thiosulfate was added to the mixture until the color turned yellow. Water was then added until a yellow precipitate formed. The yellow solid was filtered, washed with water and dried to give 3- (4-fluorophenyl) -5-iodo-1H-pyrrole-2, 4-dicarboxylic acid dimethyl ester (4.3g, crude) as a yellow solid. 1H NMR (400MHz, chloroform-d) δ 9.38(br.s.,1H),7.23-7.17(m,2H),7.07-6.99(m,2H),3.67(s,3H),3.60(s, 3H).

3- (4-fluorophenyl) -5- ((triisopropylsilyl) ethynyl) -1H-pyrrole-2, 4-dicarboxylic acid dimethyl ester, S182B to a solution of 3- (4-fluorophenyl) -5-iodo-1H-pyrrole-2, 4-dicarboxylic acid dimethyl ester (4.3g,10.7mmol,1.0eq.) in THF (100mL) was added ethynyl (triisopropyl) silane (2.9g,16mmol,3.6mL,1.5eq.), Pd (PPh)₃)₂Cl₂(748mg,1.07mmol,0.1eq.), CuI (406mg,2.1mmol,0.2eq.), and TEA (3.2g,32mmol,4.4mL,3.0eq.) and the mixture was heated at 70 ℃ under N₂Stirring for 16 hr. The mixture was concentrated and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 50:1 to 5:1) to give 3- (4-fluorophenyl) -5- ((triisopropylsilyl) ethynyl) -1H-pyrrole-2, 4-dicarboxylic acid dimethyl ester (4.0g, crude) as a yellow solid. ESI [ M + H ]]＝458.3

Dimethyl 5-ethynyl-3- (4-fluorophenyl) -1H-pyrrole-2, 4-dicarboxylate, s182c to a solution of dimethyl 3- (4-fluorophenyl) -5- ((triisopropylsilyl) ethynyl) -1H-pyrrole-2, 4-dicarboxylate (1.0g,2.2mmol,1.0eq.) in THF (20mL) was added TBAF (1M,6.6mL,3.0eq.) and the mixture was stirred at 26 ℃ for 0.5 hr. The mixture was concentrated and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 5:1 to 1:1) to give 5-ethynyl-3- (4-fluorophenyl) -1H-pyrrole-2, 4-dicarboxylic acid dimethyl ester (650mg, crude) as a pale red solid. 1H NMR (400MHz, chloroform-d) δ 9.49(br.s.,1H),7.27-7.24(m,1H),7.24-7.20(m,1H),7.04(t, J ═ 8.8Hz,2H),3.68(s,3H),3.65(s,3H),3.48(s, 1H).

2-azido-5-bromobenzaldehyde, S184. to a solution of 5-bromo-2-fluoro-benzaldehyde (5.0g,24.6mmol,1.0eq.) in HMPA (100mL) was added sodium azide (4.8g,73.9mmol,2.6mL,3.0eq.) and the mixture was stirred at 50 ℃ for 2 hr. The mixture was diluted with water (100mL), extracted with EtOAc (150 mL. times.3), dried and concentrated. The residue was purified by silica gel chromatography (50: 1 to 5:1 petroleum ether/ethyl acetate) to give 2-azido-5-bromobenzaldehyde (5.0g, crude) as a yellow solid. 1H NMR (400MHz, chloroform-d) δ 10.21(s,1H),7.93(s,1H),7.65(d, J8.4 Hz,1H),7.11(d, J8.4 Hz, 1H).

(2-azido-5-bromophenyl) methanol, S185. to a solution of 2-azido-5-bromobenzaldehyde (1.0g,4.4mmol,1.0eq.) in MeOH (50mL) was slowly added NaBH₄(501mg,13mmol,3.0eq.) and the mixture was stirred at 26 ℃ for 0.5 hr. The mixture was concentrated, diluted with ethyl acetate (30mL) and washed with H₂O (15 mL. times.2) wash. The aqueous phase was extracted with ethyl acetate (15 mL. times.3). The combined organic layers were dried over anhydrous MgSO₄Dried, filtered and concentrated to give (2-azido-5-bromophenyl) methanol (980mg, crude) as a yellow oil, which was used in the next step without further purification.

Dimethyl 1- (2-azido-5-bromobenzyl) -5-ethynyl-3- (4-fluorophenyl) -1H-pyrrole-2, 4-dicarboxylate, S186. to a solution of (2-azido-5-bromophenyl) methanol (S185) (417mg,1.8mmol,1.0eq.) in DCM (5mL) at 0 ℃ were added TEA (554mg,5.5mmol,759uL,3.0eq.) and MsCl (251mg,2.2mmol,170uL,1.2 eq.). The mixture was stirred at 20 ℃ for 0.5hr, and then cooled to 0 ℃. To the mixture was added 5-ethynyl-3- (4-fluorophenyl) -1H-pyrrole-2, 4-dicarboxylic acid dimethyl ester (S182C) (550mg,1.8mmol,1.0eq.) followed by tetrabutylammonium hydroxide (189mg,182umol,236uL, 25% purity, 0.1eq.) and NaOH (1.7g,10.9mmol, 25% purity, 6.0 eq.). Stirring the mixture at 40 deg.C for 3hr, and adding H₂O (5mL) and extracted with DCM (10 mL. times.5). The combined organic layers were washed with brine (10mL) and dried over anhydrous Na₂SO₄Dried, filtered and concentrated to give dimethyl 1- (2-azido-5-bromobenzyl) -5-ethynyl-3- (4-fluorophenyl) -1H-pyrrole-2, 4-dicarboxylate (1.0g, crude) as a yellow solid which was used in the next step without further purification. ESI [ M + H ]]＝511.0/513.1

10-bromo-5- (4-fluorophenyl) -8H-benzo [ e ] pyrrolo [1,2-a ] [1,2,3] triazolo [5,1-c ] [1,4] diazepine-4, 6-dicarboxylic acid dimethyl ester, S187. A solution of dimethyl 1- (2-azido-5-bromobenzyl) -5-ethynyl-3- (4-fluorophenyl) -1H-pyrrole-2, 4-dicarboxylate (990mg,815umol,1.0eq.) in MeCN (10mL) was stirred at 80 ℃ for 20 min. The mixture was filtered and the filtrate was concentrated to give 10-bromo-5- (4-fluorophenyl) -8H-benzo [ e ] pyrrolo [1,2-a ] [1,2,3] triazolo [5,1-c ] [1,4] diazepine-4, 6-dicarboxylic acid dimethyl ester (379mg, crude) as a light yellow solid, which was used in the next step without further purification. 1H NMR (400MHz, chloroform-d) δ 8.41(s,1H),7.94-7.87(m,2H),7.74(dd, J ═ 2.2,8.8Hz,1H),7.21-7.11(m,2H),7.09-6.97(m,2H),6.44(br s,1H),4.63(br s,1H),3.61(s,3H),3.54(s, 3H). ESI [ M + H ] ═ 511.0/513.1

10-bromo-5- (4-fluorophenyl) -8H-benzo [ e ] pyrrolo [1,2-a ] [1,2,3] triazolo [5,1-c ] [1,4] diazepine-4, 6-dicarboxylic acid, S188. to a solution of 10-bromo-5- (4-fluorophenyl) -8H-benzo [ e ] pyrrolo [1,2-a ] [1,2,3] triazolo [5,1-c ] [1,4] diazepine-4, 6-dicarboxylic acid dimethyl ester (150mg,293umol,1.0eq.) in EtOH (2mL)/THF (1mL) was added KOH (82mg,1.5mmol,5.0eq.) in water (2.0 mL). The resulting mixture was stirred at 60 ℃ for 20hr, and then cooled to 0 ℃. The pH of the mixture was adjusted to pH 6-7 with 6M HCl and concentrated to remove EtOH and THF. It was then used directly in the next step as a solution in water (2 mL). ESI [ M + H ] ═ 482.9/484.9

10-bromo-5- (4-fluorophenyl) -8H-benzo [ e]Pyrrolo [1,2-a][1,2,3]Triazolo [5,1-c][1,4]Diazepine, S189, to 10-bromo-5- (4-fluorophenyl) -8H-benzo [ e]Pyrrolo [1,2-a][1,2,3]Triazolo [5,1-c][1,4]Diazepine-4, 6-dicarboxylic acid (141mg,291umol,1.0eq.) in H₂To the suspension in O (2 mL)/dioxane (2mL) was added HCl (2M,4.5mL,31.2eq.) until pH 1. The resulting mixture was stirred at 100 ℃ for 10 hr. Followed by saturation with Na₂CO₃The solution was adjusted to pH 8. The mixture was concentrated, diluted with 5mL water and extracted with EtOAc/THF (5:1,6mL x 3). The combined organic layers were concentrated and the residue was purified by preparative HPLC (TFA conditions) to give 10-bromo-5- (4-fluorophenyl) -8H-benzo [ e ] as a light brown solid]Pyrrolo [1,2-a][1,2,3]Triazolo [5,1-c][1,4]Diazepine (42mg,95umol, 32.8% yield, 90% purity). 1H NMR (400MHz, DMSO-d6) δ 8.17(s,1H),8.00(d, J2.1 Hz,1H),7.94-7.89(m,1H),7.87-7.81(m,1H),7.62-7.53(m,3H),7.19(t, J8.9 Hz,2H),7.02(d, J1.9 Hz,1H),5.30(s, 2H). ESI [ M + H ]]＝394.9/396.9

Scheme 51:

the chemical experiment method comprises the following steps:

5-bromo-3-methyl-2-nitrobenzoic acid, S191, 3-bromo-5-methyl-benzoic acid (9.5g,44.2mmol,1.0eq.) at 0 deg.C in H₂SO₄(50mL) to the solution was added HNO₃(2.8g,44mmol,1.99mL,1.0 eq.). The mixture was then stirred at 20 ℃ for 1 hr. The solution was poured slowly into ice (500g) with vigorous stirring. Some white solid formed. The mixture was extracted with ethyl acetate (300mL x 3), dried, filtered and concentrated. This gave a mixture (10g, mixture) of 5-bromo-3-methyl-2-nitrobenzoic acid (S191) and 3-bromo-5-methyl-2-nitrobenzoic acid as a yellow solid.

(5-bromo-3-methyl-2-nitrophenyl) methanol, S192. to a solution of 5-bromo-3-methyl-2-nitrobenzoic acid (S191) and 3-bromo-5-methyl-2-nitrobenzoic acid (9.9g,38mmol,1.0eq.) in THF (50mL) was added BH₃THF (1M,190mL,5.0eq.) and the mixture was stirred at 70 ℃ for 1 hr. The mixture was cooled to 0 ℃, quenched with MeOH (20mL), and then concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 20:1 to 5:1) to give the product (5-bromo-3-methyl-2-nitrophenyl) methanol (2.1g) as a white solid. 1H NMR (400MHz, chloroform-d) δ 7.56-7.52(m,1H),7.36(d, J1.5 Hz,1H),4.60(d, J6.4 Hz,2H),2.29(s,3H)

1- (5-bromo-3-methyl-2-nitrobenzyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester, S193. at 0 ℃ in N₂To (5-bromo-3-methyl-2-nitrophenyl) methanol (2.0g,8.1mmol,1.0eq.) and Et under atmosphere₃N (1.6g,15.7mmol,2.2mL,1.9eq.) to a solution in anhydrous DCM (50mL) was added dropwise MsCl (1.1g,9.6mmol,743uL,1.2 eq.). The mixture was stirred at 0 ℃ for 1 hr. Methyl 4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (S108) (1.6g,7.3mmol,0.9eq.) was then added followed by tetrabutylammonium hydroxide (800mg,770umol,1.0mL, 25% purity, 0.09eq.) and aqueous NaOH (8.0g,50mmol, 25% purity, 6.1 eq.). The mixture was warmed to 25 ℃ and stirred for 16 hr. The mixture was washed with water (50mL) and brine (30mL) over Na₂SO₄Dried, filtered and concentrated to give methyl 1- (5-bromo-3-methyl-2-nitrobenzyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (3.5g, crude) as a brown solid, which was used directly. ESI [ M + H ]]＝447.0/449.0

1- (2-amino-5-bromo-3-methylbenzyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester, S194 to a mixture of 1- (5-bromo-3-methyl-2-nitrobenzyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylic acid methyl ester (3.4g,7.6mmol,1.0eq.) in EtOH (100mL), THF (50mL) and H₂NH was added to a solution in O (50mL)₄Cl (406mg,7.6mmol,265uL,1.0eq.) and Fe (2.1g,38mmol,5.0eq.) and the mixture was stirred at 90 ℃ for 2 hr. The mixture was filtered and the filtrate was concentrated to remove THF and EtOH. The aqueous phase was extracted with ethyl acetate (100mL x 3). The combined organic phases were washed with brine (100mL) over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to afford methyl 1- (2-amino-5-bromo-3-methylbenzyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (3.0g, crude) as a yellow solid, which was used without purification. ESI [ M + H ]]＝417.0/419.0

7-bromo-2- (4-fluorophenyl) -9-methyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Azadipine-11 (10H) -one, S195, to a solution of methyl 1- (2-amino-5-bromo-3-methylbenzyl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (2.9g,6.9mmol,1.0eq.) in toluene (100mL) at 0 deg.C was added AlMe dropwise₃(2M,17mL,5.0eq.) and the mixture was heated at 26 ℃ under N₂Stirring for 6 hr. The mixture was passed through saturated NH₄Cl (100mL) was quenched and extracted with ethyl acetate (100mL x 3). The combined organic phases were washed with brine (100mL) over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. To the residue was added petroleum ether, ethyl acetate (20mL,4:1) and stirred for 2 hr. The solid was collected by filtration to give 7-bromo-2- (4-fluorophenyl) -9-methyl-5H-benzo [ e ] as a light yellow solid]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one (1.6g, crude). 1H NMR (400MHz, DMSO-d6) δ 9.45(s,1H),7.61-7.48(m,3H),7.44(s,2H),7.20-7.00(m,3H),5.17(s,2H),2.33(s, 3H). ESI [ M + H ]]＝385.1/387.1

7-bromo-11-chloro-2- (4-fluorophenyl) -9-methyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine, S196, preparation of 7-bromo-2- (4-fluorophenyl) -9-methyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one (300mg,778umol,1.0eq.) in POCl₃(5mL) at 80 ℃ for 1hr and concentrated to give 7-bromo-11-chloro-2- (4-fluorophenyl) -9-methyl-5H-benzo [ e ] as a yellow solid]Pyrrolo [1,2-a][1,4]Diazepine (300mg, crude), which may be used without any purification.

