Tricyclic heterocyclic compounds as iap antagonists

Abstract

The present disclosure relates to compounds that inhibit IAP (preferably cIAP1, cIAP2 or XIAP) proteins, pharmaceutical compositions comprising these compounds and methods of using IAP protein inhibitors to treat diseases and conditions in which inhibition of IAP proteins provides a benefit.

Description

Technical Field

[0001] This disclosure relates to novel inhibitory apoptosis protein (IAP) inhibitors / antagonists and treatments for conditions and diseases in which the inhibitory / antagonistic effects of IAP proteins provide benefit. The inhibitors of this invention bind effectively to IAP proteins, including cIAP1, cIAP2, and XIAP. Background Technology

[0002] Apoptosis, or programmed cell death, is a cellular process crucial for homeostasis, normal development, host defense, and tumorigenesis suppression. Malregulation of apoptosis is associated with many human diseases, including cancer, and resistance to apoptosis is now recognized as a hallmark of cancer. Therefore, targeting key regulators of apoptosis has become an attractive strategy for developing novel therapies for human cancers.

[0003] Most current cancer therapies (including chemotherapy agents, radiation, and immunotherapy) indirectly induce apoptosis in cancer cells. Therefore, the inability of cancer cells to execute the apoptotic program (due to defects in normal apoptosis mechanisms) is often associated with increased resistance to apoptosis induced by chemotherapy, radiation, or immunotherapy. This primary or acquired resistance in human cancers to current therapies (due to defects in apoptosis) is a major problem in current cancer treatments.

[0004] To improve the survival and quality of life of cancer patients, current and future efforts in designing and developing novel molecular target-specific anticancer therapies include strategies that specifically target cancer cells' resistance to apoptosis. In this regard, targeting negative regulators that play a central role in directly inhibiting cancer cell apoptosis represents a very promising new anticancer drug design strategy.

[0005] One class of central negative regulators of apoptosis are inhibitory apoptosis proteins (IAPs). The IAP protein family comprises eight members: XIAP, cIAP1, cIAP2, NAIP, ILP2, ML-IAP, survivin, and BRUCE (also known as apollon). Members of the IAP family have been shown to inhibit programmed cell death through their ability to directly inhibit members of the caspase family, an apoptosis-inducing enzyme, although the exact roles of all eight members are not fully determined. A common structural feature of all IAP family members is a zinc-binding fold of 70 amino acids (called the baculovirus IAP repeat (BIR) domain), present in one to three copies.

[0006] Many interactions between IAP and other proteins are mediated via surface grooves on BIR domains. BIR domains can be classified according to their peptide-binding specificity. There are three types of BIR domains: type III domains (which bind caspase (and caspase-like) peptides, specific for proline at the third (P3) position, e.g., XIAP BIR3), type II domains (similar to type III domains but lacking proline requirement, e.g., XIAP BIR2), and type I domains (which do not bind caspase or similar peptides, e.g., XIAP BIR1) (Eckelman et al., Cell Death and Differentiation, 2008; 15:920-928). BIRs are small (-70 amino acids) Zn-coordinated domains, and many proteins use their N-terminus to interact with the BIR domain grooves. BIR antagonists prevent caspase from binding to BIRs and thus lead to increased caspase activity, thereby inducing IAP autoubiquitination and proteasome degradation.

[0007] IAP is overexpressed in many cancers, including kidney cancer, melanoma, colon cancer, lung cancer, breast cancer, ovarian cancer, and prostate cancer (Tamm et al., Clin. Cancer Research 2000; 6(5):1796-803), and is associated with tumor growth, pathogenesis, and resistance to chemotherapy and radiotherapy (Tamm 2000).

[0008] Small molecule inhibitors of IAP proteins are known. For example, U.S. Patent Publication No. 2005 / 0197403 and U.S. Patent No. 7,960,372 disclose dimer Smac mimicry compounds, each of which is incorporated herein by reference in its entirety.

[0009] Despite the discovery of small-molecule inhibitors of the IAP protein, the design of effective inhibitors remains a significant challenge in modern drug discovery. Therefore, there is still a need in the art for IAP inhibitors possessing physical and pharmacological properties that allow for their use in therapeutic applications. This invention provides compounds designed to bind to and inhibit the activity of the IAP protein. Summary of the Invention

[0010] In one respect, this disclosure provides compounds represented by formulas I, II, II-A, II-B, or II-C, and their pharmaceutically acceptable salts and solvates (e.g., hydrates), collectively referred to as "the compounds disclosed herein". The compounds disclosed herein are inhibitors of IAP (especially cIAP1, cIAP2, or XIAP) and are therefore used to treat or prevent diseases or conditions (such as IAP-related cancers) in which inhibition of IAP provides benefit.

[0011] On the other hand, this disclosure provides pharmaceutical compositions comprising the compounds disclosed herein and pharmaceutically acceptable carriers.

[0012] On the other hand, this disclosure provides a method for inhibiting the activity of IAP protein in cells, the method comprising contacting the cell (in which inhibition of IAP protein activity is desired) with an effective amount of the compound of this disclosure or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of this disclosure.

[0013] On the other hand, this disclosure provides a method for treating a disease or condition in which inhibition of the IAP protein provides benefit, the method comprising administering a therapeutically effective amount of the compound of this disclosure or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of this disclosure.

[0014] In one embodiment, the disease or condition is cancer. In another embodiment, the disease or condition is selected from the group consisting of: T-cell and B-cell mediated autoimmune diseases; inflammatory diseases; infections; proliferative disorders; AIDS; degenerative diseases; vascular diseases, etc. In another embodiment, the disease or condition is selected from the group consisting of: HBV, autoimmune hemolytic anemia, autoimmune hepatitis, Bergey's disease or IgA nephropathy, stomatitis, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft-versus-host disease, Graves' disease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, vitiligo, etc.

[0015] On the other hand, this disclosure provides compounds or pharmaceutical compositions disclosed herein for use in inhibiting the activity of IAP proteins in cells.

[0016] On the other hand, this disclosure provides compounds or pharmaceutical compositions disclosed herein for use in treating diseases or conditions in which inhibition of the IAP protein provides benefit.

[0017] On the other hand, this disclosure provides the use of the compounds or pharmaceutical compositions disclosed herein in the manufacture of a medicament for inhibiting the activity of IAP proteins in cells.

[0018] On the other hand, this disclosure provides for the use of the compounds or pharmaceutical compositions disclosed herein in the manufacture of a medicament for treating a disease or condition in which inhibition of the IAP protein provides benefit.

[0019] On the other hand, this disclosure provides a kit containing the compounds disclosed herein and instructions for administering the compounds disclosed herein to a subject (e.g., a patient) for whom inhibition of the IAP protein provides a benefit.

[0020] Further embodiments and advantages of this disclosure will be set forth in part in the description which follows, and will be apparent from the description or may be learned by practice of this disclosure. These embodiments and advantages of this disclosure will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims.

[0021] It should be understood that both the foregoing overview and the following detailed description are exemplary and illustrative only, and do not limit the invention as claimed. Detailed Implementation

[0022] This disclosure relates to compounds that inhibit IAP. In particular, this disclosure relates to compounds that inhibit the activity of cIAP1, cIAP2, or XIAP, pharmaceutical compositions comprising these compounds, and methods of using them.

[0023] Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to the term "technical" as used herein are intended to refer to technology as commonly understood in the art, including obvious technical changes or equivalent substitutions to those skilled in the art. While it is believed that those skilled in the art are familiar with the following terms, the following definitions are set forth to better interpret this disclosure.

[0024] I. Definition

[0025] As used herein, the terms “comprising,” “including,” “having,” “containing,” or “including,” and other variations thereof, are inclusive or open-ended and do not exclude other elements or method steps not listed.

[0026] Unless otherwise stated, in the context of describing this disclosure (especially in the context of the claims), the use of the terms "a / an," "the," and similar designations is to be interpreted as encompassing both the singular and plural. Unless otherwise stated herein, statements herein relating to ranges of values ​​are intended only as a way of individually referring to each independent value within that range, and each independent value is incorporated into the specification as if it were individually stated herein. Unless otherwise required, the use of any and all instances or exemplary language (e.g., "such") provided herein is intended to better illustrate this disclosure and is not a limitation on the scope of this disclosure. The language in the specification should not be construed as indicating that any unclaimed element is necessary for the practice of this disclosure.

[0027] As used herein, the term "IAP protein" refers to any known member of the family of apoptosis inhibitory proteins, including but not limited to XIAP, cIAP-1, cIAP-2, ML-IAP, HIAP, TSIAP, KIAP, NAIP, survival protein, survival protein, ILP-2, apollon, and BRUCE.

[0028] As used herein, the term “IAP overexpression” refers to elevated (e.g., abnormal) levels of mRNA encoding one or more IAP proteins and / or elevated levels of one or more IAP proteins in similar corresponding cells compared to basal levels of mRNA encoding IAP proteins or non-pathological cells with basal levels of IAP proteins.

[0029] The term "disease or condition in which inhibition of IAP protein provides benefit" refers to a condition in which the IAP protein and / or the function of the IAP protein, for example, is important or necessary for the onset, progression, or expression of the disease or condition, or a disease or condition known to be treated with an IAP protein inhibitor. Examples of such conditions include, but are not limited to, cancer. Those skilled in the art can readily determine, for example, by an assay readily available for assessing the activity of a particular compound, whether a compound treats a disease or condition mediated by IAP protein of any particular cell type.

[0030] The term "disease" or "symptom" refers to a disorder and / or abnormality that is generally considered a pathological condition or function and can manifest as specific signs, symptoms, and / or dysfunctions. As shown below, compounds having structural formula (I) are potent inhibitors of the IAP protein and can be used to treat diseases and symptoms in which inhibition of the IAP protein provides benefit.

[0031] As used herein, the terms "treat / treating / treatment," etc., refer to the elimination, reduction, or improvement of a disease or condition and / or its associated symptoms. While not excluded, treating a disease or condition does not require the complete elimination of the disease, condition, or its associated symptoms. As used herein, the terms "treat / treating / treatment," etc., can include "preventive treatment," which refers to reducing the likelihood of recurrence or relapse of a previously controlled disease or condition in a subject who does not have or has not relapsed the disease or condition, but is at risk or prone to recurrence or relapse of the disease or condition. The term "treatment" and its synonyms refer to the administration of a therapeutically effective amount of the compounds of the present invention to an individual who requires such treatment.

[0032] Within the meaning of this invention, "treatment" also includes prevention of relapse or interim prevention, as well as treatment of acute or chronic signs, symptoms, and / or functional impairments. Treatment can be symptomatic, such as symptom suppression. This can be achieved in the short term, targeted in the medium term, or long-term, for example, within the scope of maintenance therapy.

[0033] As used herein, the term "prevent / preventing / prevention" refers to methods of preventing the onset of a disease or condition and / or its accompanying symptoms, or preventing a subject from developing a disease. As used herein, "prevent / preventing / prevention" also includes delaying the onset of a disease and / or its accompanying symptoms and reducing the subject's risk of developing the disease. The term "prevent / preventing / prevention" can include "preventive treatment," which refers to reducing the likelihood of the recurrence or relapse of a previously controlled disease or condition in subjects who do not have a disease or condition or whose disease or condition has not recurred, but who are at risk of developing or relapsing into the disease or condition, or who are prone to developing or relapsing into the disease or condition.

[0034] The terms “inhibitor” and “antagonist” are used interchangeably herein and refer to any agent that has inhibitory or antagonistic activity against IAP proteins, including but not limited to small molecule compounds, biological macromolecules, etc. For the same reason, the terms “inhibition” and “antagonism” are also used interchangeably herein.

[0035] As used herein, the terms “subject,” “individual,” or “patient,” which may be used interchangeably, refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, a patient is a person. In some embodiments, a subject has experienced and / or exhibited at least one symptom of a disease or disorder to be treated and / or prevented.

[0036] As used herein, the terms "therapeutic effective amount" or "effective dose" refer to an amount of one or more active ingredients sufficient to effectively deliver one or more active ingredients to treat a target condition or disease when administered to a subject in need by the methods disclosed herein. In the case of cancer or other proliferative disorders, a therapeutically effective amount of a drug may reduce (i.e., to some extent delay or stop) unwanted cell proliferation; reduce the number of cancer cells; reduce tumor size; inhibit (i.e., to some extent delay or stop) cancer cell infiltration into peripheral organs; inhibit (i.e., to some extent delay or stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with cancer to some extent. It may inhibit cell growth and / or be cytotoxic to the extent that the administered compound or composition prevents growth and / or kills existing cancer cells.

[0037] As used herein, the term “halogenated” or “halogen” itself or as part of another group refers to -Cl, -F, -Br, or -I.

[0038] As used herein, the term "cyano" itself, or as part of another group, refers to -CN.

[0039] As used herein, the term "hydroxyl group" itself, or as part of another substituent, refers to -OH.

[0040] As used herein, the term "alkyl" itself, or as part of another group, refers to a group containing one to twelve carbon atoms (i.e., C1-C1). 12 Alkyl group or a straight-chain or branched aliphatic hydrocarbon with a specified number of carbon atoms (e.g., C1 alkyl such as methyl, C2 alkyl such as ethyl, etc.). In one embodiment, the alkyl group is C1-C2. 10 Alkyl group. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1-C3 alkyl group, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting exemplary C1-C 12Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. In another embodiment, one or more hydrogen atoms of the alkyl group are replaced by deuterium atoms, i.e., the alkyl group is labeled with a deuterium isotope. A non-limiting exemplary deuterated alkyl group is -CD3. In another embodiment, no hydrogen atoms of the alkyl group are replaced by deuterium atoms, i.e., the alkyl group is labeled with a deuterium isotope.

[0041] As used herein, the term "haloalkyl" itself, or as part of another group, refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In one embodiment, the alkyl group is substituted with one, two, or three fluorine and / or chlorine atoms. In another embodiment, the alkyl group is substituted with one, two, or three fluorine atoms. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

[0042] As used herein, the term "hydroxyalkyl" or "(hydroxy)alkyl" itself, or as part of another substituent, refers to an alkyl group substituted with one, two, or three hydroxyl groups. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. In another embodiment, the hydroxyalkyl group is a monohydroxyalkyl group, i.e., substituted with one hydroxyl group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxyl groups. Non-limiting exemplary (hydroxy)alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxypropyl-2-yl.

[0043] As used herein, the term "alkoxy" itself, or as part of another group, refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl group is a C1-C6 alkyl group, and the resulting alkoxy group is referred to as "C1-C6 alkoxy". In another embodiment, the alkyl group is a C1-C4 alkyl group, and the resulting alkoxy group is referred to as C1-C4 alkoxy. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0044] As used herein, the term "carbocyclic" itself, or as part of another group, refers to a monocyclic, bicyclic, or tricyclic aliphatic hydrocarbon containing three to twelve carbon atoms, whether saturated or partially unsaturated (e.g., containing one or two double bonds). 3-12 The carbon ring, for example, is a C5 or C6 carbon ring. When saturated with aliphatic hydrocarbons, the carbon ring can also be called a cycloalkyl group, such as a C3 cycloalkyl group like cyclopropyl, a C4 cycloalkyl group like cyclobutyl, etc. In one embodiment, the carbon ring is a cycloalkyl group. In one embodiment, the cycloalkyl group is bicyclic, i.e., having two rings. In another embodiment, the cycloalkyl group is monocyclic, i.e., having one ring. In yet another embodiment, the cycloalkyl group is C5 or C6. 3-8 Cycloalkyl. In another embodiment, the cycloalkyl group is C10. 3-6 Cycloalkyl, i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another embodiment, the cycloalkyl is a C5 cycloalkyl, i.e., cyclopentyl. In another embodiment, the cycloalkyl is a C6 cycloalkyl, i.e., cyclohexyl. Non-limiting exemplary C 3-12 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, naphthane, adamantyl, cyclohexenyl and spiroheptane[3.3].

[0045] As used herein, the term "heterocyclic group" itself, or as part of another group, refers to a saturated and partially unsaturated (e.g., containing one or two double bonds) monocyclic, bicyclic, or tricyclic group containing one, two, three, or four heteroatoms, such as 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycles. Each heteroatom is independently oxygen, sulfur, or nitrogen. Each sulfur atom is independently oxidized to give a sulfoxide (i.e., S(=O)) or a sulfone (i.e., S(=O)2).

[0046] The term heterocyclic group includes groups in which one or more -CH2- groups are replaced by one or more -C(=O)- groups, including cyclic ureido groups such as imidazolidin-2-one, cyclic amide groups such as pyrrolidine-2-one or piperidin-2-one, and cyclic carbamate groups such as oxazolidin-2-one.

[0047] The term heterocyclic also includes groups having fused optional substituted aryl or optional substituted heteroaryl groups, such as indoline, indoline-2-one, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, 2,3,4,5-tetrahydro-1H-benzo[d]azapyrrolidone, or 1,3,4,5-tetrahydro-2H-benzo[d]azapyrrolidone.

[0048] In one embodiment, the heterocyclic group is a 4- to 8-membered ring group containing one ring and one or two oxygen atoms (e.g., tetrahydrofuran or tetrahydropyran), or one or two nitrogen atoms (e.g., pyrrolidine, piperidine, or piperazine), or one oxygen atom and one nitrogen atom (e.g., morpholine), and optionally, a -CH2- group is substituted with a -C(=O)- group (e.g., pyrrolidine-2-one or piperazine-2-one). In another embodiment, the heterocyclic group is a 5- to 8-membered ring group containing one ring and one or two nitrogen atoms, and optionally, a -CH2- group is substituted with a -C(=O)- group. In another embodiment, the heterocyclic group is a 5- or 6-membered ring group containing one ring and one or two nitrogen atoms, and optionally, a -CH2- group is substituted with a -C(=O)- group. In yet another embodiment, the heterocyclic group is an 8- to 12-membered ring group containing two rings and one or two nitrogen atoms. The heterocycle can be attached to the rest of the molecule by any available carbon or nitrogen atom. Non-limiting exemplary heterocyclic groups include:

[0049]

[0050] As used herein, the term "aryl" itself, or as part of another group, refers to an aromatic ring system having six to fourteen carbon atoms, i.e., C6-C. 14 Aryl, C9-C 10 Aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthraceneyl, indene, azulel, biphenyl, biphenylene, and fluorene groups. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl.

[0051] As used herein, the term "heteroaryl" itself, or as part of another group, refers to a monocyclic and bicyclic aromatic ring system having five to fourteen ring members (i.e., 5 to 14-membered heteroaryls, 5 to 10-membered heteroaryls, 5 to 7-membered (preferably 5- or 6-membered)), comprising one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In another embodiment, the heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, the heteroaryl has five ring atoms, such as a thiophene group, a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl has six ring atoms, such as a pyridinyl group, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianyl, furanyl, benzofuranyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthonyl, 2H-pyrroleyl, pyrroleyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, inzolyl, purinel, isoquinolinyl, quinolinyl, phthalazinyl, naphridinyl, cinnamyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbazolyl, phenanthridine, acridineyl, pyrimidinyl, phenanthridine, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazinyl, and phenothiazinyl. In one embodiment, the heteroaryl group is selected from thienyl (e.g., thien-2-yl and thien-3-yl), furanyl (e.g., 2-furanyl and 3-furanyl), pyrroloyl (e.g., 1H-pyrrolo-2-yl and 1H-pyrrolo-3-yl), imidazoyl (e.g., 2H-imidazo-2-yl and 2H-imidazo-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), and pyridyl (e.g., pyridin-2-yl, pyridin-3-yl). The terms heteroaryl (e.g., pyridin-2-yl, pyrimin-4-yl, and pyrimin-5-yl), thiazolyl (e.g., thiazolyl-2-yl, thiazolyl-4-yl, and thiazolyl-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl), and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is a pyridinyl N-oxide.

[0052] As used herein, the term "(cycloalkyl)alkyl" itself, or as part of another group, refers to an alkyl group substituted with one or two optionally substituted cycloalkyl groups. In one embodiment, one or more cycloalkyl groups are optionally substituted C3-C6 cycloalkyl groups. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. In another embodiment, the alkyl group is substituted with one optionally substituted cycloalkyl group. In another embodiment, the alkyl group is substituted with two optionally substituted cycloalkyl groups. Non-limiting exemplary (cycloalkyl)alkyl groups include:

[0053]

[0054] If used, the term "carboxyl group" itself or as part of another group refers to a group having the formula -C(=O)OH.

[0055] As used herein, the term "(heterocyclic)alkyl" itself, or as part of another group, refers to an alkyl group substituted with one, two, or three optionally substituted heterocyclic groups. In one embodiment, the alkyl group is substituted with one optionally substituted 5- to 8-membered heterocyclic group. In another embodiment, the alkyl group is a C1-C6 alkyl group. In yet another embodiment, the alkyl group is a C1-C4 alkyl group. The heterocyclic group may be attached to the alkyl group via a carbon or nitrogen atom. Non-limiting exemplary (heterocyclic)alkyl groups include:

[0056]

[0057] As used herein, the term "(heteroaryl)alkyl" itself, or as part of another group, refers to an alkyl group substituted with one or two optionally substituted heteroaryl groups. In one embodiment, the alkyl group is substituted with one optionally substituted 5- to 14-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5- to 14-membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5- to 9-membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5- or 6-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5- or 6-membered heteroaryl groups. In one embodiment, the alkyl group is C1-C6 alkyl. In another embodiment, the alkyl group is C1-C4 alkyl. In another embodiment, the alkyl group is C1 or C2 alkyl. Non-limiting exemplary (heteroaryl)alkyl groups include:

[0058]

[0059] As used herein, the term "arylalkyl" or "(aryl)alkyl" itself, or as part of another group, refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the alkyl group is substituted with one optionally substituted aryl group. In another embodiment, the alkyl group is substituted with two optionally substituted aryl groups. In one embodiment, the aryl group is an optionally substituted phenyl or an optionally substituted naphthyl group. In another embodiment, the aryl group is an optionally substituted phenyl group. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. Non-limiting exemplary (aryl)alkyl groups include benzyl, phenethyl, -CHPh2, and -CH(4-F-Ph)2.

[0060] If used, the term "amino" itself, or as part of another group, refers to having the formula -NR. 55a R 55b The group, wherein R 55a and R 55b Independently, it is hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclic)alkyl, or (heteroaryl)alkyl.

[0061] In one embodiment, the amino group is -NH2.

[0062] This disclosure covers any compound of this disclosure that is isotopically labeled (i.e., radiolabeled), wherein such isotopic labeling (i.e., radiolabeling) is achieved by replacing one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as... 2 H (or deuterium (D)), 3 H, 11 C 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, and 36 Cl, for example, 3 H, 11 C and 14C. In one embodiment, a compound is provided in which substantially all atoms at a certain position within the disclosed compound are substituted with atoms having different atomic masses or mass numbers. In another embodiment, a compound is provided in which substantially all atoms at a certain position within the disclosed compound are substituted with deuterium atoms, for example, all hydrogen atoms of a -CH3 group are substituted with deuterium atoms to give a -CD3 group. In another embodiment, a compound is provided in which a subset of atoms at a certain position within the disclosed compound are substituted, i.e., the disclosed compound is enriched at a certain position with atoms having different atomic masses or mass numbers. In another embodiment, a compound is provided in which the atoms of the disclosed compound are not substituted with atoms having different atomic masses or mass numbers. Isotopically labeled compounds of the disclosed compound can be prepared by methods known in the art.

[0063] The compounds disclosed herein contain one or more asymmetric centers, and therefore can produce enantiomers, diastereomers, and other stereoisomers. This disclosure covers the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. In view of this disclosure, individual enantiomers can be isolated according to methods known in the art. When the compounds described herein contain an alkene double bond or other geometrically asymmetric centers, and unless otherwise specified, it is intended that these compounds include both E and Z geometric isomers. This disclosure also covers all tautomers.

[0064] As used herein, the term "stereoisomer" is a collective term for all isomers of a single molecule that differ only in the spatial orientation of its atoms. It includes enantiomers and isomers of compounds having more than one chiral center that is not a mirror image of each other (diastereomers).

[0065] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom with four different groups attached to it.

[0066] The terms “enantiomer” and “enantiomer” refer to molecules that cannot be superimposed on their mirror image and are therefore optically active, wherein an enantiomer rotates plane-polarized light in one direction, while its mirror compound rotates plane-polarized light in the opposite direction.

[0067] The term "racemic" refers to a mixture of equal amounts of enantiomers, and that the mixture is optically inactive. In one embodiment, the compound disclosed herein is racemic.

[0068] The term "absolute configuration" refers to the spatial arrangement of atoms in a chiral molecular entity (or group) and its stereochemical description, such as R or S.

[0069] Unless otherwise stated, the stereochemical terms and conventions used in this specification are intended to be consistent with those described in Pure & Appl. Chem 68:2193 (1996).

[0070] The term "enantiomer excess" or "ee" refers to a measure of the quantity of one enantiomer present in excess of another. For a mixture of R and S enantiomers, the enantiomer excess percentage is defined as |RS|*100, where R and S are the respective molar or weight fractions of the enantiomers in the mixture such that R+S=1. Knowing the optical rotation of the chiral substance, the enantiomer excess percentage is defined as ([α]). obs / [α] max )*100, where [α] obs It is the optical rotation of a mixture of enantiomers, and [α] max It is the optical rotation of the pure enantiomer. Various analytical techniques (including NMR spectroscopy, chiral column chromatography, or optical rotation) make it possible to determine the excess of enantiomers.

[0071] As used in this article, the term “about” includes ±10% of the listed numbers. Therefore, “about 10” means 9 to 11.

[0072] As used herein, the phrase “optionally substituted with one or more groups” means optionally substituted with 1 to 10 groups, preferably optionally substituted with 1 to 5 groups, and more preferably optionally substituted with 1, 2 or 3 groups.

[0073] II.Compounds

[0074] In one respect, this disclosure provides compounds having Formula I:

[0075]

[0076] in:

[0077] W represents O, S, S(O)2, and NR. a -C (=O) or CR a R b , where R a and R b Each is independently selected from H, halogenated, C1-C6 alkyl, OH, or C3-C6 cycloalkyl;

[0078] X and Y are each independently C or N;

[0079] ------ indicates a single or double bond;

[0080] That is, when ------ represents a single bond, it means that X and Y are connected by a single bond (XY); when ------ represents a double bond, it means that X and Y are connected by a double bond (X=Y).

[0081] R1 is selected from R1, which is arbitrarily selected from R1. 1A One or more groups substituted with a heterocyclic or heteroaryl group; and R 1A Selected from CN, -C1-C6 alkyl-CN, -C(=O)-NH2, halogenated, OH, COOH, NH2, oxo-, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -C(=O)-C1-C6 alkyl, -C(=O)-O-C1-C6 alkyl, -C1-C6 alkyl-C1-C6 alkoxy, -C1-C6 alkyl-OH, -C1-C6 alkyl-NH2, -S(O)2-C1-C6 alkyl, or 4-6 membered heterocyclic groups; or two R groups. 1A Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or -C (=O);

[0082] R2 and R3 are each independently selected from H or C1-C6 alkyl; or R2 and R3 together with the carbon atoms to which they are attached form C3-C6 cycloalkyl or C3-C6 heterocyclic groups;

[0083] R4 is selected from one or more R4s. 4a Substituted phenyl, C2-C6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, or C1-C6 alkyl or -C1-C6 alkyl-C3-C6 cycloalkyl; and R 4a Selected from CN, halogenated, OH, NH2, oxo, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; optionally, R a and R 4a Together with the atoms to which they are attached, they can form 5-6 membered carbocyclic groups, 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups, which may optionally be substituted by one or more of halogen, C1-C6 alkyl, or OH;

[0084] R5 and R6 are each independently selected from H or C1-C6 alkyl groups;

[0085] R7 is selected from C1-C6 alkyl groups, preferably C1-C3 alkyl groups;

[0086] Ring A is selected from 5-8 aryl, 5-8 heteroaryl, or 5-8 heterocyclic groups, optionally substituted by one or more groups selected from R8; and R8 is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 haloalkyl-OH, C1-C6 alkoxy, C1-C6 alkyl(C1-C6 alkoxy)-C1-C6 alkoxy, C3-C6 cycloalkyl, -C1-C6 alkyl-C3-C6 cycloalkyl, oxo, 4-7 heterocyclic, -NH-4-7 heterocyclic. Cycloyl, -C1-C6 alkyl-4-7 heterocyclic, -C1-C6 alkyl(OH)-4-7 heterocyclic, CN, -C1-C6 alkyl-CN, -COOH, -OH, amino, halogenated, -NH-S(O)2-C1-C6 alkyl, -N(S(O)2-C1-C6 alkyl)2, -C1-C6 alkyl-OH, -C1-C6 haloalkyl-OH, -C1-C6 alkyl(OH)-OH, -S(O)2-C1-C6 alkyl, -C1-C6 alkyl-S(O )2-C1-C6 alkyl, -P(O)-(C1-C6 alkyl)2, -C1-C6 alkyl-N(C1-C6 alkyl)2, -C(=O)-NH2, -C1-C6 alkyl-C(=O)-NH2, -C(=O)-NH-C1-C6 alkyl, -C(=O)-NH-C3-C6 cycloalkyl, -C(=O)-NH-(deuterated C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, -C(=O)-O-C1-C6 alkyl, -C(= O)-C1-C6 alkyl, -NH-C(=O)-C1-C6 alkyl, -NH-C(=O)-H, -N(C1-C6 alkyl)-C(=O)-H, -NH-C(=O)-O-C1-C6 alkyl, -N(C1-C6 alkyl)-C(=O)-C1-C6 alkyl, 5-6-membered heteroaryl, -C1-C6 alkyl-(5-6-membered heteroaryl), or phenyl, wherein the C3-C6 cycloalkyl, 4-7-membered heterocyclic, 5-6-membered heteroaryl, or phenyl is optionally separated by one or more R 8a Replace, and R 8a Selected from halogenated, -OH, C1-C6 alkyl, or oxo-substituted compounds;

[0087] Or ring A does not exist;

[0088] Or its pharmaceutically acceptable salts or solvates.

[0089] On the other hand, this disclosure provides compounds having Formula I:

[0090]

[0091] in:

[0092] W represents O, S, NR a, or CR a R b , where R a and R b Each is independently selected from H, halogenated, C1-C6 alkyl, OH, or C3-C6 cycloalkyl;

[0093] X and Y are each independently C or N;

[0094] ------ indicates a single or double bond;

[0095] That is, when ------ represents a single bond, it means that X and Y are connected by a single bond (XY); when ------ represents a double bond, it means that X and Y are connected by a double bond (X=Y).

[0096] R1 is selected from R1, which is arbitrarily selected from R1. 1A A heterocyclic or heteroaryl group substituted with one or more (e.g., 1-10, 1-5, 1-3, or 1-2) groups; and R 1A Selected from CN, halogen, OH, COOH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -C(=O)-C1-C6 alkyl, -C1-C6 alkyl-OC1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C6 alkyl-NH2, or two R 1A Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups or -C (=O);

[0097] R2 and R3 are each independently selected from H or C1-C6 alkyl; or R2 and R3 together with the carbon atoms to which they are attached form C3-C6 cycloalkyl;

[0098] R4 is selected from one or more (e.g., 1-10, 1-5, 1-3, or 1-2) R 4a Substituted phenyl or pyridyl, or C1-C6 alkyl or -C1-C6 alkyl-C3-C6 cycloalkyl; and R 4a Selected from CN, halogenated, OH, NH2, COOH, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy groups;

[0099] R5 and R6 are each independently selected from H or C1-C6 alkyl groups;

[0100] R7 is selected from C1-C6 alkyl groups, preferably C1-C3 alkyl groups;

[0101] Ring A is selected from 5-8 membered (preferably 5 or 6 membered) aryl or 5-8 membered (preferably 5 or 6 membered) heteroaryl, which is optionally substituted by one or more groups selected from R8; and R8 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5 or 6 membered heterocyclic group containing one or more heteroatoms selected from N, O and S (e.g., tetrahydropyranyl), CN, -COOH, -OH, amino, halogen, -NH-S(O)2-C1-C6 alkyl, -N(S(O)2-C1-C6 alkyl)2, -C1-C6 alkyl-OH, -C(=O)-NH2, -C(=O)-NH-C1-C6 alkyl, -C(=O)-O-C1-C6 alkyl, -NH-C(=O)-C1-C6 alkyl, phenyl, which is optionally substituted by one or more halogens;

[0102] Or its pharmaceutically acceptable salts or solvates.

[0103] On the other hand, this disclosure provides compounds having formula II:

[0104]

[0105] All of the groups are as defined above.

[0106] Or its pharmaceutically acceptable salts or solvates.

[0107] On the other hand, this disclosure provides compounds having formula II-A, II-B or II-C:

[0108]

[0109] All of the groups are as defined above.

[0110] Or its pharmaceutically acceptable salts or solvates.

[0111] In some embodiments, ring A contains 1, 2, or 3 nitrogen atoms.

[0112] In some embodiments, X is N, Y is C, and Selected from:

[0113] It may optionally be substituted with one or more groups selected from R8.

[0114] In some embodiments, X is N, Y is C, and Selected from:

[0115] It may optionally be substituted with one or more groups selected from R8.

[0116] In some embodiments, X is C, Y is N, and Selected from:

[0117] It may optionally be substituted with one or more groups selected from R8.

[0118] In some embodiments, X is C, Y is C, and Selected from:

[0119]

[0120] It may optionally be substituted with one or more groups selected from R8.

[0121] In some embodiments, Choose from the following groups:

[0122]

[0123]

[0124] In some embodiments, Choose from the following groups:

[0125]

[0126] In some embodiments, R1 has formula III:

[0127]

[0128] in:

[0129] Z is selected from O, S, NR a , or CR a R b , where R a and R b Each is independently selected from CN, halogenated, OH, COOH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -C(=O)-C1-C6 alkyl, -C1-C6 alkyl-OC1-C6 alkyl, -C1-C6 alkyl-OH or -C1-C6 alkyl-NH2;

[0130] R 1a R 1b R 1c R 1d R 1e R 1f R 1g and R 1hIndependently selected from CN, halogenated, OH, COOH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -C(=O)-C1-C6 alkyl, -C1-C6 alkyl-OC1-C6 alkyl, -C1-C6 alkyl-OH, -C1-C6 alkyl-CN, -S(O)2-C1-C6 alkyl, 4-7 membered heterocyclic, oxo, -C(=O)-NH2, -C(=O)-O-C1-C6 alkyl, or -C1-C6 alkyl-NH2; or

[0131] R 1a and R 1b R 1c and R 1d R 1e and R 1f , and / or R 1g and R 1h Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups; or

[0132] R on different carbon atoms 1a R 1b R 1c R 1d R 1e R 1f R 1g and R 1h Any two of them pass through -(CH2) n - The connectors are joined together to form a bridge ring, where n is 1, 2 or 3.

[0133] In some embodiments, R1 has formula III:

[0134]

[0135] in:

[0136] Z is selected from O, S, NR a , or CR a R b , where R a and R b Each is independently selected from CN, halogenated, OH, COOH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -C(=O)-C1-C6 alkyl, -C1-C6 alkyl-OC1-C6 alkyl, -C1-C6 alkyl-OH or -C1-C6 alkyl-NH2;

[0137] R 1a R 1b R 1c R 1d R 1e R 1f R1g and R 1h Independently selected from CN, halogenated, OH, COOH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -C(=O)-C1-C6 alkyl, -C1-C6 alkyl-OC1-C6 alkyl, -C1-C6 alkyl-OH or -C1-C6 alkyl-NH2; or

[0138] R 1a and R 1b R 1c and R 1d R 1e and R 1f , and / or R 1g and R 1h Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl groups; or

[0139] R on different carbon atoms 1a R 1b R 1c R 1d R 1e R 1f R 1g and R 1h Any two of them pass through -(CH2) n - The connectors are joined together to form a bridge ring, where n is 1, 2 or 3.

[0140] In some embodiments, R1 is selected from the group consisting of the following:

[0141]

[0142] In some embodiments, R1 is selected from the group consisting of the following:

[0143]

[0144] In some embodiments, R1 is selected from the group consisting of the following:

[0145]

[0146] It may optionally be substituted with one or more groups selected from the following: CN, halogen, OH, -COOH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -C(=O)-C1-C6 alkyl, -C1-C6 alkyl-OC1-C6 alkyl, -C1-C6 alkyl-OH, and -C1-C6 alkyl-NH2.

[0147] In some embodiments, R1 is selected from the group consisting of the following:

[0148]

[0149] Where R 1i R 1j and R 1K Independently selected from CN, halogenated, OH, -COOH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -C(=O)-C1-C6 alkyl, -C1-C6 alkyl-OC1-C6 alkyl, -C1-C6 alkyl-OH, and -C1-C6 alkyl-NH2.

[0150] In some embodiments, R1 is selected from the group consisting of the following:

[0151]

[0152] In some embodiments, both R2 and R3 are methyl groups.

[0153] In some embodiments, W is CR a R b And R a and R b Each is independently selected from H, halogenated, C1-C6 alkyl, OH, or C3-C6 cycloalkyl.

[0154] In some embodiments, R4 is selected from the following group:

[0155]

[0156] In some embodiments, R4 is selected from the following group:

[0157]

[0158] In some embodiments, -W-R4 is selected from the following:

[0159]

[0160] In some embodiments, both R5 and R6 are hydrogen.

[0161] In some embodiments, the halogen is preferably selected from F or Cl.

[0162] In some embodiments, the C1-C6 alkyl group is preferably selected from the C1-C4 alkyl group, and more preferably from the methyl or ethyl group.

[0163] In some embodiments, for the above aspects of this disclosure, the compounds are selected from the group consisting of:

[0164]

[0165]

[0166]

[0167]

[0168] Or its pharmaceutically acceptable salts or solvates.

[0169] In some embodiments, for the above aspects of this disclosure, the compounds are selected from the group consisting of:

[0170]

[0171]

[0172]

[0173]

[0174]

[0175] Or its pharmaceutically acceptable salts or solvates.

[0176] This disclosure covers the preparation and use of salts of the compounds disclosed herein. As used herein, the term "pharmaceutically acceptable salt" refers to a salt or zwitterionic form of a compound of this disclosure suitable for administration to a subject (e.g., a human). Salts of the compounds of this disclosure may be prepared during the final separation and purification of the compound, or separately prepared by reacting the compound with a suitable acid. Pharmaceutically acceptable salts of the compounds of this disclosure may be acid addition salts formed with a pharmaceutically acceptable acid. Examples of acids that can be used to form pharmaceutically acceptable salts include inorganic acids such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Non-limiting examples of salts of the compounds disclosed herein include, but are not limited to, hydrochlorides, hydrobroms, hydroiodates, sulfates, hydrogen sulfates, 2-hydroxyethanesulfonates, phosphates, hydrogen phosphates, acetates, adipates, alginates, aspartates, benzoates, hydrogen sulfates, butates, camphorates, camphor sulfonates, digluconate, glyceryl phosphates, hemisulfates, heptanates, hexanoates, formates, succinates, fumarates, maleates, ascorbic acid salts, hydroxyethyl sulfonates, salicylates, methanesulfonates, trimethylbenzenesulfonates, naphthalenesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, dihydroxynaphthaleneates, pectinates, persulfates, 3-phenylpropionates, picrates, neopentanoates, propionates, trichloroacetates, trifluoroacetates, phosphates, glutamates, bicarbonates, p-toluenesulfonates, undecanoates, lactates, citrates, tartrates, gluconates, methanesulfonates, ethanedisulfonates, benzenesulfonates, and p-toluenesulfonates. Additionally, the available amino groups present in the compounds disclosed herein may be quaternized with: chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl; dimethyl, diethyl, dibutyl, and dipentyl sulfates; chlorides, bromides, and iodides of decyl, lauryl, myristyl, and steroidal; and bromides of benzyl and phenethyl. In view of the foregoing, any reference to compounds of this disclosure appearing herein is intended to include compounds of this disclosure and their pharmaceutically acceptable salts, hydrates, or solvates.

[0177] This disclosure covers the preparation and use of solvates of the compounds disclosed herein. Typically, solvates do not significantly alter the physiological activity or toxicity of the compounds and thus can serve as pharmacological equivalents. As used herein, the term "solvate" is a combination, physical association, and / or solvation of the compounds disclosed herein with solvent molecules (e.g., disolvates, monosolvates, or hemisolvates) in ratios of about 2:1, about 1:1, or about 1:2, respectively. Such physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates can be separable, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid. Therefore, "solvate" encompasses both solution-phase solvates and separable solvates. The compounds disclosed herein may exist in solvated forms with pharmaceutically acceptable solvents (e.g., water, methanol, and ethanol), and this disclosure is intended to include both solvated and unsolvated forms of the compounds disclosed. One type of solvate is a hydrate. "Hydrates" refer to a specific subgroup of solvates in which the solvent molecule is water. Typically, solvates can act as pharmacological equivalents. The preparation of solvates is known in the art. See, for example, M. Caira et al., J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of solvates from fluconazole with ethyl acetate and water. EC van Tonder et al., AAPSPharm. Sci. Tech., 5(1):Article 12 (2004) and ALBingham et al., Chem. Commun. 603-604 (2001) describe similar preparations of solvates, semisolvates, hydrates, etc. Typical and non-limiting methods for preparing solvates involve dissolving the disclosed compound in a desired solvent (organic, water, or a mixture thereof) at a temperature above 20°C to 25°C, then cooling the solution at a rate sufficient to form crystals, and separating the crystals by known methods (e.g., filtration). The presence of the solvate in the crystals can be confirmed using analytical techniques such as infrared spectroscopy.

[0178] III. Composition

[0179] In one respect, this disclosure provides compositions comprising the compounds disclosed herein or pharmaceutically acceptable salts or solvates thereof and pharmaceutically acceptable carriers.

[0180] The pharmaceutical compositions used according to this disclosure can be formulated in a conventional manner using one or more physiologically acceptable carriers (including excipients and / or adjuvants that facilitate the processing of the compounds disclosed herein).

[0181] These pharmaceutical compositions can be prepared, for example, by conventional methods of mixing, dissolving, granulating, forming into sugar-coated pellets, emulsifying, encapsulating, embedding, or lyophilizing. Suitable formulations depend on the chosen route of administration. When a therapeutically effective amount of the disclosed compound is administered orally, the composition is typically in the form of tablets, capsules, powders, solutions, or elixirs. When administered in tablet form, the composition may additionally contain a solid carrier, such as gelatin or an adjuvant. Tablets, capsules, and powders contain about 0.01% to about 95%, and preferably about 1% to about 50%, of the disclosed compound. When administered in liquid form, a liquid carrier, such as water, petroleum, or an oil of animal or plant origin, may be added. The liquid form of the composition may further contain an aqueous solution of physiological saline, a solution of dextran or other sugars, or a diol. When administered in liquid form, the composition contains about 0.1% to about 90%, and preferably about 1% to about 50% by weight of the disclosed compound.

[0182] When a therapeutically effective amount of the disclosed compound is administered via intravenous, transdermal, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such a parenterally acceptable solution should take into account pH, isotonicity, stability, etc., and is within the scope of the art. Preferred compositions for intravenous, transdermal, or subcutaneous injection typically contain an isotonic agent.

[0183] The compounds disclosed herein can be readily combined with pharmaceutically acceptable carriers well known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 19th edition, 1995. Such carriers enable the formulation of active agents into tablets, pills, sugar-coated pills, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by a subject to treatment. Pharmaceutical formulations for oral use can be obtained by adding the compounds disclosed herein to a solid excipient, optionally grinding the resulting mixture, and processing the granular mixture (if desired) after adding suitable excipients to obtain a tablet or sugar-coated pill core. Suitable excipients include, for example, fillers and cellulose formulations. Disintegrants may be added if desired.

[0184] The compounds disclosed herein can be formulated for parenteral administration via injection (e.g., by bolus or continuous infusion). Injectable formulations can be presented in unit dosage forms (e.g., in ampoules or in multi-dose containers) and contain preservatives. Compositions can be in the form of suspensions, solutions, or emulsions, for example, in oily or aqueous media, and may contain formulations such as suspending agents, stabilizers, and / or dispersants.

[0185] Pharmaceutical compositions for parenteral administration comprise aqueous solutions of the active agent in a water-soluble form. Alternatively, suspensions of the disclosed compounds can be prepared as suitable oily injectable suspensions. Suitable lipophilic solvents or mediators include fatty oils or synthetic fatty acid esters. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound and allow for the preparation of highly concentrated solutions. Alternatively, the compositions of the invention may be in powder form for preparation with a suitable mediator (e.g., sterile, pyrogen-free water) prior to use.

[0186] The compounds disclosed herein can also be formulated in rectal compositions, such as suppositories or retention enemas (e.g., containing a conventional suppository matrix). In addition to the formulations previously described, the compounds disclosed herein can also be formulated as long-acting preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Therefore, for example, the compounds disclosed herein can be formulated with suitable polymeric or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion-exchange resins.

[0187] Specifically, the compounds disclosed herein can be administered orally, buccally, or sublingually in the form of tablets containing excipients (e.g., starch or lactose), or in capsules or ovules alone or in combination with excipients, or in elixirs or suspensions containing flavorings or colorings. Such liquid formulations can be prepared with pharmaceutically acceptable additives (e.g., suspensions). The compounds disclosed herein can also be administered parenterally (e.g., intravenously, intramuscularly, subcutaneously, or intracoronary). For parenteral administration, the compounds disclosed herein are typically used in the form of sterile aqueous solutions, which may contain other substances, such as salts or monosaccharides (e.g., mannitol or glucose), to make the solution isotonic with blood.

[0188] IV. Methods and Applications

[0189] In one aspect, this disclosure provides a method for inhibiting the activity of IAP protein in cells, the method comprising contacting the cell (in which inhibition of IAP protein activity is desired) with an effective amount of the compound of this disclosure or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition of this disclosure.

[0190] In one embodiment, the contact is outside the body. In another embodiment, the contact is inside the body.

[0191] As used herein, the term “contact” refers to bringing together an indicated portion in an in vitro or in vivo system. For example, “contacting” the IAP protein with a compound provided herein includes administering the compound provided herein to an individual or patient, such as a human, and, for example, introducing the compound provided herein into a sample containing cells or a purified formulation (containing the IAP protein).

[0192] On the other hand, this disclosure provides methods for treating diseases or conditions in which inhibition of the IAP protein provides benefit, the method comprising administering to an individual in need a therapeutically effective amount of the compound of this disclosure or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition of this disclosure.

[0193] In some embodiments, the diseases and conditions that can be treated according to this disclosure may include, for example, cancer. A variety of cancers can be treated, including but not limited to: carcinomas, including bladder cancer (including accelerated and metastatic bladder cancer), breast cancer, colon cancer (including colorectal cancer), kidney cancer, liver cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and lung adenocarcinoma), ovarian cancer, prostate cancer, testicular cancer, genitourinary tract cancer, lymphatic system cancers, rectal cancer, laryngeal cancer, pancreatic cancer (including pancreatic exocrine carcinoma), esophageal cancer, stomach cancer, gallbladder cancer, cervical cancer, thyroid cancer, kidney cancer, and skin cancer (including squamous cell carcinoma); lymphoid hematopoietic tumors, including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, and non-Hodgkin lymphoma. Golden lymphoma, pilocellular lymphoma, histiocytic lymphoma, and Burkitt's lymphoma; bone marrow hematopoietic tumors, including acute and chronic myeloid leukemia, myelodysplastic syndromes, myeloid leukemia, and promyelocytic leukemia; tumors of the central and peripheral nervous systems, including astrocytoma, neuroblastoma, glioma, and schwannoma; mesenchymal tumors, including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma; and other tumors, including melanoma, xeroderma pigmentosum, keratoacanthoma, seminoma, follicular thyroid carcinoma, teratoma, renal cell carcinoma (RCC), pancreatic cancer, myeloma, myeloblastic and lymphoblastic leukemia, neuroblastoma, and glioblastoma.

[0194] Other forms of cancer that can be treated with the IAP protein inhibitors disclosed herein include, for example, adult and pediatric oncology, growth of solid tumors / malignancies, myxoid and round cell carcinomas, locally advanced tumors, metastatic cancers, human soft tissue sarcomas (including Ewing's sarcoma), cancer metastases (including lymph node metastases), squamous cell carcinomas (particularly head and neck squamous cell carcinomas, esophageal squamous cell carcinomas), oral cancers, hematologic malignancies (including multiple myeloma), leukemias (including acute lymphoblastic leukemia, acute non-lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia), exudative lymphomas (body cavity-based lymphomas), thymic lymphomas, lung cancers (including small cell carcinomas), cutaneous T-cell lymphomas, Hodgkin's lymphomas, non-Hodgkin's lymphomas, adrenocortical carcinomas, ACTH-producing tumors, non-small cell carcinomas, breast cancers (including small cell carcinomas and ductal carcinomas), and gastrointestinal cancers (including gastric cancer, colon cancer, colorectal cancer, and related cancers). Colorectal cancer (polyps associated with colorectal tumors), pancreatic cancer, liver cancer, urinary tract cancers (including bladder cancer, such as primary superficial bladder tumor, invasive transitional cell carcinoma of the bladder, and invasive bladder cancer), prostate cancer, malignant tumors of the female reproductive tract (including ovarian cancer, primary peritoneal epithelial tumors, cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, uterine cancer, and solid tumors in ovarian follicles), malignant tumors of the male reproductive tract (including testicular cancer and penile cancer), kidney cancer (including renal cell carcinoma), brain cancer (including intrinsic brain tumors, neuroblastoma, astrocytoma, glioma, and metastatic tumor cells in the central nervous system), bone cancer (including osteoma and osteosarcoma), skin cancer (including malignant melanoma, tumor progression of human skin keratinocytes, squamous cell carcinoma), thyroid cancer, retinoblastoma, neuroblastoma, ascites, malignant pleural effusion, mesothelioma, nephroblastoma, gallbladder cancer, trophoblastic tumors, hemangiopericytoma, and Kaposi's sarcoma.

[0195] Another embodiment of this disclosure involves inducing apoptosis and enhancing the induction of apoptosis (in response to apoptosis-inducing signals) by using the IAP protein inhibitors of this disclosure. The IAP protein inhibitors of the present invention also sensitize cells to apoptosis inducers, including cells resistant to such inducers. The IAP protein inhibitors of this disclosure can be used to induce apoptosis in any disorder that can be treated, improved, or prevented by inducing apoptosis. Therefore, this disclosure provides compositions and methods for targeting animals characterized by overexpression of IAP proteins. In some embodiments, cells (e.g., cancer cells) exhibit elevated IAP protein expression levels compared to non-pathological samples (e.g., non-cancerous cells). In other embodiments, cells operationally exhibit elevated IAP protein expression levels by executing an apoptosis program and dying in response to a therapeutically effective amount of the compounds of this disclosure, the response occurring at least in part because the survival of such cells depends on IAP protein function.

[0196] In another embodiment, this disclosure relates to modulating apoptosis-related states associated with one or more apoptosis modulators. Examples of apoptosis modulators include, but are not limited to, Fas / CD95, TRAMP, TNF RI, DR1, DR2, DR3, DR4, DR5, DR6, FADD, RIP, TNFα, Fas ligands, TRAIL, antibodies to TRAIL-R1 or TRAIL-R2, Bcl-2, p53, BAX, BAD, Akt, CAD, PI3 kinase, PP1, and caspase proteins. Other agents involved in the initiation, determination, and degradation phases of apoptosis are also included. Examples of apoptosis modulators include agents whose activity, presence, or concentration changes can modulate apoptosis in a subject. Preferred apoptosis modulators are apoptosis inducers, such as TNF or TNF-related ligands, particularly TRAMP ligands, Fas / CD95 ligands, TNFR-1 ligands, or TRAIL.

[0197] These therapies can be used in a variety of settings for treating various cancers. In certain embodiments, the individual requiring treatment has previously received cancer treatment. Such prior treatment includes, but is not limited to, previous chemotherapy, radiation therapy, surgery, or immunotherapy, such as cancer vaccines.

[0198] In another embodiment, the IAP protein inhibitor of the present invention is used to treat the following: T-cell and B-cell mediated autoimmune diseases; inflammatory diseases; infections; proliferative disorders; AIDS; degenerative diseases; vascular diseases, etc. In some embodiments, infections suitable for treatment with the compositions and methods of the present invention include, but are not limited to, infections caused by viruses, bacteria, fungi, mycoplasma, prions, etc.

[0199] The compounds and methods of this invention can also be used to treat autoimmune disorders or chronic inflammatory conditions. As used herein, the term "autoimmune disorder" refers to any condition in which an organism produces antibodies or immune cells that recognize its own molecules, cells, or tissues. Non-limiting examples of autoimmune disorders include autoimmune hemolytic anemia, autoimmune hepatitis, Bergey's disease or IgA nephropathy, stomatitis, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft-versus-host disease, Graves' disease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, vitiligo, etc.

[0200] U.S. Patent No. 7,960,372 (incorporated herein by reference in its entirety) discloses other diseases and conditions (including cancer) that can be treated by administering the IAP protein inhibitor of the present invention.

[0201] The therapeutically effective amount of the disclosed compound required for treatment varies depending on the nature of the condition being treated, the desired duration of activity, and the age and condition of the subject, and is ultimately determined by the attending physician. Dosage and intervals can be individually adjusted to provide plasma levels of the disclosed compound sufficient to maintain the desired therapeutic effect. The desired dose can be administered as a single dose or as multiple doses at appropriate intervals, such as one, two, three, four, or more sub-dose per day. Multiple doses are often desired or required. For example, the disclosed compound can be administered at the following frequencies: four doses delivered as one dose per day, with four-day intervals (q4d x 4); four doses delivered as one dose per day, with three-day intervals (q3d x 4); one dose delivered per day, with five-day intervals (qd x 5); one dose per week for three weeks (qwk3); five doses per day, with two days of rest, then five doses per day again (5 / 2 / 5); or, whatever dosing regimen is suitable for the situation.

[0202] The compounds disclosed herein used in the methods disclosed herein can be administered in amounts of about 0.005 to about 500 mg / dose, about 0.05 to about 250 mg / dose, or about 0.5 to about 100 mg / dose. For example, the compounds disclosed herein can be administered in amounts of about 0.005, about 0.05, about 0.5, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg per dose (including all doses between 0.005 and 500 mg).

[0203] The dosage of a composition containing or containing a compound disclosed herein may be from about 1 ng / kg to about 200 mg / kg, from about 1 μg / kg to about 100 mg / kg, or from about 1 mg / kg to about 50 mg / kg. The dosage of the composition may be any dosage, including but not limited to about 1 μg / kg. The dosage of the composition may be any dosage, including but not limited to about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg. g, approximately 325 μg / kg, approximately 350 μg / kg, approximately 375 μg / kg, approximately 400 μg / kg, approximately 425 μg / kg, approximately 450 μg / kg, approximately 475 μg / kg, approximately 500 μg / kg, approximately 525 μg / kg, approximately 550 μg / kg, approximately 575 μg / kg, approximately 600 μg / kg, approximately 625 μg / kg, approximately 650 μg / kg, approximately 675 μg / kg, approximately 700 μg / kg, approximately 725 μg / kg, approximately 750 μg / kg, approximately 775 μg / kg, approximately 800 μg / kg, approximately 825 μg / kg, approximately 850 μg / kg, approximately 875 μg / kg, approximately 900 μg / kg, approximately 925 μg / kg, approximately 950 μg / kg, approximately 975 μg / kg, approximately 1 mg / kg, approximately 5 mg / kg, approximately 10 mg / kg, approximately 15 mg / kg Approximately 20 mg / kg, approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 60 mg / kg, approximately 70 mg / kg, approximately 80 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, approximately 125 mg / kg, approximately 150 mg / kg, approximately 175 mg / kg, approximately 200 mg / kg, or more. The above dosages are general examples, but individual cases may exist requiring higher or lower doses, and these are within the scope of this disclosure. In practice, physicians determine the actual dosing regimen best suited for the individual subject, which varies depending on the subject's age, weight, and response.

[0204] In some embodiments, the therapeutically effective amount of the compound is between about 0.01 and 100 mg / kg / day.

[0205] On the other hand, this disclosure provides the compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof, for use in inhibiting the activity of IAP proteins in cells.

[0206] On the other hand, this disclosure provides the compounds disclosed herein, or their pharmaceutically acceptable salts or solvates, for use in treating diseases or conditions in which inhibition of the IAP protein provides benefit.

[0207] On the other hand, this disclosure provides for the use of the disclosed compounds or their pharmaceutically acceptable salts or solvates, or the pharmaceutical compositions disclosed, in the manufacture of a medicament for inhibiting the activity of IAP proteins in cells.

[0208] On the other hand, this disclosure provides for the use of the disclosed compounds or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, in the manufacture of a medicament for treating a disease or condition in which inhibition of the IAP protein provides benefit.

[0209] V. Reagent Kit

[0210] In another embodiment, this disclosure provides kits containing a compound (or a composition containing a compound of the disclosure) packaged in a manner conducive to its use in practicing the methods of this disclosure. In one embodiment, the kit contains a compound (or a composition containing a compound of the disclosure) and instructions for administering the compound or a pharmaceutically acceptable salt or solvate thereof to a subject (e.g., a cancer patient) for which inhibition of the IAP protein provides benefit. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit may further include means suitable for administering the composition according to the intended route of administration.

[0211] In some embodiments of the above aspects, IAP is preferably selected from cIAP1, cIAP2 and XIAP.

[0212] Example

[0213] To make the purpose and technical solutions of this disclosure clearer, specific examples will be used to further describe this disclosure below. It should be understood that these examples are not intended to limit the scope of the invention. Furthermore, specific experimental methods not mentioned in the following examples are all performed according to conventional experimental methods.

[0214] intermediate

[0215] As reported in the literature, the following key intermediates were synthesized.

[0216]

[0217] Representative Synthesis Examples

[0218] Example 1: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 1)

[0219]

[0220]

[0221] Step 1: tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

[0222]

[0223] In a flame-dried 100 mL round-bottom flask under nitrogen atmosphere at room temperature, tert-butyl 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate I (3 g, 9.17 mmol), potassium trifluoro(4-fluorobenzyl)borate (3.96 g, 18.34 mmol), and Cs₂CO₃ (8.96 g, 27.5 mmol) were dissolved in 1,4-dioxane (50 mL) / water (5 mL) to give a colored solution. CataCXium-A-Pd-G₃ (0.668 g, 0.92 mmol) was added to the reaction mixture at room temperature. The reaction mixture was filled with N₂ three times and stirred at 95 °C for 10 h, then saturated NaHCO₃ (100 mL) was added to the reaction mixture, followed by extraction with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane at a ratio of 1:10 to give tert-butyl-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (2.9 g, 89%) as a white solid. MS (ESI) m / z 357.2 [M+H] + .

[0224] Step 2: 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0225]

[0226] TFA (10 mL) was added to a solution of tert-butyl-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (1 g, 2.81 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated and diluted with EtOAc, and washed with saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with DCM / MeOH (DCM:MeOH, 10:1) to give the title compound (660 mg, 93%) as a white solid. MS (ESI) m / z 257.2 [M+H] + .

[0227] Step 3: 5-Bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0228]

[0229] In a flame-dried 50 mL round-bottom flask under nitrogen atmosphere, 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (0.6 g, 2.341 mmol) was dissolved in DMF (20 mL) to give a colored solution. NBS (0.42 g, 2.341 mmol) was added dropwise to the reaction mixture at -5°C to 0°C. The reaction mixture was stirred at 0°C for 2 h. Saturated NaHCO3 was added to the reaction mixture, followed by extraction with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (ethyl acetate:hexane = 1:5) to give 5-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (0.6 g, 76%) as a white solid. MS(ESI)m / z335.1[M+H] + .

[0230] Step 4: 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxaldehyde

[0231]

[0232] Methyllithium (1.6 M, in Et₂O; 6.25 mL, 10 mmol) was added over 15 min to 5-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (2.5 g, 7.46 mmol) cooled to -78 °C in 40 mL of THF, followed by the addition of tert-butyllithium (1.7 M, in hexane; 10.5 mL, 17.9 mmol) over 30 min. After 15 min, DMF (3 mL) was added, and the mixture was stirred at -78 °C for another 50 min. A saturated aqueous solution of NH₄Cl (45 mL) was added, and the mixture was stirred at room temperature for 10 min. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na₂SO₄, and evaporated to give a crude residue. This crude residue was purified by rapid silica gel column chromatography (eluting with ethyl acetate / hexane) to give 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxaldehyde (1.3 g, 61% yield) as a white solid. MS (ESI) m / z 285.3 [M+H] + .

[0233] Step 5: 1-(2-chloroacetyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxaldehyde

[0234]

[0235] In a flame-dried 50 mL round-bottom flask under nitrogen atmosphere, 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxaldehyde (1 g, 3.52 mmol, 1.0 equivalent) and DIPEA (0.909 g, 7.03 mmol, 2.0 equivalent) were dissolved in CH₂Cl₂ (50 mL) to give a solution. 2-Chloroacetyl chloride (0.477 g, 4.22 mmol, 1.2 equivalent) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at 22 °C for 1 h, then saturated NaHCO₃ (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (15 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane at a ratio of 1:2 to give 1-(2-chloroacetyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxaldehyde (1 g, 79%) as a grayish-white solid. MS (ESI) m / z 361.5 [M+H] + .

[0236] Step 6: 2-Chloro-1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one

[0237]

[0238] In a flame-dried 100 mL round-bottom flask under nitrogen atmosphere, 1-(2-chloroacetyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxaldehyde (40 mg, 0.111 mmol, 1.0 equivalent) and ammonium acetate (51.3 mg, 0.665 mmol, 6.0 equivalent) were dissolved in acetic acid (1.0 mL) to give a solution. Formaldehyde (16.64 mg, 0.554 mmol, 5.0 equivalent) was added dropwise to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 16 h. Saturated NaHCO3 (10 mL) was then added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane at a ratio of 1:2 to give a grayish-white solid of 2-chloro-1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one (30 mg, 72.8%). MS (ESI) m / z 387.3 [M+H] + .