7-bromo-N- (2, 2-Dimethoxyethyl) -2- (4-fluorophenyl) -9-methyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Azadipine-11-amine, S197. to 7-bromo-11-chloro-2- (4-fluorophenyl) -9-methyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]To a solution of diazepine (300mg,743umol,1.0eq.) in THF (15mL) and dioxane (15mL) was added 2, 2-dimethoxyethylamine (781mg,7.4mmol,805uL,10eq.) and the mixture was stirred at 130 ℃ in a sealed tube for 16 hr. The mixture was poured into ice water (150mL) and extracted with ethyl acetate (100mL x 3). The combined organic phases were washed with brine (100mL) over anhydrous Na₂SO₄Dried, filtered and concentrated to give 7-bromo-N- (2, 2-dimethoxyethyl) -2- (4-fluorophenyl) -9-methyl-5H-benzo [ e ] as a dark brown solid]Pyrrolo [1,2-a][1,4]Diazepine-11-amine (350mg), which may be used without any purification. ESI [ M + H ]]＝472.1/474.1

7-bromo-12- (4-fluorophenyl) -5-methyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine, S198 to a solution of 7-bromo-N- (2, 2-dimethoxyethyl) -2- (4-fluorophenyl) -9-methyl-5H-benzo [ e ] pyrrolo [1,2-a ] [1,4] diazepine-11-amine (350mg,741umol,1.0eq.) in dioxane (10mL) is added 2M HCl (7.4mL,20eq.) and the mixture is stirred at 100 ℃ for 16 hr. The mixture was concentrated and the residue was purified by acidic preparative HPLC to give 7-bromo-12- (4-fluorophenyl) -5-methyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine (100mg,232umol, 31.4% yield, 95% purity) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.03(s,1H),7.81-7.63(m,3H),7.60-7.49(m,3H),7.22-7.10(m,2H),7.03(s,1H),5.31-5.07(m,2H),2.36(s, 3H). ESI [ M + H ] ═ 408.0/410.0

Scheme 52:

the chemical experiment method comprises the following steps:

10-amino-7-bromo-2- (4-fluorophenyl) -9-methyl-5H-benzo [ e]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one, S199. preparation of 7-bromo-2- (4-fluorophenyl) -9-methyl-5H-benzo [ e ] at 0 deg.C]Pyrrolo [1,2-a][1,4]To a solution of diazepine-11 (10H) -one (S195) (500mg,1.3mmol,1.0eq.) in DMF (10mL) was added NaH (100mg,2.5mmol, 60% purity, 1.9 eq.). After stirring at 0 ℃ for 30min, (aminooxy) diphenylphosphine oxide (400mg,1.7mmol,1.3eq.) was added, and the mixture was heated to 20 ℃ and stirred for 1 hr. The mixture was saturated with ice-cold NH₄Aqueous Cl (100mL) was quenched and extracted with ethyl acetate (50mL x 3). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried and concentrated to give 10-amino-7-bromo-2- (4-fluorophenyl) -9-methyl-5H-benzo [ e ] as a light brown solid]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one (400mg), which is used as such. ESI [ M + H ]]＝400.0/402.0

7-bromo-12- (4-fluorophenyl) -5-methyl-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [5,1-c][1,4]Diazepine, S200, to ZnCl at 200 deg.C₂(50mg,366umol,17uL,2.9eq.) in NH₂To the mixture in CHO (1.0mL) was added 10-amino-7-bromo-2- (4-fluorophenyl) -9-methyl-5H-benzo [ e ]]Pyrrolo [1,2-a][1,4]Diazepine-11 (10H) -one (50mg,124umol,1.0eq.) and the mixture was stirred for 1 hr. The mixture was then diluted with water (50mL) and extracted with ethyl acetate/THF (5:1,30mL x 3). Subjecting the organic layer to Na₂SO₄Dried, filtered and concentrated. The residue was purified by acidic preparative HPLC to give 7-bromo-12- (4-fluorophenyl) -5-methyl-9H-benzo [ e ] as a white solid]Pyrrolo [1,2-a][1,2,4]Triazolo [5,1-c][1,4]Diazepine (20mg,44umol, 35% yield, 90.9% purity). 1HNMR (400MHz, DMSO-d6) δ 8.33(s,1H),7.77(d, J2.0 Hz,1H),7.68(d, J ═ d2.0Hz,1H),7.63-7.56(m,2H),7.54(d,J＝1.8Hz,1H),7.16(t,J＝8.9Hz,2H),7.08(d,J＝1.8Hz,1H),5.37-5.24(m,1H),5.10-4.98(m,1H),2.39(s,3H)。ESI[M+H]＝409.0/411.0

General procedure for amines.

The chemical experiment method comprises the following steps: general procedure a1 is as follows.

(trans) -3-cyano-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M66. to 6-oxa-3-azabicyclo [3.1.0 ]]Hexane-3-carboxylic acid tert-butyl ester (43.00g,232.16mmol,1.00eq) and LiClO₄(37.05g,348.24mmol,15.31mL,1.50eq) in CH₃KCN (30.24g,464.32mmol,19.89mL,2.00eq) was added to the mixture in CN (1.00L) in one portion. The mixture was stirred at 70 ℃ for 20 hr. The mixture was concentrated under reduced pressure at 40 ℃. The residue was poured into ice water (300mL) and extracted with ethyl acetate (150 mL. times.3). The combined organic phases were washed with brine (100mL) and Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using petroleum ether ethyl acetate (20:1 to 5: 1). Tert-butyl (trans) -3-cyano-4-hydroxypyrrolidine-1-carboxylate was obtained as a yellow oil (31.00g,131.45mmol, 56.62% yield based on HNMR, 90% purity).¹H NMR (400MHz, chloroform-d) δ 4.65-4.52(m,1H),3.76(br.s.,3H),3.45-3.28(m,1H),3.04(br.s.,1H),2.83(br.s.,1H),1.46-1.41(m, 9H).

(cis) -3-cyano-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester, M67. at-78 ℃ under N₂Atmosphere down to (trans) -3To a solution of tert-butyl (10.0g,47.11mmol,1.0eq) cyano-4-hydroxy-pyrrolidine-1-carboxylate in DCM (100mL) was added DAST (15.19g,94.23mmol,12.45mL,2.0eq) dropwise. The reaction mixture was stirred at-78 ℃ for 2hr, and then saturated Na was used₂CO₃The solution (100mL) was quenched. The mixture was extracted with DCM (100 mL. times.3). The combined organic phases are passed over Na₂SO₄Dried, then filtered and concentrated. The residue was purified by silica gel column chromatography using petroleum ether ethyl acetate (20:1 to 10:1) to give (cis) -3-cyano-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (9.0g,42mmol, 89% yield) as a pale yellow oil.¹H NMR (400MHz, methanol-d)₄)δ＝5.42-5.22(m,1H),3.97-3.87(m,1H),3.73-3.55(m,2H),3.53-3.43(m,2H),1.56-1.38(m,9H)。

(cis) -3- (aminomethyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester, M68. to a solution of (cis) -3-cyano-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (11.0g,51.34mmol,1.0eq.) in THF (15.00mL) at 10 deg.C was added dropwise BH₃THF (1M,250mL,5.0eq.) and refluxing the reaction mixture at 70 ℃ for 2 hr. The reaction mixture was cooled to 0 ℃ and EtOH was added dropwise until no gas was formed. The mixture was concentrated, dissolved in EtOH (30mL) and refluxed for 16 hr. The mixture was concentrated to give (cis) -3- (aminomethyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil (11.0g, crude), which was used without purification. ESI [ M + H ]]＝219.1

(cis) -3- ((((benzyloxy) carbonyl) amino) methyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester, M69. (cis) -3- (aminomethyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (11g,50.40mmol,1.0eq) and Na at 10 deg.C₂CO₃(10.68g,100.8mmol,2.0eq) in THF (100mL) and H₂To the mixture in O (100mL) was added CbzCl (17.19g,100.8mmol,2.0eq) dropwise. The reaction mixture was stirred for 2hr and extracted with EtOAc (100 mL. times.2). The combined organic phases are passed over Na₂SO₄Dried, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether ethyl acetate (8:1) to give (cis) -3- ((((benzyloxy) carbonyl) amino) methyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (9.0g,25.54mmol, 50% yield) as a colorless oil.¹H NMR (400MHz, chloroform-d) δ 7.33(d, J4.4 Hz,4H),7.24(d, J4.4 Hz,1H),5.17-5.05(m,2H),4.99(br.s.,1H),3.81-3.64(m,2H),3.63-3.52(m,1H),3.47-3.32(m,2H),3.11(d, J7.5 Hz,1H),2.63-2.43(m,1H),1.44(d, J4.0 Hz, 9H). ESI [ M + H ]]＝353.2

Tert-butyl (cis) -3- (((benzyloxy) carbonyl) (methyl) amino) methyl) -4-fluoropyrrolidine-1-carboxylate, M70. to a solution of (cis) -3- ((((benzyloxy) carbonyl) amino) methyl) -4-fluoropyrrolidine-1-carboxylate (9.0g,25.5mmol,1.0eq) and MeI (7.25g,51mmol,3.18mL,2.0eq) in DMF (80mL) at 0 deg.C was added NaH (2.04g,51.08mmol, 60% purity, 2.0eq) portionwise and the mixture was warmed to 10 deg.C and stirred for 0.5 hr. The reaction mixture was cooled to 0 ℃ and saturated ice NH₄Cl solution (500mL quench). The resulting mixture was extracted with EtOAc: THF (1:1,200 mL. times.2). The combined organic phases are passed over Na₂SO₄Dried, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether ethyl acetate (15:1 to 4:1) to give (cis) -3- ((((benzyloxy) carbonyl) (methyl) amino) methyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (9.0g,24.56mmol, 96% yield) as a colorless oil.¹H NMR (400MHz, methanol-d)₄)δ＝7.39-7.24(m,5H),5.19-5.01(m,3H),3.56(br.s.,5H),3.14-3.03(m,1H),2.96(d,J＝11.0Hz,3H),2.59(br.s.,1H),1.44(s,9H)。ESI[M+H]＝367.2

Benzyl ((cis) -4-fluoropyrrolidin-3-yl) methyl) (methyl) carbamate, M71. a solution of (cis) -3- ((((benzyloxy) carbonyl) (methyl) amino) methyl) -4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (9.0g,24.56mmol,1.0eq) in HCl/MeOH (4M,150mL) was stirred at 30 ℃ for 0.5 hr. The reaction mixture was concentrated, dissolved in MeOH (50mL) and basified to pH 7-8 with basic resin. The mixture was filtered and the filtrate was concentrated to dryness. Benzyl (((cis) -4-fluoropyrrolidin-3-yl) methyl) (methyl) carbamate (6.0g,22.5mmol, 91.7% yield) was obtained as a pale yellow oil.¹H NMR (400MHz, methanol-d)₄)δ＝7.44-7.19(m,5H),5.34-5.13(m,1H),5.11(s,2H),3.71-3.62(m,1H),3.52-3.34(m,4H),3.10-2.91(m,4H),2.74-2.53(m,1H)。ESI[M+H]＝267.1

The chemical experiment method comprises the following steps:

general procedure a2 is as follows.

3- (((1-methoxy-2-methyl-1-oxopropan-2-yl) amino) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester, M73. to a solution of 3-formylpyrrolidine-1-carboxylic acid tert-butyl ester (500mg,2.5mmol,1.0eq) and 2-amino-2-methyl-propionic acid methyl ester (352mg,3.0mmol,1.2eq) in MeOH (20mL) was added NaBH₃CN (315mg,5mmol,2.0 eq). The mixture was stirred at 20 ℃ for 12 hr. By preparative HPLC (column: Luna C18100 x 305 u; mobile phase: [ water (0.1% TFA) -ACN](ii) a B%: 5% -35%, 12min) to give tert-butyl 3- (((1-methoxy-2-methyl-1-oxoprop-2-yl) amino) methyl) pyrrolidine-1-carboxylate (300mg,998umol, 39.79% yield) as a yellow oil. ESI [ M + H ]]＝301.2

Methyl 2-methyl-2- ((pyrrolidin-3-ylmethyl) amino) propionate, M74. tert-butyl 3- (((1-methoxy-2-methyl-1-oxoprop-2-yl) amino) methyl) pyrrolidine-1-carboxylate (300mg,998.7umol,1.0eq) in CH₂Cl₂To a solution in (10mL) was added TFA (1.14g,9.99mmol,739uL,10 eq). The mixture was stirred at 45 ℃ for 15min and concentrated at 40 ℃ under reduced pressure. The residue was dissolved in MeOH (50mL) and basified with basic resin to pH 9. The mixture was filtered and the filtrate was concentrated to dryness. Methyl 2-methyl-2- ((pyrrolidin-3-ylmethyl) amino) propionate (200mg, crude) was obtained as a yellow oil, which was used without purification.¹H NMR (400MHz, methanol-d)₄)δ＝3.71(s,3H),3.45-3.42(m,1H),3.36-3.33(m,1H),3.25-3.15(m,1H),3.03-2.98(m,1H),2.61-2.57(m,2H),2.44-2.35(m,1H),2.25-2.15(m,1H),1.76-1.71(m,1H),1.32(s,6H)。ESI[M+H]＝201.1

The chemical experiment method comprises the following steps: general procedure a3 is as follows.

(3R,4S) -3- (((benzyloxy) carbonyl) amino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, m75. synthesized using general procedure L replacing (3S,4S) -3- (benzylamino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester with (3R,4R) -3- (benzylamino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester. ESI [ M + Na ] ═ 359.0

(3aR,6aS) -hexahydro-2H-pyrrolo [3,4-d]Oxazol-2-one, M77 (3R,4S) -3- (((benzyloxy) carbonyl) amino) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (700mg,2.08mmol,1.0eq) was dissolved in HCl/MeOH (4M,20 mL). The mixture was stirred at 26 ℃ for 16hr and concentrated under reduced pressure. By preparative HPLC (column: Boston Green ODS 150 x 305 u; mobile phase: [ water (0.1% TFA) -ACN](ii) a B%: 12% -42%, 10min) the residue was purified and lyophilized. The product was dissolved in MeOH (10mL) and the pH was adjusted to 8-9 with basic resin. The mixture was filtered and the filtrate was concentrated under reduced pressure. Benzyl ((3R,4S) -4-hydroxypyrrolidin-3-yl) carbamate (M76) (300mg, crude) was obtained as a yellow solid. HNMR (¹H NMR (400MHz, chloroform-d) δ 7.30-7.25(m,3H),7.24-7.20(m,2H),5.00(br.s.,2H),4.26(br.s.,2H),3.48(br.s.,1H),3.40-3.18(m,2H),3.07(br.s.,1H)) showed correct structure but not sufficient purity. ESI [ M + H ]]＝237.1

By preparative HPLC (column: Gemini 150 x 255 u; mobile phase: [ water (10mM NH)₄HCO₃)-ACN](ii) a B%: 1% -30%, 15min) and again purified. During concentration at 50 ℃ under reduced pressure, benzyl ((3R,4S) -4-hydroxypyrrolidin-3-yl) carbamate (M76) changed to (3aR,6aS) -hexahydro-2H-pyrrolo [3, 4-d)]Oxazol-2-one (M77). (3aR,6aS) -hexahydro-2H-pyrrolo [3, 4-d) is obtained aS a white solid]Oxazol-2-one (M77) (50mg,234umol, 22% yield, about 60% purity based on HNMR).¹H NMR (400MHz, chloroform-d) δ 5.05-5.02(m,1H),4.26-4.26(m,1H),3.32-3.28(m,1H),3.04-3.00(m,1H),2.72-2.67(m, 2H). ESI [ M + H ]]＝129.1

The chemical experiment method comprises the following steps: general procedure a4 is as follows.