[0239] Step 7: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0240]

[0241] In a flame-dried 50 mL round-bottom flask under nitrogen atmosphere, 2-chloro-1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one (30 mg, 0.081 mmol, 1.0 equivalent), potassium iodide (20.09 mg, 0.121 mmol, 1.5 equivalent), and K₂CO₃ (33.5 mg, 0.242 mmol, 3.0 equivalent) were dissolved in acetonitrile (5 mL) to give a solution. At 0 °C, tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate II (27.8 mg, 0.089 mmol, 1.1 equivalent) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:20 to give a grayish-white solid of tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (35 mg, 66.9%). MS (ESI) m / z 649.9 [M+H] + .

[0242] Step 8: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetoone

[0243]

[0244] In a flame-dried 50 mL round-bottom flask under nitrogen, tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (45 mg, 0.069 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (1 mL) to give a solution. HCl (1 mL, 4 M, in 1,4-dioxane) was added to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 2 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:20 to give a grayish-white solid of 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethyl-1-one (7.3 mg, 19%). 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.53(s,1H),7.73(s,1H),7.57(s,1H),7.36(dd,J=8.5,5.7Hz,2H),7.12(t,J=8.9Hz,2H),4.10(s,2H),4.07(d,J=10.6Hz ,1H),3.86(d,J=10.6Hz,1H),3.77(d,J=16.5Hz,1H),3.61(d,J=16.4Hz,1H),3.50(d,J=10.9Hz,2H),3.21(t,J=9.4Hz,1H),3.00-2 .89(m,2H),2.85(t,J=10.8Hz,2H),2.71(d,J=9.3Hz,1H),2.61(d,J=8.9Hz,2H),2.45(t,J=11.1Hz,1H),2.28(t,J=11.1Hz,1H),2. 16(brs,1H),1.93(t,J=9.4Hz,1H),1.75(d,J=11.5Hz,1H),1.56(s,3H),1.52(s,3H),0.91(d,J=6.2Hz,3H),0.88(d,J=6.1Hz,3H). MS(ESI)m / z 549.7[M+H] + .

[0245] Example 2: 1-(4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 2)

[0246]

[0247] Step 1: 2-Chloro-1-(4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one

[0248]

[0249] In a flame-dried 100 mL round-bottom flask under nitrogen atmosphere, 1-(2-chloroacetyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxaldehyde (50 mg, 0.139 mmol, 1.0 equivalent) and ammonium acetate (64.1 mg, 0.831 mmol, 6.0 equivalent) were dissolved in acetic acid (1.0 mL) to give a solution. Acetaldehyde (30.5 mg, 0.693 mmol, 5.0 equivalent) was added dropwise to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 16 h. Saturated NaHCO3 (10 mL) was then added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:40 to give a grayish-white solid of 2-chloro-1-(4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one (32 mg, 59.8%). MS (ESI) m / z 386.4 [M+H] + .

[0250] Step 2: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0251]

[0252] In a flame-dried 50 mL round-bottom flask under nitrogen atmosphere, 2-chloro-1-(4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one (32 mg, 0.083 mmol, 1.0 equivalent), potassium iodide (20.65 mg, 0.124 mmol, 1.5 equivalent), and K₂CO₃ (34.4 mg, 0.249 mmol, 3.0 equivalent) were dissolved in acetonitrile (5 mL) to give a solution. At 0 °C, tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate II (28.6 mg, 0.091 mmol, 1.1 equivalent) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:20 to give a grayish-white solid of tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (40 mg, 72.8%). MS (ESI) m / z 663.7 [M+H] + .

[0253] Step 3: 1-(4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetoone

[0254]

[0255] In a flame-dried 50 mL round-bottom flask under nitrogen, tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (40 mg, 0.060 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (1.0 mL) to give a solution. HCl (1 mL, 4 M, in 1,4-dioxane) was added to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 2 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:20 to give a grayish-white solid of 1-(4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethyl-1-one (15 mg, 44.2%). 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)7.70(s,1H),7.48(s,1H),7.34(dd,J=8.5,5.6Hz,2H),7.11(t,J=8.9Hz,2H),4.05(d,J=9.9Hz ,3H),3.87-3.76(m,2H),3.62-3.45(m,3H),3.23(t,J=9.8Hz,1H),2.99-2.77(m,7H),2.72(d,J=10.8Hz ,1H),2.61(d,J=8.9Hz,2H),2.41(t,J=11.0Hz,1H),2.28(t,J=10.7Hz,1H),2.16(brs,1H),1.94(t,J=9 .4Hz, 1H), 1.75 (d, J = 11.3Hz, 1H), 1.54 (d, J = 16.4Hz, 6H), 0.91 (d, J = 6.2Hz, 3H), 0.88 (d, J = 6.1Hz, 3H). MS(ESI)m / z

[0256] 563.5 [M+H] + .

[0257] Example 3: 1-(1-Cyclopropyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 3)

[0258]

[0259] Step 1: 2-Chloro-1-(1-Cyclopropyl-4-(4-Fluorobenzyl)-8,8-Dimethyl-7,8-Dihydro-6H-Imidazolo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one

[0260]

[0261] In a flame-dried 100 mL round-bottom flask under nitrogen atmosphere, 1-(2-chloroacetyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxaldehyde (50 mg, 0.139 mmol, 1.0 equivalent) and ammonium acetate (64.1 mg, 0.831 mmol, 6.0 equivalent) were dissolved in acetic acid (1 mL) to give a solution. Cyclopropanecarboxaldehyde (48.6 mg, 0.693 mmol, 5.0 equivalent) was added dropwise to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 16 h, then saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:40 to give a grayish-white solid of 2-chloro-1-(1-cyclopropyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one (40 mg, 70%). MS (ESI) m / z 413.4 [M+H] + .

[0262] Step 2: tert-butyl(2R,5S)-4-(2-(1-cyclopropyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0263]

[0264] In a flame-dried 50 mL round-bottom flask under nitrogen atmosphere, 2-chloro-1-(1-cyclopropyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl) acetonitrile (35 mg, 0.085 mmol, 1.0 equivalent), potassium iodide (28.2 mg, 0.170 mmol, 2.0 equivalent), and K₂CO₃ (35.2 mg, 0.255 mmol, 3.0 equivalent) were dissolved in acetonitrile (5.0 mL) to give a solution. At 0 °C, tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate II (27 mg, 0.093 mmol, 1.1 equivalent) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane = 1:20 to give a grayish-white solid of tert-butyl(2R,5S)-4-(2-(1-cyclopropyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (45 mg, 77%). MS (ESI) m / z 690.1 [M+H] + .

[0265] Step 3: 1-(1-Cyclopropyl-4-(4-Fluorobenzyl)-8,8-Dimethyl-7,8-Dihydro-6H-Imidazolo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetoone

[0266]

[0267] In a flame-dried 50 mL round-bottom flask under nitrogen, tert-butyl(2R,5S)-4-(2-(1-cyclopropyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (45 mg, 0.065 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (1 mL) to give a solution. HCl (1 mL, 4 M, 1,4-dioxane) was added to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 2 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:20 to give a grayish-white solid of 1-(1-cyclopropyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (15 mg, 39%). 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)7.67(s,1H),7.44(s,1H),7.34(dd,J=8.5,5.6Hz,2H),7.11(t,J=8.9Hz,2H),4.08(d,J=10.8Hz,1H),4.02(s,2H),3.88-3.76(m,2H),3. 59(d,J=16.6Hz,1H),3.51(d,J=11.1Hz,2H),3.22(t,J=10.1Hz,1H),2. 99-2.89(m,2H),2.87(d,J=12.8Hz,1H),2.82(d,J=11.8Hz,1H),2.72(d, J=10.3Hz,1H),2.61(d,J=8.9Hz,2H),2.42(t,J=10.7Hz,1H),2.37(dd,J=9.4,4.4Hz,1H),2.28(t,J=10.8Hz,1H),2.15(brs,1H),1.93(t,J=9.6 Hz,1H),1.75(d,J=11.9Hz,1H),1.63(d,J=18.0Hz,6H),1.14(t,J=11.1Hz,1H),1.10-1.01(m,3H),0.91(d,J=6.1Hz,3H),0.88(d,J=6.1Hz,3H). MS(ESI)m / z 589.6[M+H] + .

[0268] Example 4: 1-(1-Ethyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 4)

[0269]

[0270] Step 1: 2-Chloro-1-(1-ethyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one

[0271]

[0272] In a flame-dried 100 mL round-bottom flask under nitrogen atmosphere, 1-(2-chloroacetyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxaldehyde (55 mg, 0.152 mmol, 1.0 equivalent) and ammonium acetate (70.5 mg, 0.915 mmol, 6.0 equivalent) were dissolved in acetic acid (1 mL) to give a solution. Propanal (44.3 mg, 0.762 mmol, 5.0 equivalent) was added dropwise to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 16 h, then saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:40 to give a grayish-white solid of 2-chloro-1-(1-ethyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one (45 mg, 73.8%). MS (ESI) m / z 401.4 [M+H] + .

[0273] Step 2: tert-butyl(2R,5S)-4-(2-(1-ethyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0274]

[0275] In a flame-dried 50 mL round-bottom flask under nitrogen atmosphere, 2-chloro-1-(1-ethyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one (45 mg, 0.113 mmol, 1.0 equivalent), potassium iodide (37.4 mg, 0.225 mmol, 2.0 equivalent), and K₂CO₃ (46.7 mg, 0.338 mmol, 3.0 equivalent) were dissolved in acetonitrile (5 mL) to give a solution. At 0 °C, tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate II (36 mg, 0.12 mmol, 1.1 equivalent) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:20 to give a grayish-white solid of tert-butyl(2R,5S)-4-(2-(1-ethyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (50 mg, 65.6%). MS (ESI) m / z 677.6 [M+H] + .

[0276] Step 3: 1-(1-Ethyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetoone

[0277]

[0278] In a flame-dried 50 mL round-bottom flask under nitrogen, tert-butyl(2R,5S)-4-(2-(1-ethyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (45 mg, 0.066 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (1 mL) to give a solution. HCl (1 mL, 4 M, in 1,4-dioxane) was added to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 2 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:20 to give a grayish-white solid of 1-(1-ethyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethyl-1-one (8.5 mg, 22.17%). 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)7.69(s,1H),7.54(s,1H),7.34(dd,J=8.5,5.6Hz,2H),7.11(t,J=8.9Hz,2H),4.06(d,J=11.5Hz,3H),3.82(d,J=10 .7Hz,2H),3.57(d,J=16.3Hz,1H),3.54-3.45(m,2H),3.23(t,J=9.8Hz,1H),3.12(tt,J=7.4,3.9Hz,2H),2.99-2.78(m,4H), 2.73(d,J=10.6Hz,1H),2.61(d,J=8.9Hz,2H),2.41(t,J=11.0Hz,1H),2.28(t,J=10.8Hz,1H),2.16(brs,1H),2.04-1.88(m ,1H),1.75(d,J=11.4Hz,1H),1.56(s,3H),1.52(s,3H),1.39(t,J=7.3Hz,3H),0.91(d,J=6.2Hz,3H),0.87(t,J=7.0Hz,3H). MS(ESI)m / z577.6[M+H] + .

[0279] Example 5: 1-(4-(4-fluorobenzyl)-1-isopropyl-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 5)

[0280]

[0281] Step 1: 2-Chloro-1-(4-(4-fluorobenzyl)-1-isopropyl-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one

[0282]

[0283] In a flame-dried 100 mL round-bottom flask under nitrogen atmosphere, 1-(2-chloroacetyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxaldehyde (55 mg, 0.152 mmol, 1.0 equivalent) and ammonium acetate (70.5 mg, 0.915 mmol, 6.0 equivalent) were dissolved in acetic acid (1 mL) to give a solution. Isobutyraldehyde (55.0 mg, 0.762 mmol, 5.0 equivalent) was added dropwise to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 16 h, then saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:40 to give a grayish-white solid of 2-chloro-1-(4-(4-fluorobenzyl)-1-isopropyl-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one (50 mg, 79%). MS (ESI) m / z 415.4 [M+H] + .

[0284] Step 2: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1-isopropyl-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0285]

[0286] In a flame-dried 50 mL round-bottom flask under nitrogen atmosphere, 2-chloro-1-(4-(4-fluorobenzyl)-1-isopropyl-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl) acetonitrile (50 mg, 0.121 mmol, 1.0 equivalent), potassium iodide (40.1 mg, 0.242 mmol, 2.0 equivalent), and K₂CO₃ (50.1 mg, 0.362 mmol, 3.0 equivalent) were dissolved in acetonitrile (5 mL) to give a solution. At 0 °C, tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate II (38 mg, 0.13 mmol, 1.1 equivalent) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:20 to give a grayish-white solid of tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1-isopropyl-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (50 mg, 59.9%). MS (ESI) m / z 691.7 [M+H] + .

[0287] Step 3: 1-(4-(4-fluorobenzyl)-1-isopropyl-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetoone

[0288]

[0289] In a flame-dried 50 mL round-bottom flask under nitrogen, tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1-isopropyl-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (50 mg, 0.072 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (1 mL) to give a solution. HCl (1 mL, 4 M, 1,4-dioxane) was added to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 2 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:20 to give a grayish-white solid of 1-(4-(4-fluorobenzyl)-1-isopropyl-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethyl-1-one (6.5 mg, 15.20%). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.68 (s, 1H), 7.62 (s, 1H), 7.39 (dd, J = 8.5, 5.7Hz, 2H), 7.16 (dd, J = 12.3, 5.5Hz, 2H), 4.13 (d, J = 10.4Hz, 1 H),4.07(s,2H),3.86(t,J=13.8Hz,2H),3.71-3.58(m,2H),3.54(d,J=11.1Hz,2H),3.27(t,J=10.4Hz,1H),3.03-2.94(m,2H),2.88(dd, J=21.9,12.7Hz,2H),2.77(d,J=9.9Hz,1H),2.65(d,J=8.9Hz,2H),2.46(t,J=10.9Hz,1H),2.33(t,J=11.1Hz,1H),2.20(brs,1H),2.09 -1.92(m,1H),1.80(d,J=11.3Hz,1H),1.60(d,J=7.9Hz,6H),1.39(d,J=6.6Hz,3H),1.35(d,J=6.6Hz,3H),0.94(dd,J=10.8,6.2Hz,6H). MS(ESI)m / z 591.6[M+H] + .

[0290] Example 6: 1-(1-Cyclobutyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 6)

[0291]

[0292] Step 1: 2-Chloro-1-(1-cyclobutyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one

[0293]

[0294] In a flame-dried 100 mL round-bottom flask under nitrogen atmosphere, 1-(2-chloroacetyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxaldehyde (45 mg, 0.125 mmol, 1.0 equivalent) and ammonium acetate (57.7 mg, 0.748 mmol, 6.0 equivalent) were dissolved in acetic acid (1 mL) to give a solution. Cyclobutanaldehyde (52.5 mg, 0.624 mmol, 5.0 equivalent) was added dropwise to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 16 h, then saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:40 to give a grayish-white solid of 2-chloro-1-(1-cyclobutyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one (40 mg, 75%). MS (ESI) m / z 427.4 [M+H] + .

[0295] Step 2: tert-butyl(2R,5S)-4-(2-(1-cyclobutyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0296]

[0297] In a flame-dried 50 mL round-bottom flask under nitrogen atmosphere, 2-chloro-1-(1-cyclobutyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl) acetonitrile (5 mL) (40 mg, 0.094 mmol, 1.0 equivalent), potassium iodide (31.2 mg, 0.188 mmol, 2.0 equivalent), and K₂CO₃ (38.9 mg, 0.282 mmol, 3.0 equivalent) were dissolved in acetonitrile (5 mL) to prepare a solution. At 0 °C, tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (30 mg, 0.10 mmol, 1.1 equivalent) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:20 to give a grayish-white solid of tert-butyl(2R,5S)-4-(2-(1-cyclobutyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (35 mg, 53.0%). MS (ESI) m / z 703.8 [M+H] + .

[0298] Step 3: 1-(1-Cyclobutyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetoone

[0299]

[0300] In a flame-dried 50 mL round-bottom flask under nitrogen, tert-butyl(2R,5S)-4-(2-(1-cyclobutyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (45 mg, 0.064 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (1 mL) to give a solution. HCl (1 mL, 4 M, in 1,4-dioxane) was added to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 2 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:20 to give a grayish-white solid of 1-(1-cyclobutyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethyl-1-one (9.5 mg, 24.62%). 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.67 (s, 1H), 7.63 (s, 1H), 7.34 (dd, J = 8.5, 5.6Hz, 2H), 7.12 (t, J = 8.9Hz, 2H), 4.15-3 .98(m,4H),3.86-3.73(m,2H),3.60(d,J=16.4Hz,1H),3.50(d,J=11.2Hz,2H),3.21(t,J=10.2Hz,1H),3.01-2.84(m ,3H),2.78(dd,J=23.7,12.0Hz,2H),2.62(d,J=9.1Hz,2H),2.41(ddd,J=11.5,10.6,6.8Hz,3H),2.35-2.25(m,1H) ,2.16(brs,1H),1.96(td,J=14.4,8.0Hz,3H),1.76(d,J=11.2Hz,1H),1.57(d,J=8.2Hz,6H),0.90(t,J=6.2Hz,6H). MS(ESI)m / z 603.6[M+H] + .

[0301] Example 7: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 7)

[0302]

[0303] Step 1: 2-Chloro-1-(4-(4-fluorobenzyl)-8,8-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one

[0304]

[0305] In a flame-dried 100 mL round-bottom flask under nitrogen atmosphere, 1-(2-chloroacetyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxaldehyde (45 mg, 0.125 mmol, 1.0 equivalent) and ammonium acetate (57.7 mg, 0.748 mmol, 6.0 equivalent) were dissolved in acetic acid (1 mL) to give a solution. Tetrahydro-2H-pyran-4-carboxaldehyde (71.2 mg, 0.624 mmol, 5.0 equivalent) was added dropwise to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 16 h, and then saturated NaHCO3 (10 mL) was added subsequently to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:40 to give a grayish-white solid of 2-chloro-1-(4-(4-fluorobenzyl)-8,8-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one (20 mg, 35.2%). MS (ESI) m / z 456.3 [M+H] + .

[0306] Step 2: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0307]

[0308] In a flame-dried 50 mL round-bottom flask under nitrogen atmosphere, 2-chloro-1-(4-(4-fluorobenzyl)-8,8-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl) acetonitrile (20 mg, 0.044 mmol, 1.0 equivalent), potassium iodide (10.9 mg, 0.066 mmol, 1.5 equivalent), and K₂CO₃ (18.2 mg, 0.132 mmol, 3.0 equivalent) were dissolved in acetonitrile (5 mL) to give a solution. At 0 °C, tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate II (15.1 mg, 0.048 mmol, 1.1 equivalents) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:20 to give a grayish-white solid: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (20 mg, 62.2%). MS (ESI) m / z 733.6 [M+H] + .

[0309] Step 3: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetoone

[0310]

[0311] In a flame-dried 50 mL round-bottom flask under nitrogen atmosphere, tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (25 mg, 0.034 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (1 mL) to give a solution. HCl (1 mL, 4 M, in 1,4-dioxane) was added to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 2 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:20 to give a grayish-white solid 1-(4-(4-fluorobenzyl)-8,8-dimethyl-1-(tetrahydro-2H-pyran-4-yl)-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridine-6-

[0312] 2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethyl-1-one (5mg,

[0313] 23.16%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.67 (s, 1H), 7.62 (s, 1H), 7.35 (dd, J = 8.4, 5.7Hz, 2H), 7.12 ( t,J=8.8Hz,2H),4.14-4.02(m,2H),3.97(d,J=10.6Hz,2H),3.90-3.75(m,2H),3.68-3.41(m ,6H),3.21(t,J=10.0Hz,1H),3.06-2.72(m,6H),2.71-2.58(m,3H),2.36-2.25(m,1H),2.1 5(brs,1H),2.11-1.90(m,3H),1.85-1.65(m,3H),1.58(d,J=8.3Hz,6H),0.98-0.84(m,6H). MS(ESI)m / z 633.5[M+

[0314] H] + .

[0315] Example 8: 1-(4-(4-fluorobenzyl)-1-(4-fluorophenyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 8)

[0316]

[0317] Step 1: 2-Chloro-1-(4-(4-fluorobenzyl)-1-(4-fluorophenyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one

[0318]

[0319] In a flame-dried 100 mL round-bottom flask under nitrogen atmosphere, 1-(2-chloroacetyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-5-carboxaldehyde (50 mg, 0.139 mmol, 1.0 equivalent) and ammonium acetate (64.1 mg, 0.831 mmol, 6.0 equivalent) were dissolved in acetic acid (1 mL) to give a solution. 4-fluorobenzaldehyde (86 mg, 0.693 mmol, 5.0 equivalent) was added dropwise to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 16 h, then saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:40 to give a grayish-white solid of 2-chloro-1-(4-(4-fluorobenzyl)-1-(4-fluorophenyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one (35 mg, 54%). MS (ESI) m / z 466.3 [M+H] + .

[0320] Step 2: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1-(4-fluorophenyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0321]

[0322] In a flame-dried 50 mL round-bottom flask under nitrogen atmosphere, 2-chloro-1-(4-(4-fluorobenzyl)-1-(4-fluorophenyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one (30 mg, 0.064 mmol, 1.0 equivalent), potassium iodide (21.38 mg, 0.129 mmol, 2.0 equivalent), and K₂CO₃ (26.7 mg, 0.193 mmol, 3.0 equivalent) were dissolved in acetonitrile (5 mL) to give a solution. At 0 °C, tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (21 mg, 0.07 mmol, 1.1 equivalent) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane = 1:20 to give tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1-(4-fluorophenyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (20 mg, 41.8%) as a grayish-white solid. MS (ESI) m / z 743.8 [M+H] + .

[0323] Step 3: 1-(4-(4-fluorobenzyl)-1-(4-fluorophenyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetoone

[0324]

[0325] In a flame-dried 50 mL round-bottom flask under nitrogen, tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1-(4-fluorophenyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (40 mg, 0.054 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (1.0 mL) to give a solution. HCl (1 mL, 4 M, in 1,4-dioxane) was added to the reaction mixture at 22 °C. The reaction mixture was stirred at 22 °C for 2 h. Saturated NaHCO3 (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:20 to give a grayish-white solid of 1-(4-(4-fluorobenzyl)-1-(4-fluorophenyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethyl-1-one (8 mg, 23%). 1 HNMR(400MHz,DMSO-d6)δ(ppm)7.78(s,1H),7.73(s,1H),7.62(dd,J=8.4,5.6Hz,2H),7.41(dd,J=8.4,5.7Hz,2H),7.32(t,J=8.8Hz,2H),7. 15(t,J=8.9Hz,2H),4.12(s,2H),3.81(dd,J=17.1,14.0Hz,2H),3.58(dd,J=18.5,13.3Hz,2H),3.48(t,J=8.9Hz,2H),3.20(t,J=9.9Hz,1H), 2.90(t,J=9.5Hz,2H),2.85-2.76(m,2H),2.69(d,J=12.6Hz,1H),2.58(d,J=8.9Hz,2H),2.40(t,J=11.3Hz,1H),2.25(t,J=10.9Hz,1H),2.12 (brs,1H),2.00(dd,J=14.1,6.6Hz,1H),1.91(t,J=10.0Hz,1H),1.72(d,J=11.3Hz,1H),0.92(s,3H),0.87(s,3H),0.86(s,3H),0.77(s,3H). MS(ESI)m / z 643.6[M+H] + .

[0326] Example 9: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 9)

[0327]

[0328] Step 1: 1-(5-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one

[0329]

[0330] Acetyl chloride (0.281 g, 3.58 mmol) was added dropwise to a solution of 5-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (1 g, 2.98 mmol, 1.0 equivalent) in acetonitrile (20 mL). The mixture was stirred at room temperature for 1 h. The mixture was quenched with a saturated aqueous solution of NaHCO3 and diluted with ethyl acetate, and then washed with water and saturated brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (ethyl acetate:hexane = 1:3) to give 1-(5-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one (1.0 g, 89%) as a white solid. MS(ESI) m / z 377.1 [M+H] + .

[0331] Step 2: tert-butyl-2-(1-acetyl-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)hydrazine-1-carboxylate

[0332]

[0333] To a solution of 1-(5-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethyl-1-one (600 mg, 1.59 mmol) in 1,4-dioxane (10 mL), tert-butyl hydrazine carboxylate (252 mg, 1.91 mmol), Cs₂CO₃ (1555 mg, 4.77 mmol), [1,1'-dinaphthyl]-2-yldi-tert-butylphosphine (127 mg, 0.32 mmol), and Pd₂(dba)₃ (146 mg, 0.16 mmol) were added. The mixture was packed with N₂ three times and stirred at 130 °C for 2 h. The mixture was cooled to room temperature and diluted with ethyl acetate, and then washed with water and saturated brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (ethyl acetate:hexane = 7:10) to give tert-butyl 2-(1-acetyl-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)hydrazine-1-carboxylate (0.36 g, 52.8%) as a white solid. MS (ESI) m / z 429.2 [M+H] + .

[0334] Step 3: 1-(6-(4-fluorobenzyl)-5-hydrazino-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one (intermediate 1)

[0335]

[0336] TFA (1 ml) was added to a solution of tert-butyl 2-(1-acetyl-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)hydrazine-1-carboxylate (0.36 g, 0.84 mmol) in DCM (1 ml). The mixture was stirred at room temperature for 1 h. The mixture was concentrated to give 280 mg of crude product, which was used directly in the next step. MS (ESI) m / z 329.2 [M+H] + .

[0337] Step 4: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl) ethyl-1-one

[0338]

[0339] 4-Methylbenzenesulfonic acid (47.2 mg, 0.27 mmol) was added to a solution of 1-(6-(4-fluorobenzyl)-5-hydrazino-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one (90 mg, 0.27 mmol) in trimethoxymethane (2 mL). The mixture was stirred at 50 °C for 1 h. The mixture was cooled to room temperature and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (methanol:dichloromethane = 1:20) to give 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl) ethyl-1-one (40 mg, 43.1%) as a yellow oil. MS(ESI) m / z 339.2 [M+H] + .

[0340] Step 5: 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine

[0341]

[0342] Add 5M HCl (2 mL) to a solution of 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl-1-one (40 mg, 0.12 mmol) in EtOH (2 mL). Stir the mixture at 95 °C for 6 h. Concentrate the mixture and dilute with ethyl acetate, washing with saturated NaHCO3 aqueous solution and brine. Dry the organic layer with Na2SO4, filter and concentrate to give 30 mg of crude product, which was used directly in the next step. MS (ESI) m / z 297.1 [M+H] + .

[0343] Step 6: 2-Chloro-1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl) ethyl-1-one

[0344]

[0345] To a solution of 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (30 mg, 0.1 mmol) in DCM (2 ml), N-ethyl-N-isopropylpropyl-2-amine (26.2 mg, 0.2 mmol) and 2-chloroacetyl chloride (17.1 mg, 0.15 mmol) were added. The mixture was stirred at room temperature for 1 h. The mixture was then concentrated to give a crude product, which was added to a silica gel column and eluted with ethyl acetate / hexane (ethyl acetate:hexane = 1:3) to give a yellow oily substance, 2-chloro-1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl-1-one (31 mg, 82%). MS (ESI) m / z 373.1 [M+H] + .

[0346] Step 7: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0347]

[0348] To a solution of 2-chloro-1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl-1-one (31 mg, 0.08 mmol) in acetonitrile (2 mL), tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (26.1 mg, 0.08 mmol), potassium iodide (20.7 mg, 0.12 mmol), and K₂CO₃ (34.5 mg, 0.24 mmol) were added. The mixture was stirred at 29 °C for 2 h. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated to give a yellow oil. This yellow oil was added to a silica gel column and eluted with DCM / MeOH (DCM:MeOH = 10:1) to give the title compound (36 mg, 66%) as a white solid. MS (ESI) m / z 650.4 [M+H] + .

[0349] Step 8: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetoone

[0350]

[0351] TFA (2 ml) was added to a solution of tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (36 mg, 0.06 mmol) in DCM (2 ml). The mixture was stirred at room temperature for 1 h. The mixture was concentrated and diluted with ethyl acetate, and washed with saturated NaHCO3 aqueous solution and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give a yellow oil. This yellow oil was added to a preparative HPLC column and eluted with water / acetonitrile (5%-50%) to give a white solid 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)aceto-1-one (5.7 mg, 18.72%). 1 H NMR (400MHz, CD3OD) δ (ppm) 9.44 (s, 1H), 8.22 (s, 1H), 7.36 (dd, J = 8.5, 5.4Hz, 2H),7.02(t,J=8.8Hz,2H),4.45-4.25(m,2H),4.15-3.93(m,3H),3.71-3.50( m,3H),3.45-3.32(m,1H),3.13-2.76(m,7H),2.54-2.39(m,2H),2.31-1.80(m ,3H),1.65(s,3H),1.62(s,3H),1.02(d,J=6.3Hz,3H),0.95(d,J=6.3Hz,3H). MS(ESI) m / z 550.3 [M+H] + .

[0352] Example 10: 1-(4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 10)

[0353]

[0354] Following the synthesis of Example 9, Example 10 (5.1 mg) was obtained as a white solid. 1 H NMR (400MHz, CD3OD) δ (ppm) 8.22 (s, 1H), 7.34 (dd, J = 8.5, 5.4Hz, 2H), 7.02 (t, J = 8.8Hz, 2H), 4.40-4.23 (m, 2H), 4.17-3.90 (m, 3H), 3.69-3.51 (m, 3H), 3.47-3.32(m,1H),3.10-2.79(m,10H),2.54-2.40(m,2H),2.31-1.81(m,3 H), 1.66 (s, 3H), 1.62 (s, 3H), 1.02 (d, J = 6.3Hz, 3H), 0.95 (d, J = 6.3Hz, 3H). MS(ESI)m / z 564.3[M+H] + .

[0355] Example 11: 1-(4-(4-fluorobenzyl)-1-isopropyl-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 11)

[0356]

[0357] Following the synthesis of Example 9, Example 11 (2.9 mg) was obtained as a white solid. 1H NMR (400MHz, CD3OD) δ (ppm) 8.20 (s, 1H), 7.35 (dd, J = 8.6, 5.4Hz, 2H), 7.02 (t, J = 8.8Hz ,2H),4.40-4.23(m,2H),4.17-3.93(m,3H),3.89-3.76(m,1H),3.66-3.54(m,3H),3.4 4-3.33(m,1H),3.09-2.77(m,7H),2.55-2.40(m,2H),2.28-1.81(m,3H),1.68(s,3H), 1.66 (s, 3H), 1.53 (dd, J = 6.7, 4.4Hz, 6H), 1.02 (d, J = 6.3Hz, 3H), 0.95 (d, J = 6.3Hz, 3H). MS(ESI)m / z 592.4[M+H] + .

[0358] Example 12: 1-(1-Cyclopropyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 12)

[0359]

[0360] Following the synthesis of Example 9, Example 12 (9.5 mg) was obtained as a white solid. 1 H NMR (400MHz, CD3OD) δ (ppm) 8.21 (s, 1H), 7.34 (dd, J = 8.5, 5.5Hz, 2H), 7.01 (t, J=8.8Hz,2H),4.37-4.21(m,2H),4.16-3.95(m,3H),3.69-3.53(m,3H),3.38( m,1H),3.10-2.77(m,7H),2.53-2.38(m,3H),2.33-1.82(m,3H),1.75(s,3H), 1.71(s,3H),1.37-1.24(m,4H),1.02(d,J=6.2Hz,3H),0.95(d,J=6.2Hz,3H). MS(ESI) m / z 590.4 [M+

[0361] H] + .

[0362] Example 13: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-1-(trifluoromethyl)-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 13)

[0363]

[0364] Following the synthesis of Example 9, Example 13 (17.5 mg) was obtained as a white solid. 1 H NMR (400MHz, CD3OD) δ (ppm) 8.26 (s, 1H), 7.39 (dd, J = 8.4, 5.4Hz, 2H), 7.11 (t, J = 8.7Hz, 2H), 4.61-4.37 (m, 2 H),4.12-3.82(m,5H),3.71-3.33(m,11H),3.18-2.90(m,3H),1.59(s,3H),1.58(s,3H),1.41-1.18(m,6H). MS(ESI)m / z 618.5[M+H] + .

[0365] Example 14: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 14)

[0366]

[0367] Step 1: tert-butyl (1-acetyl-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate

[0368]

[0369] To a solution of 1-(5-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one (300 mg, 0.795 mmol) in 1,4-dioxane (10 mL), tert-butyl carbamate (112 mg, 0.95 mmol), Cs₂CO₃ (777 mg, 2.39 mmol), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (85 mg, 0.16 mmol) and Pd₂(dba)₃ (72.8 mg, 0.08 mmol) were added. The mixture was packed with N₂ three times and stirred at 90 °C for 2 h. The mixture was cooled to room temperature and diluted with ethyl acetate, then washed with H₂O and saturated brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (ethyl acetate:hexane = 7:10) to give a white solid tert-butyl (1-acetyl-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl) carbamate (0.19 g, 57.8%). MS (ESI) m / z 414.2 [M+H] + .

[0370] Step 2: 1-(5-amino-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one (intermediate 2)

[0371]

[0372] At room temperature, TFA (1 ml) was added to a solution of tert-butyl(1-acetyl-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate (0.1 g, 0.24 mmol) in DCM (1 ml), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated to give 90 mg of crude product, which was used for the next step without further purification. MS (ESI) m / z 314.2 [M+H] + .

[0373] Step 3: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl) ethyl-1-one

[0374]

[0375] Add 1,1-dimethoxy-N,N-dimethylmethylamine (51.3 mg, 0.43 mmol) to a solution of 1-(5-amino-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethyl-1-one (90 mg, 0.29 mmol) in i-PrOH (2 mL). Stir the mixture at 80 °C for 2 h. Then add hydroxylamine hydrochloride (39.9 mg, 0.57 mmol) to the mixture and stir at 50 °C for 1 h. Concentrate the mixture to give 100 mg of crude product, which was used in the next step without further purification. Add 2,2,2-trifluoroacetic anhydride (88 mg, 0.42 mmol) to a solution of (E)-N-(1-acetyl-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-N'-hydroxyformamide (100 mg, 0.281 mmol) in THF (2 mL). Stir the mixture at room temperature for 2 h. Concentrate the mixture and add the crude product to a silica gel column and elute with methanol / dichloromethane (methanol:dichloromethane = 1:20) to give a yellow oily product of 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)ethyl-1-one (50 mg, 52.7%). MS(ESI) m / z 339.2 [M+H] + .

[0376] Step 4: 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine

[0377]

[0378] Add 5M HCl (2 mL) to a solution of 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)ethyl-1-one (50 mg, 0.15 mmol) in EtOH (2 mL). Stir the mixture at 95 °C for 6 h. Concentrate the mixture and dilute with ethyl acetate, washing with saturated aqueous NaHCO3 solution and brine. Dry the organic layer over Na2SO4, filter, and concentrate to give 45 mg of crude product, which was used for the next step without further purification. MS (ESI) m / z 297.1 [M+H] + .

[0379] Step 5: 2-Chloro-1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl) ethyl-1-one

[0380]

[0381] To a solution of 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine (45 mg, 0.15 mmol) in DCM (2 ml), N-ethyl-N-isopropylpropyl-2-amine (39.3 mg, 0.3 mmol) and 2-chloroacetyl chloride (25.7 mg, 0.23 mmol) were added. The mixture was stirred at room temperature for 1 h. The mixture was then concentrated to give a yellow oil, which was added to a silica gel column and eluted with ethyl acetate / hexane (ethyl acetate:hexane = 1:3) to give a yellow oil of 2-chloro-1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl-1-one (49 mg, 88%). MS (ESI) m / z 373.1 [M+H] + .

[0382] Step 6: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0383]

[0384] Potassium iodide (32.7 mg, 0.2 mmol), K₂CO₃ (54.5 mg, 0.4 mmol), and tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate II (41.2 mg, 0.13 mmol) were added to a solution of 2-chloro-1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)acetonitrile (2 mL). The mixture was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated to give a yellow oil. This yellow oil was added to a silica gel column and eluted with DCM / MeOH (DCM:MeOH = 10:1) to give the title compound as a white solid (50 mg, 58.5%). MS (ESI) m / z 650.4 [M+H] + .

[0385] Step 7: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetoone

[0386]

[0387] Add 1 ml of TFA to a solution of tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (50 mg, 0.08 mmol) in DCM (2 ml). Stir the mixture at room temperature for 1 h. Concentrate the mixture and dilute with ethyl acetate, then wash with saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give a yellow oil. This yellow oil was added to a preparative HPLC column and eluted with water / acetonitrile (5%-50%) to give a white solid 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)aceto-1-one (23.9 mg, 56.5%). 1H NMR (400MHz, CD3OD) δ (ppm) 8.41 (s, 1H), 8.38 (s, 1H), 7.32 (dd, J = 8.5, 5.5Hz, 2H),7.01(t,J=8.7Hz,2H),4.41-4.25(m,2H),4.18-3.98(m,3H),3.73-3.52( m,3H),3.43-3.33(m,1H),3.08-2.77(m,7H),2.56-2.41(m,2H),2.33-1.82(m ,3H),1.70(s,3H),1.66(s,3H),1.02(d,J=6.3Hz,3H),0.95(d,J=6.3Hz,3H). MS(ESI) m / z 550.3 [M+H] + .

[0388] Example 15: N-(4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2-yl)methanesulfonamide (Compound 15)

[0389]

[0390] Step 1: 1-(2-amino-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl) ethyl-1-one

[0391]

[0392] O-O-isothiocyanate ethoxycarbonyl (109 mg, 0.83 mmol) was added to a solution of 1-(5-amino-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one (200 mg, 0.638 mmol) in 1,4-dioxane (6 mL). The mixture was stirred at room temperature for 1 h. The mixture was then concentrated and the residue was dissolved in methanol (6.00 mL) / ethanol (6.00 mL). Hydroxylamine hydrochloride (133 mg, 1.92 mmol) and N-ethyl-N-isopropylpropyl-2-amine (247 mg, 1.92 mmol) were then added to the mixture and stirred at 70 °C for 5 h. The mixture was cooled to room temperature and filtered. The reaction mixture was diluted with dichloromethane and then washed with saturated brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated to give a yellow oil. This yellow oil was added to a silica gel column and eluted with methanol / dichloromethane (methanol:dichloromethane = 1:10) to give a white solid, 1-(2-amino-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)ethyl-1-one (100 mg, 44.3%). MS (ESI) m / z 354.2 [M+H] + .

[0393] Step 2: N-(6-acetyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2-yl)methanesulfonamide

[0394]

[0395] At 0 °C, triethylamine (43.0 mg, 0.42 mmol) and methanesulfonyl chloride (42.1 mg, 0.39 mmol) were added to a solution of 1-(2-amino-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)ethyl-1-one (100 mg, 0.28 mmol) in DCM (3 mL). The mixture was stirred at room temperature for 2 h. The mixture was then quenched with a saturated aqueous solution of NaHCO3 and diluted with dichloromethane, followed by washing with H2O and saturated brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give a yellow oil. This yellow oil was added to a silica gel column and eluted with methanol / dichloromethane (methanol:dichloromethane = 1:10) to give the title compound (80 mg) as a yellow oil. MS(ESI) m / z 432.1 [M+H] + .

[0396] Step 3: N-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2-yl)methanesulfonamide

[0397]

[0398] A mixture (80 mg) of N-(6-acetyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2-yl)methanesulfonamide was dissolved in EtOH (2 mL) and 5 M HCl (2 mL) was added. The mixture was stirred at 95 °C for 6 h. The mixture was concentrated and diluted with ethyl acetate, and washed with saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude title compound, which was used for the next step without further purification. MS (ESI) m / z 390.1 [M+H] + .

[0399] Step 4: N-(6-(2-chloroacetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2-yl)methanesulfonamide

[0400]

[0401] N-ethyl-N-isopropylpropyl-2-amine (66.4 mg, 0.51 mmol) and 2-chloroacetyl chloride (13.9 mg, 0.12 mmol) were added to a solution of N-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2-yl)methanesulfonamide (40 mg) in DCM (2 mL). The mixture was stirred at room temperature for 1 h. The mixture was then concentrated to give a yellow oil, which was added to a silica gel column and eluted with ethyl acetate / hexane (ethyl acetate:hexane = 1:3) to give a mixed title compound (41 mg) as a yellow oil. MS (ESI) m / z 466.1 [M+H] + .

[0402] Step 5: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-2-(methanesulfonylamino)-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0403]

[0404] To a solution of N-(6-(2-chloroacetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2-yl)methanesulfonamide in acetonitrile (2 ml), tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate II (27.6 mg, 0.09 mmol), K₂CO₃ (36.5 mg, 0.26 mmol), and potassium iodide (21.9 mg, 0.13 mmol) were added. The mixture was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated to give a yellow oil. This yellow oil was added to a silica gel column and eluted with DCM / MeOH (DCM:MeOH = 10:1) to give the title compound (26 mg) as a yellow oil. MS (ESI) m / z 743.3 [M+H] + .

[0405] Step 6: N-(4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2-yl)methanesulfonamide

[0406] To tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-2-(methanesulfonylamino)-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate and tert-butyl(2R,5S)-4-(2-(4-(4-) A mixture (26 mg) of 1,8-dimethyl-2-(N-(methanesulfonyl)methylsulfonylamino)-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate was added to a solution of TFA (1 ml) in DCM (2 ml). The mixture was stirred at room temperature for 1 h. The mixture was concentrated and diluted with ethyl acetate, and washed with saturated aqueous NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give a yellow oil, which was added to a preparative HPLC column and eluted with water / acetonitrile (5%-50%) to give the title compound (11 mg) as a white solid. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.11(s,1H),7.37(dd,J=8.4,5.7Hz,2H),7.10(t,J=8.9Hz,2H), 4.22-4.09(m,2H),4.05-3.99(m,1H),3.89-3.66(m,2H),3.55-3.39(m,6 H),3.11(s,3H),3.09-2.73(m,6H),2.61-2.51(m,2H),2.22-1.78(m,3H) ,1.58(s,3H),1.54(s,3H),1.08(d,J=6.2Hz,3H),0.89(d,J=6.2Hz,3H). MS(ESI)m / z 643.3[M+H] + .

[0407] Example 16: N-(4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2-yl)-N-(methanesulfonyl)methanesulfonamide (Compound 16)

[0408]

[0409] Following the synthesis of Example 15, Example 16, which is a white solid, was obtained. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.19(s,1H),7.35(dd,J=8.5,5.7Hz,2H),7.13(t,J=8.9Hz,2H),4.27-4 .15(m,2H),4.07-4.01(m,1H),3.98-3.85(m,2H),3.74-3.45(m,4H),3.27(s,3H) ,3.22-3.02(m,5H),2.94-2.80(m,3H),2.78-2.57(m,2H),2.30(s,3H),2.21-1.8 6(m,3H),1.60(s,3H),1.56(s,3H),1.14(d,J=6.2Hz,3H),0.91(d,J=6.2Hz,3H). MS(ESI)m / z 721.3[M+H] + .

[0410] Example 17: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 17)

[0411]

[0412]

[0413] Step 1: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one

[0414]

[0415] In a flame-dried 100 mL round-bottom flask under nitrogen atmosphere, 1-(5-amino-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethyl-1-one (115 mg, 0.367 mmol, 1.0 equivalent) and NaHCO3 (154 mg, 1.835 mmol, 5.0 equivalent) were dissolved in 2-propanol (10 mL) / water (1 mL) to give a solution. 2-Chloroacetaldehyde (216 mg, 1.101 mmol, 3.0 equivalent) was added dropwise to the reaction mixture at 80 °C. The reaction mixture was stirred at 80 °C for 16 h. Saturated NaHCO3 (10 mL) was then added to the reaction mixture, followed by extraction with ethyl acetate (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane at a ratio of 1:50 to give a grayish-white solid of 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one (90 mg, 72.7%). MS (ESI) m / z 338.4 [M+H] + .

[0416] Steps 2-5:

[0417] Following the synthesis of Example 1, steps 2-5 were performed to give 7 mg of Example 17 as a grayish-white solid. 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.10(d,J=1.1Hz,1H),8.08(s,1H),7.67(d,J=1.1Hz,1H),7.40(dd,J=8.5,5.7Hz,2H),7.09(t,J=8.9Hz,2H),4.2 5(q,J=14.5Hz,2H),4.08(d,J=10.6Hz,1H),3.87(d,J=10.6Hz,1H),3.77(d,J=16.7Hz,1H),3.63(d,J=16.2Hz,1H),3.51-3 .41(m,2H),3.15(t,J=9.9Hz,1H),2.99(s,1H),2.94-2.77(m,3H),2.73(d,J=9.8Hz,1H),2.62(d,J=8.8Hz,2H),2.28(d,J =10.9Hz,1H),2.15(brs,1H),1.92(t,J=9.3Hz,1H),1.75(d,J=11.4Hz,1H),1.53(d,J=16.9Hz,6H),0.90(t,J=5.9Hz,6H). MS(ESI)m / z 549.5[M+H] + .

[0418] Example 18: Ethyl 4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-2-carboxylate (Compound 18)

[0419]

[0420]

[0421] Step 1: Ethyl 6-acetyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-2-carboxylate

[0422]

[0423] Under argon atmosphere, 1-(5-amino-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one (0.25 g, 0.798 mmol, 1.0 equivalent), ethyl 3-bromo-2-oxopropionate (0.467 g, 2.393 mmol, 3.0 equivalent), and sodium bicarbonate (0.335 g, 3.99 mmol, 5.0 equivalent) were dissolved in water (1 mL) and 2-propanol (10.00 mL) to give a yellow solution. The reaction mixture was stirred at 80 °C for 12 h. Saturated brine (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (40 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (0% to 4%) to give a product as a yellow oil (0.26 g, 80%). MS (ESI) m / z 410.72 [M+H] + .

[0424] Steps 2-5:

[0425] Following the synthesis of Example 1, steps 2-5 were performed to give Example 18, which is a white solid at 17.4 mg. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.56(s,1H),8.10(s,1H),7.37(dd,J=8.5,5.7Hz,2H),7.13(t,J=8.9Hz,2H),4.39-4.33(m,2H),4.27(t,J=12.0Hz,2H),4.09(d, J=10.6Hz,1H),3.87(d,J=10.6Hz,1H),3.80(d,J=16.6Hz,1H),3.60(d,J=16.5Hz,1H),3.51-3.43(m,2H),3.14(t,J=9.8Hz,1H),2.94(d, J=9.0Hz,1H),2.85(ddd,J=26.9,19.3,11.6Hz,3H),2.71(d,J=9.5Hz,1H),2.60(d,J=8.6Hz,2H),2.43(t,J=10.9Hz,1H),2.28(t,J=11.0 Hz, 1H), 2.13 (s, 1H), 1.90 (t, J = 9.4Hz, 1H), 1.74 (d, J = 12.0Hz, 1H), 1.54 (d, J = 17.0Hz, 6H), 1.34 (t, J = 7.1Hz, 3H), 0.88 (t, J = 6.7Hz, 6H). MS(ESI)m / z 621.44[M+H] + .

[0426] Example 19: 1-(4-(4-fluorobenzyl)-2-(hydroxymethyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 19)

[0427]

[0428] Example 18 (0.047 g, 0.076 mmol, 1.0 equivalent) was dissolved in THF (10 mL) under argon atmosphere to give a solution. The reaction mixture was cooled to 0 °C in an ice / water bath. LiBH4 (3.30 mg, 0.151 mmol, 2.0 equivalent) was added to the reaction mixture in a single addition. The reaction mixture was stirred at room temperature for 4 h. Saturated NH4Cl (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give a product as a white solid (8.0 mg, 18.26%). 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.56(s,1H),8.10(s,1H),7.37(dd,J=8.5,5.7Hz,2H),7.13(t,J=8.9Hz,2H),4.39-4.33(m,2H),4.27(t,J=12.0Hz,2H),4.09(d,J=10.6 Hz,1H),3.87(d,J=10.6Hz,1H),3.80(d,J=16.6Hz,1H),3.60(d,J=16.5Hz,1H),3.51-3.43(m,2H),3.14(t,J=9.8Hz,1H),2.94(d,J=9.0Hz,1H), 2.85(ddd,J=26.9,19.3,11.6Hz,3H),2.71(d,J=9.5Hz,1H),2.60(d,J=8.6Hz,2H),2.43(t,J=10.9Hz,1H),2.28(t,J=11.0Hz,1H),2.13(s,1H), 1.99(dd,J=14.7,7.1Hz,1H), 1.90(t,J=9.4Hz,1H), 1.74(d,J=12.0Hz,1H), 1.54(d,J=17.0Hz,6H), 1.34(t,J=7.1Hz,3H), 0.88(t,J=6.7Hz,6H). MS(ESI)m / z579.40[M+H] + .

[0429] Example 20: 4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-2-carboxamide (Compound 20)

[0430]

[0431] Step 1: Under argon atmosphere, ethyl 6-(2-((2S,5R)-4-(tert-butoxycarbonyl)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-2-carboxylate (0.06 g, 0.083 mmol, 1.0 equivalent) was dissolved in MeOH (4 mL) and ammonium hydroxide (2 mL) to give a yellow solution. The reaction mixture was stirred at 30 °C for 16 h. Saturated NaCl (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (40 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (0% to 8%) to give a product as a yellow oil (0.04 g, 69.5%). MS (ESI) m / z 692.58 [M+H] + .

[0432] Step 2: Under argon atmosphere, tert-butyl(2R,5S)-4-(2-(2-carbamoyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (0.04 g, 0.058 mmol, 1.0 equivalent) was dissolved in DCM (4.00 mL) and TFA (2 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 h. Saturated NaHCO3 (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (40 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give a product as a white solid (13.9 mg, 40.6%). 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.56(s,1H),8.10(s,1H),7.37(dd,J=8.5,5.7Hz,2H),7.13(t,J=8.9Hz,2H),4.39-4.33(m,2H),4.27(t,J=12.0Hz,2H),4.09(d, J=10.6Hz,1H),3.87(d,J=10.6Hz,1H),3.80(d,J=16.6Hz,1H),3.60(d,J=16.5Hz,1H),3.51-3.43(m,2H),3.14(t,J=9.8Hz,1H),2.94(d, J=9.0Hz,1H),2.85(ddd,J=26.9,19.3,11.6Hz,3H),2.71(d,J=9.5Hz,1H),2.60(d,J=8.6Hz,2H),2.43(t,J=10.9Hz,1H),2.28(t,J=11.0 Hz, 1H), 2.13 (s, 1H), 1.90 (t, J = 9.4Hz, 1H), 1.74 (d, J = 12.0Hz, 1H), 1.54 (d, J = 17.0Hz, 6H), 1.34 (t, J = 7.1Hz, 3H), 0.88 (t, J = 6.7Hz, 6H). MS(ESI)m / z 592.42[M+H] + .

[0433] Example 21: 4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-2-carboxynitrile (Compound 21)

[0434]

[0435] Step 1: Under argon atmosphere, tert-butyl(2R,5S)-4-(2-(2-carbamoyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (0.044 g, 0.064 mmol, 1.0 equivalent), pyridine (0.013 g, 0.159 mmol, 2.5 equivalent), and TFAA (0.033 g, 0.159 mmol, 2.5 equivalent) were dissolved in DCM (5 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 3 h. Saturated NaHCO3 (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (0% to 8%) to give a product as a yellow oil (0.034 g, 79%). MS (ESI) m / z 674.79 [M+H] + .

[0436] Step 2: Under argon atmosphere, tert-butyl(2R,5S)-4-(2-(2-cyano-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (0.034 g, 0.050 mmol, 1.0 equivalent) was dissolved in DCM (4 mL) and TFA (2 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 h. Saturated NaHCO3 (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (40 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give a product as a white solid (13.2 mg, 45.6%). 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.56(s,1H),8.10(s,1H),7.37(dd,J=8.5,5.7Hz,2H),7.13(t,J=8.9Hz,2H),4.39-4 .33(m,2H),4.27(t,J=12.0Hz,2H),4.09(d,J=10.6Hz,1H),3.87(d,J=10.6Hz,1H),3.80(d,J=

[0437] 16.6Hz,1H),3.60(d,J=16.5Hz,1H),3.51-3.43(m,2H),3.14(t,J=9.8Hz,1H),2.94(d,J=9.0Hz,1 H),2.85(ddd,J=26.9,19.3,11.6Hz,3H),2.71(d,J=9.5Hz,1H),2.60(d,J=8.6Hz,2H),2.43(t,J= 10.9Hz,1H),2.28(t,J=11.0Hz,1H),2.13(s,1H),1.99(dd,J=14.7,7.1Hz,1H),1.90(t,J=9.4Hz, 1H), 1.74 (d, J = 12.0Hz, 1H), 1.54 (d, J = 17.0Hz, 6H), 1.34 (t, J = 7.1Hz, 3H), 0.88 (t, J = 6.7Hz, 6H). MS(ESI)m / z

[0438] 574.40 [M+H] + .

[0439] Example 22: 1-(5-(4-fluorobenzyl)-9,9-dimethyl-3-(trifluoromethyl)-8,9-dihydro-7H-pyrrolo[3,2-c][1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 22)

[0440]

[0441] Step 1: 2,6-Dibromo-3-iodopyridine-4-amine

[0442]

[0443] 2,6-Dibromopyridin-4-amine (4.8 g, 1.0 equivalent) was dissolved in DCM (35 mL) and acetic acid (35 mL). The mixture was then cooled to 0 °C, and NIS (4.3 g, 1.0 equivalent) was added in portions. The reaction was stirred at room temperature under N2 for 12 h. TLC indicated that the starting material was consumed. The reaction mixture was quenched by adding an aqueous solution of NaHCO3 and then extracted with EA (200 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2,6-dibromo-3-iodopyridin-4-amine (5.04 g, 70%), LCMS: [M+H]. + =376 / 378.

[0444] Step 2: 2,6-Dibromo-3-iodo-N-(2-methylallyl)pyridine-4-amine

[0445]

[0446] Potassium tert-butoxide (3.3 g, 1.2 equivalents) was added to a solution of 2,6-dibromo-3-iodopyridin-4-amine (9.298 g, 1.0 equivalents) in dry THF (47 mL) at 0 °C. 3-Bromo-2-methylpropene (3.98 g, 1.2 equivalents) was added while the mixture was heated to 25 °C. The reaction was stirred overnight at room temperature. TLC indicated that the starting material was consumed. The reaction mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The residue was purified by silica gel column chromatography to give 2,6-dibromo-3-iodo-N-(2-methylallyl)pyridin-4-amine (6.36 g, 60%). LCMS: [M+H] + =431 / 433.

[0447] Step 3: 4,6-Dibromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine

[0448]

[0449] To a stirred solution of 2,6-dibromo-3-iodo-N-(2-methylallyl)pyridin-4-amine (6.6 g, 1.0 equivalent) in toluene (132 mL) and H₂O (6.6 mL), TBAC (5.11 g, 1.2 equivalent), sodium acetate (1.56 g, 1.5 equivalent), Pd(OAc)₂ (0.34 g, 0.1 equivalent), and TEA (4.64 g, 3.0 equivalent) were added. The mixture was purged with nitrogen and heated to 100 °C for 15 h. TLC showed the reaction was complete. The reaction mixture was diluted with saturated aqueous NaHCO₃ and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO₄. The residue was purified by silica gel column chromatography to give the desired product (2.3 g, 50%). LCMS: [M+H] + =305 / 307.

[0450] Step 4: tert-butyl 4,6-dibromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

[0451]

[0452] Boc₂O (6.58 g, 4.0 equivalent) and DMAP (1.38 g, 1.5 equivalent) were added to a solution of 4,6-dibromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (2.3 g, 1.0 equivalent) in THF (40 mL). The reaction mixture was stirred at 60 °C for 15 h. TLC showed that the starting material was completely consumed. The reaction mixture was then concentrated under reduced pressure and the resulting residue was purified by rapid silica gel chromatography. The desired product (2.754 g, 90%) was obtained as a yellow foam. LCMS: [M+H] + =405 / 407.

[0453] Step 5: tert-butyl-4-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

[0454]

[0455] A vial was filled with tert-butyl-4,6-dibromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (2.1 g, 5.19 mmol), potassium 4-fluorobenzyl-trifluoroborate (1.68 g, 7.78 mmol) (CAS: 1494466-28-2), Pd(dppf)Cl2 (190 mg, 0.26 mmol), Cs2CO3 (6.77 g, 20.8 mmol), and toluene / H2O (200 mL). The mixture was purged with nitrogen and heated to 75 °C for 12 h. TLC showed the reaction was complete. The mixture was diluted with 100 mL H2O and extracted with ethyl acetate, and dried over sodium sulfate. The solvent was removed by fungal treatment to give the desired product (680 mg, 30%). LCMS: [M+H] + =435.1. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)7.34-7.27(m,2H),7.18-7.10(m,2H),4.00(s,2H),3.70(s,2H),1.44(s,9H),1.40(s,6H).

[0456] Step 6: tert-butyl-4-(2-acetylhydrazyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

[0457]

[0458] Under a nitrogen atmosphere, a mixture of the intermediate obtained above (200 mg, 0.46 mmol), acetylhydrazine (136 mg, 1.84 mmol), Pd2(dba)3 (42.2 mg, 0.046 mmol), BINAP (57.3 mg, 0.092 mmol), and sodium tert-butoxide (88.4 mg, 0.92 mmol) in 1,4-dioxane (10 mL) was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over Na2SO4, and concentrated to give a crude product. The crude product was purified by silica gel chromatography to obtain the desired product (100 mg, 51%). LCMS: [M+H] + =429.26. 1 ¹H NMR (400MHz, chloroform-d) δ (ppm) 7.20-7.13 (m, 2H), 6.95 (m, 2H), 6.83 (s, 1H), 3.93 (s, 2H), 3.69 (s, 2H), 1.98 (s, 3H), 1.48 (s, 9H), 1.44 (s, 6H).

[0459] Step 7: tert-butyl 5-(4-fluorobenzyl)-9,9-dimethyl-3-(trifluoromethyl)-8,9-dihydro-7H-pyrrolo[3,2-c][1,2,4]triazolo[4,3-a]pyridine-7-carboxylate

[0460]

[0461] Trifluoroacetic anhydride (2 mL) was added to a solution of the intermediate obtained above (100 mg, 0.234 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature for 5 h, and then concentrated. The crude product was purified by silica gel chromatography to obtain the desired product (30 mg, 26%). LCMS: [M+H] + =465.22. 1 ¹H NMR (400MHz, chloroform-d) δ (ppm) 7.24-7.17 (m, 2H), 7.11 (m, 2H), 4.34 (s, 2H), 3.85 (s, 2H), 1.65 (s, 9H), 1.59 (s, 6H).

[0462] Step 8: 5-(4-fluorobenzyl)-9,9-dimethyl-3-(trifluoromethyl)-8,9-dihydro-7H-pyrrolo[3,2-c][1,2,4]triazolo[4,3-a]pyridine

[0463]

[0464] The compound obtained above (30 mg, 0.062 mmol) was stirred at 0 °C for 1 h in hydrogen chloride (4 M solution, dioxane). The solvent was removed to give the title compound (15 mg, crude product), LCMS: [M+H]. + =365.22.

[0465] Steps 9-11: 1-(5-(4-fluorobenzyl)-9,9-dimethyl-3-(trifluoromethyl)-8,9-dihydro-7H-pyrrolo[3,2-c][1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetoone

[0466]

[0467] At 0°C, DIPEA (2.0 equivalents) and 2-chloroacetyl chloride (1.5 equivalents) were added to a solution of the above-obtained compound (15 mg, crude product) in DCM. After stirring for 1.5 h, water was added to the residue, and the mixture was extracted with DCM. The solvent was removed under vacuum to give the crude product, which was used directly in the next step. At 25°C, a mixture of K₂CO₃ (2.0 equivalents), KI (1.5 equivalents), and tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate II (1.2 equivalents) was added to a solution of the above crude product. The reaction was stirred at room temperature for 1 h. LC-MS indicated that the starting material was completely consumed and new peaks were formed.

[0468] ([M+H)) + =718.23). The reaction mixture was quenched by adding water, then extracted with EA, washed with brine, dried (Na2SO4), and concentrated under reduced pressure to give the residue, which was dissolved in 4M HCl / dioxane. The mixture was stirred at room temperature for 1 h. UPLC-MS indicated the formation of a new main peak with the desired MS, which was then quenched with water and purified by preparative HPLC (20% to 50% acetonitrile, 45 mL / min over 30 min). After lyophilization, the desired product was given as a white solid (3 steps, 40% yield). LCMS: [M+H] + =618.23. 1H NMR (400MHz, methanol-d4) δ (ppm) 7.50 (s, 1H), 7.43 (dd, J = 8.3, 5.2Hz, 2H), 7.22 (t, J = 8.6Hz, 2H), 4.44 (s, 2H), 4.17 (d, J = 10.5Hz ,1H),4.07(d,J=10.0Hz,2H),3.91(m,3H),3.71-3.36(m,7H),3.23-2.87(m,5H),1.69(d,J=9.0Hz,6H),1.44-1.24(m,6H).