(3S,4S) -3- (((((benzyloxy) carbonyl) amino) methyl) -4- ((tert-butyl)Dimethylsilyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester, m78 to a solution of (3S,4S) -3- ((((benzyloxy) carbonyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (500mg,1.43mmol,1.0eq) in DCM (10mL) was added DMAP (522.9mg,4.28mmol,3.0eq) and TBSCl (1.08g,7.1mmol,874uL,5.0eq) and the mixture was stirred at 26 ℃ for 32 hr. Pouring the mixture into ice-cold saturated KHSO₄The solution (100mL) was extracted with DCM (50 mL. times.3). The combined organic phases were passed over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using petroleum ether ethyl acetate (20:1 to 1:1) to give (3S,4S) -3- ((((benzyloxy) carbonyl) amino) methyl) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil (580mg, crude). ESI [ M + Na ]]＝487.2

Tert-butyl (3S,4S) -3- ((((benzyloxy) carbonyl) (methyl) amino) methyl) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidine-1-carboxylate, to a solution of (3S,4S) -3- (((((benzyloxy) carbonyl) amino) methyl) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidine-1-carboxylate (580mg,1.25mmol,1.0eq) in DMF (10mL) was added NaH (75.2mg,1.88mmol, 60% purity, 1.5eq) at 0 ℃. After stirring for 0.2hr at 26 ℃, MeI (532mg,3.7mmol,233uL,3.0eq) was added and the mixture was stirred for 0.3hr at 26 ℃. The mixture was passed over saturated NH at 0 deg.C₄The Cl solution (20mL) was quenched, poured into ice-cold water (100mL) and extracted with ethyl acetate (50 mL. times.3). The combined organic phases were washed with brine (50mL) over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate 20:1 to 2:1) to give (3S,4S) -3- ((((benzyloxy) carbonyl) (methyl) amino) methyl) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil (550mg, crude).¹H NMR (400MHz, chloroform-d) δ 7.28(br.s.,5H),5.15-4.96(m,2H),4.18(d, J ═ 18.4Hz,1H),3.64-3.04(m,6H),2.88(d,J＝5.1Hz,3H),2.49-2.16(m,1H),1.39(s,9H),0.81(br.s.,9H),0.00(br.s.,6H)。ESI[M+Na]＝501.2

Benzyl ((3R,4S) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamate, M80 tert-butyl (3S,4S) -3- ((((benzyloxy) carbonyl) (methyl) amino) methyl) -4- ((tert-butyldimethylsilyl) oxy) pyrrolidine-1-carboxylate (550mg,1.15mmol,1.0eq) was dissolved in HCl/MeOH (4M,20 mL). The mixture was stirred at 40 ℃ for 2hr, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA conditions) to give benzyl (((3R,4S) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamate (420mg, crude, TFA) as a yellow oil. ESI [ M + H ] ═ 265.1

The chemical experiment method comprises the following steps: general procedure a5 is as follows.

Ethyl (trans) -4-hydroxypyrrolidine-3-carboxylate, M81 to a mixture of tert-butyl (trans) -3-cyano-4-hydroxypyrrolidine-1-carboxylate (70g,329mmol,1.0eq) in anhydrous EtOH (50mL) at 15 ℃ HCl/EtOH (anhydrous, 5M, 1.0L) was added dropwise. The mixture was stirred at 15 ℃ for 4 days and then concentrated to give ethyl (trans) -4-hydroxypyrrolidine-3-carboxylate (70g, crude, HCl salt), which was used directly in the next step without further purification.

(trans) -4-hydroxypyrrolidine1-tert-butyl 3-ethyl 1, 3-dicarboxylate M82 reaction of (trans) -4-hydroxypyrrolidine-3-carboxylic acid ethyl ester (64.5g,329mmol,1.0eq, HCl) in H at 0 deg.C₂To a solution in O (400mL) was added solid NaHCO in portions₃Until the pH was adjusted to about 7, followed by the addition of NaHCO₃(45g,535mmol,1.6 eq). Dropwise adding Boc to the above mixture₂A solution of O (85g,389mmol,89.4mL,1.18eq) in THF (400 mL). The mixture was warmed to 15 ℃ and stirred for 16 hr. The aqueous layer was separated and extracted with EtOAc (200 mL. times.3). The combined organic layers were passed over Na₂SO₄Dried, filtered and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether ethyl acetate (10:1 to 3: 1). This gave (trans) -4-hydroxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl 3-ethyl ester (50g,173.7mmol, 52.7% yield, 90% purity) as a yellow oil.¹H NMR (400MHz, chloroform-d) δ 4.55(q, J5.7 Hz,1H),4.20(quin, J7.3 Hz,2H),3.71(br s,2H),3.61-3.51(m,1H),3.28(br s,1H),2.99(br s,1H),2.74(br s,1H),1.45(s,9H),1.34-1.24(m, 3H).

(3R,4S) -4-acetoxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester, M83.

(3S,4R) -4-hydroxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl 3-ethyl ester, M84.

To a mixture of 1-tert-butyl 3-ethyl (trans) -4-hydroxypyrrolidine-1, 3-dicarboxylate (27g,104.13mmol,1.0eq) and vinyl acetate (27g,313.6mmol,29mL,3.01eq) in MTBE (1.3L) was added Novozyme 435(11g) in portions. The reaction mixture was stirred at 20 ℃ for 20hr (two batches). The two batch mixture was filtered through celite and the solid was washed with EtOAc (300mL × 2). The combined filtrates were washed with saturated NaHCO₃Aqueous solution (1L) and brine (500mL) were washed with Na₂SO₄Dried, filtered and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether ethyl acetate (10:1 to 2: 1). To give (3R,4S) -4-acetoxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl ester as a yellow oil3-Ethyl ester, M83(26g,83mmol, 39.9% yield, 96.3% purity). This gave (3S,4R) -4-hydroxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl 3-ethyl ester, M84(31g,100mmol, 48.2% yield, 83.9% purity, ee%: 95.58%) as a yellow oil.

1-tert-butyl (3-ethyl) (3R,4S) -4-hydroxypyrrolidine-1, 3-dicarboxylate to a solution of 1-tert-butyl (3R,4S) -4-acetoxypyrrolidine-1, 3-dicarboxylate (30g,99.6mmol,1.0eq) in EtOH (300mL) was added concentrated HCl (12M,15mL,4.2eq) portionwise, M85. The reaction mixture was heated to 60 ℃ and stirred for 10 hr. The reaction mixture was cooled to 0 ℃ and H was added₂O (200 mL). With solid NaHCO₃The pH was adjusted to about 7, followed by the addition of NaHCO₃(15g,178mmol,6.9mL,1.79eq) followed by the addition of Boc₂O (25g,114.5mmol,26.3mL,1.15 eq). The mixture was warmed to 15 ℃ and stirred for 16 hr. The mixture was extracted with EtOAc (300 mL. times.3). The combined organic layers were washed with brine (200mL) and Na₂SO₄Dried, filtered and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether ethyl acetate (10:1 to 3: 1). This gave (3R,4S) -4-hydroxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (22g,80mmol, 80.4% yield, 94.3% purity, ee% ═ 89%) as a yellow oil.¹H NMR (400MHz, chloroform-d) δ 4.54(q, J5.5 Hz,1H),4.23-4.13(m,2H),3.80-3.62(m,2H),3.56(d, J6 Hz,1H),3.27(t, J10.5 Hz,1H),2.97(dd, J6.8, 13.6Hz,2H),1.45(s,9H),1.32-1.24(m, 3H). ESI [ M + Na ]]＝282.1

(3R,4S) -4-acetoxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester, m86. (3R,4S) -4-hydroxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (22g,80.4mmol,1.0eq, ee%: 89%) and vinyl acetate (40g,464.6mmol,43mL,5.8eq) in MTBE (1.0L)Novozyme 435(12g) was added to the mixture. The reaction mixture was stirred at 10 ℃ for 20 hr. The mixture was filtered and the solid was washed with EtOAc (300 mL. times.2). The combined filtrates were washed with saturated NaHCO₃Aqueous solution (1L) and brine (500mL) were washed with Na₂SO₄Dried, then filtered and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether ethyl acetate (10:1 to 2: 1). This gave (3R,4S) -4-acetoxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (20g,59.7mmol, 74.3% yield based on HNMR, 90% purity) as a yellow oil.¹HNMR (400MHz, chloroform-d) δ 5.45(br.s.,1H),4.18(q, J ═ 7.1Hz,2H),3.72(br.s.,3H),3.51-3.31(m,1H),3.14-3.05(m,1H),2.08(s,3H),1.46(s,9H),1.27(t, J ═ 7.2Hz, 3H). ESI [ M + H ]]＝302.1

1-tert-butyl (3-ethyl) (3R,4S) -4-hydroxypyrrolidine-1, 3-dicarboxylate to a solution of 1-tert-butyl (3R,4S) -4-acetoxypyrrolidine-1, 3-dicarboxylate (20g,66.3mmol,1.0eq) in EtOH (200mL) was added concentrated HCl (12M,20mL,3.6eq) in portions, M87. The reaction mixture was heated to 65 ℃ and stirred for 6 hr. The reaction mixture was cooled to 0 ℃ and H was added₂O (200 mL). With solid NaHCO₃The pH was adjusted to about 7, followed by the addition of NaHCO₃(10g,119mmol,1.8eq) followed by the addition of Boc₂O (16g,73.3mmol,16.8mL,1.1 eq). The reaction mixture was warmed to 15 ℃ and stirred for 16 hr. The mixture was extracted with EtOAc (300 mL. times.3). The combined organic layers were washed with brine (200mL) and Na₂SO₄Dried, then filtered and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether ethyl acetate (10:1 to 3: 1). (3R,4S) -4-hydroxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl 3-ethyl ester was obtained as a yellow oil (13.0g,50.1mmol, 75.6% yield, 100% purity, ee%: 99.86%).¹H NMR (400MHz, chloroform-d) δ 4.54-4.44(m,1H),4.17-4.08(m,2H),3.73-3.58(m,2H),3.50(d, J ═ 4.4Hz,1H),3.21(br.s.,1H),2.93(br.s.,1H),2.78(br.s.,1H),1.39(s,9H),1.25-1.18(m, 3H). ESI [ M + Na ]]＝282.1

Tert-butyl (3S,4S) -3- ((tert-butyldiphenylsilyl) oxy) -4- (hydroxymethyl) pyrrolidine-1-carboxylate, m88. to a mixture of tert-butyl (3R,4S) -1-4-hydroxypyrrolidine-1, 3-carboxylate 3-ethyl ester (200mg,771.3umol,1.0eq) and DMAP (150mg,1.23mmol,1.59eq) in DCM (10mL) was added TBDPSCl (220mg,800umol,205.6uL,1.04 eq). The reaction mixture was stirred at 15 ℃ for 16hr, washed with aqueous HCl (0.5M,10mL) and brine (10mL), and Na₂SO₄Dried, filtered and concentrated. To a solution of the residue and MeOH (40mg,1.25mmol,2.07eq) in anhydrous THF (4.0mL) was added LiBH4(40mg,1.8mmol,3.05 eq). The mixture was stirred at 30 ℃ for 16 hr. The mixture was washed with saturated NaHCO₃Quenched (20mL) and extracted with EtOAc (20 mL. times.3). The combined organic layers were washed with brine (20mL) and Na₂SO₄Dried, then filtered and concentrated. The residue was purified by preparative TLC using petroleum ether ethyl acetate (4: 1). Tert-butyl (3S,4S) -3- ((tert-butyldiphenylsilyl) oxy) -4- (hydroxymethyl) pyrrolidine-1-carboxylate (160mg,316umol, 52.4% yield based on HNMR, 90% purity) was obtained as a pale yellow oil.¹H NMR (400MHz, chloroform-d) δ 7.73-7.59(m,4H),7.51-7.33(m,6H),4.27-4.06(m,1H),3.68-3.09(m,7H),2.28(d, J ═ 5.3Hz,1H),1.45(br.s.,9H),1.08(s, 9H). ESI [ M + Na ]]＝478.2

((3S,4S) -4- ((tert-butyldiphenylsilyl) oxy) pyrrolidin-3-yl) methanol, M89 (3S,4S) -3- ((tert-butyldiphenylsilyl) oxy) -4- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (160mg,351umol,1.0eq) was dissolved in HCl/MeOH (4M,20mL) and stirred at 30 ℃ for 0.5 hr. The reaction mixture was concentrated and dissolved with MeOH (20 mL). The mixture was basified to pH 7-8 with basic resin, then filtered and concentrated. To obtain((3S,4S) -4- ((tert-butyldiphenylsilyl) oxy) pyrrolidin-3-yl) methanol (120mg,337.5umol, 96.1% yield) was pale yellow oil.¹H NMR (400MHz, methanol-d)₄)δ＝7.74-7.57(m,4H),7.49-7.31(m,6H),4.26-4.13(m,1H),3.62-3.51(m,1H),3.31(br.s.,1H),3.21-3.07(m,1H),2.97-2.78(m,3H),2.33-2.19(m,1H),1.06(s,5H),1.01-0.98(m,4H)。ESI[M+H]＝356.4

The chemical experiment method comprises the following steps: general procedure a6 is as follows.