[0469] Example 23: 1-(5-(4-fluorobenzyl)-9,9-dimethyl-8,9-dihydro-7H-pyrrolo[3,2-c][1,2,4]triazolo[4,3-a]pyridin-7-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 23)

[0470]

[0471] Step 1: tert-butyl 6-(4-fluorobenzyl)-4-(2-formylhydrazyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

[0472]

[0473] Under a nitrogen atmosphere, a mixture of tert-butyl-4-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (30 mg, 0.069 mmol), formyl hydrazide (16.6 mg, 0.276 mmol), Pd2(dba)3 (6.33 mg, 0.0069 mmol), BINAP (7.64 mg, 0.0138 mmol), and sodium tert-butoxide (13.2 mg, 0.138 mmol) in 1,4-dioxane (10 mL) was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over Na2SO4, and concentrated to give a crude product, which was purified by silica gel chromatography to obtain the desired product (5 mg, 17%). LCMS: [M+H] + =415.16.

[0474] Step 2: tert-butyl 5-(4-fluorobenzyl)-9,9-dimethyl-8,9-dihydro-7H-pyrrolo[3,2-c][1,2,4]triazolo[4,3-a]pyridine-7-carboxylate

[0475]

[0476] The mixture of the above-obtained compound (5 mg, 0.012 mmol), p-toluenesulfonic acid (1 mg), and toluene (2 mL) was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature and concentrated to give a crude product, which was purified by silica gel chromatography to obtain the desired product (5 mg, 100%). LCMS: [M+H] + =397.31.

[0477] The following steps:

[0478]

[0479] Following the synthesis in Example 22, the desired product, a white solid, was obtained after lyophilization. LCMS: [M+H] + =550.31. 1 ¹H NMR (400MHz, methanol-d⁴) δ (ppm) 9.59 (s, 1H), 7.71 (s, 1H), 7.46 (dd, J = 8.3, 5.2Hz, 2H), 7.23 (t, J = 8.5Hz, 2H), 4.53 (s, 2H), 4.30–4.09 (m, 3H), 4.01 (m, 3H), 3.64 (m, 6H), 3.10 (m, 5H), 1.67 (m, 6H), 1.39 (m, 6H).

[0480] Example 24: 1-(5-(4-fluorobenzyl)-9,9-dimethyl-8,9-dihydro-7H-imidazo[1,2-a]pyrrolo[3,2-c]pyridin-7-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 24)

[0481]

[0482]

[0483] Step 1: tert-butyl 6-(4-fluorobenzyl)-4-((4-methoxybenzyl)amino)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

[0484]

[0485] Under a nitrogen atmosphere, a mixture of tert-butyl-4-bromo-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (200 mg, 0.46 mmol), 4-methoxybenzylamine (126 mg, 0.92 mmol), Pd2(dba)3 (42.2 mg, 0.046 mmol), BINAP (57.3 mg, 0.092 mmol), and sodium tert-butoxide (88.4 mg, 0.92 mmol) in 1,4-dioxane (10 mL) was stirred at 100 °C for 12 h. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over Na2SO4, and concentrated to give a crude product, which was purified by silica gel chromatography to obtain the desired product (90 mg, 40%). LCMS: [M+H] + =492.28. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)7.21-7.11(m,4H),6.96(t,J=8.7Hz,2H),6.82-6.75(m,2H),6.04(t,J=6.1Hz,1 H), 4.50 (d, J = 6.0Hz, 2H), 3.70 (d, J = 2.7Hz, 5H), 3.55 (s, 2H), 1.41 (s, 9H), 1.32 (s, 6H).

[0486] Step 2: tert-butyl-4-amino-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

[0487]

[0488] DDQ (83.1 mg, 0.366 mmol) was added to a solution of the above-obtained compound (90 mg, 0.183 mmol) in DCM / H₂O (2 mL / 0.2 mL). The resulting mixture was stirred at room temperature for 2 h and quenched with saturated NaHCO₃. The layers were separated, and the aqueous layer was extracted with DCM (15 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give a crude product, which was purified by silica gel chromatography to obtain the desired product (60 mg, 88%). LCMS: [M+H] + =372.32.

[0489] Step 3: tert-butyl 5-(4-fluorobenzyl)-9,9-dimethyl-8,9-dihydro-7H-imidazo[1,2-a]pyrrolo[3,2-c]pyridine-7-carboxylate

[0490]

[0491] 3-Chloropropanol (40% aqueous solution) (74.5 mg, 0.324 mmol) was added to a mixture of the above-obtained compound (60 mg, 0.162 mmol) and NaHCO3 (16.3 mg, 0.194 mmol) in ethanol / H2O (5 mL / 5 mL). The resulting mixture was stirred at 80 °C for 12 h and diluted with H2O (20 mL). The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give a crude product, which was purified by silica gel chromatography to obtain the desired product (35 mg, 55%). LCMS: [M+H] + =396.30. 1 ¹H NMR (400MHz, chloroform-d) δ (ppm) 7.78-7.39 (m, 2H), 7.24-7.13 (m, 2H), 7.10-6.91 (m, 2H), 4.19 (s, 2H), 3.82 (s, 2H), 1.69-1.31 (m, 15H).

[0492] The following steps:

[0493]

[0494] Following the synthesis of Example 22, the desired product, Example 24, was obtained as a white solid after lyophilization. LCMS:

[0495] [M+H] + =549.3. 1 H NMR (400MHz, methanol-d4) δ (ppm) 8.30 (d, J = 2.4Hz, 1H), 8.09 (d, J = 2.4Hz, 1H), 7.85 (s, 1H), 7.42 (dd, J = 8.4, 5.3Hz, 2 H),7.20(t,J=8.5Hz,2H),4.49(s,2H),4.26-4.10(m,4H),3.64(m,6H),3.10(m,5H),1.64(m,6H),1.33(m,6H).

[0496] Example 25: 1-(5-(4-fluorobenzyl)-9,9-dimethyl-8,9-dihydro-7H-pyrrolo[3,2-c][1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 25)

[0497]

[0498] Step 1: tert-butyl(E)-6-(4-fluorobenzyl)-4-(N'-hydroxyformamidinium)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

[0499]

[0500] DMF-DMA (32 mg, 0.27 mmol) was added to a stirred solution of tert-butyl-4-amino-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (50 mg, 0.135 mmol) in DMF (5 mL). The reaction mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. After completion, the reaction was cooled to 50 °C and hydroxylamine hydrochloride (18.6 mg, 0.27 mmol) was added. The mixture was continuously stirred overnight and diluted with H₂O (20 mL). The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na₂SO₄, filtered, and concentrated to give a crude product, which was purified by silica gel chromatography to obtain the desired product (50 mg, 89%). LCMS: [M+H] + =415.30.

[0501] Step 2: tert-butyl 5-(4-fluorobenzyl)-9,9-dimethyl-8,9-dihydro-7H-pyrrolo[3,2-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxylate

[0502]

[0503] Trifluoroacetic anhydride (0.5 mL) was added to a solution of the above-obtained compound (50 mg, 0.121 mmol) in THF (5 mL). The resulting mixture was stirred at room temperature for 3 h and then quenched with saturated NaHCO3. The layers were separated, and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give a crude product, which was purified by silica gel chromatography to obtain the desired product (30 mg, 62%). LCMS: [M+H] + =397.30. 1 ¹H NMR (600MHz, chloroform-d) δ (ppm) 8.19 (s, 1H), 7.26 (t, J = 6.9Hz, 2H), 7.00-6.88 (m, 2H), 4.35 (s, 2H), 3.77 (s, 2H), 1.55-1.27 (m, 15H).

[0504] The following steps:

[0505] Following the synthesis of Example 22, the desired product, Example 25, was obtained as a white solid after lyophilization. LCMS: [M+H] + =550.30. 1 H NMR (400MHz, methanol-d4) δ (ppm) 8.49 (s, 1H), 7.62 (s, 1H), 7.36 (dd, J = 8.4, 5.4Hz, 2H), 7.09 (t, J = 8.7Hz, 2H), 4.48 (d, J = 3 .2Hz,2H),4.11-3.98(m,4H),3.92(m,3H),3.69-3.39(m,6H),3.18-2.79(m,5H),1.57(d,J=5.3Hz,6H),1.28(m,6H).

[0506] Example 26: 1-(5-(4-fluorobenzyl)-9,9-dimethyl-8,9-dihydro-7H-pyrrolo[3,2-f]quinoxalin-7-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 26)

[0507]

[0508] Step 1: 3-Bromo-5-nitrobenzene-1,2-diamine

[0509]

[0510] NH4Cl (12.2 g, 1.0 equivalent) was added to a solution of 2-bromo-4,6-dinitroaniline (60 g, 1.0 equivalent) in EtOH (240 mL) and H2O (60 mL). Simultaneously, a mixture of Na2S (55 g, 1.0 equivalent) and sulfur powder (7.4 g, 1.0 equivalent) in EtOH (240 mL) and H2O (60 mL) was added to the above solution of 2-bromo-4,6-dinitroaniline at 25 °C. The mixture was heated at 65 °C for 0.5 h, and then NaOH (2 mol / L, 270 mL) was slowly added to the mixture while stirring for 30 min. The reaction was allowed to cool, and 2 M HCl aqueous solution (270 mL) was slowly added dropwise. The mixture was partitioned between ethyl acetate and water, the organic extract was dried over Na2SO4, concentrated, and the residue (LCMS: [M+H)) was collected. + =232 / 234) can be used directly in the next step without further purification.

[0511] Step 2: 5-Bromo-7-nitroquinoxaline

[0512]

[0513] Glyoxal (63.5 g, 1.9 equivalent, 40% aqueous solution) was added to a solution of the intermediate obtained above (48 g, 1.0 equivalent) in H2O (1500 mL), and the mixture was stirred at 100 °C for 4 h. TLC (PE:EA = 1:1) indicated that the starting material was completely consumed and new spots were formed. The reaction was allowed to cool and the solid was filtered to give the desired compound (53 g, crude) as a yellow solid. LCMS: [M+H] + =254 / 256.

[0514] Step 3: 8-Bromoquinoxaloline-6-amine

[0515]

[0516] Ammonia solution (31 g, 10 equivalents) was added to a solution of the intermediate obtained above (15 g, 1.0 equivalents) in EtOH (150 mL) and H2O (50 mL). Iron powder (33 g, 10 equivalents) was added in portions, and the mixture was stirred at 90 °C for 2–3 h, then diluted with H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (6.8 g, 51%) as a brown solid. LCMS: [M+H] + =224 / 226.

[0517] Step 4: 8-(4-fluorobenzyl)quinoxaline-6-amine

[0518]

[0519] Pd(dppf)Cl2 (1.0 g, 0.1 equivalent) was added to a solution of the intermediate obtained above (3 g, 1.0 equivalent), potassium 4-fluorobenzyl-trifluoroborate (8 g, 2.5 equivalent) (CAS: 1494466-28-2), and Cs2CO3 (10.9 g, 2.5 equivalent) in dioxane / H2O (50 mL / 10 mL). The mixture was degassed by vacuum and refilled with nitrogen (x3), and then heated at 100 °C for 3 h. The reaction was allowed to cool, and then partitioned between ethyl acetate and water. The phases were separated, and then MgSO4 was added. The solid was filtered, and then the filtrate was evaporated. The resulting residue was redissolved in a minimal amount of dichloromethane and then purified by rapid column chromatography (on a silica column) to give the desired compound (1.3 g, 38%), LCMS: [M+H]. + =254.12.

[0520] Step 5: 8-(4-fluorobenzyl)-5-iodoquinoxaline-6-amine

[0521]

[0522] The compound obtained above (1.3 g, 1.0 equivalent) was dissolved in DCM (20 mL) and acetic acid (20 mL). The mixture was then cooled to 0 °C, and NIS (1.4 g, 2.2 equivalent) was added in portions. The reaction was stirred at room temperature under N2 for 12 h. TLC indicated that the starting material was consumed. The reaction mixture was quenched by adding an aqueous solution of NaHCO3 and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound (1.1 g, 55%), LCMS: [M+H]. + =380.2.

[0523] Step 6: 8-(4-fluorobenzyl)-5-iodo-N-(2-methylallyl)quinoxaline-6-amine

[0524]

[0525] Potassium tert-butoxide (0.68 g, 2.0 equivalent) was added to a solution of the intermediate obtained above (1.1 g, 1.0 equivalent) in dry THF (20 mL) at 0 °C. 3-Bromo-2-methylpropene (0.45 g, 1.1 equivalent) was added while the mixture was heated to 70 °C. The reaction mixture was stirred overnight at 70 °C. TLC indicated that the starting material was consumed. The reaction mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The residue was purified by silica gel column chromatography to give the desired compound (0.3 g, 23%), LCMS: [M+H]. + =434.

[0526] Step 7: 5-(4-fluorobenzyl)-9,9-dimethyl-8,9-dihydro-7H-pyrrolo[3,2-f]quinoxaline

[0527]

[0528] To a stirred solution of the above-obtained compound (0.3 g, 1.0 equivalent) in toluene (10 mL) and H₂O (0.5 mL), TBAC (0.238 g, 1.2 equivalent), sodium acetate (0.073 g, 1.5 equivalent), Pd(OAc)₂ (0.016 g, 0.1 equivalent), and TEA (0.217 g, 3.0 equivalent) were added. The mixture was purged with nitrogen and heated to 100 °C for 15 h. TLC showed the reaction was complete. The reaction mixture was diluted with saturated aqueous NaHCO₃ solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO₄. The residue was purified by preparative HPLC to give the desired compound (20 mg, 10%), LCMS: [M+H]. + =308.2.

[0529] The following steps:

[0530] Following the synthesis of Example 22, the desired product, Example 26, was obtained as a white solid after lyophilization. LCMS:

[0531] [M+H] + =560.2. 1 H NMR (600MHz, methanol-d4) δ (ppm) 8.87 (d, J = 1.8Hz, 1H), 8.83 (d, J = 1.8Hz, 1H), 8.43 (s, 1H), 7.36-7.21 (m, 2H), 7.08-6.98 (m, 2H), 4.69 (d, J=15.8Hz,1H),4.58(d,J=15.9Hz,1H),4.17-4.03(m,3H),3.69(m,2H),3.62-3.55(m,2H),1.75(d,J=13.9Hz,6H),1.33-1.28(m,6H).

[0532] Example 27: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-thiazo[5,4-e]indole-6-

[0533] 2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 27)

[0534]

[0535]

[0536] Step 1: 4-Bromo-6-nitrobenzo[d]thiazole

[0537]

[0538] NBS (9.2 g, 1.2 equivalent) was added in portions to a solution of 6-nitrobenzo[d]thiazole (7.7 g, 1.0 equivalent) in concentrated H₂SO₄ (70 mL) at 10 °C. The reaction mixture was stirred at 60 °C for 12 h. TLC showed that the starting material was completely consumed and new spots were formed. The reaction mixture was slowly poured into ice water, then extracted with ethyl acetate, washed with saturated brine, dried over Na₂SO₄, and concentrated under reduced pressure to give the residue, which was purified by silica gel rapid chromatography to give the desired compound (7 g, 63%), LCMS: [M+H]. + =259 / 261.

[0539] Step 2: 4-Bromobenzo[d]thiazol-6-amine

[0540]

[0541] Ammonia solution (6.3 g, 10 equivalents) was added to a solution of the above-obtained compound (3 g, 1.0 equivalents) in EtOH (60 mL) and H₂O (20 mL). Iron powder (6.5 g, 10 equivalents) was added in portions, and the mixture was stirred at 90 °C for 2–3 h, then diluted with H₂O and extracted with ethyl acetate. The organic matter was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (2.4 g, 90%) as a brown solid. LCMS: [M+H] + =229 / 231.

[0542] Step 3: 4-(4-fluorobenzyl)benzo[d]thiazol-6-amine

[0543]

[0544] Pd(dppf)Cl2 (0.8 g, 0.1 equivalent) was added to a solution of the above-obtained compound (2.4 g, 1.0 equivalent), potassium 4-fluorobenzyl-trifluoroborate (6.3 g, 2.5 equivalent) (CAS: 1494466-28-2), and Cs2CO3 (8.6 g, 2.5 equivalent) in dioxane / H2O (50 mL / 10 mL). The mixture was degassed by vacuum and refilled with nitrogen (x3), then heated at 100 °C for 3 h. The reaction was allowed to cool, and then partitioned between EtOAc and water. The phases were separated, and then MgSO4 was added. The solid was filtered, and then the filtrate was evaporated. The resulting residue was redissolved in a minimal amount of dichloromethane and then purified by rapid column chromatography (on a silica column) to give the desired compound (1.85 g, 77%), LCMS: [M+H]. + =259.

[0545] Step 4: 4-(4-fluorobenzyl)-7-iodobenzo[d]thiazol-6-amine

[0546]

[0547] The compound obtained above (1.87 g, 1.0 equivalent) was dissolved in DCM (20 mL) and acetic acid (20 mL). The mixture was then cooled to 0 °C, and NIS (1.63 g, 1.0 equivalent) was added in portions. The reaction was stirred at room temperature under N2 for 12 h. TLC indicated that the starting material was consumed. The reaction mixture was quenched by adding an aqueous solution of NaHCO3 and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound (2.08 g, 74%), LCMS: [M+H]. + =385.2.

[0548] Step 5: 4-(4-fluorobenzyl)-7-iodo-N-(2-methylallyl)benzo[d]thiazol-6-amine

[0549]

[0550] Potassium tert-butoxide (0.234 g, 2.0 equivalent) and KI (0.037 g, 0.2 equivalent) were added to a solution of the above-obtained compound (0.4 g, 1.0 equivalent) in dry THF (20 mL) at 0 °C. 3-Bromo-2-methylpropene (0.142 g, 1.1 equivalent) was added while simultaneously raising the temperature of the mixture to 70 °C. The reaction was stirred overnight at 70 °C. TLC indicated that the starting material was consumed. The reaction mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The residue was purified by silica gel column chromatography to give the desired compound (0.34 g, 23%), LCMS: [M+H]. + =439.

[0551] Step 6: 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-thiazo[5,4-e]indole

[0552]

[0553] To a stirred solution of the above-obtained compound (0.339 g, 1.0 equivalent) in toluene (10 mL) and H₂O (0.5 mL), TBAC (0.258 g, 1.2 equivalent), sodium acetate (0.079 g, 1.5 equivalent), Pd(OAc)₂ (0.018 g, 0.1 equivalent), and TEA (0.235 g, 3.0 equivalent) were added. The mixture was purged with nitrogen and heated to 100 °C for 15 h. TLC showed the reaction was complete. The reaction mixture was diluted with saturated aqueous NaHCO₃ solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO₄. The residue was purified by preparative HPLC to give the desired compound (20 mg, 16%), LCMS: [M+H]. + =313.2.

[0554] The following steps:

[0555] Following the synthesis of Example 22, the desired product, Example 27, was obtained as a white solid after lyophilization. LCMS:

[0556] [M+H] + =566.2. 1 H NMR (400MHz, methanol-d4) δ (ppm) 9.23 (s, 1H), 8.16 (s, 1H), 7.38-7.28 (m, 2H), 7.06 (t, J = 8.7Hz, 2H), 4.70-4.44 (m, 2H), 4.09 (m, 6H), 3 .68(m,3H),3.45(m,3H),3.24(m,2H),3.08(m,2H),2.21(t,J=7.6Hz,1H),2.05(m,2H),1.57(d,J=6.1Hz,6H), 1.34-1.30(m,6H).

[0557] Example 28: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-thiazo[4,5-e]indole-6-

[0558] 2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 28)

[0559]

[0560] Step 1: 7-Bromo-5-nitrobenzo[d]thiazole

[0561]

[0562] NBS (7.3 g, 1.2 equivalent) was added in portions to a solution of 5-nitrobenzo[d]thiazole (5.0 g, 1.0 equivalent) in concentrated H₂SO₄ (50 mL) at 10 °C. The reaction mixture was stirred at 60 °C for 12 h. TLC showed that the starting material was completely consumed and new spots were formed. The reaction mixture was slowly poured into ice water, then extracted with ethyl acetate, washed with saturated brine, dried over Na₂SO₄, and concentrated under reduced pressure to give the residue, which was purified by silica gel rapid chromatography to give the desired compound (5 g, 70%), LCMS: [M+H]. + =259 / 261.

[0563] Step 2: 7-(4-fluorobenzyl)-5-nitrobenzo[d]thiazole

[0564]

[0565] Pd(dppf)Cl2 (0.82 g, 0.1 equivalent) was added to a solution of the above-obtained compound (2.9 g, 1.0 equivalent), potassium 4-fluorobenzyl-trifluoroborate (6.6 g, 2.5 equivalent) (CAS: 1494466-28-2), and Cs2CO3 (9.2 g, 2.5 equivalent) in dioxane / H2O (50 mL / 10 mL). The mixture was degassed by vacuum and refilled with nitrogen (x3), then heated at 100 °C for 3 h. The reaction was allowed to cool, and then partitioned between ethyl acetate and water. The phases were separated, and then MgSO4 was added. The solid was filtered, and then the filtrate was evaporated. The resulting residue was redissolved in a minimal amount of dichloromethane and then purified by rapid column chromatography (on a silica column) to give the desired compound (1.0 g, 30%), LCMS: [M+H]. + =289.

[0566] Step 3: 7-(4-fluorobenzyl)benzo[d]thiazol-5-amine

[0567]

[0568] Ammonia solution (3.8 g, 10 equivalents) was added to a solution of the above-obtained compound (2 g, 1.0 equivalents) in EtOH (60 mL) and H2O (20 mL). Iron powder (3.9 g, 10 equivalents) was added in portions, and the mixture was stirred at 90 °C for 2–3 h, then diluted with H2O and extracted with ethyl acetate. The organic matter was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.1 g, 62%) as a brown solid. LCMS: [M+H] + =259.

[0569] Step 4: 7-(4-fluorobenzyl)-4-iodobenzo[d]thiazol-5-amine

[0570]

[0571] The compound obtained above (0.87 g, 1.0 equivalent) was dissolved in DCM (10 mL) and acetic acid (10 mL). The mixture was then cooled to 0 °C, and NIS (0.68 g, 1.0 equivalent) was added in portions. The reaction was stirred at room temperature under N2 for 12 h. TLC indicated that the starting material was consumed. The reaction mixture was quenched by adding an aqueous solution of NaHCO3 and then extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the desired compound (0.65 g, 56%), LCMS: [M+H]. + =385.2.

[0572] Step 5: 7-(4-fluorobenzyl)-4-iodo-N-(2-methylallyl)benzo[d]thiazol-5-amine

[0573]

[0574] Potassium tert-butoxide (0.382 g, 2.0 equivalent) and KI (0.057 g, 0.2 equivalent) were added to a solution of the above-obtained compound (0.65 g, 1.0 equivalent) in dry THF (20 mL) at 0 °C. 3-Bromo-2-methylpropene (0.276 g, 1.1 equivalent) was added while simultaneously raising the temperature of the mixture to 70 °C. The reaction was stirred overnight at 70 °C. TLC indicated that the starting material was consumed. The reaction mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The residue was purified by silica gel column chromatography to give the desired compound (0.1 g, 13%), LCMS: [M+H]. + =439.

[0575] Step 6: 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-thiazo[4,5-e]indole

[0576]

[0577] To a stirred solution of compound 7 (0.168 g, 1.0 equivalent) in toluene (10 mL) and H₂O (0.5 mL), TBAC (0.128 g, 1.2 equivalent), sodium acetate (0.04 g, 1.5 equivalent), Pd(OAc)₂ (0.01 g, 0.1 equivalent), and TEA (0.117 g, 3.0 equivalent) were added. The mixture was purged with nitrogen and heated to 100 °C for 15 h. TLC showed the reaction was complete. The reaction mixture was diluted with saturated aqueous NaHCO₃ and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO₄. The residue was purified by preparative HPLC to give the desired compound (20 mg, 16%), LCMS: [M+H]. + =313.2. 1 ¹H NMR (400MHz, chloroform-d) δ (ppm) 8.94 (s, 1H), 7.22 (dd, J = 8.5, 5.5Hz, 2H), 7.00 (t, J = 8.7Hz, 2H), 6.64 (s, 1H), 4.11 (s, 2H), 3.45 (s, 2H), 1.61 (s, 6H).

[0578] The following steps:

[0579] Following the synthesis of Example 22, the desired product, Example 28, was obtained as a white solid after lyophilization. LCMS:

[0580] [M+H] + =566.2. 1 H NMR (600MHz, chloroform-d) δ (ppm) 9.22 (s, 1H), 7.98 (s, 1H), 7.22 (dd, J = 8.3, 5.3Hz, 2H), 7.04 (t, J = 8. 4Hz,2H),4.22(s,2H),4.12-2.76(m,17H),2.02(s,3H),1.64(m,6H),1.36(m,6H),1.26(m,6H).

[0581] Example 29: N-(4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2-yl)acetamide (Compound 29)

[0582]

[0583] Compound 29 (6.0 mg), a white solid, was synthesized in a manner similar to that described in compound 15. ¹H NMR (400 MHz, DMSO-d6) δ (ppm) 10.79 (s, ¹H), 8.31 (s, ¹H), 7.37 (dd, J = 8.5, 5.7 Hz, 2H), 7.12 (t, J = 8.9 Hz, 2H), 4.32–4.09 (m, 3H), 3.97–3.77 (m, 2H), 3.68–3.41 (m, 3H), 3.15 (t, J = 10.2 Hz, 1H), 3.00– 2.76(m,4H),2.75-2.65(m,1H),2.65-2.55(m,2H),2.48-2.38(m,1H),2.33-2.23(m,1H),2.15(s, 3H), 1.98-1.86 (m, 1H), 1.80-1.70 (m, 1H), 1.60 (s, 3H), 1.55 (s, 3H), 0.89 (dd, J = 12.3, 6.1Hz, 6H). MS:607.3(M+H+).

[0584] Example 30: 1-(2-amino-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 30)

[0585]

[0586] Compound 30 (10.0 mg) was synthesized as a white solid in a manner similar to that described in Compound 15. 1 H NMR (400MHz, CD3OD) δ (ppm) 8.29-8.07 (s, 1H), 7.30 (dd, J = 8.8, 5.5Hz, 2H), 7.01 (t, J =8.8Hz,2H),4.24-4.11(m,2H),4.10-3.95(m,3H),3.67-3.52(m,3H),3.41-3.33(m,1 H),3.09-2.78(m,7H),2.55-2.44(m,2H),2.31-2.18(m,1H),2.11-1.96(m,1H),1.92 -1.79(m,1H),1.66(s,3H),1.62(s,3H),1.04(d,J=6.3Hz,3H),0.96(d,J=6.3Hz,3H). MS:565.3(M+H + ).

[0587] Example 31: 4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (Compound 31)

[0588]

[0589] Step 1: Benzyl 5-((1,2-diethoxy-2-oxoethylidene)amino)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

[0590]

[0591] In a 25 mL vial, benzyl 5-amino-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (1 g, 2.466 mmol, 1.0 equivalent), 4-methylbenzenesulfonic acid (0.425 g, 2.466 mmol, 1.0 equivalent), and ethyl 2,2,2-triethoxyethyl acetate (2.173 g, 9.87 mmol, 4.0 equivalent) were dissolved in 10 mL of DMF. The reaction mixture was heated to 100 °C MW and stirred for 50 min. The crude product was used directly in the next step. MS (ESI) m / z 534.5 [M+H] + .

[0592] Step 2: Benzyl(Z)-5-(2-ethoxy-N'-hydroxy-2-oxoacetamidine)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

[0593]

[0594] In a 25 mL vial, benzyl 5-((1,2-diethoxy-2-oxoethylidene)amino)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (1.3 g, 2.436 mmol, 1.0 equivalent), hydroxylamine hydrochloride (0.846 g, 12.18 mmol, 5.0 equivalent), and DIEA (1.889 g, 14.62 mmol, 6.0 equivalent) were dissolved in DMF (10 mL). The reaction mixture was heated to 90 °C MW and stirred for 50 min. H2O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine and dried over Na2SO4, filtered, and concentrated to give the title compound (1.2 g, 95%) as a pale yellow oil. MS(ESI) m / z 522.1 [M+H] + .

[0595] Step 3: 6-Benzyl-2-ethyl 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2,6-dicarboxylate

[0596]

[0597] In a flame-dried 100 mL round-bottom flask, benzyl(Z)-5-(2-ethoxy-N'-hydroxy-2-oxoacetamidine)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (1.3 g, 2.497 mmol, 1.0 equivalent) was dissolved in THF (15 mL). The reaction mixture was cooled to 0 °C in an ice / water bath. TFAA (0.787 g, 3.75 mmol, 1.5 equivalent) was added to the reaction mixture. The reaction mixture was stirred for 14 h. Saturated NaHCO3 (15 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (0%–25%) to give 6-benzyl-2-ethyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2,6-dicarboxylate (650 mg, 51.8%) as a white solid. MS (ESI) m / z 504.0 [M+H] + .

[0598] Step 4: Ethyl 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0599]

[0600] Pd / C (10%, 20 mg) was added to a solution of 6-benzyl-2-ethyl 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2,6-dicarboxylate (80 mg, 0.16 mmol) in THF (10.0 mL). The mixture was packed three times with H2 and stirred at room temperature for 1 h. The mixture was filtered and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (1:20) to give ethyl 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (40 mg, 68.2%) as a colorless oil. MS: 369.2 (M+H) + ).

[0601] Step 5: Ethyl 6-(2-chloroacetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0602]

[0603] 2-Chloroacetyl chloride (14.7 mg, 0.13 mmol) was added to a solution of ethyl 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (40 mg, 0.11 mmol) in DCM (2.0 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated to give 45 mg of crude product, which was used directly in the next step. MS: 445.1 (M+H) + ).

[0604] Step 6: Ethyl 6-(2-((2S,5R)-4-(tert-butoxycarbonyl)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0605]

[0606] To a solution of ethyl 6-(2-chloroacetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (45 mg, 0.1 mmol) in acetonitrile (3.0 mL), tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (31.7 mg, 0.1 mmol), potassium iodide (25.2 mg, 0.15 mmol), and K₂CO₃ (41.9 mg, 0.3 mmol) were added. The mixture was stirred at 29 °C for 2 h. The mixture was filtered and concentrated to give a crude product, which was added to a silica gel column and eluted with DCM / MeOH (10:1) to give the title compound (60 mg, 82%) as a white solid. MS: 722.4 (M+H) + ).

[0607] Step 7: 6-(2-((2S,5R)-4-(tert-butoxycarbonyl)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid

[0608]

[0609] In a flame-dried 100 mL round-bottom flask, ethyl 6-(2-((2S,5R)-4-(tert-butoxycarbonyl)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (850 mg, 1.177 mmol, 1.0 equivalent) and LiOH (113 mg, 4.71 mmol, 4.0 equivalent) were dissolved in THF (2 mL) and water (2 mL). The reaction was stirred for 4 h. The aqueous layer was adjusted to pH 7 with 1 N HCl. H₂O (5 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (5 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to give the title compound (800 mg, 98%) as a colorless oil. MS (ESI) m / z 594.6 [M+H] + .

[0610] Step 8: tert-butyl(2R,5S)-4-(2-(2-carbamoyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0611]

[0612] In a flame-dried 100 mL round-bottom flask, 6-(2-((2S,5R)-4-(tert-butoxycarbonyl)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (130 mg, 0.187 mmol, 1.0 equivalent), DIPEA (97 mg, 0.749 mmol, 4.0 equivalent), ammonium chloride (20.04 mg, 0.375 mmol, 2.0 equivalent), and HATU (107 mg, 0.281 mmol, 1.5 equivalent) were dissolved in DMF (5 mL). The reaction was stirred for 14 h. H₂O (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (5 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with MeOH / DCM (0%–5%) to give the title compound (130 mg, 100%) as a grayish-white solid. MS (ESI) m / z 693.5 [M+H] + .

[0613] Step 9: 4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (Compound 31)

[0614] Compound 31, a white solid, was obtained under similar deprotection conditions. MS (ESI) m / z 593.5 [M+H] + . 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.44(s,1H),8.11(s,1H),7.87(s,1H),7.50-7.42(m,2H),7.15(dd,J=10.2,7.6Hz,2H),4.35(d,J=4.1Hz,2H),4.19(d,J=10. 5Hz,1H),3.98(d,J=10.6Hz,1H),3.87(d,J=16.6Hz,1H),3.67(d,J=16.7Hz,1H),3.49(dt,J=11.1,3.3Hz,2H),3.17(t,J=10.3Hz,1H) ,3.01-2.80(m,3H),2.73(dd,J=11.8,2.8Hz,1H),2.68-2.57(m,2H),2.56-2.53(m,2H),2.46(t,J=10.9Hz,1H),2.31(t,J=11.0Hz,1H ), 2.17 (s, 1H), 1.95 (t, J = 10.5Hz, 1H), 1.78 (d, J = 12.4Hz, 1H), 1.66 (s, 3H), 1.62 (s, 3H), 0.93 (d, J = 6.3Hz, 3H), 0.90 (d, J = 5.9Hz, 3H).

[0615] Example 32: 4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-carboxynitrile (Compound 32)

[0616]

[0617] Step 1: 6-(2-((2S,5R)-4-(tert-butoxycarbonyl)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid

[0618]

[0619] In a flame-dried 50 mL round-bottom flask, tert-butyl(2R,5S)-4-(2-(2-carbamoyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (85 mg, 0.123 mmol, 1.0 equivalent), TFAA (77 mg, 0.368 mmol, 3.0 equivalent), and pyridine (38.8 mg, 0.491 mmol, 4.0 equivalent) were dissolved in DCM (5 mL). The resulting mixture was stirred for 14 h. The reaction mixture was washed with 1 M HCl, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (0%–40%) to give the title compound (60 mg, 72.5%) as a pale yellow solid. MS (ESI) m / z 675.6 [M+H] + .

[0620] The following steps were performed to obtain compound 32 in a manner similar to that described in compound 31. MS (ESI) m / z 575.6 [M+H] + .

[0621] Example 33: 1-(4-(4-fluorobenzyl)-2,8,8-trimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 36)

[0622]

[0623] Compound 36, a white solid, was synthesized using 1,1-dimethoxy-N,N-dimethylethyl-1-amine as a starting material, in a manner similar to that described in Compound 14. 1H NMR (400MHz, CD3OD) δ (ppm) 8.31 (s, 1H), 7.31 (dd, J = 8.5, 5.4Hz, 2H), 7.02 (t, J = 8.8Hz ,2H),4.37-4.21(m,2H),4.13-3.98(m,3H),3.67-3.51(m,3H),3.36(m,1H),3.08-2.78 (m,7H),2.59(s,3H),2.48(t,J=11.3Hz,2H),2.32-2.18(m,1H),2.09-1.97(m,1H),1.9 0-1.81(m,1H),1.69(s,3H),1.65(s,3H),1.02(d,J=6.4Hz,3H),0.96(d,J=6.4Hz,3H). MS:564.3(M+H + ).

[0624] Example 34: 1-(4-(4-fluorobenzyl)-2-(hydroxymethyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 37)

[0625]

[0626] Step 1: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-2-(hydroxymethyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0627]

[0628] LiBH4 (9.1 mg, 0.42 mmol) was added to a solution of ethyl 6-(2-((2S,5R)-4-(tert-butoxycarbonyl)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (50 mg, 0.069 mmol) in THF (2.0 mL) / EtOH (2.0 mL). The mixture was stirred at room temperature for 1 h. After concentration, the crude product was added to a silica gel column and eluted with methanol / dichloromethane (1:10) to give the title compound (26 mg, 55.2%) as a white solid. MS: 680.5 (M+H) + ).

[0629] Step 2: Using similar deprotection conditions, compound 37 (8 mg, 36.1%) was obtained as a white solid. 1 HNMR (400MHz, CD3OD) δ (ppm) 8.35 (s, 1H), 7.33 (dd, J = 8.5, 5.5Hz, 2H), 7.02 (t, J = 8.8Hz ,2H),4.86(s,2H),4.42-4.25(m,2H),4.16-4.00(m,3H),3.70-3.52(m,3H),3.39-3.33 (m,1H),3.11-2.78(m,7H),2.58-2.43(m,2H),2.33-2.18(m,1H),2.09-1.96(m,1H),1. 92-1.80(m,1H),1.71(s,3H),1.67(s,3H),1.03(d,J=6.4Hz,3H),0.96(d,J=6.4Hz,3H). MS:580.3(M+H + ).

[0630] Example 35: 1-(4-(2-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 38)

[0631]

[0632] Compound 38 was synthesized in a manner similar to that described in compound 14. MS (ESI) m / z 550.6 [M+H] + . 1 H NMR (400MHz, DMSO-d)6 )δ(ppm)8.55(s,1H),8.35(s,1H),7.50-7.40(m,1H),7.38-7.27(m,1H),7.27-7.10(m,2H),4.45-4.26(m,2H),4.18 (d,J=10.6Hz,1H),3.96(d,J=10.6Hz,1H),3.81(d,J=16.7Hz,1H),3.68(d,J=16.6Hz,1H),3.54-3.44(m,2H),3.19- 3.10(m,1H),3.06-2.95(m,1H),2.94-2.78(m,3H),2.75-2.67(m,1H),2.65-2.57(m,2H),2.51-2.43(m,1H),2.35-2 .25(m,1H),2.22-2.11(m,1H),1.98-1.87(m,1H),1.77(d,J=12.3Hz,1H),1.62(d,J=18.4Hz,6H),1.01-0.85(m,6H).

[0633] Example 36: 1-(4-(3-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 39)

[0634]

[0635] Compound 39 was synthesized in a manner similar to that described in Compound 14. 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.51(s,1H),8.41(s,1H),7.38-7.27(m,1H),7.22-7.16(m,2H),7.09-6.97(m,1H),4.38-4.27(m,2H),4.1 5(d,J=10.6Hz,1H),3.97-3.91(m,1H),3.81(d,J=16.6Hz,1H),3.65(d,J=16.6Hz,1H),3.49-3.42(m,2H),3.21-3. 09(m,1H),3.00-2.93(m,1H),2.91-2.78(m,3H),2.75-2.65(m,1H),2.64-2.55(m,2H),2.46-2.38(m,1H),2.33-2. 21(m,1H),2.21-2.08(m,1H),1.95-1.86(m,1H),1.75(d,J=12.0Hz,1H),1.59(d,J=16.9Hz,6H),0.91-0.80(m,6H).

[0636] Example 37: 1-(4-(2,4-difluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 40)

[0637]

[0638] Compound 40 was synthesized in a manner similar to that described in compound 14. MS (ESI) m / z 568.5 [M+H] + . 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.55(s,1H),8.35(s,1H),7.56-7.43(m,1H),7.34-7.20(m,1H),7.16-7.01(m,1H),4.45-4.25(m,2H),4.18 (d,J=10.6Hz,1H),3.97(d,J=10.6Hz,1H),3.83(d,J=16.7Hz,1H),3.68(d,J=16.7Hz,1H),3.49(d,J=11.1Hz,2H),3 .23-3.09(m,1H),3.05-2.95(m,1H),2.93-2.78(m,3H),2.76-2.68(m,1H),2.66-2.56(m,2H),2.51-2.42(m,1H),2. 36-2.25(m,1H),2.23-2.09(m,1H),2.01-1.88(m,1H),1.82-1.71(m,1H),1.62(d,J=18.0Hz,6H),0.98-0.84(m,6H).

[0639] Example 38: 1-(4-(4-fluoro-2-methoxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 41)

[0640]

[0641] Step 1: tert-butyl 6-((4-fluoro-2-methoxyphenyl)(hydroxy)methyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

[0642]

[0643] Butyllithium (0.881 g, 13.75 mmol, 1.5 equivalent) was added to a solution of tert-butyl-6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (3 g, 9.17 mmol, 1.0 equivalent) in THF (15 mL) at -78 °C under N2, and the mixture was stirred at -78 °C for 30 min. Then, 5-fluoro-2-methoxybenzaldehyde (2.120 g, 13.75 mmol, 1.5 equivalent) was added at -78 °C, and the mixture was stirred at -78 °C for 1 h. The result was then added to a saturated aqueous solution of NH4Cl and ethyl acetate. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with PE / EA = 2 / 1 to give the title compound (3.3 g, 89%) as a white solid.

[0644] Step 2: 6-(4-fluoro-2-methoxybenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0645]

[0646] Triethylsilane (3.47 g, 29.8 mmol, 5.0 equivalent) and TFA (8.00 mL) were added to a solution of tert-butyl 6-((4-fluoro-2-methoxyphenyl)(hydroxy)methyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (2.4 g, 5.96 mmol, 1.0 equivalent) in DCM (16 mL) under N2 conditions. The mixture was stirred at 25 °C for 6 h. After concentration, a saturated aqueous solution of NaHCO3 and ethyl acetate were added. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with PE / EA = 1 / 1 to give the title compound (1.6 g, 94%) as a white solid.

[0647] Step 3: 5-Bromo-6-(4-fluoro-2-methoxybenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine

[0648]

[0649] At 0 °C, 1-bromopyrrolidine-2,5-dione (0.995 g, 5.59 mmol, 1.0 equivalent) was added to a solution of 6-(4-fluoro-2-methoxybenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (1.6 g, 5.59 mmol, 1.0 equivalent) in DMF (15 mL). The mixture was stirred at 0 °C for 30 min and saturated aqueous NaHCO3 solution and ethyl acetate were added. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The crude product was added to a column and eluted with PE / EA = 1 / 1 to give the title compound (1.2 g, 58.8%) as a yellow solid. MS (ESI) m / z 366.5 [M+H] +

[0650] Step 4: 1-(5-bromo-6-(4-fluoro-2-methoxybenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one

[0651]

[0652] Acetyl chloride (129 mg, 1.643 mmol, 1.2 equivalent) was added to a solution of 5-bromo-6-(4-fluoro-2-methoxybenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (500 mg, 1.369 mmol, 1.0 equivalent) in acetonitrile (15 mL) at 0 °C under N2 conditions, and the mixture was stirred at 0 °C for 30 min. A saturated aqueous solution of NaHCO3 was added to the mixture, the solution was extracted with ethyl acetate, and the organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (eluting with PE / EA = 1 / 1) to give the title compound (547 mg, 98%) as a white solid.

[0653] Step 5: 1-(5-amino-6-(4-fluoro-2-methoxybenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one

[0654]

[0655] At 25 °C, tert-butyl carbamate (189 mg, 1.612 mmol, 1.2 equivalents), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (144 mg, 0.269 mmol, 0.2 equivalents), Cs2CO3 (1313 mg, 4.03 mmol, 3.0 equivalents) and Pd2(dba)3 (123 mg, 0.134 mmol, 0.1 equivalents) were added to a solution of 1-(5-bromo-6-(4-fluoro-2-methoxybenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one (547 mg, 1.343 mmol, 1.0 equivalents) in dioxane (15 mL). The mixture was heated to 100°C overnight under N2. After concentration, the residue was purified by rapid silica gel column chromatography (eluting with PE / EA = 1 / 2) to give the title compound (175 mg, 37.9%) as a yellow solid. MS (ESI) m / z 344.8 [M+H] + .

[0656] Step 6: (E)-N-(1-acetyl-6-(4-fluoro-2-methoxybenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-N'-hydroxyformamide)

[0657]

[0658] At 25°C, 1,1-dimethoxy-N,N-dimethylmethylamine (91 mg, 0.764 mmol, 1.5 equivalence) was added to a solution of 1-(5-amino-6-(4-fluoro-2-methoxybenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethyl-1-one (175 mg, 0.510 mmol, 1.0 equivalent) in 15 mL of 2-propanol. The mixture was heated to 80°C for 2 h under N2, and then hydroxylamine hydrochloride (70.8 mg, 1.019 mmol, 2.0 equivalent) was added at room temperature. The mixture was heated to 50°C for 1 h under N2. After concentration, the residue, which was a yellow solid, was used directly for the next step. MS (ESI) m / z 388.0 [M+H] + .

[0659] Step 7: 1-(4-(4-fluoro-2-methoxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl) ethyl-1-one

[0660]

[0661] At 25 °C, 2,2,2-trifluoroacetic anhydride (161 mg, 0.765 mmol, 1.5 equivalent) was added to a solution of (E)-N-(1-acetyl-6-(4-fluoro-2-methoxybenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-N'-hydroxyformamide (197 mg, 0.510 mmol, 1.0 equivalent) in THF (15 mL). The mixture was stirred at 25 °C under N2 for 2 h. The solution was concentrated and the residue was purified by rapid silica gel column chromatography (eluting with DCM / CH3OH = 20 / 1) to give the title compound (119 mg, 63.4%) as a white solid. MS (ESI) m / z 369.8 [M+H] + .

[0662] Step 8: 4-(4-fluoro-2-methoxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine

[0663]

[0664] At 25 °C, 5N HCl (2 mL) was added to a solution of 1-(4-(4-fluoro-2-methoxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)ethyl-1-one (119 mg, 0.323 mmol, 1.0 equivalent) in EtOH (10 mL). The mixture was stirred at 80 °C for 2 h. After concentration, saturated aqueous NaHCO3 solution and ethyl acetate were added. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by rapid silica gel column chromatography (eluting with PE / EA = 1 / 1) to give the title compound (100 mg, 95%) as a yellow solid. MS (ESI) m / z 327.8 [M+H] + .

[0665] Step 9: 2-Chloro-1-(4-(4-fluoro-2-methoxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl) ethyl-1-one

[0666]

[0667] At 0 °C, N-ethyl-N-isopropylpropyl-2-amine (119 mg, 0.919 mmol, 3.0 equivalent) and 2-chloroacetyl chloride (41.5 mg, 0.368 mmol, 1.2 equivalent) were sequentially added to a solution of 4-(4-fluoro-2-methoxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine (100 mg, 0.306 mmol, 1.0 equivalent) in CH2Cl2 (15 mL), and the mixture was stirred at room temperature for 3 h (under N2). Water and DCM were added to the reaction mixture. The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (eluting with PE / EA = 1 / 1) to give the title compound (120 mg, 97%) as a white solid. MS (ESI) m / z 404.5 [M+H] + .

[0668] Step 10: tert-butyl(2R,5S)-4-(2-(4-(4-fluoro-2-methoxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0669]

[0670] At 25 °C, tert-butyl-(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate II (93 mg, 0.298 mmol, 1.0 equivalent), potassium iodide (74.2 mg, 0.447 mmol, 1.5 equivalent), and K₂CO₃ (124 mg, 0.894 mmol, 3.0 equivalent) were added to a solution of 2-chloro-1-(4-(4-fluoro-2-methoxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)acetonitrile (15 mL) and the mixture was stirred at room temperature for 3 h (under N₂). Water and ethyl acetate were then added. The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (eluting with DCM / CH₃OH = 50 / 1) to give the title compound (195 mg, 96%) as a yellow solid. MS (ESI) m / z 681.1 [M+H] + .

[0671] Step 11: 1-(4-(4-fluoro-2-methoxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 41)

[0672]

[0673] A solution of tert-butyl(2R,5S)-4-(2-(4-(4-fluoro-2-methoxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (195 mg, 0.287 mmol, 1.0 equivalent) in HCl / dioxane (3 mL) was stirred at 25 °C for 30 min. The solvent was evaporated and 7.0 N NH3 was added to CH3OH (5 mL). After concentration, the residue was purified by rapid silica gel column chromatography (eluting with DCM / CH3OH = 5 / 1) to give the title compound (144 mg, 87%) as a white solid. MS(ESI) m / z 580.6 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.48(s,1H),8.22(s,1H),7.29-7.17(m,1H),6.99-6.84(m,1H),6.78-6.60 (m,1H),4.23-4.11(m,3H),3.92(d,J=10.6Hz,1H),3.82-3.74(m,4H),3.60(d,J=16.5Hz,1H),3.49-3.41 (m,2H),3.18-3.07(m,1H),2.96-2.75(m,4H),2.72-2.65(m,1H),2.61-2.52(m,2H),2.42-2.33(m,1H),2 .31-2.21(m,1H),2.13(m,1H),1.97-1.84(m,1H),1.79-1.68(m,1H),1.58(d,J=17.1Hz,6H),0.87(m,6H).

[0674] Example 39: 1-(4-(4-fluoro-2-hydroxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 42)

[0675]

[0676] At 0 °C, 1N tribromoborane (0.5 mL) was added to a solution of 1-(4-(4-fluoro-2-methoxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethyl-1-one (30 mg, 0.052 mmol, 1.0 equivalent) in CH2Cl2 (15 mL). The mixture was stirred at 25 °C under N2 for 5 h. A saturated aqueous solution of NaHCO3 was added. The solution was extracted with ethyl acetate and the organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (5.1 mg, 17.42%) as a yellow solid. MS(ESI) m / z 566.3 [M+H] +1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.49(s,1H),8.29(s,1H),7.27-7.13(m,1H),6.62-6.48(m,2H),4. 23-4.06(m,3H),3.91(d,J=10.6Hz,1H),3.78(d,J=16.6Hz,1H),3.63(d,J=

[0677] 16.6Hz,1H),3.47-3.41(m,2H),3.15-3.04(m,1H),3.01-2.91(m,1H),2.91-2.73(m,3H),2.73-2.62(m,1H),2.63-2.54(m,2H),2.46 -2.38(m,1H),2.33-2.18(m,1H),2.17-2.03(m,1H),1.97-1.83(m,1H),1.79-1.67(m,1H),1.57(d,J=19.7Hz,6H),0.92-0.81(m,6H).

[0678] Example 40: 1-(4-(4-chlorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 44)

[0679]

[0680] Compound 44 was synthesized in a manner similar to that described in Compound 14. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.50(s,1H),8.40(s,1H),7.45-7.28(m,4H),4.34-4.22(m,2H),4.15(d,J=10.6Hz,1H), 3.97-3.89(m,1H),3.85-3.76(m,1H),3.68-3.58(m,1H),3.49-3.44(m,2H),3.22-3.07(m,1H),2 .99-2.79(m,4H),2.74-2.66(m,1H),2.65-2.54(m,2H),2.46-2.38(m,1H),2.34-2.23(m,1H),2. 20-2.08(m,1H),1.99-1.90(m,1H),1.79-1.70(m,1H),1.58(d,J=16.6Hz,6H),0.91-0.85(m,6H).

[0681] Example 41: 1-(4-(1-(4-fluorophenyl)ethyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 45)

[0682]

[0683] Compound 45 was synthesized in a manner similar to that described in compound 41. MS (ESI) m / z 564.7 [M+H] + . 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.57-8.37(m,2H),7.47-7.26(m,2H),7.16-7.01(m,2H),4.90-4.70(m,1H),4.23-4 .09(m,1H),4.00-3.89(m,1H),3.86-3.75(m,1H),3.75-3.62(m,1H),3.58-3.38(m,3H),3.23 -3.15(m,1H),3.13-2.97(m,2H),2.96-2.77(m,3H),2.75-2.67(m,1H),2.66-2.56(m,2H),2. 35-2.22(m,1H),2.22-2.06(m,1H),2.01-1.80(m,1H),1.78-1.48(m,9H),0.96-0.78(m,6H).

[0684] Example 42: 1-(4-((4-fluorophenyl)thio)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 49)

[0685]

[0686] Compound 49 was synthesized in a manner similar to that described in Compound 168. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.57(s,1H),8.14(s,1H),7.72-7.60(m,2H),7.45-7.33(m,2H),4.21(d ,J=10.4Hz,1H),3.97(d,J=10.4Hz,1H),3.85(d,J=16.4Hz,1H),3.62-3.47(m,3 H),3.27-3.13(m,2H),3.00-2.60(m,7H),2.41-2.26(m,2H),2.23-2.13(m,1H), 2.00-1.91(m,1H),1.83-1.73(m,1H),1.62(d,J=16.4Hz,6H),0.98-0.83(m,6H). MS(ESI)m / z 568.50[M+H] + .

[0687] Example 43: 1-(4-((2,4-difluorophenyl)(hydroxy)methyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 50)

[0688]

[0689] Step 1: tert-butyl(2R,5S)-4-(2-(4-((2,4-difluorophenyl)(hydroxy)methyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0690]

[0691] At -78°C under N2, 2.5N butyllithium (4.8 mL, 0.121 mmol, 1.5 equivalent) was added to a solution of tert-butyl(2R,5S)-4-(2-(4-bromo-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (50 mg, 0.081 mmol, 1.0 equivalent) in 15 mL of THF. The mixture was stirred at -78°C for 1 h. 2,4-Difluorobenzaldehyde (17.17 mg, 0.121 mmol, 1.5 equivalent) was added at -78°C and stirred at -78°C for 2 h. Saturated aqueous NH4Cl solution and ethyl acetate were then added. The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (eluting with DCM / CH₃OH = 50 / 1) to give the title compound (17 mg, 30.9%) as a yellow solid. MS (ESI) m / z 684.6 [M+H] + .

[0692] Step 2: After deprotection under normal acidic conditions, compound 50 was obtained as a white solid. MS (ESI) m / z 584.6 [M+H] + .

[0693] Example 44: 1-(4-(2-cyclopropyl-1,1-difluoroethyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 53)

[0694]

[0695] Compound 53 (11.6 mg) was synthesized as a white solid in a manner similar to that described in compound 166. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.79(s,1H),8.62(s,1H),4.22(d,J=10.6Hz,1H),4.03(d,J=10.6Hz,1H),3.86(d,J=16.7Hz,1H),3.72(d,J= 16.7Hz,1H),3.60(t,J=6.5Hz,1H),3.53-3.47(m,2H),3.22-3.18(m,1H),3.07-3.01(m,1H),2.95-2.82(m,3H),2.76( d,J=9.6Hz,1H),2.69-2.63(m,2H),2.61-2.54(m,2H),2.35-2.29(m,1H),2.20-2.12(m,1H),1.99-1.93(m,1H),1.83- 1.77(m,1H),1.64(d,J=12.9Hz,6H),0.92(t,J=6.0Hz,6H),0.68-0.55(m,1H),0.38-0.27(m,2H),0.11--0.09(m,2H). MS(ESI)m / z 546.5[M+H] + .

[0696] Example 45: 1-(4'-(4-fluorobenzyl)spiro[cyclopropane-1,8'-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine]-6'(7'H)-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetoone

[0697] (Compound 56)

[0698]

[0699] Step 1: 6'-Bromospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one

[0700]

[0701] 6-Bromo-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (19.0 g, 1.0 equivalent) was dissolved in 200 mL of LMF. NaH (9.0 g, 2.5 equivalent) was added dropwise at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 1-1.5 h. 1,2-Dibromoethane (25.0 g, 1.5 equivalent) was added dropwise at 0-5 °C. The reaction mixture was warmed to room temperature and stirred at room temperature for 16 h. The reaction mixture was poured into 1000 mL of ice water and extracted four times with ethyl acetate. The combined organic phases were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography to give the title compound (8.5 g, 40% yield). LC-MS: [M+H] + 239.2.

[0702] Step 2: 6'-(4-fluorobenzyl)spiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one

[0703]

[0704] The above intermediate (8.5 g, 1.0 equivalent), 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (31.5 g, 4.0 equivalent), and Cs₂CO₃ (57.9 g, 6.0 equivalent) were added to 80 mL of dioxane and 15 mL of H₂O. Pd(dppf)Cl₂ (5.2 g, 0.2 equivalent) was added. The reaction was heated to 90 °C and reacted for 4 h (under N₂ atmosphere). The reaction was cooled to room temperature and concentrated. The residue was purified by chromatography to give the title compound (7.5 g, 78% yield).

[0705] Step 3: 6'-(4-fluorobenzyl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]

[0706]

[0707] The above intermediate (7.5 g, 1.0 equivalent) was dissolved in 80 mL of THF. LiAlH4 (4.24 g, 4.0 equivalent) was added dropwise at -10 °C to -5 °C. The reaction mixture was stirred for 30 min and then heated to 50 °C for 1 h. The reaction was then cooled to 0 °C to -5 °C. 4 mL of H2O, 4 mL of 15% NaOH aqueous solution, and 12 mL of H2O were added sequentially. The solution was filtered, and the filter cake was washed three times with ethyl acetate. The combined filtrates were concentrated and purified by silica gel chromatography to give the title compound (5.2 g, 73% yield). LC-MS: [M+H] + 255.2.

[0708] Step 4: 5'-Bromo-6'-(4-fluorobenzyl)-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[3,2-b]pyridine]

[0709]

[0710] The above intermediate (800 mg, 1.0 equivalent) was dissolved in 10 mL of DMF. At -20 °C, 5 mL of NBS (589 mg, 1.05 equivalent) in DMF was added dropwise. The reaction was stirred for 2 h and quenched with 50 mL of H₂O. The mixture was extracted four times with ethyl acetate. The combined organic phases were washed with water and brine and dried over Na₂SO₄. The solution was filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound (460 mg, 44% yield). 1 H NMR (400MHz, chloroform-d) δ (ppm) 7.23-7.10 (m, 2H), 7.07-6.91 (m, 2H), 6.51 (s, 1H), 3.95 (s,2H),3.81(brs,1H),3.70(s,2H),1.36(q,J=4.3Hz,2H),0.96(q,J=4.3Hz,2H). HPLC-MS:[M+H] + =333.20 / 335.20 (measured value).

[0711] The following steps were performed: Compound 56 (30.6 mg), a white solid, was synthesized in a manner similar to that described in Compound 14. MS (ESI) m / z 548.5 [M+H] + . 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.42(s,1H),8.38(s,1H),7.41-7.26(m,2H),7.13-7.00(m,2H),4.35-4.23(m,3H),4. 22-4.11(m,1H),3.74-3.56(m,2H),3.49-3.40(m,2H),3.14-3.05(m,1H),3.00-2.92(m,1H),2 .91-2.73(m,4H),2.69-2.64(m,1H),2.60-2.55(m,2H),2.34-2.20(m,1H),2.18-2.09(m,1H), 2.05-1.98(m,2H),1.96-1.82(m,1H),1.80-1.66(m,1H),1.17-1.07(m,2H),0.93-0.80(m,7H).

[0712] Example 46: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-2-methyl-4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)piperazin-1-yl)acet-1-one (Compound 63)

[0713]

[0714] Compound 63 (57 mg) was synthesized as a white solid in a manner similar to that described in compound 174. 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.50(d,J=0.9Hz,1H),8.38(s,1H),7.39(dd,J=8.4,5.7Hz,2H),7.10(t,J=8.4Hz,2H),4.35-4.23(m,2H) ,4.14(d,J=10.5Hz,1H),3.93(d,J=10.6Hz,1H),3.83(d,J=16.6Hz,1H),3.70-3.58(m,1H),3.04-2.90(m,2H),2.8 9-2.70(m,5H),2.67-2.57(m,3H),2.47-2.42(m,1H),2.35-2.27(m,1H),2.25-2.14(m,2H),2.03(t,J=9.5Hz,1H) ,1.93(t,J=10.6Hz,1H),1.75(d,J=13.0Hz,1H),1.59(d,J=19.3Hz,6H),0.96(d,J=6.0Hz,3H),0.93-0.87(m,3H). MS(ESI)m / z 631.6[M+H] + .

[0715] Example 47: 2-((2R,5R)-2-(((R)-4,4-difluoro-2-methylpiperidin-1-yl)methyl)-5-methylpiperazin-1-yl)-1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)acet-1-one (Compound 75)

[0716]

[0717] Compound 75 (27 mg), a white solid, was synthesized in a manner similar to that described in compound 174. MS (ESI) m / z 584.5 [M+H] + .

[0718] Example 48: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-2-(((2R)-4-hydroxy-2,4-dimethylpiperidin-1-yl)methyl)-5-methylpiperazin-1-yl)acet-1-one (Compound 77)

[0719]

[0720] Step 1: tert-butyl(2R)-4-hydroxy-2,4-dimethylpiperidine-1-carboxylate

[0721]

[0722] MeMgBr (4.8 mL, 23.4 mmol, 10.0 equivalent) was slowly added to a solution of tert-butyl(R)-2-methyl-4-oxopiperidin-1-carboxylate (0.5 g, 2.34 mmol, 1.0 equivalent) in dry THF (10 mL) at -78 °C. The mixture was then stirred for 30 min. The mixture was warmed to room temperature and stirred for 18 h. The mixture was quenched with NH4Cl solution and diluted with ethyl acetate (200 mL). The organic phase was collected and dried over anhydrous Na2SO4. After concentration, the residue was used directly for the next step (0.50 g, crude product).

[0723] Step 2: (2R)-2,4-dimethylpiperidin-4-ol

[0724]

[0725] The above intermediate (0.5 g, 2.18 mmol) was stirred in concentrated hydrogen chloride (1 mL) and MeOH (5 mL) at room temperature for 2 h. The solvent was removed to obtain the title compound (0.25 g, crude product), which was used directly in the next step.

[0726] Step 3: tert-butyl(2R,5S)-4-benzyl-5-(((2R)-4-hydroxy-2,4-dimethylpiperidin-1-yl)methyl)-2-methylpiperazine-1-carboxylate

[0727]

[0728] The intermediate above (0.25 g, 1.0 equivalent), tert-butyl(2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine-1-carboxylate (0.25 g, 0.4 equivalent), Cs₂CO₃ (0.68 g, 1.0 equivalent), KI (0.04 g, 0.1 equivalent), and CH₃CN (10 mL) were charged into a vial. The mixture was purged with nitrogen and heated to 80 °C for 15 h. LC-MS showed the reaction was complete. The mixture was diluted with 50 mL H₂O and extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give the title compound (0.28 g, 55%). LC-MS (m / z): 432.1 [M+H] + .