Trans-1-benzyl-4- (methoxycarbonyl) pyrrolidine-3-carboxylic acid, M91. at 0 ℃ under N₂To a mixture of (E) -4-methoxy-4-oxo-but-2-enoic acid (50g,384mmol,1.0eq.) and TFA (4.4g,38mmol,2.8mL,0.1eq.) in anhydrous DCM (1.0L) under atmosphere was added N- (methoxymethyl) -1-phenyl-N- (trimethylsilylmethyl) methylamine (183.4g,772mmol,2.0eq.) dropwise. The reaction mixture was stirred at 0 ℃ for 30min, then warmed to 20 ℃ and stirred for a further 48 hr. The mixture was concentrated and purified by column chromatography on silica gel with DCM/MeOH (100:1 to 15:1) to obtain (trans) -1-benzyl-4-methoxycarbonyl-pyrrolidine-3-carboxylic acid (60g,205.1mmol, 53.4% yield, 90% purity) as a light yellow solid. 1H NMR (400MHz, DMSO-d6) δ 12.44(s,1H),7.36-7.21(m,5H),3.66-3.50(m,5H),3.36-3.28(m,1H),3.26-3.18(m,1H),2.85-2.75(m,2H),2.72-2.62(m, 2H). ESI [ M + H ]]＝264.1

Trans-1-benzyl-4- ((tert-butoxycarbonyl) amino) pyrrolidine-3-carboxylic acid methyl ester, M92. preparation of (trans) -1-benzyl-4-methoxycarbonyl-pyrrolidine-3-carboxylic acid (20g,75.9mmol,1.0eq.), TEA (9.9)A mixture of 9g,98mmol,13.7mL,1.3eq.), DPPA (25.09g,91.15mmol,19.75mL,1.20eq.), t-BuOH (28g,379.8mmol,36.1mL,5.0eq.) in toluene (200mL) was refluxed at 110 ℃ for 16 hr. The reaction was concentrated and then saturated NaHCO₃The solution (300mL) was washed, extracted with DCM (200mL × 3), dried, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to obtain trans-1-benzyl-4- ((tert-butoxycarbonyl) amino) pyrrolidine-3-carboxylic acid methyl ester (14g,41.8mmol, 55% yield) as a yellow oil.¹H NMR (400MHz, chloroform-d) δ 7.33-7.18(m,5H),5.00(br s,1H),4.37(br s,1H),3.70-3.64(m,3H),3.61-3.52(m,2H),3.09(t, J ═ 9.0Hz,1H),2.82(dt, J ═ 4.0,8.0Hz,1H),2.70-2.58(m,2H),2.45(dd, J ═ 7.8,9.2Hz,1H),1.45-1.34(m, 9H). ESI [ M + H ]]＝335.1

Tert-butyl (trans-1-benzyl-4- (hydroxymethyl) pyrrolidin-3-yl) carbamate, m93. trans-1-benzyl-4- ((tert-butoxycarbonyl) amino) pyrrolidine-3-carboxylate (14g,41.8mmol,1.0eq.) was dissolved in THF (100mL) followed by addition of MeOH (2.35g,73.3mmol,1.75eq.) and LiBH to the reaction mixture₄(1.37g,62.8mmol,1.5 eq.). The mixture was stirred at 30 ℃ for 0.5hr and quenched by MeOH (50 mL). It was concentrated and diluted with saturated NaHCO₃The solution (200mL) was diluted, extracted with DCM (300mL × 3), dried, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1 to dichloromethane: methanol ═ 40:1) and by preparative HPLC (neutral conditions) to obtain tert-butyl (trans-1-benzyl-4- (hydroxymethyl) pyrrolidin-3-yl) carbamate (8.0g,26.1mmol, 62% yield) as a light yellow oil. 1H NMR (400MHz, chloroform-d) δ 7.36-7.19(m,5H),5.04(d, J6.6 Hz,1H),3.83(td, J3.5, 7.1Hz,1H),3.64-3.42(m,4H),2.90(t, J8.6 Hz,1H),2.74-2.63(m,1H),2.47(dd, J2.9, 9.9Hz,1H),2.22-2.10(m,1H),2.06-1.97(m,1H),1.51-1.31(m, 9H). ESI [ M + H ]]＝307.4

Trans-4-amino-1-benzylpyrrolidin-3-yl) methanol, M94 to a solution of tert-butyl (trans-1-benzyl-4- (hydroxymethyl) pyrrolidin-3-yl) carbamate (1.5g,4.9mmol,1.0eq.) in MeOH (5mL) was added HCl/MeOH (4M,50mL) portionwise. The reaction mixture was heated to 40 ℃ and stirred for 2 hr. The mixture was concentrated to give trans-4-amino-1-benzylpyrrolidin-3-yl) methanol (1.4g, crude, 2HCl) as an off white solid which was used directly. ESI [ M + H ] ═ 207.1

N- (trans-1-benzyl-4- (hydroxymethyl) pyrrolidin-3-yl) -2,2, 2-trifluoroacetamide, M95.

To a solution of trans-4-amino-1-benzylpyrrolidin-3-yl) methanol (300mg,1.45mmol,1.0eq.) in DCM (15mL) was added TEA (880mg,8.7mmol,1.2mL,6.0eq.) and 2,2, 2-trifluoroacetic acid (2,2, 2-trifluoroacetyl) ester (1.07g,5.07mmol,705.9uL,3.5eq.) at 0 ℃. The mixture was then stirred at 26 ℃ for 2 hr. The mixture was concentrated and purified by acidic preparative HPLC to give N- (trans-1-benzyl-4- (hydroxymethyl) pyrrolidin-3-yl) -2,2, 2-trifluoroacetamide (550mg, crude, TFA) as a yellow oil. ESI [ M + H ] ═ 303.1

2,2, 2-trifluoro-N- (trans-4- (hydroxymethyl) pyrrolidin-3-yl) acetamide, m96 to a solution of N- (trans-1-benzyl-4- (hydroxymethyl) pyrrolidin-3-yl) -2,2, 2-trifluoroacetamide (740mg,1.78mmol,1.0eq, TFA) in MeOH (20mL) was added Pd/C (1.0g,1.78mmol, 10% purity) followed by stirring at 50Psi hydrogen for 16hr at 50 ℃. The mixture was filtered and the filtrate was concentrated to give 2,2, 2-trifluoro-N- (trans-4- (hydroxymethyl) pyrrolidin-3-yl) acetamide (520mg, crude, TFA) as a colorless oil. 1H NMR (400MHz, methanol-d 4) δ 3.76-3.52(m,6H),3.27-3.21(m,1H),2.61-2.48(m, 1H). ESI [ M + H ] ═ 212.9

The chemical experiment method comprises the following steps: general procedure a7 is as follows.

N- (trans-1-benzyl-4- (hydroxymethyl) pyrrolidin-3-yl) carboxamide, M97 to a mixture of trans-4-amino-1-benzylpyrrolidin-3-yl) methanol (1.0g,3.6mmol,1.0eq, 2HCl) in anhydrous MeOH (20mL) was added NaOMe in MeOH (1.6g,7.4mmol, 25% purity, 2.07eq.) dropwise followed by methyl formate (1.0g,16.6mmol,1mL,4.6 eq.). The mixture was warmed to 40 ℃ and stirred for 3 hr. The mixture was concentrated and purified by preparative HPLC (neutral conditions) to give N- (trans-1-benzyl-4- (hydroxymethyl) pyrrolidin-3-yl) carboxamide (550mg,2.1mmol, 58.9% yield, 90% purity) as a colorless oil. 1H NMR (400MHz, methanol-d 4) δ 7.96(s,1H),7.34-7.19(m,5H),4.12-4.02(m,1H),3.65-3.46(m,5H),2.91-2.82(m,1H),2.77(dd, J7.2, 9.8Hz,1H),2.53-2.46(m,1H),2.33(dd, J6.8, 9.7Hz,1H),2.19-2.10(m, 1H). ESI [ M + H ] ═ 234.9

N- (trans-4- (hydroxymethyl) pyrrolidin-3-yl) carboxamide, M98. at H₂(50Psi) reacting N- [ (trans) -1-benzyl-4- (hydroxymethyl) pyrrolidin-3-yl at 50 deg.C]A solution of formamide (550mg,2.35mmol,1.0eq.) in anhydrous MeOH (20mL) over Pd (OH)₂(200mg,1.42mmol,0.61eq.) was hydrogenated for 3 hr. The mixture was filtered and the filtrate was concentrated to give N- (trans-4- (hydroxymethyl) pyrrolidin-3-yl) carboxamide (320mg, crude) as a grey oil which was used directly. 1H NMR (400MHz,methanol-d 4) δ is 8.03(s,1H),4.11-4.02(m,1H),3.67-3.59(m,1H),3.57-3.48(m,1H),3.21-3.06(m,2H),2.78-2.63(m,2H),2.19-2.08(m, 1H). ESI [ M + H ]]＝145.1

The chemical experiment method comprises the following steps: general procedure A8 is as follows.

Trans-3- (cyanomethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M99. in N₂To a mixture of LDA (2M,80mL,1.48eq.) in anhydrous THF (350mL) was added MeCN (8.0g,195mmol,10.3mL,1.8eq.) dropwise at-70 ℃ under an atmosphere. After addition, the mixture was warmed to 20 ℃ and stirred for 30 min. The mixture was cooled to-5 ℃ and 6-oxa-3-azabicyclo [3.1.0 ] was added dropwise]Hexane-3-carboxylic acid tert-butyl ester (20g,108mmol,1.0eq.) in anhydrous THF (50 mL). The reaction mixture was warmed to 15 ℃ and stirred for 16 hr. The mixture was poured into ice-cold saturated NH₄Aqueous Cl (500mL) and concentrated to remove THF. The aqueous layer was extracted with EtOAc (200 mL. times.3). The combined organic layers were washed with brine (300mL) and Na₂SO₄Dried, filtered and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether ethyl acetate (10:1 to 2:1) to give trans-3- (cyanomethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (10g,42mmol, 38.88% yield, 95% purity) as a pale yellow oil. 1HNMR (400MHz, chloroform-d) δ 4.22-4.17(m,1H),3.71(br.s.,2H),3.31-3.17(m,2H),2.68-2.36(m,4H),1.47(s, 9H).

Trans-3- (2-aminoethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M100. at 35Psi H₂Under an atmosphere of 30 deg.CTrans-3- (cyanomethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (7.5g,33mmol,1.0eq.) in MeOH (150mL) and NH at deg.C₃.H₂A mixture of O (30mL) was hydrogenated over Ni (3.0g,51mmol,1.5eq.) for 4 hr. The mixture was filtered and the filtrate was concentrated to give trans-3- (2-aminoethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (8.0g, crude) as a dark yellow oil, which was used directly.

Trans-3- (2- (((benzyloxy) carbonyl) amino) ethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M101. tert-butyl trans-3- (2-aminoethyl) -4-hydroxypyrrolidine-1-carboxylate (7.6g,33.1mmol,1.0eq.) and K at 0 deg.C₂CO₃(10g,72.3mmol,2.2eq.) in H₂To a mixture of O (60mL) and THF (60mL) was added CbzCl (10g,58.6mmol,8.3mL,1.8eq.) dropwise. The mixture was warmed to 15 ℃ and stirred for 2 hr. The aqueous layer was separated and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with brine (50mL) and Na₂SO₄Dried, filtered and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether ethyl acetate (8:1 to 1:1) to give trans-3- (2- (((benzyloxy) carbonyl) amino) ethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (10g,26mmol, 78.7% yield, 95% purity). 1H NMR (400MHz, chloroform-d) δ 7.42-7.30(m,5H),5.10(s,2H),4.03(br.s.,1H),3.63(d, J ═ 7.9Hz,2H),3.44-3.31(m,1H),3.29-3.11(m,2H),3.01(d, J ═ 5.7Hz,1H),2.77(d, J ═ 12.1Hz,1H),2.05(s,1H),1.69-1.50(m,2H),1.46(s, 9H).

Benzyl (2- (trans-4-hydroxypyrrolidin-3-yl) ethyl) carbamate, M102 to a solution of trans-3- (2- (((benzyloxy) carbonyl) amino) ethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1.3g,3.6mmol,1.0eq.) in MeOH (5mL) was added HCl/MeOH in portions(4M,40 mL). The mixture was stirred at 15 ℃ for 4 hr. The mixture was concentrated. The residue was dissolved in MeOH (20mL) and the pH was adjusted to 10 with basic resin. Subjecting the mixture to Na₂SO₄Dried, filtered and concentrated to give benzyl (2- (trans-4-hydroxypyrrolidin-3-yl) ethyl) carbamate (950mg, crude) as a yellow oil, which was used as such. 1H NMR (400MHz, methanol-d 4) δ 7.41-7.26(m,5H),5.07(s,2H),4.17-4.06(m,1H),3.73(t, J ═ 6.3Hz,1H),3.50(dd, J ═ 7.6,11.3Hz,1H),3.30-3.25(m,1H),3.06(dd, J ═ 2.0,12.1Hz,1H),2.97-2.88(m,1H),2.23-2.11(m,1H),1.87(t, J ═ 6.4Hz,1H),1.69(qd, J ═ 7.0,13.8Hz,1H),1.53-1.42(m, 1H). ESI [ M + H ]]＝265.2

The chemical experiment method comprises the following steps: general procedure a9 is as follows.

Trans-3- (2- (dimethylamino) ethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, M103. trans-3- (2- (((benzyloxy) carbonyl) amino) ethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2g,5.5mmol,1.0eq.) was dissolved in MeOH (50mL), followed by addition of HCHO (164mg,5.5mmol,151uL,1.0eq.) and Pd (OH)₂(3.0g,10.7mmol, 50% purity, 1.95eq.) and the reaction mixture was heated at 50 ℃ at 50Psi H₂Stirring for 2 hr. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 40:1 to 10:1) to give trans-3- (2- (dimethylamino) ethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1.3g,5mmol, 91.6% yield) as a light yellow oil. 1H NMR (400MHz, methanol-d 4) δ 3.90(q, J6.3 Hz,1H),3.64-3.52(m,2H),3.07(dd, J6.2, 10.6Hz,1H),2.98(q, J9.3 Hz,1H),2.51-2.40(m,1H),2.39-2.29(m,1H),2.26(s,6H),1.99-1.88(m,1H),1.73-1.59(m,1H),1.54-1.39(m, 10H). ESI [ M + H ]]＝259.1

Trans-4- (2- (dimethylamino) ethyl) pyrrolidin-3-ol, m104. trans-3- (2- (dimethylamino) ethyl) -4-hydroxypyrrolidine-1-carboxylate tert-butyl (1.3g,5mmol,1.0eq.) was dissolved in HCl/MeOH (50mL,4 mol/L). The mixture was stirred at 30 ℃ for 0.5hr and concentrated. The residue was dissolved in MeOH (30mL) and basified to pH 7-8 by basic resin (800 mg). It was filtered and concentrated to give trans-4- (2- (dimethylamino) ethyl) pyrrolidin-3-ol (780mg,4.9mmol, 98% yield) as a yellow oil. 1H NMR (400MHz, methanol-d 4) δ 4.18(q, J4.4 Hz,1H),3.54(dd, J7.5, 11.9Hz,1H),3.42(dd, J5.3, 12.3Hz,1H),3.11(dd, J4.0, 12.3Hz,1H),3.01(dd, J7.1, 11.9Hz,1H),2.96-2.77(m,2H),2.62(s,6H),2.24-2.12(m,1H),1.88-1.74(m,1H),1.74-1.61(m, 1H). ESI [ M + H ] ═ 159.0

The chemical experiment method comprises the following steps: general procedure a10 is as follows.

(trans-4- (hydroxymethyl) pyrrolidin-3-yl) carbamic acid tert-butyl ester, M105 to a solution of (trans-1-benzyl-4- (hydroxymethyl) pyrrolidin-3-yl) carbamic acid tert-butyl ester (900mg,2.9mmol,1.0eq.) in MeOH (50mL) was added Pd (OH)₂(998mg,7.1mmol,2.4eq.) and the reaction mixture was brought to 50Psi H at 30 deg.C₂Stirring for 1 hr. The reaction mixture was filtered and concentrated to give tert-butyl (trans-4- (hydroxymethyl) pyrrolidin-3-yl) carbamate (600mg,2.7mmol, 94% yield) as a white solid. 1H NMR (400MHz, methanol-d 4) δ 3.72(q, J5.9 Hz,1H),3.62(dd, J5.7, 10.8Hz,1H),3.50(dd, J7.2, 10.8Hz,1H),3.14-3.03(m,2H),2.73-2.59(m,2H),2.12-2.02(m,1H),1.51-1.38(m,9H)。ESI[M+H]＝217.0

(trans-4-Aminopyrrolidin-3-yl) methanol, M106. A solution of tert-butyl (trans-4- (hydroxymethyl) pyrrolidin-3-yl) carbamate (270mg,1.25mmol,1.0eq.) in HCl/MeOH (20mL,4mol/L) was stirred at 10 ℃ for 0.5hr and concentrated. The residue was dissolved in MeOH (30mL) and basified with basic resin (500mg) to pH 7-8. It was filtered and concentrated to give (trans-4-aminopyrrolidin-3-yl) methanol (140mg,1.2mmol, 96.8% yield) as a pale yellow oil. 1H NMR (400MHz, methanol-d 4) δ 3.69-3.59(m,2H),3.51-3.36(m,3H),3.12-3.01(m,1H),2.96(dd, J ═ 6.0,11.7Hz,1H),2.27-2.16(m,1H)

The chemical experiment method comprises the following steps: general procedure a11 is as follows.

Trans-1- (tert-Butoxycarbonyl) -4-hydroxypyrrolidine-3-carboxylic acid, M107. (trans) -4-hydroxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.4g,5.4mmol,1.0eq) in THF (10mL), H₂To a solution in O (10mL) and EtOH (30mL) was added NaOH (413mg,10.8mmol,2.0eq) and the mixture was stirred at 25 ℃ for 1 hr. The mixture was concentrated and the residue was dissolved in water (50 mL). The aqueous phase was extracted with DCM (50ml x 2). The aqueous phase was adjusted to pH 2 by HCl solution (0.5M) and concentrated to give trans-1- (tert-butoxycarbonyl) -4-hydroxypyrrolidine-3-carboxylic acid (1.25g, crude) as a white solid, which was used without any purification. ESI [ M + H ]]＝232.1

Trans-3- (azetidine-1-carbonyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, m108. to a solution of (trans) -1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-3-carboxylic acid (892mg,3.8mmol,1.0eq) in DCM (30mL) was added DIEA (1.7g,13.5mmol,2.3mL,3.5eq), HATU (1.7g,4.6mmol,1.2eq) and azetidine (541mg,5.8mmol,636uL,1.5eq, HCl). The mixture was stirred at 25 ℃ for 2hr and concentrated in vacuo. The residue was purified by acidic preparative HPLC to give trans-3- (azetidine-1-carbonyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil (750mg,2.5mmol, 64.7% yield, 90% purity). ESI [ M + H ] ═ 271.2

Azetidin-1-yl (trans-4-hydroxypyrrolidin-3-yl) methanone, m109. trans-3- (azetidine-1-carbonyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (800mg,2.9mmol,1.0eq) was dissolved in TFA (5.0mL) and the mixture was stirred at 25 ℃ for 5 min. The mixture was concentrated and then dissolved in THF (10 mL). The mixture was adjusted to pH 9 by basic resin. It was filtered and concentrated to give azetidin-1-yl (trans-4-hydroxypyrrolidin-3-yl) methanone (450mg,2.5mmol, 84.8% yield, 95% purity) as a yellow oil. ESI [ M + H ] ═ 171.2

The chemical experiment method comprises the following steps: general procedure a12 is as follows.

3- (2-amino-2-oxoethyl) pyrrolidine-1-carboxylic acid tert-butyl ester, M111. reaction of 2- (1-tert-butyl)Butoxycarbonylpyrrolidin-3-yl) acetic acid (1.4g,6.1mmol,1.0eq), NH₄A mixture of Cl (979mg,18mmol,3.0eq) and DIEA (2.7g,21.4mmol,3.7mL,3.5eq) in DMF (20mL) was stirred at 20 ℃ for 10min, followed by the addition of HATU (2.8g,7.3mmol,1.2eq) in one portion and the mixture stirred at 20 ℃ for 50 min. The mixture was poured into cold water (200mL) and extracted with ethyl acetate (100mL x 3). The combined organic phases were washed with brine (200mL) over anhydrous Na₂SO₄Dried, filtered and concentrated to give tert-butyl 3- (2-amino-2-oxoethyl) pyrrolidine-1-carboxylate (2.0g, crude) as a colorless oil, which was used without any purification. ESI [ M + H ]]＝229.1

3- (2-aminoethyl) pyrrolidine-1-carboxylic acid tert-butyl ester, M112 to a solution of 3- (2-amino-2-oxo-ethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (2.0g,8.7mmol,1.0eq) in THF (10mL) at 0 deg.C was added BH dropwise₃THF (1M,50mL,5.7 eq). The mixture was stirred at 70 ℃ for 30 min. The mixture was cooled to 0 ℃ and quenched with MeOH (50 mL). The mixture was then stirred at 70 ℃ for 2hr and concentrated to give 3- (2-aminoethyl) pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil (1.8g, crude), which was used without any purification. ESI [ M + H ]]＝215.1

3- (2- (((benzyloxy) carbonyl) amino) ethyl) pyrrolidine-1-carboxylic acid tert-butyl ester, M113. to a solution of 3- (2-aminoethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.8g,7.8mmol,1.0eq) in THF (30mL) and water (30mL) at 0 deg.C was added Na in one portion₂CO₃(1.6g,15.7mmol,2.0 eq.) and CbzCl (1.5g,8.6mmol,1.2mL,1.1 eq.). The mixture was stirred at 30 ℃ for 1hr, poured into ice water (50mL) and extracted with ethyl acetate (200mL × 3). The combined organic phases were washed with brine (200mL x 2) and dried over anhydrous Na₂SO₄Dried, filtered and concentrated to give 3- (2- (((benzyloxy) carbonyl) amino) ethyl) pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil (1.0g, crude), which was used without any purification. ESI [ M + H ]]＝349.2

Tert-butyl 3- (2- (((benzyloxy) carbonyl) (methyl) amino) ethyl) pyrrolidine-1-carboxylate, m114. to a solution of tert-butyl 3- (2- (((benzyloxy) carbonyl) amino) ethyl) pyrrolidine-1-carboxylate (500mg,1.4mmol,1.0eq) in DMF (10mL) at 0 ℃ was added NaH (85mg,2.1mmol, 60% purity, 1.5 eq). The mixture was stirred at 0 ℃ for 0.1hr and then MeI (608mg,4.2mmol,267uL,3.0eq) was added. The mixture was stirred at 26 ℃ for 0.4hr and saturated by cold NH₄The Cl solution (100mL) was quenched. The mixture was extracted with ethyl acetate (50mL x 3). The combined organic phases were washed with brine (50mL) over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by acidic preparative HPLC to give tert-butyl 3- (2- (((benzyloxy) carbonyl) (methyl) amino) ethyl) pyrrolidine-1-carboxylate (500mg) as a yellow oil. ESI [ M + H ]]＝363.2

Benzyl methyl (2- (pyrrolidin-3-yl) ethyl) carbamate, M115. a solution of tert-butyl 3- (2- (((benzyloxy) carbonyl) (methyl) amino) ethyl) pyrrolidine-1-carboxylate (400mg,1.1mmol,1.0eq) in HCl/MeOH (30mL,4M) was stirred at 30 ℃ for 0.5hr and then concentrated. The residue was dissolved in MeOH (30mL) and basified to pH 8-9 by basic resin. It was filtered and concentrated to give methyl (2- (pyrrolidin-3-yl) ethyl) carbamic acid benzyl ester (250mg,952umol, 86.6% yield) as a pale yellow oil. 1H NMR (400MHz, methanol-d 4) δ 7.34(br.s.,5H),5.14-5.05(m,2H),3.48-3.30(m,3H),3.22-3.04(m,1H),2.98-2.87(m,3H),2.87-2.70(m,1H),2.19(br.s.,2H),1.75-1.51(m, 3H). ESI [ M + H ] ═ 263.2

Synthesis of other amines.

(S) -N- (pyrrolidin-3-ylmethyl) ethylamine, M116. synthesized using general procedure A12 with (R) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid instead of 2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) acetic acid and ethylamine instead of ammonium chloride. ESI [ M + H ] ═ 129.1

(R) -2, 2-difluoro-N- (pyrrolidin-3-ylmethyl) ethylamine, m117. was synthesized using general procedure a12 with (R) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid instead of 2- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) acetic acid and 2, 2-difluoroethylamine instead of ammonium chloride. 1H NMR (400MHz, chloroform-d) δ 5.88-5.58(m,1H),3.34-3.29(m,2H),3.19(br.s.,1H),3.04-3.02(m,1H),2.93-2.89(m,2H),2.74-2.72(m,1H),2.64(m,1H),2.42-2.41(m,1H),2.12-2.10(m,1H),1.72-1.68(m, 1H). ESI [ M + H ] ═ 165.0

(trans) -4- (pyrrolidin-1-ylmethyl) pyrrolidin-3-ol, m118. synthesized using general procedure Q trans-1-benzyl-4- (benzyloxy) pyrrolidine-3-carboxylic acid instead of 1- ((benzyloxy) carbonyl) pyrrolidine-3-carboxylic acid and pyrrolidine instead of tert-butyl (3-aminopropyl) carbamate. 1H NMR (400MHz, methanol-d 4) δ 4.29-4.27(m,1H),3.72(s,1H),3.59-3.58(m,1H),3.37-3.34(m,1H),3.16-3.09(m,2H),2.88-2.83(m,4H),2.79-2.76(m,1H),2.50-2.49(m,1H),1.92-1.85(m, 4H). ESI [ M + H ] ═ 171.1

Benzyl (2- (pyrrolidin-3-yl) ethyl) carbamate, m119. was synthesized using general procedure a12 substituting tert-butyl 3- (2- (((benzyloxy) carbonyl) (methyl) amino) ethyl) pyrrolidine-1-carboxylate with tert-butyl 3- (2- (((benzyloxy) carbonyl) (methyl) amino) ethyl) pyrrolidine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 7.41-7.23(m,5H),5.13-5.01(m,2H),3.48-3.32(m,2H),3.23-3.09(m,3H),2.79(t, J10.4 Hz,1H),2.36-2.12(m,2H),1.73-1.50(m, 3H). ESI [ M + H ] ═ 249.1

1- (pyrrolidin-3-ylmethyl) piperidine-4-carboxylic acid methyl ester, m120. synthesized using general procedure a2 with piperidine-4-carboxylic acid methyl ester instead of methyl 2-amino-2-methylpropionate. 1H NMR (400MHz, methanol-d 4) δ 3.72-3.66(m,3H),3.42-3.39(m,1H),3.34(m,1H),3.25(m,1H),3.00-2.95(m,3H),2.49-2.48(m,3H),2.46(m,1H),2.21-2.16(m,3H),1.93-1.90(m,2H),1.74-1.70(m, 3H). ESI [ M + H ] ═ 227.0

(((3S,4R) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamic acid benzyl ester, M121.

Synthesized using general procedure a4 substituting (3R,4R) -3- ((((benzyloxy) carbonyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester for (3S,4S) -3- ((((benzyloxy) carbonyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) d 7.45-7.21(m,5H),5.12(s,2H),4.28(br.s.,1H),3.67(br.s.,1H),3.56-3.40(m,2H),3.40-3.30(m,2H),3.08(t, J ═ 11.4Hz,1H),2.99(s,3H),2.54(br.s., 1H). ESI [ M + H ] ═ 265.2

Benzyl (2- (trans-4-hydroxypyrrolidin-3-yl) ethyl) (methyl) carbamate, M122.

Synthesized using general procedure a4 substituting trans-3- (2- (((benzyloxy) carbonyl) amino) ethyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester for (3S,4S) -3- ((((benzyloxy) carbonyl) amino) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) d 7.36(d, J3.5 Hz,5H),5.12(br.s.,2H),4.24-4.10(m,1H),3.61-3.33(m,3H),3.29-3.23(m,1H),3.17-2.88(m,5H),2.14(br.s.,1H),1.77(td, J6.8, 13.6Hz,1H),1.49(dtd, J5.6, 8.2,13.9Hz, 1H). ESI [ M + H ] ═ 279.0

(3R,4R) -4- (hydroxymethyl) pyrrolidin-3-ol, m123. synthesized using general procedure a5 substituting (3R,4S) -4-hydroxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester for (3R,4S) -4-hydroxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester. 1H NMR (400MHz, methanol-d 4) d 4.24-4.16(m,1H),3.61-3.50(m,2H),3.35(dd, J7.9, 11.5Hz,1H),3.16(dd, J5.1, 12.1Hz,1H),3.00-2.88(m,2H),2.31-2.22(m, 1H). ESI [ M + H ] ═ 117.8

(3S,4R) -N-cyclopropyl-4-hydroxypyrrolidine-3-carboxamide, m124. was synthesized using general procedure a11 with (3S,4R) -4-hydroxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester instead of trans-4-hydroxypyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester, cyclopropylamine instead of azetidine. 1H NMR (400MHz, methanol-d 4) d 4.46(br.s.,1H),3.52(d, J4.4 Hz,2H),3.42(dd, J3.5, 11.9Hz,1H),3.21(d, J11.9 Hz,1H),3.02(br.s.,1H),2.67(dd, J3.5, 7.1Hz,1H),0.73(d, J6.6 Hz,2H),0.50(br.s., 2H). ESI [ M + H ] ═ 171.0

Synthesis of other targets.