[0729] Step 4: tert-butyl(2R,5S)-5-(((2R)-4-hydroxy-2,4-dimethylpiperidin-1-yl)methyl)-2-methylpiperazine-1-carboxylate

[0730]

[0731] Pd / C (0.2 g, 10%, on carbon, wetted with about 55% water) was added to a solution of the above intermediate (0.28 g, 1 equivalent) in CF3CH2OH (15 mL), and the mixture was stirred at room temperature under H2 (balloon) for 5 hours. TLC was performed to monitor the progress of the reaction. Once the reaction was complete, the catalyst was removed by filtration and the filtrate was concentrated to give the title compound (0.19 g, 86%). LC-MS: 342.42 [M+H] + . 1 H NMR (600MHz, chloroform-d) δ (ppm) 4.16 (brs, 1H), 3.63 (d, J = 13.7Hz, 1H), 3.30 (dd, J = 13.7, 3.8Hz, 1H), 3.12-3.00 (m, 3H), 2.93 (d, J = 12.2Hz, 1H), 2.50 (dd, J = 12.4,2.7Hz,1H),2.10(m,2H),1.91(dd,J=11.8,3.5Hz,1H),1.71-1.57(m, 3H), 1.45 (s, 9H), 1.26 (d, J = 6.8Hz, 3H), 1.24 (s, 3H), 1.07 (d, J = 6.1Hz, 3H).

[0732] The following steps were performed: Compound 77 (43.5 mg) was synthesized as a white solid in a manner similar to that described in Compound 174. MS (ESI) m / z 578.6 [M+H] + .

[0733] Example 49: 2-((2R,5R)-2-((2-oxa-5-azabicyclo[2.2.1]hept-5-yl)methyl)-5-methylpiperazin-1-yl)-1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)ethyl-1-one (compounds 78 and 79)

[0734] Compounds 78 and 79 (45 mg) were synthesized as a mixture of diastereomers in the form of a white solid, similar to that described in compound 174. 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.50(s,1H),8.40(s,1H),7.39(dd,J=8.3,5.7Hz,2H),7.11(t,J=8.8Hz,2H),4.30( s,2H),4.24-4.17(m,2H),4.00(d,J=10.6Hz,1H),3.83(d,J=16.0Hz,1H),3.73(d,J=7.3Hz,

[0735] 1H),3.41(s,2H),3.38(s,1H),2.84(d,J=9.5Hz,1H),2.78-2.68(m,2H),2.68-2.53(m,3H),2.36-2.2 2(m,4H),1.57(d,J=10.2Hz,6H),1.50(d,J=9.2Hz,1H),1.39(d,J=9.1Hz,1H),0.87(d,J=6.1Hz,3H). MS(ESI)m / z 548.4[M+H] + .

[0736] Example 50: 2-((2S,5R)-2-((8-oxa-3-azabicyclo[3.2.1]oct-3-yl)methyl)-5-methylpiperazin-1-yl)-1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)acet-1-one (Compound 80)

[0737]

[0738] Compound 80 (45 mg) was synthesized as a white solid in a manner similar to that described in compound 174. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.50(s,1H),8.42(s,1H),7.39(dd,J=8.2,5.8Hz,2H),7.11(t,J=8.7Hz,2H),4.30(s,2H),4.23(d,J=1 0.6Hz,1H),4.12(s,2H),4.01(d,J=10.6Hz,1H),3.90(d,J=16.2Hz,1H),3.43(d,J=16.2Hz,1H),2.85-2.77(m,

[0739] 1H),2.77-2.67(m,2H),2.65-2.52(m,3H),2.48-2.41(m,1H),2.30-2.18(m,2H),2.06(d,J=10.4Hz,1H),1.93(dd ,J=18.6,6.3Hz,2H),1.72-1.62(m,2H),1.58(s,6H),1.55-1.51(m,1H),1.49-1.39(m,1H),0.87(d,J=6.0Hz,3H). MS(ESI)m / z

[0740] 562.5 [M+H] + .

[0741] Example 51: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-((2-methyl-1H-imidazo[1-1-yl]methyl)piperazin-1-yl)acetyl-1-one (Compound 91)

[0742]

[0743] Compound 91 (9 mg), a white solid, was synthesized in a manner similar to that described in compound 146. MS (ESI) m / z 531.4 [M+H] + .

[0744] Example 52: 2-(((2R,5R)-1-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo)

[0745] [2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)isoindoline-1-one (compound 94)

[0746]

[0747] Following the synthesis of compound 207, compound 94, a white solid, was synthesized. MS (ESI) m / z 582.5 [M+H] + . 1 HNMR (400MHz, DMSO-d) 6)δ(ppm)8.48(s,1H),8.00(s,1H),7.49-7.37(m,4H),7.27(t,J=7.5Hz,1H),7.22-7.12(m,2H),7.06(t,J=7.4Hz,1H ),4.63(d,J=17.5Hz,1H),4.41(d,J=17.5Hz,1H),4.27(d,J=14.7Hz,1H),4.15(d,J=14.7Hz,1H),3.99(d,J=10.4Hz ,1H),3.92(dd,J=15.2,7.7Hz,1H),3.82(d,J=10.4Hz,1H),3.70(s,2H),3.32-3.23(m,3H),2.82(dd,J=11.8,2.6Hz ,1H),2.77-2.61(m,2H),2.60-2.55(m,1H),2.44(t,J=11.0Hz,1H),1.57(s,3H),1.45(s,3H),0.91(d,J=6.0Hz,3H).

[0748] Example 53: 6-(((2R,5R)-1-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 95)

[0749]

[0750] Following the synthesis of compound 207, compound 95, a white solid, was synthesized. MS (ESI) m / z 583.5 [M+H] + . 1 HNMR (400MHz, DMSO-d) 6)δ(ppm)8.56(dd,J=5.0,1.6Hz,1H),8.50(s,1H),7.94(s,1H),7.85(dd,J=7.6,1.6Hz,1H),7.46-7.37( m,2H),7.20-7.13(m,2H),7.11(dd,J=7.7,4.9Hz,1H),4.68(d,J=18.0Hz,1H),4.52(d,J=18.0Hz,1H),4. 31(d,J=14.9Hz,1H),4.12(d,J=14.9Hz,1H),4.11-3.85(m,3H),3.79-3.64(m,2H),3.32-3.21(m,3H),2 .92-2.84(m,1H),2.77-2.66(m,2H),2.51-2.43(m,2H),1.61(s,3H),1.49(s,3H),0.93(d,J=6.2Hz,3H).

[0751] Example 54: 2-(((2R,5R)-1-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Compound 96)

[0752]

[0753] Following the synthesis of compound 207, compound 96, a white solid, was synthesized. MS (ESI) m / z 584.1 [M+H] + . 1 HNMR (400MHz, DMSO-d) 6)δ(ppm)8.65(s,1H),8.49(s,1H),8.40(d,J=5.0Hz,1H),7.98(s,1H),7.51(d,J=5.1Hz,1H),7.46-7.38(m,2H),7.17(t ,J=8.8Hz,2H),4.70(d,J=18.7Hz,1H),4.53(d,J=18.7Hz,1H),4.27(d,J=14.7Hz,1H),4.17(d,J=14.7Hz,1H),4.01(d,J =10.4Hz,1H),3.91(dd,J=15.3,7.5Hz,1H),3.85(d,J=10.5Hz,1H),3.70(s,2H),3.31-3.25(m,3H),2.85(dd,J=11.7,2. 6Hz, 1H), 2.75-2.64 (m, 2H), 2.52-2.50 (m, 1H), 2.45 (t, J = 11.0Hz, 1H), 1.59 (s, 3H), 1.47 (s, 3H), 0.92 (d, J = 5.9Hz, 3H).

[0754] Example 55: 2-(((2R,5R)-1-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (Compound 97)

[0755]

[0756] Following the synthesis of compound 207, compound 97, a white solid, was synthesized. MS (ESI) m / z 583.5 [M+H] + . 1 HNMR (400MHz, DMSO-d) 6)δ(ppm)8.65(s,1H),8.49(d,J=2.1Hz,1H),8.40(dd,J=5.2,2.4Hz,1H),7.97(s,1H),7.51(t,J=3.8Hz,1H),7.42 (dd,J=7.8,5.0Hz,2H),7.21-7.13(m,2H),4.70(d,J=18.7Hz,1H),4.53(d,J=18.7Hz,1H),4.27(d,J=14.5Hz,1H), 4.17(d,J=14.8Hz,1H),4.01(d,J=10.5Hz,1H),3.92(d,J=9.4Hz,1H),3.88-3.81(m,1H),3.73-3.68(m,2H),3.32 -3.23(m,3H),2.86(s,1H),2.77-2.64(m,3H),2.51-2.31(m,2H),1.59(s,3H),1.47(s,3H),0.92(d,J=6.2Hz,3H).

[0757] Example 56: 6-(((2R,5R)-1-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Compound 98)

[0758]

[0759] Following the synthesis of compound 207, compound 98, a white solid, was synthesized. MS (ESI) m / z 583.5 [M+H] + . 1 HNMR (400MHz, DMSO-d) 6)δ(ppm)8.49(s,1H),8.10(dd,J=4.8,1.4Hz,1H),7.91(s,1H),7.78(dd,J=7.7,1.4Hz,1H),7.44(dd,J=8.6,5.7Hz, 2H),7.23-7.14(m,2H),7.06(dd,J=7.7,4.8Hz,1H),4.62(d,J=17.8Hz,1H),4.41(d,J=17.7Hz,1H),4.26(d,J=14.6 Hz,1H),4.15(d,J=14.7Hz,1H),4.00(dd,J=14.5,7.7Hz,1H),3.94-3.84(m,2H),3.80(d,J=17.4Hz,1H),3.62(d,J= 17.5Hz,1H),3.33(s,2H),3.23(dd,J=14.6,2.6Hz,1H),2.84(dd,J=11.7,2.7Hz,1H),2.71-2.60(m,3H),2.44(t,J=

[0760] 11.1Hz, 1H), 1.66 (s, 3H), 1.44 (s, 3H), 0.92 (d, J = 5.4Hz, 3H).

[0761] Example 57: 4-Fluoro-2-(((2R,5R)-1-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)isoindoline-1-one (Compound 99)

[0762]

[0763] Following the synthesis of compound 207, compound 99, a white solid, was synthesized. MS (ESI) m / z 601.1 [M+H] + . 1 HNMR (400MHz, DMSO-d) 6)δ(ppm)8.49(s,1H),8.01(d,J=8.9Hz,1H),7.38(dd,J=8.5,5.7Hz,2H),7.34(d,J=7.2Hz,1H),7.21(t,J=8.6Hz,1 H),7.17-7.11(m,3H),4.76-4.64(m,1H),4.53(d,J=17.6Hz,1H),4.33(d,J=14.9Hz,1H),4.11(d,J=14.9Hz,1H),4 .05-3.98(m,1H),3.93(dd,J=15.4,7.6Hz,1H),3.85(d,J=10.4Hz,1H),3.72(d,J=10.2Hz,2H),3.32-3.22(m,3H), 2.86(d,J=11.4Hz,1H),2.72(d,J=11.7Hz,2H),2.52-2.34(m,2H),1.60(s,3H),1.47(s,3H),0.93(d,J=5.9Hz,3H).

[0764] Example 58: 5-Fluoro-2-(((2R,5R)-1-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)isoindoline-1-one (Compound 100)

[0765]

[0766] Following the synthesis of compound 207, compound 100, a white solid, was synthesized. MS (ESI) m / z 601.1 [M+H] + . 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.49(s,1H),8.00(s,1H),7.47(dd,J=8.4,5.1Hz,1H),7.43-7.34(m,3H),7.20-7.10(m,2H),6.86(td,J=9.0,2. 3Hz,1H),4.64(d,J=17.9Hz,1H),4.43(d,J=17.8Hz,1H),4.30(d,J=14.6Hz,1H),4.13(d,J=14.7Hz,1H),3.99(d,J=10.4 Hz,1H),3.90(dd,J=14.4,6.9Hz,1H),3.83(d,J=10.4Hz,1H),3.78-3.58(m,2H),3.33-3.22(m,3H),2.83(dd,J=11.7,2. 5Hz,1H),2.73-2.62(m,2H),2.59-2.51(m,1H),2.43(t,J=11.1Hz,1H),1.60(s,3H),1.45(s,3H),0.91(d,J=6.0Hz,3H).

[0767] Example 59: 6-Fluoro-2-(((2R,5R)-1-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)isoindoline-1-one (Compound 101)

[0768]

[0769] Following the synthesis of compound 207, compound 101, a white solid, was synthesized. MS (ESI) m / z 601.1 [M+H] + . 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.49(s,1H),7.98(s,1H),7.50-7.38(m,2H),7.25-7.07(m,4H),4.61(d,J=17.5Hz,1H),4.41(d ,J=17.5Hz,1H),4.29(d,J=14.8Hz,1H),4.15(d,J=14.7Hz,1H),4.00(d,J=10.4Hz,1H),3.91(dd,J=15.2 ,7.6Hz,1H),3.84(d,J=10.4Hz,1H),3.69(s,2H),3.32-3.24(m,3H),2.82(dd,J=11.8,2.6Hz,1H),2.73- 2.62(m,2H),2.43(t,J=11.0Hz,1H),2.12-1.97(m,1H),1.61(s,3H),1.46(s,3H),0.91(d,J=6.0Hz,3H).

[0770] Example 60: 4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyridine-3-carboxylonitrile (Compound 105)

[0771]

[0772]

[0773] Steps 1-2: tert-butyl-3-cyano-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[4,3-a]pyridine-6-carboxylate

[0774]

[0775] At 0 °C, MSH (2.41 g, 11.2 mmol, 3.5 equivalents) was added to a solution of tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (1.14 g, 3.2 mmol, 1.0 equivalent) in DCM (15 mL), and the resulting solution was stirred at room temperature for 18 h. TLC showed that the reaction was complete. The reaction solution was evaporated. At room temperature, the crude product was dissolved in DMF (30 mL), and 2-chloroacrylonitrile (CAS: 920-37-6, 0.57 g, 6.4 mmol, 2.0 equivalents) and K2CO3 (1.33 g, 9.6 mmol, 3.0 equivalents) were added sequentially, and the resulting solution was stirred for 4 h. TLC showed that the reaction was complete. The mixture was diluted with 100 mL of H₂O and extracted with ethyl acetate, dried over sodium sulfate, concentrated under vacuum, and purified by rapid silica gel column chromatography to give the title compound (0.05 g, 3.7%, two steps), LCMS: [M+H]. + =421.2.

[0776] The following steps were performed: Following the synthesis of compound 14, compound 105 was obtained as a white solid. MS (ESI) m / z 574.5 [M+H] + . 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.71(s,1H),8.16(s,1H),7.42-7.28(m,2H),7.25-7.12(m,2H),4.52-4.34 (m,2H),4.11(d,J=10.6Hz,1H),3.98-3.81(m,2H),3.73(d,J=17.3Hz,1H),3.53-3.4 2(m,2H),3.17-2.64(m,8H),2.59-2.53(m,2H),2.27-2.14(m,1H),2.05-1.93(m,1H) ,1.92-1.82(m,1H),1.69-1.57(m,6H),1.06(d,J=6.1Hz,3H),0.92(d,J=6.2Hz,3H).

[0777] Example 61: 1-(3-chloro-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 106)

[0778]

[0779] Step 1: tert-butyl-3-chloro-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyridine-6-carboxylate

[0780]

[0781] Sodium bicarbonate (27 mg, 0.327 mmol, 1.2 equivalence) and NCS (44 mg, 0.327 mmol, 1.2 equivalence) were added to a solution of 6-(tert-butoxycarbonyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyridine-3-carboxylic acid (120 mg, 0.27 mmol, 1.0 equivalence) in DMF (10 mL) at room temperature, and the resulting solution was stirred at room temperature for 18 h. TLC showed the reaction was complete. The mixture was diluted with 100 mL of H₂O and extracted with ethyl acetate, dried over sodium sulfate, concentrated under vacuum, and purified by rapid silica gel column chromatography to give the pure product (10 mg, 37%). LCMS: [M+H] + =430.2.

[0782] The following steps were performed: Following the synthesis of compound 14, compound 106 (18.1 mg) was obtained as a white solid. MS (ESI) m / z 583.5 [M+H] + . 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.12(s,1H),8.01(s,1H),7.32-7.21(m,2H),7.20-7.08(m,2H),4.54-4.36(m,2H),4.10(d ,J=10.5Hz,1H),3.91(d,J=10.6Hz,1H),3.81-3.61(m,2H),3.54-3.44(m,2H),3.21-3.13(m,1H),3 .07-2.97(m,1H),2.95-2.73(m,4H),2.71-2.60(m,2H),2.58-2.52(m,1H),2.37-2.27(m,1H),2.23 -2.11(m,1H),1.98-1.88(m,1H),1.77(d,J=13.2Hz,1H),1.61(d,J=16.8Hz,6H),0.93-0.88(m,6H).

[0783] Example 62: 1-(4-(4-fluorobenzyl)-1,2,8,8-tetramethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 109)

[0784]

[0785] Compound 109 (20.8 mg) was synthesized as a white solid in a manner similar to that described in compound 116. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.00(s,1H),7.35(dd,J=8.5,5.7Hz,2H),7.09(t,J=8.9Hz,2H),4.20(dd,J=31.7,14.6Hz,2H),4.05( d,J=10.3Hz,1H),3.90-3.77(m,2H),3.56(d,J=16.3Hz,1H),3.50-3.42(m,2H),3.20-3.13(m,1H),2.96-2.77 (m,4H),2.71(d,J=9.9Hz,1H),2.65-2.56(m,5H),2.42(d,J=11.1Hz,1H),2.33(s,3H),2.27(t,J=10.9Hz,1H) ,2.18-2.08(m,1H),1.92(d,J=9.5Hz,1H),1.74(d,J=12.1Hz,1H),1.53(d,J=18.2Hz,6H),0.92-0.85(m,6H). MS(ESI)m / z 577.4[M+H] + .

[0786] Example 63: 4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-1-carboxylonitrile (Compound 111)

[0787]

[0788]

[0789] Steps 1-4: Ethyl 6-(2-((2S,5R)-4-(tert-butoxycarbonyl)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-1-carboxylate

[0790]

[0791] Following the synthesis of compound 116, steps 1-4 were performed to yield the title compound (30 mg). MS (ESI) m / z 721.6 [M+H] + .

[0792] Step 5: 6-(2-((2S,5R)-4-(tert-butoxycarbonyl)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-1-carboxylic acid

[0793]

[0794] Under argon atmosphere, ethyl 6-(2-((2S,5R)-4-(tert-butoxycarbonyl)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-1-carboxylate (0.03 g, 0.042 mmol, 1.0 equivalent) and NaOH (0.017 g, 0.416 mmol, 10 equivalent) were dissolved in water (2 mL), THF (2.0 mL), and MeOH (2.0 mL) to give a yellow solution. The reaction mixture was stirred at 50 °C for 48 h. 1 M HCl (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to give the product (0.029 g, 100%). MS (ESI) m / z 693.5 [M+H] + .

[0795] Step 6: tert-butyl(2R,5S)-4-(2-(1-carbamoyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0796]

[0797] Under argon atmosphere, 6-(2-((2S,5R)-4-(tert-butoxycarbonyl)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-1-carboxylic acid (0.029 g, 0.042 mmol, 1.0 equivalent), BOP (0.037 g, 0.084 mmol, 2.0 equivalent), DIEA (0.081 g, 0.628 mmol, 15 equivalent), and NH4Cl (0.022 g, 0.419 mmol, 10 equivalent) were dissolved in DMF (5 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 12 h. H₂O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (0% to 8%) to give a product as a yellow solid (0.016 g, 55.3%). MS (ESI) m / z 692.5 [M+H] + .

[0798] Steps 7-8: Following the synthesis of compound 153, compound 111 (3.6 mg) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.57(s,1H),8.44(s,1H),7.38(dd,J=8.5,5.7Hz,2H),7.11(t,J=8.9Hz,2H),4.34(q,J=14.6Hz,2H),4.16( d,J=10.5Hz,1H),3.93(d,J=10.6Hz,1H),3.81(d,J=16.6Hz,1H),3.66(d,J=16.7Hz,1H),3.49-3.44(m,2H),3.15-3. 09(m,1H),3.00-2.94(m,1H),2.92-2.79(m,3H),2.75-2.68(m,1H),2.61(d,J=8.6Hz,2H),2.47-2.42(m,1H),2.35-2 .24(m,1H),2.20-2.10(m,1H),1.97-1.87(m,1H),1.75(d,J=12.9Hz,1H),1.68(d,J=12.7Hz,6H),0.91-0.86(m,6H). MS(ESI)m / z 574.6[M+H] + .

[0799] Example 64: 1-(2-chloro-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 113)

[0800]

[0801] Step 1: N-(1-acetyl-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-2-bromoacetamide

[0802]

[0803] Under argon atmosphere, 1-(5-amino-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one (0.06 g, 0.191 mmol, 1.0 equivalent), 2-bromoacetic acid (0.040 g, 0.287 mmol, 1.5 equivalent), TEA (0.058 g, 0.574 mmol, 3.0 equivalent), and T3P (0.244 g, 0.383 mmol, 2.0 equivalent) were dissolved in DCM (10 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 16 h. Saturated NaCl (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (0% to 80%) to give a product as a yellow oil (0.05 g, 60.1%). MS (ESI) m / z 434.2 [M+H] + .

[0804] Step 2: 1-(4-(4-fluorobenzyl)-2-hydroxy-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one

[0805]

[0806] Under argon atmosphere, N-(1-acetyl-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)-2-bromoacetamide (0.05 g, 0.115 mmol, 1.0 equivalent) and DIEA (0.015 g, 0.115 mmol, 1.0 equivalent) were dissolved in EtOH (5 mL) to give a yellow solution. The reaction mixture was stirred at 70 °C for 16 h. Saturated NaCl (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (0% to 5%) to give a product as a yellow solid (0.0256 g, 62.9%). MS (ESI) m / z 354.4 [M+H] + .

[0807] Step 3: 1-(2-chloro-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one

[0808]

[0809] Under argon atmosphere, 1-(4-(4-fluorobenzyl)-2-hydroxy-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one (0.0256 g, 0.072 mmol, 1.0 equivalent) and POCl3 (0.111 g, 0.724 mmol, 10 equivalent) were dissolved in 1,2-dichloroethane (10 mL) to give a solution. The reaction mixture was stirred at 90 °C for 3 h. Saturated NaHCO3 (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (0% to 50%) to give a product (0.02 g, 74.3%) as a yellow oil. MS(ESI) m / z 372.4 [M+H] + .

[0810] Steps 4-7: Following the synthesis of compound 14, compound 113 (6.9 mg) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.26(s,1H),8.11(s,1H),7.36(dd,J=8.4,5.7Hz,2H),7.12(t,J=8.9Hz,2H),4.21(q,J=14.6Hz,2 H),4.07(d,J=10.5Hz,1H),3.86(d,J=10.6Hz,1H),3.76(d,J=16.9Hz,1H),3.64(d,J=16.5Hz,1H),3.48-3. 43(m,2H),3.13(t,J=9.4Hz,1H),3.06-2.98(m,1H),2.89-2.71(m,3H),2.70-2.57(m,3H),2.34-2.28(m,2H ),2.20-2.09(m,1H),1.96-1.86(m,1H),1.75(d,J=12.1Hz,1H),1.51(d,J=16.5Hz,6H),0.92-0.87(m,6H). MS(ESI)m / z 583.5[M+H] + .

[0811] Example 65: 1-(4-(4-fluoro-2-methylbenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 115)

[0812]

[0813] Compound 115 was synthesized in a manner similar to that described in compound 14. MS (ESI) m / z 564.5 [M+H] + . 1 HNMR (400MHz, DMSO-d) 6)δ(ppm)8.54(s,1H),8.19(s,1H),7.33-7.21(m,1H),7.15-7.06(m,1H),7.05-6.93(m,1H),4.41-4.24(m,2H), 4.17(d,J=10.6Hz,1H),3.97(d,J=10.6Hz,1H),3.81(d,J=16.7Hz,1H),3.67(d,J=16.6Hz,1H),3.52-3.46(m,2 H),3.19-3.08(m,1H),3.06-2.95(m,1H),2.94-2.72(m,4H),2.69-2.58(m,2H),2.51-2.43(m,1H),2.37-2.25( m,4H),2.22-2.11(m,1H),2.04-1.89(m,1H),1.77(d,J=12.0Hz,1H),1.63(d,J=17.6Hz,6H),0.96-0.87(m,6H).

[0814] Example 66: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-2-(trifluoromethyl)-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 116)

[0815]

[0816] Step 1: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-2-(trifluoromethyl)-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one

[0817]

[0818] Under argon atmosphere, 1-(5-amino-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethyl-1-one (0.09 g, 0.287 mmol, 1.0 equivalent) and 3-bromo-1,1,1-trifluoroprop-2-one (0.274 g, 1.436 mmol, 5.0 equivalent) were dissolved in EtOH (5 mL) to give a yellow solution. The reaction mixture was stirred at 80 °C for 16 h. Saturated NaHCO3 (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (0% to 5%) to give a product (0.095 g, 82%) as a yellow oil. MS(ESI) m / z 406.3 [M+H] + .

[0819] Steps 2-5: Following the synthesis of compound 14, compound 116 (26.1 mg) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.70(s,1H),8.19(s,1H),7.38(dd,J=8.5,5.7Hz,2H),7.13(t,J=8.9Hz,2H),4.28(q,J=15.0Hz,2H),4.10(d,J=10 .6Hz,1H),3.88(d,J=10.6Hz,1H),3.78(d,J=16.6Hz,1H),3.63(d,J=16.6Hz,1H),3.50-3.42(m,2H),3.13(t,J=9.9Hz,1H), 2.97(t,J=8.7Hz,1H),2.91-2.76(m,3H),2.69(dd,J=11.6,2.2Hz,1H),2.65-2.55(m,2H),2.45(t,J=11.0Hz,1H),2.27(t, J=11.0Hz,1H),2.19-2.08(m,1H),1.90(t,J=9.4Hz,1H),1.73(d,J=12.4Hz,1H),1.55(d,J=17.3Hz,6H),0.95-0.82(m,6H). MS(ESI)m / z 617.6[M+H] + .

[0820] Example 67: 4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-2-carboxylic acid (compound 117)

[0821]

[0822] After hydrolysis of compound 18, compound 117 (2.5 mg) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.31(s,1H),8.02(s,1H),7.37(s,2H),7.12(t,J=8.3Hz,2H),4.29(q,J=15.2Hz,2 H),4.04(s,1H),3.86(d,J=10.6Hz,1H),3.76-3.65(m,4H),3.12-3.10(m,1H),2.89-2.79(m ,4H),2.78-2.73(m,2H),2.68-2.60(m,2H),2.43-2.34(m,1H),2.20-2.09(m,1H),1.92(t, J=9.0Hz, 1H), 1.78 (d, J=13.2Hz, 1H), 1.53 (d, J=16.5Hz, 6H), 0.92 (dd, J=27.2, 6.1Hz, 6H). MS(ESI)m / z 593.5[M+H] + .

[0823] Example 68: 1-(1-chloro-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo)

[0824] [2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (compound 118)

[0825]

[0826] Step 1: tert-butyl(2R,5S)-4-(2-(1-chloro-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0827]

[0828] Under argon atmosphere, tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (0.02 g, 0.031 mmol, 1.0 equivalent) and NCS (4.12 mg, 0.031 mmol, 1.0 equivalent) were dissolved in acetonitrile (5 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 48 h. H2O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (0% to 5%) to give a product as a yellow oil (0.017 g, 81%). MS (ESI) m / z 683.5 [M+H] + .

[0829] Step 2: 1-(1-chloro-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 118)

[0830]

[0831] Under argon atmosphere, the compound obtained above (0.017 g, 0.025 mmol, 1.0 equivalent) was dissolved in TFA (1 mL) and DCM (3.00 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 2 h. Saturated NaHCO3 (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give a product as a white solid (5.1 mg, 35.2%). 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.13(s,1H),7.74(s,1H),7.35(dd,J=8.2,5.8Hz,2H),7.12(t,J=8.8Hz,2H ),4.26(q,J=14.9Hz,2H),4.06-3.80(m,3H),3.68-3.46(m,3H),3.25-3.01(m,4H),3 .01-2.78(m,3H),2.73(d,J=10.6Hz,1H),2.69-2.57(m,1H),2.27-2.12(m,1H),2.0 9-1.82(m,3H),1.69(d,J=12.3Hz,6H),1.15(d,J=4.6Hz,3H),0.91(d,J=5.7Hz,3H). MS(ESI)m / z 583.8[M+H] + .

[0832] Example 69: 1-(1-bromo-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 119)

[0833]

[0834] Compound 119 (7.7 mg) was synthesized as a white solid in a manner similar to that described in compound 118. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.22(s,1H),7.72(s,1H),7.37(dd,J=8.3,5.8Hz,2H),7.10(t,J=8.8Hz,2H),4.25(q,J=14.5 Hz,2H),4.10(d,J=10.4Hz,1H),3.91-3.77(m,2H),3.62(d,J=16.4Hz,1H),3.49-3.43(m,2H),3.15(t, J=10.3Hz,1H),2.97-2.76(m,4H),2.71(d,J=9.9Hz,1H),2.60(d,J=8.9Hz,2H),2.43(d,J=10.8Hz,1H ),2.32-2.23(m,1H),2.19-2.07(m,1H),2.04-1.86(m,2H),1.74(d,J=13.1Hz,6H),0.96-0.86(m,6H). MS(ESI)m / z 626.6[M+H] + .

[0835] Example 70: Ethyl 4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyridine-3-carboxylate (Compound 120)

[0836]

[0837] Steps 1-2: 6-(tert-butyl)3-ethyl 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyridine-3,6-dicarboxylate

[0838]

[0839] At 0 °C, MSH (2.41 g, 11.2 mmol, 3.5 equivalence) was added to a solution of tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (1.14 g, 3.2 mmol, 1.0 equivalence) in DCM (15 mL), and the resulting solution was stirred at room temperature for 18 h. TLC showed that the reaction was complete. The reaction solution was evaporated. The crude product was dissolved in DMF (30 mL) at room temperature. Ethyl propynate (0.63 g, 6.4 mmol, 2.0 equivalence) and K2CO3 (1.33 g, 9.6 mmol, 3.0 equivalence) were added sequentially, and the resulting solution was stirred for 4 h. TLC showed that the reaction was complete. The mixture was diluted with 100 mL of H₂O and extracted with ethyl acetate, dried over sodium sulfate, concentrated under vacuum, and purified by rapid silica gel column chromatography to give the title compound (0.25 g, 16.8%, two steps). LCMS: [M+H] + =468.1.

[0840] Step 3: Ethyl 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyridine-3-carboxylate

[0841]

[0842] The above intermediate (50 mg, 0.107 mmol) was stirred at 0 °C for 1 h in hydrogen chloride (4 M solution, dioxane). The solvent was removed to give the title compound (50 mg, crude product), LCMS: [M+H]. + =368.2.

[0843] Step 4: Ethyl 6-(2-chloroacetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyridine-3-carboxylate

[0844]

[0845] At 0°C, DIPEA (2.0 equivalents) was added to a solution of the above intermediate (50 mg, crude product) in DCM. After stirring for 1.5 h, water was added to the residue, and the mixture was extracted with DCM. The solvent was removed under vacuum to give the crude product, which was used directly in the next step.