7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2,1c ]]Pyrrolo [1,2-a][1,4]Diazepine, 463, see S116 in general procedure J.¹H NMR(400MHz,DMSO-d₆)δ＝7.91(dd,J＝1.9,7.2Hz,2H),7.73(dd,J＝2.3,8.7Hz,1H),7.59-7.51(m,3H),7.46(d,J＝2.0Hz,1H),7.38(s,1H),7.18-7.09(m,2H),6.96(d,J＝1.8Hz,1H),5.23(s,2H)。ESI[M+H]＝394.0/396.0

(S) -N- ((1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) methyl) ethylamine, 464 using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (S) -N- (pyrrolidin-3-ylmethyl) ethylamine in place of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝8.00-7.99(m,1H),7.74-7.73(m,1H),7.59-7.52(m,4H),7.19-7.18(m,1H),7.10-7.06(m,2H),6.80-6.79(m,1H),6.75-6.65(m,1H),5.27(s,2H),3.64-3.42(m,3H),3.20-3.08(m,5H),2.73-2.69(m,1H),2.34-2.32(m,1H),1.92-1.86(m,1H),1.33(t,J＝7.4Hz,3H)。ESI[M+H]＝442.1

(S) -2, 2-difluoro-N- ((1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) methyl) ethylamine, 465 using general procedure A with 7-bromo-12- (4-fluorophenyl)) -9H-benzo [ e ]]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and (R) -2, 2-difluoro-N- (pyrrolidin-3-ylmethyl) ethylamine in place of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝8.01(br.s.,1H),7.75(br.s.,1H),7.65-7.52(m,4H),7.20(s,1H),7.09(t,J＝8.6Hz,2H),6.81(s,1H),6.76(d,J＝9.0Hz,1H),6.49-6.18(m,1H),5.28(s,2H),3.70-3.40(m,6H),3.34(br.s.,1H),3.21(t,J＝8.6Hz,1H),2.86-2.73(m,1H),2.36(d,J＝6.3Hz,1H),2.00-1.84(m,1H)。ESI[M+H]＝478.1

1- ((3S,4S) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine, 467 prepared using general procedure U with 1- ((3S,4S) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-7-yl) pyrrolidin-3-yl) -N-methylmethanamine instead of 1- ((cis) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) -N-methylmethanamine.¹H NMR (400MHz, methanol-d)₄)δ＝8.02(d,J＝1.3Hz,1H),7.75(d,J＝1.3Hz,1H),7.62-7.54(m,4H),7.20(s,1H),7.09(t,J＝8.6Hz,2H),6.85(s,1H),6.79(d,J＝8.8Hz,1H),5.55-5.38(m,1H),5.29(s,2H),3.84(t,J＝9.0Hz,2H),3.79-3.67(m,2H),3.63(dd,J＝6.8,13.5Hz,1H),3.43(dd,J＝6.8,13.5Hz,1H),3.02(s,7H)。ESI[M+H]＝460.1

1- ((3R,4R) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine, 475. Using general procedure U with 1- ((3R,4R) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-7-yl) pyrrolidin-3-yl) -N-methylmethanamine instead of 1- ((cis) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) -N-methylmethanamine.¹H NMR (400MHz, methanol-d)₄)δ＝8.01(s,1H),7.75(d,J＝1.8Hz,1H),7.63-7.54(m,4H),7.20(s,1H),7.09(t,J＝8.6Hz,2H),6.85(s,1H),6.79(d,J＝8.8Hz,1H),5.56-5.37(m,1H),5.29(s,2H),3.84(t,J＝8.8Hz,2H),3.80-3.67(m,2H),3.63(dd,J＝6.6,13.2Hz,1H),3.43(dd,J＝6.6,13.2Hz,1H),3.02(s,7H)。ESI[M+H]＝460.1

(trans) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) -4- (pyrrolidin-1-ylmethyl) pyrrolidin-3-ol, 472.¹H NMR (400MHz, methanol-d)₄)δ＝8.00(d,J＝1.6Hz,1H),7.45(s,1H),7.60-7.55(m,4H),7.20(s,1H),7.12-7.03(m,2H),6.82-6.75(m,2H),5.29(s,2H),4.31-4.30(m,1H),3.80-3.76(m,3H),3.47-3.37(m,2H),3.27-3.16(m,4H),2.69-2.64(m,1H),2.20-2.07(s,4H),1.33-1.29(m,1H)。ESI[M+H]＝484.1

All three of the above compounds (470, 471, 472) were synthesized using general procedure E using 7-bromo-12- (4-fluorophenyl) -9H-benzo [ E ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine in place of 4- (7-bromo-9H-benzo [ E ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and (trans) -4- (pyrrolidin-1-ylmethyl) pyrrolidin-3-ol in place of N, N-dimethyl-1- (morpholin-2-yl) methylamine.

(3R,4S) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) -4- (pyrrolidin-1-ylmethyl) pyrrolidin-3-ol, 470.¹H NMR(400MHz,DMSO-d₆)δ＝7.64(s,1H),7.54(dd,J＝5.5,8.2Hz,2H),7.39(s,1H),7.31(d,J＝8.8Hz,1H),7.17-7.07(m,3H),6.81(s,1H),6.71(br.s.,1H),6.56(d,J＝8.4Hz,1H),5.14-4.98(m,3H),4.07(br.s.,1H),3.53-3.41(m,2H),3.15-3.01(m,2H),2.45-2.24(m,6H),1.67(br.s.,4H)。ESI[M+H]＝484.2

(3S,4R) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) -4- (pyrrolidin-1-ylmethyl) pyrrolidin-3-ol, 471.¹H NMR (400MHz, methanol-d)₄)δ＝7.96(s,1H),7.69(s,1H),7.58-7.54(m,4H),7.16(s,1H),7.11-7.07(m,2H),6.82-6.75(m,2H),5.26(s,2H),4.31-4.30(m,1H),3.77-3.32(m,13H),2.20-2.07(s,2H)。ESI[M+H]＝484.2

(3R,4S) -4- ((cyclopropylamino) methyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-ol, 473 using general procedure V instead of azetidin-1-yl ((trans) -4-hydroxypyrrolidin-3-yl) methanone with (3S,4R) -N-cyclopropyl-4-hydroxypyrrolidine-3-carboxamide.¹H NMR (400MHz, methanol-d)₄)δ＝8.00(s,1H),7.74(s,1H),7.64-7.51(m,4H),7.19(s,1H),7.09(t,J＝8.6Hz,2H),6.82(br.s.,1H),6.75(d,J＝8.8Hz,1H),5.28(s,2H),4.37-4.25(m,1H),3.79-3.69(m,2H),3.49-3.34(m,2H),3.27-3.14(m,2H),2.84(br.s.,1H),2.61(dd,J＝7.1,14.1Hz,1H),0.94(br.s.,4H)。ESI[M+H]＝470.1

2- (6- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) -2, 6-diazaspiro [3.4] oct-2-yl) acetic acid, 478. synthesized using general procedure J, using 2-bromoacetic acid instead of 2-bromoethanol. 1HNMR (400MHz, methanol-d 4) δ 7.57-7.49(m,3H),7.37(d, J8.8 Hz,1H),7.27(s,1H),7.18(s,1H),7.03(t, J8.8 Hz,2H),6.90(s,1H),6.75(s,1H),6.68(br d, J8.6 Hz,1H),5.05(s,2H),4.19(s,4H),3.81(s,2H),3.62(s,2H),3.43(br t, J6.8 Hz,2H),2.38(br t, J7.1 Hz, 2H). ESI [ M + H ] ═ 484.1

1- ((1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) methyl) piperidine-4-carboxylic acid, 480. synthesized using general procedure R with methyl 1- (pyrrolidin-3-ylmethyl) piperidine-4-carboxylate instead of methyl 2-methyl-2- ((pyrrolidin-3-ylmethyl) amino) propionate.¹H NMR (400MHz, methanol-d)₄)δ＝8.01(d,J＝1.3Hz,1H),7.74(d,J＝1.8Hz,1H),7.63-7.50(m,4H),7.20(s,1H),7.09(t,J＝8.8Hz,2H),6.81(br.s.,1H),6.76(d,J＝8.8Hz,1H),5.27(s,2H),3.79-3.67(m,2H),3.54(t,J＝7.5Hz,2H),3.49-3.38(m,1H),3.18(t,J＝8.6Hz,2H),3.07(t,J＝12.3Hz,2H),2.89(br.s.,1H),2.73-2.60(m,1H),2.42-2.21(m,3H),2.13(br.s.,1H),2.05-1.83(m,3H)。ESI[M+H]＝526.2

(3aR,6aS) -5- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) hexahydro-2H-pyrrolo [3,4-d]Oxazol-2-one, 481 using general procedure a with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Novel use of (3aR,6aS) -hexahydro-2H-pyrrolo [3,4-d ] aS a combined preparation of diazepine-12-yl) benzonitrile]Oxazol-2-one was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR (400MHz, methanol-d)₄)δ＝8.11(d,J＝1.8Hz,1H),8.04(d,J＝2.2Hz,1H),7.91-7.84(m,1H),7.84-7.76(m,2H),7.63(d,J＝1.3Hz,1H),7.56(dd,J＝5.3,8.4Hz,2H),7.24(d,J＝1.3Hz,1H),7.08(t,J＝8.8Hz,2H),5.51-5.45(m,1H),5.44-5.37(m,3H),3.88(d,J＝13.7Hz,1H),3.73-3.65(m,1H),3.64-3.53(m,2H)。ESI[M+H]＝442.0

(3S,4S) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadizepine-7-yl) -4- ((methylamino) methyl) pyrrolidin-3-ol, 482. Using general procedure G with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]The diazepine-12-yl) benzonitrile and benzyl (((3R,4S) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamate is used in place of benzyl (((trans) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamate.¹HNMR (400MHz, methanol-d)₄)δ＝7.98(d,J＝2.2Hz,1H),7.72(d,J＝2.2Hz,1H),7.62-7.48(m,4H),7.18(d,J＝1.8Hz,1H),7.07(t,J＝8.8Hz,2H),6.78(d,J＝2.2Hz,1H),6.71(dd,J＝2.4,9.0Hz,1H),5.25(s,2H),4.56(t,J＝3.5Hz,1H),3.69-3.56(m,2H),3.46-3.36(m,2H),3.32(br.s.,1H),3.22(dd,J＝6.2,12.8Hz,1H),2.81-2.65(m,4H)。ESI[M+H]＝444.1

(3R,4R) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) -4- ((methylamino) methyl) pyrrolidin-3-ol, 483 using general procedure G with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]The diazocapside-12-yl) benzonitrile and benzyl (((3S,4R) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamate in place of the (((trans) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamateBenzyl ester.¹HNMR (400MHz, methanol-d)₄)δ＝7.99(d,J＝2.0Hz,1H),7.73(d,J＝2.0Hz,1H),7.63-7.50(m,4H),7.18(d,J＝1.8Hz,1H),7.08(t,J＝8.7Hz,2H),6.79(d,J＝2.4Hz,1H),6.73(dd,J＝2.4,8.8Hz,1H),5.27(s,2H),4.56(t,J＝3.4Hz,1H),3.72-3.57(m,2H),3.47-3.35(m,2H),3.22(dd,J＝6.0,12.8Hz,2H),2.76(s,3H),2.71(d,J＝5.3Hz,1H)。ESI[M+H]＝444.1

(3R,4R) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) -4- (hydroxymethyl) pyrrolidin-3-ol 484. use of general procedure A in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile and (3R,4R) -4- (hydroxymethyl) pyrrolidin-3-ol was synthesized instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.98(s,1H),7.71(s,1H),7.61-7.53(m,3H),7.50(d, J ═ 8.8Hz,1H),7.16(s,1H),7.07(t, J ═ 8.6Hz,2H),6.78(s,1H),6.72(d, J ═ 8.8Hz,1H),5.25(s,2H),4.33(d, J ═ 4.9Hz,1H),3.68-3.58(m,3H),3.55-3.44(m,1H),3.27-3.23(m,2H),2.44(br.s., 1H). ESI [ M + H ] ═ 431.2

(3S,4S) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) -4- (hydroxymethyl) pyrrolidin-3-ol, 485 using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and ((3S,4S) -4- ((tert-butyldiphenylsilyl) oxy) pyrrolidin-3-yl) methanol in place of tert-butyl piperazine-1-carboxylate.¹H NMR (400MHz, methanol-d)₄)δ＝8.00(d,J＝1.8Hz,1H),7.72(s,1H),7.63-7.54(m,3H),7.51(d,J＝8.8Hz,1H),7.17(s,1H),7.08(t,J＝8.6Hz,2H),6.78(s,1H),6.72(d,J＝8.8Hz,1H),5.26(s,2H),4.33(br.s.,1H),3.68-3.58(m,3H),3.55-3.43(m,1H),3.35(br.s.,2H),2.44(br.s.,1H)。ESI[M+H]＝431.2

2- (1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) ethylamine, 486 using general procedure G with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and benzyl (2- (pyrrolidin-3-yl) ethyl) carbamate in place of benzyl (((trans) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamate.¹H NMR (400MHz, methanol-d)₄)δ＝7.99(d,J＝2.2Hz,1H),7.73(d,J＝1.8Hz,1H),7.62-7.47(m,4H),7.18(d,J＝1.3Hz,1H),7.08(t,J＝8.8Hz,2H),6.78(d,J＝2.6Hz,1H),6.72(dd,J＝2.6,8.8Hz,1H),5.26(s,2H),3.64-3.56(m,1H),3.54-3.45(m,1H),3.43-3.33(m,1H),3.08-2.96(m,3H),2.50-2.35(m,1H),2.34-2.21(m,1H),1.95-1.66(m,3H)。ESI[M+H]＝428.1

2- (1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) -N-methylethylamine, 487 using general procedure G with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and benzyl methyl (2- (pyrrolidin-3-yl) ethyl) carbamate in place of benzyl (((trans) -4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamate.¹H NMR (400MHz, methanol-d)₄)δ＝7.99(d,J＝2.2Hz,1H),7.73(d,J＝2.2Hz,1H),7.61-7.49(m,4H),7.18(d,J＝1.8Hz,1H),7.08(t,J＝8.8Hz,2H),6.78(d,J＝2.6Hz,1H),6.72(dd,J＝2.6,8.8Hz,1H),5.26(s,2H),3.64-3.56(m,1H),3.53-3.46(m,1H),3.43-3.36(m,1H),3.14-3.00(m,3H),2.72(s,3H),2.46-2.34(m,1H),2.28(d,J＝12.3Hz,1H),1.92-1.72(m,3H)。ESI[M+H]＝442.2

2- (1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) -N, N-dimethylethylamine, 488 using general procedure U with 2- (1- (12- (4-fluorophenyl) -9H-benzo [ e ]]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azadipine-7-yl) pyrrolidin-3-yl) ethylamine in place of 1- ((cis) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) -N-methylmethanamine.¹H NMR (400MHz, methanol-d)₄)δ＝7.98(d,J＝2.2Hz,1H),7.72(d,J＝2.2Hz,1H),7.62-7.46(m,4H),7.19(d,J＝1.8Hz,1H),7.08(t,J＝8.8Hz,2H),6.78(d,J＝2.6Hz,1H),6.72(dd,J＝2.4,9.0Hz,1H),5.25(s,2H),3.59(t,J＝8.4Hz,1H),3.54-3.44(m,1H),3.43-3.34(m,1H),3.26-3.15(m,2H),3.10-3.01(m,1H),2.90(s,6H),2.45-2.20(m,2H),1.99-1.71(m,3H)。ESI[M+H]＝456.2

((trans) -4- (dimethylamino) -1- (12- (4-fluorophenyl) -9H-benzo [ e)]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Diazepine-7-yl) pyrrolidin-3-yl) methanol, 490 using general procedure A with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e]Imidazo [2, 1-c)]Pyrrolo [1,2-a][1,4]Azepine in place of 4- (7-bromo-9H-benzo [ e]Pyrrolo [1,2-a][1,2,4]Triazolo [3,4-c][1,4]Diazepine-12-yl) benzonitrile and ((trans) -4- (dimethylamino) pyrrolidin-3-yl) methanol in place of piperazine-1-carboxylic acid tert-butyl ester.¹H NMR(400MHz, methanol-d₄)δ＝8.04(s,1H),7.77(s,1H),7.62-7.55(m,4H),7.21(s,1H),7.10(t,J＝8.8Hz,2H),6.97(s,1H),6.91(d,J＝9.0Hz,1H),5.32(s,2H),4.08(d,J＝3.3Hz,1H),3.91-3.81(m,2H),3.80-3.71(m,2H),3.66-3.57(m,1H),3.22(dd,J＝4.8,10.1Hz,1H),2.95(s,7H)。ESI[M+H]＝458.1

((trans) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) -4- (methylamino) pyrrolidin-3-yl) methanol, 491 using general procedure V with N- ((trans) -4- (hydroxymethyl) pyrrolidin-3-yl) carboxamide instead of azetidin-1-yl ((trans) -4-hydroxypyrrolidin-3-yl) methanone. 1H NMR (400MHz, methanol-d 4) δ 8.03(br.s.,1H),7.76(br.s.,1H),7.60(d, J ═ 10.4Hz,4H),7.21(br.s, 1H),7.10(t, J ═ 8.0Hz,2H),6.98-6.79(m,2H),5.31(br.s, 2H),3.89(br.s, 1H),3.83-3.74(m,3H),3.70-3.60(m,2H),3.25(br.s, 1H),2.99-2.90(m,1H),2.86-2.70(m, 3H). ESI [ M + H ] ═ 444.1

Trans-4- (2-aminoethyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 492 use general procedure G to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) azepine, Was synthesized by substituting (2- ((trans) -4-hydroxypyrrolidin-3-yl) ethyl) carbamic acid benzyl ester for ((trans-4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamic acid benzyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.00(d, J1.6 Hz,1H),7.74(d, J1.6 Hz,1H),7.63-7.51(m,4H),7.20(s,1H),7.09(t, J8.7 Hz,2H),6.80(d, J2.2 Hz,1H),6.74(dd, J2.2, 8.8Hz,1H),5.28(s,2H),4.19(q, J6.2 Hz,1H),3.76-3.65(m,2H),3.25(dd, J5.7, 9.8Hz,1H),3.18-3.06(m,3H),2.29 (d, J1.86, 1.7, 14H), 1.85 (q, 1H), 1.85H). ESI [ M + H ] ═ 444.1

Trans-1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) -4- (2- (methylamino) ethyl) pyrrolidin-3-ol, 493 use of general procedure G in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) diazepin, Was synthesized by substituting benzyl (2- (trans-4-hydroxypyrrolidin-3-yl) ethyl) (methyl) carbamate for benzyl ((trans-4-hydroxypyrrolidin-3-yl) methyl) (methyl) carbamate. 1HNMR (400MHz, methanol-d 4) δ is 8.00(d, J is 1.8Hz,1H),7.74(d, J is 1.8Hz,1H),7.64-7.50(m,4H),7.20(s,1H),7.09(t, J is 8.6Hz,2H),6.80(d, J is 2.0Hz,1H),6.73(dd, J is 2.1,8.9Hz,1H),5.27(s,2H),4.20(q, J is 6.0Hz,1H),3.76-3.63(m,2H),3.27-3.10(m,4H),2.74(s,3H),2.28 (d, J is 7.0,14.1, 1H), 2.01-1H), 1.87 (m, 1H). ESI [ M + H ] ═ 458.2

Trans-4- (2- (dimethylamino) ethyl) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 494 use general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) diazepin, Trans-4- (2- (dimethylamino) ethyl) pyrrolidin-3-ol was used instead of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.01(br.s.,1H),7.75(br.s.,1H),7.64-7.51(m,4H),7.21(br.s.,1H),7.10(t, J ═ 7.9Hz,2H),6.81(br.s.,1H),6.75(d, J ═ 8.8Hz,1H),5.29(br.s.,2H),4.23(d, J ═ 5.3Hz,1H),3.77-3.65(m,2H),3.26(d, J ═ 8.8Hz,2H),3.16(t, J ═ 8.2Hz,1H),2.93(br.s, 7H),2.26(d, J ═ 8.8Hz,1H), 1.00 (br.h), 1H, 2H. ESI [ M + H ] ═ 472.2

(trans-4- ((12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) amino) pyrrolidin-3-yl) methanol 495 use of general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine and (trans-4-aminopyrrolidin-3-yl) methanol for piperazin-1-methyl-carbonitrile Tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.99(d, J7.0 Hz,1H),7.74(d, J7.0 Hz,1H),7.65-7.45(m,4H),7.20(d, J6.7 Hz,1H),7.08(d, J7.8 Hz,2H),6.96-6.80(m,2H),5.25(d, J6.7 Hz,2H),4.21(br.s.,1H),3.72(br.s.,3H),3.60(d, J8.6 Hz,1H),3.20(br.s.,2H),2.52(br.s., 1H). ESI [ M + H ] ═ 430.1

(R) - (1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methylamine, 496. use of general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzazepine, (S) - (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester was used instead of piperazine-1-carboxylic acid tert-butyl ester for synthesis. 1H NMR (400MHz, methanol-d 4) δ 8.13(s,1H),7.67-7.65(m,1H),7.57-7.54(m,2H),7.41-7.40(m,1H),7.08-7.04(m,3H),6.72-6.70(m,2H),5.15(s,2H),3.57-3.37(m,3H),3.13-3.09(m,1H),2.84-2.82(m,2H),2.53-2.49(m,1H),2.26-2.24(m,1H),1.84-1.81(m, 1H). ESI [ M + H ] ═ 415.1

1- ((3S,4S) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmethylamine, 497 using general procedure T to replace 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine. 1H NMR (400MHz, methanol-d 4) δ 8.16(s,1H),7.71(d, J9.0 Hz,1H),7.54(dd, J5.5, 8.2Hz,2H),7.40(s,1H),7.12-7.02(m,3H),6.78-6.71(m,2H),5.52-5.34(m,1H),5.15(s,2H),3.88-3.79(m,1H),3.79-3.71(m,2H),3.70-3.63(m,1H),3.45(dd, J7.2, 12.7Hz,1H),3.26(br.s.,1H),2.82(s, 4H). ESI [ M + H ] ═ 447.1

1- ((3S,4S) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine 498 using general procedure U substituting 1- ((3S,4S) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmethylamine for 1- (cis-4-fluoro-1- (5, 1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmethylamine 12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-7-yl) pyrrolidin-3-yl) -N-methylmethylamine. 1H NMR (400MHz, methanol-d 4) δ 8.14(s,1H),7.70(d, J8.8 Hz,1H),7.54(dd, J5.3, 8.8Hz,2H),7.39(d, J1.3 Hz,1H),7.11-7.00(m,3H),6.79-6.71(m,2H),5.53-5.34(m,1H),5.16(s,2H),3.88-3.67(m,3H),3.66-3.58(m,1H),3.46-3.38(m,1H),3.35(br.s.,1H),3.09-2.93(m, 7H). ESI [ M + H ] ═ 461.1

1- ((3R,4R) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmethylamine 499 use of general procedure T to replace 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine. 1H NMR (400MHz, methanol-d 4) δ 8.13(s,1H),7.69(d, J8.8 Hz,1H),7.58-7.47(m,2H),7.39(s,1H),7.12-6.98(m,3H),6.79-6.66(m,2H),5.52-5.31(m,1H),5.14(s,2H),3.86-3.78(m,1H),3.78-3.69(m,2H),3.69-3.62(m,1H),3.44(dd, J ═ 7.1,12.8Hz,1H),3.25(br.s, 1H),2.93-2.77(m, 4H). ESI [ M + H ] ═ 447.2

1- ((3R,4R) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine 500 use general procedure U to replace 1- (cis-4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmethylmethylamine with 1- ((3R,4R) -4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmethylamine 12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepine-7-yl) pyrrolidin-3-yl) -N-methylmethylamine. 1H NMR (400MHz, methanol-d 4) δ 8.11(s,1H),7.65(d, J8.6 Hz,1H),7.53(dd, J5.3, 8.6Hz,2H),7.39(d, J1.8 Hz,1H),7.09-6.99(m,3H),6.73-6.64(m,2H),5.38-5.20(m,1H),5.12(s,2H),3.77-3.69(m,1H),3.67-3.58(m,2H),3.15(br t, J9.6 Hz,1H),2.77-2.61(m,2H),2.60-2.53(m,1H),2.33(s, 6H). ESI [ M + H ] ═ 461.2

1- (cis-4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmethylamine, 501 using general procedure T replacing 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1 with 7-bromo-12- (4-fluorophenyl) -9H-pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin, 2-a ] [1,4] diazepine. 1H NMR (400MHz, methanol-d 4) δ 8.16(s,1H),7.71(d, J8.8 Hz,1H),7.59-7.50(m,2H),7.41(s,1H),7.12-7.00(m,3H),6.79-6.72(m,2H),5.50-5.36(m,1H),5.17(s,2H),3.88-3.80(m,1H),3.79-3.71(m,2H),3.71-3.65(m,1H),3.45(dd, J ═ 7.1,12.8Hz,1H),3.35-3.32(m,1H),2.94-2.76(m, 4H). ESI [ M + H ] ═ 447.2

1- (cis-4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N, N-dimethylmethylamine, 502. Using general procedure U1- (cis-4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,2-a ] [1,2,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmelamine was used instead of 1- (cis-4-fluoro-1- (12- (4-fluoro-phenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmelamine Phenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmethylamine. 1H NMR (400MHz, methanol-d 4) δ 8.16(s,1H),7.70(d, J8.8 Hz,1H),7.54(dd, J53, 8.4Hz,2H),7.40(s,1H),7.11-6.99(m,3H),6.78-6.71(m,2H),5.50-5.37(m,1H),5.16(s,2H),3.85-3.78(m,1H),3.76(d, J7.5 Hz,1H),3.70(d, J15.0 Hz,1H),3.66-3.57(m,1H),3.42(dd, J6, 13.2Hz,1H),3.30(br 06, 1H), 3.94-2H), 94-7.7H. ESI [ M + H ] ═ 461.2

(trans-4-amino-1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methanol, 503. use of general procedure A to replace 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepin-12-yl) benzonitrile, Synthesized using tert-butyl ((trans) -4- (hydroxymethyl) pyrrolidin-3-yl) carbamate instead of piperazine-1-carboxylate. 1H NMR (400MHz, methanol-d 4) δ 8.15(s,1H),7.70(d, J8.8 Hz,1H),7.53(dd, J5.3, 8.4Hz,2H),7.40(s,1H),7.10-7.00(m,3H),6.82-6.75(m,2H),5.16(s,2H),3.92(d, J4.9 Hz,1H),3.81-3.71(m,3H),3.67-3.60(m,1H),3.48(dd, J4.2, 10.8Hz,1H),3.23(dd, J5.7, 10.1Hz,1H),2.63(d, J5.7, 1H). ESI [ M + H ] ═ 431.1

(trans-4- (dimethylamino) -1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methanol 504. Using general procedure U (trans-4-amino-1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) methanol was used in place of 1- (cis-4-fluoro-1- (12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2 ], 1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-yl) -N-methylmethylamine. 1H NMR (400MHz, methanol-d 4) δ 8.20(s,1H),7.73(d, J8.8 Hz,1H),7.54(dd, J5.3, 8.3Hz,2H),7.41(s,1H),7.13-7.00(m,3H),6.93-6.79(m,2H),5.17(s,2H),4.10-4.00(m,1H),3.87-3.65(m,4H),3.60(dd, J7.7, 10.7Hz,1H),3.16(dd, J5.0, 9.9Hz,1H),2.94(s, 7H). ESI [ M + H ] ═ 459.2

(trans-1- (12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin-7-yl) -4- (methylamino) pyrrolidin-3-yl) methanol, 505. Using general procedure V replacing 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1, 1-c ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9H-benzo [ e ] pyrrolo [1,2-a ] [1,4 diazepine, synthesized using N- (trans-4- (hydroxymethyl) pyrrolidin-3-yl) carboxamide instead of azetidin-1-yl (trans-4-hydroxypyrrolidin-3-yl) methanone. 1H NMR (400MHz, methanol-d 4) δ 8.11(s,1H),7.66(d, J8.6 Hz,1H),7.54(dd, J5.4, 8.7Hz,2H),7.40(d, J1.5 Hz,1H),7.07-7.01(m,3H),6.75-6.70(m,2H),5.14(s,2H),3.70-3.56(m,4H),3.21(dd, J5.8, 9.8Hz,3H),2.53-2.41(m, 4H). ESI [ M + H ] ═ 445.1

(3S,4R) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -9-methyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol 507 use general procedure A to replace the 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] diazepin salt with 7-bromo-12- (4-fluorophenyl) -9-methyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin salt, 4] diazepine-12-yl) benzonitrile with (3S,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.07-7.99(m,1H),7.77(s,1H),7.68-7.62(m,1H),7.61-7.52(m,3H),7.25(s,1H),7.09(t, J ═ 8.6Hz,2H),6.78-6.69(m,2H),5.69(d, J ═ 7.1Hz,1H),4.32-4.21(m,1H),3.83-3.68(m,2H),3.43-3.33(m,2H),3.27-3.18(m,2H),2.99(br.s, 6H),2.77-2.64(m,1H),1.45(d, J ═ 7.1, 3H). ESI [ M + H ] ═ 472.2

(3S,4R) -4- ((dimethylamino) methyl) -1- ((R) -12- (4-fluorophenyl) -9-methyl-9H-benzo [ E ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 508. Using general procedure E to replace the 4- (7-bromo-9H-benzo [ E ] pyrrolo [1,2-a ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9-methyl-9H-benzo [ E ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin, 4-c ] [1,4] diazepine-12-yl) benzonitrile by replacement of N, N-dimethyl-1- (morpholin-2-yl) methylamine with (3S,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol. 1HNMR (400MHz, DMSO-d6) δ — 7.62(s,1H),7.58-7.44(m,2H),7.40(br.s.,1H),7.36-7.23(m,2H),7.16-7.05(m,2H),6.83(d, J ═ 1.8Hz,1H),6.63(br.s.,1H),6.53(d, J ═ 8.8Hz,1H),5.53(q, J ═ 6.9Hz,1H),4.06(br.s.,1H),3.47(d, J ═ 5.7Hz,2H),3.06(d, J ═ 8.8Hz,2H),2.38-2.08(m,9H),1.28-1.17(m, 3H). ESI [ M + H ] ═ 472.2

(3S,4R) -4- ((dimethylamino) methyl) -1- ((S) -12- (4-fluorophenyl) -9-methyl-9H-benzo [ E ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 509. Using general procedure E to replace the 4- (7-bromo-9H-benzo [ E ] pyrrolo [1,2-a ] [1,4] diazepin with 7-bromo-12- (4-fluorophenyl) -9-methyl-9H-benzo [ E ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin, 4-c ] [1,4] diazepine-12-yl) benzonitrile by replacement of N, N-dimethyl-1- (morpholin-2-yl) methylamine with (3S,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol. 1HNMR (400MHz, methanol-d 4) δ 8.07-7.98(m,1H),7.76(d, J1.8 Hz,1H),7.68-7.62(m,1H),7.61-7.49(m,3H),7.25(s,1H),7.09(t, J8.7 Hz,2H),6.79-6.66(m,2H),5.68(q, J7.0 Hz,1H),4.29(q, J6.5 Hz,1H),3.79-3.68(m,2H),3.43-3.32(m,2H),3.27-3.17(m,2H),2.98(br.s.,6H),2.75-2.59(m,1H),1.44(d, 1H). ESI [ M + H ] ═ 472.2

(3S,4R) -4- ((dimethylamino) methyl) -1- (5- (4-fluorophenyl) -8H-benzo [ e ] pyrrolo [1,2-a ] [1,2,3] triazolo [5,1-c ] [1,4] diazepin-10-yl) pyrrolidin-3-ol, 511. Using general procedure A, 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,3] triazolo [5,1-c ] [1,4] diazepin is used in place of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile with (3S,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.98(s,1H),7.76(d, J8.6 Hz,1H),7.55-7.47(m,2H),7.34(d, J2.0 Hz,1H),7.02(t, J8.9 Hz,2H),6.86(d, J1.8 Hz,1H),6.76-6.68(m,2H),5.06(s,2H),4.27(q, J6.8 Hz,1H),3.79-3.69(m,2H),3.44-3.32(m,2H),3.26-3.13(m,2H),2.99(brs,6H),2.75-2.64(m, 1H). ESI [ M + H ] ═ 459.1

(3S,4R) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -5-methyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin-7-yl) pyrrolidin-3-ol, 512. Using general procedure A, the 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,4] diazepin is replaced with 7-bromo-12- (4-fluorophenyl) -5-methyl-9H-benzo [ e ] imidazo [2,1-c ] pyrrolo [1,2-a ] [1,4] diazepin, 4] diazepine-12-yl) benzonitrile with (3S,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol in place of piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 7.91(s,1H),7.70(s,1H),7.60-7.49(m,3H),7.16-7.03(m,3H),6.68(d, J ═ 2.4Hz,1H),6.58(s,1H),5.19-5.06(m,2H),4.28(q, J ═ 6.9Hz,1H),3.81-3.69(m,2H),3.44-3.33(m,2H),3.28-3.17(m,2H),2.99(s,6H),2.75-2.63(m,1H),2.39(s, 3H). ESI [ M + H ] ═ 472.1

(3S,4R) -4- ((dimethylamino) methyl) -1- (12- (4-fluorophenyl) -5-methyl-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1c ] [1,4] diazepin-7-yl) pyrrolidin-3-ol 513. Using general procedure A with 7-bromo-12- (4-fluorophenyl) -5-methyl-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [5,1-c ] [1,4] diazepin instead of 4- (7-bromo-9H-benzo [ e ] pyrrolo [1,2-a ] [1,2,4] triazolo [3,4-c ] [1,4] diazepine-12-yl) benzonitrile by substituting (3S,4S) -4- ((dimethylamino) methyl) pyrrolidin-3-ol for piperazine-1-carboxylic acid tert-butyl ester. 1H NMR (400MHz, methanol-d 4) δ 8.17(s,1H),7.58-7.49(m,2H),7.37(d, J ═ 1.8Hz,1H),7.09-7.00(m,3H),6.60(d, J ═ 2.6Hz,1H),6.53(d, J ═ 2.2Hz,1H),5.10-5.00(m,1H),4.92(br s,1H),4.28(q, J ═ 6.7Hz,1H),3.78-3.69(m,2H),3.44-3.33(m,2H),3.28-3.16(m,2H),3.00(s,6H),2.75-2.64(m,1H),2.38(s, 3H). ESI [ M + H ] ═ 473.2

B. Biological analysis

The following assay was used to identify and evaluate compounds of formula (I) or formula (II) that effectively inhibit MK2 enzyme.

Example (c): MK2 enzyme assay

Inhibition of MK2 was determined for certain compounds of the invention as listed in table 5. Briefly, 5 μ L of 2 × (4 μ M) 100% phosphorylated peptide was delivered to control wells of a 384 well assay plate. 5 μ L of a2 × (1nM) MAPKAPK2 and 2 × peptide (4 μ M) mixture in assay buffer was dispensed to the remaining columns of the assay plate using an Edward electronic multichannel pipette. The assay plates were incubated for 20 minutes. 5 μ L of 2 × ATP (6 μ M) in assay buffer was dispensed to each well and the assay plate was then gently centrifuged. The assay plates were incubated for a further 120 minutes.

Table 3: conditions for MK2 enzyme assay

[MAPKAPK2]	0.5nM
		[ATP]	3μM
Peptide substrate:	2μM Ser/Thr4
		reaction time:	120 minutes
Temperature:	23℃
		total volume:	10μL

an Edwarder electronic multichannel pipette was used to dispense 5. mu.L of developing reagent to all wells. After incubation of the developing reaction for 120min, plates were read on a Perkin Elmer Envision instrument.

Table 4: conditions of development reaction

The% phosphorylation was calculated using the following formula:

wherein

Average coumarin emission signal for C100% ═ 100% phosphorylated controls

Average coumarin emission signal from C0% ═ 0% phosphorylated controls

Mean yellow fluorescence emission signal for F100% -100% phosphorylated control

Mean yellow fluorescence emission signal of 0% phosphorylated control versus F0%

The ability of compounds of formula (I) or formula (II) or pharmaceutically acceptable salts thereof to inhibit MK2 was determined using the assays described above with representative compounds of formula (I) or formula (II) listed in table 4.

Table 5: MK2 analysis

Incorporation by reference

All publications and patents mentioned herein are incorporated herein by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In the event of conflict, the present application, including any definitions herein, will control.

Equivalent content

While specific embodiments of the invention have been discussed, the above description is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the appended claims. The full scope of the invention should be determined with reference to the claims, along with the full scope of equivalents to which such claims are entitled, and the specification and variations to which such claims are entitled.

Claims (52)

1. A compound having the structure of formula I or a pharmaceutically acceptable salt thereof,

wherein

X¹、X²And X³Each occurrence is independently CR⁵Or N;

X⁵、X⁶and X⁷Each occurrence is independently CR⁷Or N;

R¹independently for each occurrence is H, halo, -OH, -CN, or optionally substituted alkyl, alkoxy, ether, carbamate, or ester;

R²is H, halo, -CN, alkyl or ester;

R³is H, alkyl or cycloalkyl;

R⁵is H, halo, -CN or optionally substituted alkyl, alkoxy, aryl, heteroaryl, carbamate, or ester;

R⁷is H, halo, -OH, -CN or optionally substituted alkyl, alkoxy, carbamate or ester;

z is halo or optionally substituted amino, alkylamino, heteroalkylamino, cycloalkylamino or heterocycloalkylamino; and is

n is an integer of 0 to 5.

2. The compound of claim 1, wherein the compound has the structure of formula II, or a pharmaceutically acceptable salt thereof,

wherein X¹Is N or CH;

X²and X³Each occurrence is independently CR⁵Or N;

R^1ais H, halo, -CN, -OH or optionally substituted alkyl;

R^1bis H, halo, -CN, -OH or optionally substituted alkyl;

R²is H or halo;

R⁵is absent or is H, halo or optionally substituted alkyl; and is

Z is halo or optionally substituted amino, alkylamino, heteroalkylamino, cycloalkylamino or heterocycloalkylamino.

3. According to claim 1The compound of (1) or (2), wherein X¹Is N; and X²And X³Is CH.

4. A compound according to claim 1 or 2, wherein X¹And X²Is N; and X³Is CH.

5. A compound according to claim 1 or 2, wherein X¹And X³Is N; and X²Is CH.

6. A compound according to claim 1 or 2, wherein X¹、X²And X³Is N.

7. A compound according to any preceding claim, wherein

Z is optionally substituted alkylamino, heterocycloalkylamino, cycloalkylamino or-NR⁸R⁹(ii) a And is

R⁸And R⁹Each independently is H or optionally substituted alkyl, cycloalkyl or heterocycloalkyl; or

R⁸And R⁹Taken together with the bound N to form an optionally substituted 4-, 5-or 6-membered heterocyclic ring.

8. The compound of any one of claims 1-7, wherein

Z isAnd is

R²⁰、R²¹、R²²And R²³Each independently is H, halo, hydroxy, amino, or optionally substituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, alkylamino, cycloalkyl, or heterocycloalkyl; or

R²³And R²⁰Combine to form an optionally substituted 3-, 4-, 5-or 6-membered ring;

R²¹and R²⁰Combine to form an optionally substituted 3-, 4-, 5-or 6-membered ring; or

R²¹And R²²The combination forms an optionally substituted 4-, 5-or 6-membered ring.

9. The compound of claim 8, wherein the optionally substituted 4-, 5-, or 6-membered ring comprises a heteroatom.

10. The compound of claim 9, wherein the heteroatom is N.

11. The compound of claim 8, wherein Z is

12. The compound of claim 8, wherein Z is

13. The compound of any one of claims 1-7, wherein

Z is

X²⁰Is CR²⁴R²⁶NH or O; and is

R²⁴、R²⁵、R²⁶And R²⁷Each independently is H, amino or optionally substituted alkyl, aminoalkyl, alkylaminoalkyl, alkylamino, cycloalkyl or heterocycloalkyl; or

R²⁴And R²⁶The combination forms an optionally substituted 4-, 5-or 6-membered ring.

14. The compound of claim 13, wherein the optionally substituted 4-, 5-, or 6-membered ring comprises a heteroatom.

15. The compound of claim 14, wherein the heteroatom is N.

16. The compound of claim 13, wherein Z is

17. The compound of any one of claims 1-7, wherein

Z isAnd is

R²⁸And R²⁹Each independently is H, amino or optionally substituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, alkylamino, cycloalkyl or heterocycloalkyl; or

R²⁸And R²⁹The combination forms an optionally substituted 4-, 5-or 6-membered ring.

18. The compound of claim 17, wherein the optionally substituted 4-, 5-, or 6-membered ring comprises a heteroatom.

19. The compound of claim 18, wherein the heteroatom is N.

20. The compound of claim 17, wherein Z is

21. The compound of any one of claims 1-6, wherein

Z is

X²¹Is NH or O.

22. The compound of claim 21, wherein Z is

23. The compound of any one of claims 1-7, wherein Z is optionally substituted alkylamino, cycloalkylamino, or heterocycloalkylamino.

24. The compound of claim 23, wherein Z is

25. The compound of claim 22, wherein Z is

26. A compound according to any preceding claim, wherein R¹Independently at each occurrence is fluoro, chloro, -CN, -O-R³¹、OCF₃、-O-C(O)-NR³¹R³²OR-C (O) -OR³¹(ii) a And is

R³¹And R³²Independently for each occurrence is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, aryl or aralkyl group.

27. The compound of claim 24, wherein R¹Is fluorine or-CN.

28. The compound of any one of claims 2-25, wherein R^1aAnd R^1bIndependently at each occurrence is fluoro, chloro, -CN, -O-R³¹、-OCF₃、-O-C(O)-NR³¹R³²OR-C (O) -OR³¹(ii) a And is

R³¹And R³²Independently for each occurrence is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, aryl or aralkyl group.

29. According to claim 2The compound of any one of claims to 25, wherein R^1aAnd R^1bIndependently at each occurrence is fluorine or-CN.

30. A compound according to any preceding claim, wherein R²is-C (O) -OR⁴¹(ii) a And is

R⁴¹Is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, aryl or aralkyl group.

31. The compound of any one of claims 1-29, wherein R²Is H or chlorine.

32. The compound of any one of claims 1, 3-27, 30, and 31, wherein R³Is optionally substituted C_1-6Alkyl or C_3-6Cycloalkyl, preferably cyclopropyl.

33. The compound of any one of claims 1, 3-27, 30, and 31, wherein R³Is H.

34. A compound according to any preceding claim, wherein R⁵Is optionally substituted alkyl, -O-C (O) -NR⁶¹R⁶²OR C (O) -OR⁶¹；

R⁶¹And R⁶²Independently for each occurrence is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, aryl or aralkyl group.

35. A compound according to any preceding claim, wherein R⁷is-O-C (O) -NR⁷¹ ₂OR-C (O) -OR⁷¹；

R⁷¹Is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, aryl or aralkyl group.

36. A compound according to any preceding claim, wherein n is 0,1 or 2.

37. A compound selected from:

or a pharmaceutically acceptable salt thereof.

38. A pharmaceutical composition comprising a compound according to any preceding claim and a pharmaceutically acceptable carrier.

39. A method of treating or preventing a mitosis promoter activated protein kinase-2 (MK2) -associated disorder comprising administering to a subject a compound according to any preceding claim.

40. The method of claim 39, wherein the MK 2-associated disorder is an inflammatory disorder or cancer.

41. The method of claim 40, wherein the cancer is a KRAS-dependent or BRAF-dependent cancer.

42. The method of claim 39, further comprising co-administering one or more other chemotherapeutic agents or combination therapy.

43. The method of claim 42, wherein the other chemotherapeutic agent is a CHK1 inhibitor or cisplatin.

44. The method of claim 43, wherein the CHK1 inhibitor is PF477736 or LY 2603618.

45. A method of inhibiting cancer cell proliferation comprising contacting a cancer cell with a compound of any one of claims 1-37.

46. A method of inhibiting MK2 activity in a cell, comprising contacting a cell with a compound of any one of claims 1-37.

47. A method of treating or preventing a metabolic disorder comprising administering to a subject a compound of any one of claims 1-37.

48. The method of claim 47, wherein the metabolic disorder is diabetes, insulin resistance, obesity, or metabolic syndrome.

49. The method of claim 48, wherein the diabetes is type I, type II, or gestational diabetes.

50. The method of claim 47, wherein the treatment or prevention affects hepatic glucose breakdown or glucose neogenesis in the individual.

51. The method of claim 47, wherein the treating or preventing reduces hepatic glucose production, hyperglycemia, fatty liver, insulin resistance-related inflammation, insulin resistance-related dyslipidemia, or any combination thereof, in the individual.

52. The method of any one of claims 47-51, further comprising co-administering one or more other anti-diabetic agents.