[0846] Steps 5-6: Ethyl 4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyridine-3-carboxylate (Compound 120)

[0847]

[0848] At 25 °C, a mixture of K₂CO₃ (2.0 equivalents), KI (1.5 equivalents), and tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate II (1.2 equivalents) was added to a solution of the crude product. The reaction was stirred at room temperature for 1 h. LC-MS indicated that the starting material was completely consumed and new peaks were formed.

[0849] ([M+H)) + =721.23). The reaction mixture was quenched by adding water, then extracted with ethyl acetate, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the key intermediate. The residue was then dissolved in 4M HCl / dioxane. The mixture was stirred at room temperature for 1 h. HPLC-MS indicated the formation of a new main peak with the desired MS, which was then quenched with water and purified by preparative HPLC (30 min, acetonitrile 20% to 50%, 45 mL / min). After lyophilization, the desired product (2 mg) was given as a white solid. MS (ESI) m / z 621.6 [M+H]+.

[0850] Example 71: 1-(4-(4-fluorobenzyl)-2-(fluoromethyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 121)

[0851]

[0852] Step 1: 1-(4-(4-fluorobenzyl)-2-(hydroxymethyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one

[0853]

[0854] Under argon atmosphere, (4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-2-yl)methanol (0.03 g, 0.092 mmol, 1.0 equivalent) and AcCl (0.014 g, 0.184 mmol, 2.0 equivalent) were dissolved in acetonitrile (5 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 2 h. Saturated NaCl (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (0% to 5%) to give a product (0.03 g, 89%) as a yellow oil. MS (ESI) m / z 368.4 [M+H] + .

[0855] Step 2: 1-(4-(4-fluorobenzyl)-2-(fluoromethyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one

[0856]

[0857] Under argon atmosphere, 1-(4-(4-fluorobenzyl)-2-(hydroxymethyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one (0.03 g, 0.082 mmol, 1.0 equivalent) was dissolved in DCM (5 mL) to give a yellow solution. The reaction mixture was cooled to -78 °C using a dry ice / acetone bath. DAST (0.039 g, 0.245 mmol, 3 equivalent) was added to the reaction mixture in a single addition. The reaction mixture was stirred at -78 °C for 3 h. H2O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (0% to 4%) to give a product as a yellow oil (0.015 g, 49.7%). MS (ESI) m / z 370.5 [M+H] + .

[0858] Step 3: 4-(4-fluorobenzyl)-2-(fluoromethyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine

[0859]

[0860] Under argon atmosphere, 1-(4-(4-fluorobenzyl)-2-(fluoromethyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)ethyl-1-one (0.015 g, 0.041 mmol, 1.0 equivalent) and HCl (6N, 2 mL) were dissolved in EtOH (4 mL) to give a yellow solution. The reaction mixture was stirred at 82 °C for 2 h. Saturated NaHCO3 (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a product (0.013 g, 98%) as a yellow oil. MS (ESI) m / z 328.6 [M+H] + .

[0861] Step 4: 2-Chloro-1-(4-(4-fluorobenzyl)-2-(fluoromethyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one

[0862]

[0863] 4-(4-fluorobenzyl)-2-(fluoromethyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine (0.013 g, 0.040 mmol, 1.0 equivalent), 2-chloroacetyl chloride (6.73 mg, 0.060 mmol, 1.5 equivalent), and DIEA (10.26 mg, 0.079 mmol, 2.0 equivalent) were dissolved in DCM (10 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 h. H2O (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (0% to 4%) to give a product as a yellow oil (0.012 g, 74.8%). MS(ESI) m / z 404.7 [M+H] + .

[0864] Step 5: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-2-(fluoromethyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0865]

[0866] Under argon atmosphere, 2-chloro-1-(4-(4-fluorobenzyl)-2-(fluoromethyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl) ethyl-1-one (0.024 g, 0.059 mmol, 1.0 equivalent), tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (0.022 g, 0.071 mmol, 1.2 equivalent), KI (0.015 g, 0.089 mmol, 1.5 equivalent), and K₂CO₃ (0.025 g, 0.178 mmol, 3.0 equivalent) were dissolved in acetonitrile (10 mL) to give a yellow suspension. The reaction mixture was stirred at room temperature for 5 h. Saturated NaCl (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (0% to 5%) to give a product as a yellow oil (0.008 g, 19.77%). MS (ESI) m / z 681.8 [M+H] + .

[0867] Step 6: 1-(4-(4-fluorobenzyl)-2-(fluoromethyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 121)

[0868]

[0869] Under argon atmosphere, tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-2-(fluoromethyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (0.008 g, 0.012 mmol, 1.0 equivalent) was dissolved in TFA (1 mL) and DCM (3.00 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 2 h. Saturated NaHCO3 (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC to give a product as a white solid (1.0 mg, 14.6%). MS(ESI)m / z581.6[M+H] + .

[0870] Example 72: 1-(2-(difluoromethyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)

[0871] Ethyl-1-one (compound 122)

[0872]

[0873] Step 1: Benzyl 4-(4-fluorobenzyl)-2-formyl-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-6-carboxylate

[0874]

[0875] Under argon atmosphere, benzyl 4-(4-fluorobenzyl)-2-(hydroxymethyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-6-carboxylate (0.05 g, 0.109 mmol, 1.0 equivalent) and DMP (0.069 g, 0.163 mmol, 1.5 equivalent) were dissolved in DCM (10 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 3 h. Saturated NaHCO3 (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (0% to 50%) to give a product (0.05 g, 100%) as a yellow oil. MS(ESI) m / z 458.6 [M+H] + .

[0876] Step 2: Benzyl 2-(difluoromethyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-6-carboxylate

[0877]

[0878] Under argon atmosphere, benzyl 4-(4-fluorobenzyl)-2-formyl-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-6-carboxylate (0.05 g, 0.109 mmol, 1.0 equivalent) was dissolved in DCM (10 mL) to give a yellow solution. The reaction mixture was cooled to -78 °C with a dry ice / acetone bath. DAST (0.053 g, 0.328 mmol, 3 equivalent) was added to the reaction mixture in a single addition. The reaction mixture was stirred at 0 °C for 16 h. Saturated NaCl (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (0% to 40%) to give a product (0.044 g, 84%) as a yellow oil. MS(ESI) m / z 480.7 [M+H] + .

[0879] Step 3: 2-(difluoromethyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine

[0880]

[0881] Under H2, benzyl 2-(difluoromethyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-imidazo[1,2-a]pyrrolo[2,3-e]pyridine-6-carboxylate (0.044 g, 0.092 mmol, 1.0 equivalent) and Pd / C (0.020 g, 0.184 mmol, 2 equivalent) were dissolved in MeOH (5 mL) to give a black suspension. The reaction mixture was stirred at room temperature for 1 h. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (0% to 50%) to give a product (0.032 g, 100%) as a yellow oil. MS (ESI) m / z 346.4 [M+H] + .

[0882] Steps 4-6: Following the synthesis of compound 14, compound 122 (2.1 mg) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.05-7.94(m,2H),7.36-7.28(m,2H),7.12-7.03(m,2H),4.04-3.89(m,3H),3.8 3-3.75(m,1H),3.73-3.60(m,2H),3.50(d,J=10.2Hz,2H),3.10-3.00(m,2H),2.96-2.89( m,1H),2.86-2.75(m,3H),2.72-2.60(m,3H),2.37-2.28(m,2H),2.21-2.10(m,1H),1.98- 1.87(m,1H), 1.77(d,J=11.6Hz,1H), 1.58(d,J=12.1Hz,6H), 0.91(dd,J=9.0,6.3Hz,6H). MS(ESI)m / z 599.8[M+H] + .

[0883] Example 73: 1-(4-(2-chloro-4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 123)

[0884]

[0885] Step 1: tert-butyl 6-bromo-3,3-dimethyl-4-(l1-oxoalkyl)-2,3-dihydro-1H-4l4-pyrrolo[3,2-b]pyridine-1-carboxylate

[0886]

[0887] At 0 °C, 1-chloro-3-hydroperoxybenzene (2.430 g, 16.81 mmol, 1.1 equivalent) was added to a solution of tert-butyl-6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (5 g, 15.28 mmol, 1.0 equivalent) in CH2Cl2 (15 mL), and the mixture was stirred at 25 °C under N2 for 16 h. A saturated aqueous solution of NaHCO3 and ethyl acetate were then added to the reaction mixture. The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (5.24 g, 100%) as a yellow solid. MS (ESI) m / z 344.6 [M+H]+.

[0888] Step 2: 1-(6-bromo-1-(tert-butoxycarbonyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)pyridin-1-onium

[0889]

[0890] At 0 °C, pyridine (6.06 g, 77 mmol, 5.0 equivalent) was added to a solution of 6-bromo-1-(tert-butoxycarbonyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine 4-oxide (5.26 g, 15.33 mmol, 1.0 equivalent) in MeCN (80 mL), followed by the addition of 2,2,2-trifluoroacetic anhydride (9.66 g, 46.0 mmol, 3.0 equivalent) at 0 °C. The mixture was stirred at room temperature for 16 h (under N2), and the mixture was concentrated to give the title compound as a yellow oil, which was used directly in the next step. MS (ESI) m / z 405.8 [M+H]+.

[0891] Step 3: tert-butyl-5-amino-6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

[0892]

[0893] A solution of 1-(6-bromo-1-(tert-butoxycarbonyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5-yl)pyridin-1-onium (6.21 g, 15.32 mmol, 1.0 equivalent) in NH3 (in CH3OH) (50 mL) was stirred in a sealed tube at 80 °C for 3 h. The mixture was then concentrated and purified by rapid silica gel column chromatography (eluting with PE / EA = 5 / 1) to give the title compound (4.7 g, 90%) as a yellow oil. MS (ESI) m / z 343.6 [M+H]+.

[0894] Step 4: tert-butyl(E)-6-bromo-5-(N'-hydroxyformamidinium)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

[0895]

[0896] At 25 °C, 1,1-dimethoxy-N,N-dimethylmethylamine (52.2 mg, 0.438 mmol, 1.5 equivalents) was added to a solution of tert-butyl 5-amino-6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (100 mg, 0.292 mmol, 1.0 equivalents) in 15 mL of 2-propanol. The mixture was heated to 80 °C for 2 h under N2, and then hydroxylamine hydrochloride (40.6 mg, 0.584 mmol, 2.0 equivalents) was added at room temperature. The mixture was then heated to 50 °C for 1 h under N2. After concentration, the residue was used directly in the next step.

[0897] Step 5: tert-butyl-4-bromo-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxylate

[0898]

[0899] At 25 °C, 2,2,2-trifluoroacetic anhydride (92 mg, 0.440 mmol, 1.5 equivalent) was added to a solution of tert-butyl(E)-6-bromo-5-(N'-hydroxymethylamidine)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (113 mg, 0.293 mmol, 1.0 equivalent) in 15 mL of THF. The mixture was stirred at 25 °C for 2 h under N2, and then the solution was concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane = 1:20 to give the title compound (100 mg, 93%) as a white solid. MS (ESI) m / z 368.6 [M+H] +.

[0900] Step 6: tert-butyl-4-(2-chloro-4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxylate

[0901]

[0902] At 25 °C, potassium (2-chloro-4-fluorobenzyl)triazolo[1,5-a]pyridine-6-carboxylate (100 mg, 0.272 mmol, 1.0 equivalent) was added to a solution of tert-butyl-4-bromo-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (100 mg, 0.272 mmol, 1.0 equivalent) in 1,4-dioxane (10 mL) / water (1.0 mL). The mixture was stirred at 95 °C under N2 for 8.0 h. H2O was added to the reaction mixture, followed by extraction with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (ethyl acetate:hexane = 1:1) to give the title compound (70 mg, 59.7%) as a yellow solid.

[0903] Step 7: 4-(2-chloro-4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine

[0904]

[0905] TFA (5 mL) was added to a solution of tert-butyl-4-(2-chloro-4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (70 mg, 0.162 mmol, 1.0 equivalent) in CH2Cl2 (10 mL) at 25 °C. The mixture was stirred at 25 °C for 2 h. After concentration, saturated aqueous solution of NaHCO3 and ethyl acetate were added. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (48 mg, 89%) as a yellow solid.

[0906] Step 8: 2-Chloro-1-(4-(2-chloro-4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl) ethyl-1-one

[0907]

[0908] At 0 °C, N-ethyl-N-isopropylpropyl-2-amine (56.3 mg, 0.435 mmol, 3.0 equivalent) was added to a solution of 4-(2-chloro-4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine (48 mg, 0.145 mmol, 1.0 equivalent) in CH2Cl2 (15 mL). At 0 °C, 2-chloroacetyl chloride (19.67 mg, 0.174 mmol, 1.2 equivalent) was added, and the mixture was stirred at room temperature for 3 h (under N2). Water and DCM were added. The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with DCM / CH3OH (50:1) to give the title compound (20 mg, 33.8%) as a white solid. MS (ESI) m / z 407.2 [M+H] + .

[0909] Step 9: tert-butyl(2R,5S)-4-(2-(4-(2-chloro-4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0910]

[0911] At 25 °C, tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (15.39 mg, 0.049 mmol, 1.0 equivalent) was added to a solution of 2-chloro-1-(4-(2-chloro-4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)acetonitrile (15 mL) at acetonitrile (15 mL). Potassium iodide (12.23 mg, 0.074 mmol, 1.5 equivalent) and K₂CO₃ (20.36 mg, 0.147 mmol, 3.0 equivalent) were added at 25 °C, and the mixture was stirred at room temperature for 3 h (under N₂). Water and ethyl acetate were added. The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography, eluting with DCM / CH₃OH (50 / 1) to give the title compound (17 mg, 50.6%) as a yellow solid. MS (ESI) m / z 684.5 [M+H] + .

[0912] Step 10: 1-(4-(2-chloro-4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 123)

[0913]

[0914] A solution of tert-butyl(2R,5S)-4-(2-(4-(2-chloro-4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (17 mg, 0.025 mmol, 1.0 equivalent) in HCl / dioxane (3 mL) was stirred at 25 °C for 30 min. The solvent was evaporated and a solution of 7.0 N NH3 (in CH3OH) (5 mL) was added. After concentration, the residue was purified by preparative HPLC to give the title compound (2.5 mg, 17.23%) as a white solid. MS (ESI) m / z 584.5 [M+H] + . 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)8.52(s,1H),8.20(s,1H),7.57-7.44(m,2H),7.28-7.15(m,1H),4.48-4.31(m,2 H),4.12(d,J=10.6Hz,1H),3.92(d,J=10.5Hz,1H),3.80-3.64(m,2H),3.47-3.43(m,2H) ,3.16-2.99(m,2H),2.91-2.60(m,6H),2.59-2.53(m,1H),2.35-2.23(m,1H),2.19-2.08 (m,1H),2.04-1.84(m,1H),1.76(d,J=12.4Hz,1H),1.68-1.53(m,6H),0.96-0.84(m,6H).

[0915] Example 74: 1-(4-(4-fluorobenzyl)-1,3,8,8-tetramethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 124)

[0916]

[0917] Step 1: tert-butyl(2R,5S)-4-(2-(3-bromo-4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0918]

[0919] Under argon atmosphere, tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (0.038 g, 0.057 mmol, 1.0 equivalent) and NBS (10.20 mg, 0.057 mmol, 1.0 equivalent) were dissolved in acetonitrile (5 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 h. Saturated NaHCO3 (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (0% to 5%) to give a product as a yellow oil (0.02 g, 47.0%). MS (ESI) m / z 741.5 [M+H] + .

[0920] Step 2: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1,3,8,8-tetramethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0921]

[0922] Under argon atmosphere, tert-butyl(2R,5S)-4-(2-(3-bromo-4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (0.02 g, 0.027 mmol, 1.0 equivalent) and 2,4,6-trimethyl-1 3,5,2,4,6-cyclotrioxatriborinane (0.017 g, 0.135 mmol, 5.0 equivalents), K₂CO₃ (0.011 g, 0.081 mmol, 3.0 equivalents), and PdCl₂ (dppf) (3.95 mg, 5.39 μmol, 0.2 equivalents) were dissolved in water (0.500 mL) and 1,4-dioxane (5 mL) to give a brown suspension. The reaction mixture was stirred at 100 °C for 6 h. Saturated NaCl (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (0% to 5%) to give a product (0.006 g, 32.9%) as a yellow oil. MS(ESI) m / z 677.8 [M+H] + .

[0923] Step 3: 1-(4-(4-fluorobenzyl)-1,3,8,8-tetramethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetoone

[0924]

[0925] Under argon atmosphere, tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1,3,8,8-tetramethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (0.01 g, 0.015 mmol, 1.0 equivalent) was dissolved in TFA (1 mL) and DCM (3.00 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 h. Saturated NaHCO3 (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give a product as a white solid (1.0 mg, 11.7%). MS(ESI) m / z 577.6 [M+H] + .

[0926] Example 75: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-3-(hydroxymethyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (compound 125)

[0927]

[0928] Step 1: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-3-carboxylo-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0929]

[0930] Under argon atmosphere, tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (0.045 g, 0.068 mmol, 1.0 equivalent) and POCl3 (0.021 g, 0.136 mmol, 2.0 equivalent) were dissolved in DMF (3 mL) to give a yellow solution. The reaction mixture was stirred at 80 °C for 3 h. Saturated NaHCO3 (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (0% to 5%) to give a product as a yellow oil (0.012 g, 25.6%). MS (ESI) m / z 691.7 [M+H] + .

[0931] Step 2: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-3-(hydroxymethyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0932]

[0933] Under argon atmosphere, tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-3-carboxylo-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (0.012 g, 0.017 mmol, 1.0 equivalent) and NaBH4 (1.971 mg, 0.052 mmol, 3.0 equivalent) were dissolved in THF (5 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 3 h. Saturated NH4Cl (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to give the product (0.012 g, 100%). MS (ESI) m / z 693.8 [M+H] + .

[0934] Step 3: 1-(4-(4-fluorobenzyl)-3-(hydroxymethyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 125)

[0935]

[0936] Under argon atmosphere, tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-3-(hydroxymethyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (0.012 g, 0.017 mmol, 1.0 equivalent) was dissolved in TFA (1 mL) and DCM (3.00 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 h. Saturated NaHCO3 (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give a white solid (0.3 mg, 2.9%). MS (ESI) m / z 593.6 [M+H] + .

[0937] Example 76: 1-(4-(4-fluorobenzyl)-2-methoxy-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 126)

[0938]

[0939] Step 1: Benzyl 4-(4-fluorobenzyl)-2-methoxy-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxylate

[0940]

[0941] A solution of benzyl 4-(4-fluorobenzyl)-2-hydroxy-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (0.1 g, 0.22 mmol) in MeOH (2.0 mL) was mixed with K₂CO₃ (0.062 g, 0.45 mmol) and iodomethane (0.064 g, 0.45 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate and then washed with H₂O and saturated NaCl. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (1:3) to give the title compound (80 mg, 78%) as a yellow oil. MS: 461.2 (M+H) + ).

[0942] The following steps are taken: Compound 126, which is a white solid, is obtained in a manner similar to that described in Compound 127. 1 HNMR(400MHz,CD3OD)δ(ppm)8.27(s,1H),7.36-7.24(m,2H),7.08-6.93(m,2H),4.23-4.16(m,2H),4.09-4.02(m,3H),3.66-3.52(m,4H),3.27 (s,3H),3.08-2.82(m,7H),2.55-2.42(m,2H),2.30-2.17(m,1H),2.07 -1.99(m,1H),1.94-1.80(m,1H),1.70-1.60(m,6H),1.06-0.91(m,6H). MS:580.3(M+H + ).

[0943] Example 77: 4-(4-fluorobenzyl)-1,8,8-trimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-1H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2(6H)-one (Compound 127)

[0944]

[0945] Step 1: Benzyl 4-(4-fluorobenzyl)-2-iodo-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxylate

[0946]

[0947] At 0 °C, a solution of 4-methylbenzenesulfonic acid (464 mg, 2.69 mmol) and benzyl-2-amino-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (200 mg, 0.45 mmol) in acetonitrile (3.0 ml) was added to a solution of sodium nitrite (155 mg, 2.25 mmol) and KI (373 mg, 2.25 mmol) in water (3.0 ml). The mixture was stirred at room temperature for 2 h. The mixture was quenched with a saturated aqueous solution of NaHCO3 and the reaction mixture was diluted with ethyl acetate and washed with H2O and saturated NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (1:5) to give the title compound (0.2 g, 80%) as a yellow oil. MS: 557.1 (M+H) + ).

[0948] Step 2: Benzyl 4-(4-fluorobenzyl)-2-hydroxy-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxylate

[0949]

[0950] Sodium 2-methylpropane-2-ol (104 mg, 1.08 mmol) and the PdCl2(dppf)-CH2Cl2 adduct (29 mg, 0.036 mmol) were added to a solution of benzyl 4-(4-fluorobenzyl)-2-iodo-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (0.2 g, 0.36 mmol) in 1,4-dioxane (5.0 mL) / water (0.5 mL). The mixture was packed with N2 and stirred at 110 °C for 2 h. The mixture was cooled to room temperature and diluted with a saturated aqueous solution of NH4Cl, and then washed with H2O and saturated brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (1:10) to give the title compound (0.1 g, 62.3%) as a yellow oil. MS: 447.2 (M+H) + ).

[0951] Step 3: Benzyl 2-(benzoyloxy)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxylate

[0952]

[0953] At 0 °C, TEA (0.16 g, 1.58 mmol) and benzoyl chloride (0.16 g, 1.18 mmol) were added to a solution of benzyl 4-(4-fluorobenzyl)-2-hydroxy-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (0.35 g, 0.79 mmol) in DCM (5.0 mL). The mixture was stirred at 20 °C for 2 h. The mixture was cooled to room temperature and diluted with a saturated aqueous solution of NaHCO3 and then washed with H2O and saturated brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (1:3) to give the title compound (0.26 g, 60.2%) as a white solid. MS: 551.2 (M+H + ).

[0954] Step 4: 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2-ylbenzoate

[0955]

[0956] Pd / C (10%, 20 mg) was added to a solution of benzyl 2-(benzoyloxy)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (260 mg, 0.47 mmol) in MeOH (10 mL). The mixture was packed three times with H2 and stirred at room temperature for 2 h. The mixture was filtered and concentrated. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (1:20) to give 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-2-ylbenzoate (180 mg, 92%) as a colorless oil. MS: 417.2 (M+H) + ).

[0957] Step 5: 6-(2-chloroacetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2-ylbenzoate

[0958]

[0959] Add 2-chloroacetyl chloride (58.6 mg, 0.52 mmol) to a solution of 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2-ylbenzoate (180 mg, 0.44 mmol) in DCM (3.0 mL). Stir the mixture at room temperature for 1 h. Concentrate the mixture to give 195 mg of crude product, which was used directly in the next step. MS: 493.1 (M+H) + ).

[0960] Step 6: tert-butyl(2R,5S)-4-(2-(2-(benzoyloxy)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0961]

[0962] To a solution of 6-(2-chloroacetyl)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2-ylbenzoate (195 mg, 0.4 mmol) in acetonitrile (3.0 mL), tert-butyl(2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (124 mg, 0.4 mmol), potassium iodide (99 mg, 0.6 mmol), and K₂CO₃ (164 mg, 1.2 mmol) were added. The mixture was stirred at 29 °C for 2 h. The mixture was filtered and concentrated to give 230 mg of crude product, which was used directly in the next step. MS: 770.4 (M+H) + ).

[0963] Step 7: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-2-hydroxy-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0964]

[0965] NH3 was added to a solution of tert-butyl(2R,5S)-4-(2-(2-(benzoyloxy)-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (230 mg, 0.3 mmol) in MeOH. The mixture was stirred at 29 °C for 2 h. The mixture was filtered and concentrated to give a crude product. The crude product was added to a silica gel column and eluted with methanol / dichloromethane (1:10) to give the title compound (150 mg, 75%) as a colorless oil. MS: 666.4 (M+H) + ).

[0966] Step 8: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1,8,8-trimethyl-2-oxo-1,2,7,8-tetrahydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0967]

[0968] Iodine (426 mg, 3.0 mmol) and Cs₂CO₃ (245 mg, 0.75 mmol) were added to a solution of tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-2-hydroxy-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (100 mg, 0.15 mmol) in MeOH (2 mL). The mixture was stirred at 80 °C for 12 h. The mixture was concentrated and the crude product was added to a silica gel column and eluted with DCM / MeOH (10:1) to give the title compound (38 mg, 37.2%) as a white solid. MS: 680.4 (M+H) + ).

[0969] Step 9: 4-(4-fluorobenzyl)-1,8,8-trimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-1H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2(6H)-one (Compound 127)

[0970]

[0971] TFA (1.0 mL) was added to a solution of tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-1,8,8-trimethyl-2-oxo-1,2,7,8-tetrahydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (38 mg, 0.06 mmol) in DCM (2.0 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated and the crude product was added to a preparative HPLC column and eluted with water / acetonitrile (5%–45%) to give the title compound (6.1 mg, 18.82%) as a white solid. 1 H NMR (400MHz, CD3OD) δ (ppm) 8.34-8.22 (s, 1H), 7.20 (dd, J = 8.5, 5.4Hz, 2H), 7.09 (t, J =8.8Hz,2H),4.52-4.40(m,2H),4.15-3.98(m,3H),3.70-3.55(m,6H),3.41-3.33(m,1 H),3.09-2.77(m,7H),2.55-2.42(m,2H),2.31-2.19(m,1H),2.09-1.97(m,1H),1.92 -1.80(m,1H),1.69(s,3H),1.66(s,3H),1.02(d,J=6.3Hz,3H),0.96(d,J=6.3Hz,3H). MS:580.3(M+H + ).

[0972] Example 78: 1-(4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,3]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 128)

[0973]

[0974] Step 1: tert-butyl(E)-6-(4-fluorobenzyl)-3,3-dimethyl-5-((2-toluenesulfonylhydrazinyl)methyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

[0975]

[0976] Under argon atmosphere, tert-butyl 6-(4-fluorobenzyl)-5-formyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (0.1 g, 0.260 mmol, 1.0 equivalent) and 4-methylbenzenesulfonyl hydrazine (0.048 g, 0.260 mmol, 1.0 equivalent) were dissolved in MeOH (3 mL) and DCM (3.00 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give the product (0.144 g, 100%). MS (ESI) m / z 553.6 [M+H] + .

[0977] Step 2: tert-butyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,3]triazolo[1,5-a]pyridine-6-carboxylate

[0978]

[0979] Under argon atmosphere, tert-butyl(E)-6-(4-fluorobenzyl)-3,3-dimethyl-5-((2-toluenesulfonylhydrazine)methyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (0.144 g, 0.261 mmol, 1.0 equivalent) was dissolved in morpholine (3 mL) to give a yellow solution. The reaction mixture was stirred at 100 °C for 2 h. H₂O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (0% to 30%) to give a product as a white solid (0.09 g, 87%). MS (ESI) m / z 397.7 [M+H] + .

[0980] Step 3: 4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,3]triazolo[1,5-a]pyridine

[0981]

[0982] Under argon atmosphere, tert-butyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,3]triazolo[1,5-a]pyridine-6-carboxylate (0.09 g, 0.227 mmol, 1.0 equivalent) was dissolved in TFA (1 mL) and DCM (3.00 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 1 h. Saturated NaHCO3 (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the product (0.067 g, 100%). MS (ESI) m / z 297.8 [M+H] + .

[0983] Steps 4-6: Following the synthesis of compound 14, compound 128 (6.7 mg) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.37(s,1H),8.17(s,1H),7.38(dd,J=8.3,5.7Hz,2H),7.14(t,J=8.8Hz,2H),4.26(s,2H),4.17(d,J=10.6Hz,1H),3.97(d,J=

[0984] 10.6Hz,1H),3.76(dd,J=37.1,17.0Hz,2H),3.48(d,J=10.9Hz,2H),3.13(d,J=11.2Hz,1H),3.08-3.01(m,1H),2.91-2.78(m,3H),2.70-2. 64(m,2H),2.36-2.28(m,2H),2.21-2.10(m,1H),1.98-1.88(m,2H),1.78(d,J=12.8Hz,1H),1.64(d,J=16.7Hz,6H),0.91(d,J=5.5Hz,6H). MS(ESI)m / z 550.5[M+H] + .

[0985] Example 79: 1-(4-(2-amino-4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 129)

[0986]

[0987] Step 1: tert-butyl(2R,5S)-4-(2-(4-(4-fluoro-2-hydroxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0988]

[0989] At 25 °C, di-tert-butyl dicarbonate (44.5 mg, 0.204 mmol, 1.5 equivalence) and triethylamine (41.3 mg, 0.408 mmol, 3.0 equivalence) were added to a solution of 1-(4-(4-fluoro-2-hydroxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethyl-1-one (77 mg, 0.136 mmol, 1.0 equivalence) in DMF (15 mL). The mixture was then stirred at 25 °C for 16 h (under N2). 2N was added to the mixture. NaOH aqueous solution was stirred at room temperature for 1 h, followed by the addition of saturated citric acid aqueous solution, and then saturated NaHCO3 aqueous solution. The solution was extracted with ethyl acetate, and the organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (eluting with DCM / CH3OH = 20 / 1) to give the title compound as a yellow solid (59 mg, 65.2%). MS (ESI) m / z 666.6 [M+H] + .

[0990] Step 2: tert-butyl(2R,5S)-4-(2-(4-(4-fluoro-2-(((trifluoromethyl)sulfonyl)oxy)benzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0991]

[0992] At 0 °C, pyridine (18.53 mg, 0.234 mmol, 3.0 equivalent) was added to a solution of tert-butyl(2R,5S)-4-(2-(4-(4-fluoro-2-hydroxybenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (52 mg, 0.078 mmol, 1.0 equivalent) in CH2Cl2 (15 mL). Trifluoromethanesulfonic anhydride (33.1 mg, 0.117 mmol, 1.5 equivalent) was added at 0 °C. The mixture was stirred at 25 °C under N2 for 16 h. The solution was extracted with ethyl acetate, and the organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (eluting with DCM / CH3OH = 20 / 1) to give the title compound (50 mg, 80%) as a yellow solid. MS (ESI) m / z 798.5 [M+H]+.

[0993] Step 3: tert-butyl(2R,5S)-4-(2-(4-(2-((diphenylmethylene)amino)-4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[0994]

[0995] At 25°C, tert-butyl(2R,5S)-4-(2-(4-(4-fluoro-2-(((trifluoromethyl)sulfonyl)oxy)benzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (50 mg, 0.0 Benzophenone imine (13.63 mg, 0.075 mmol, 1.2 equivalent), Pd2(dba)3 (5.74 mg, 6.27 μmol, 0.1 equivalent), BINAP (3.90 mg, 6.27 μmol, 0.1 equivalent), and Cs2CO3 (40.8 mg, 0.125 mmol, 2.0 equivalent) were added to a solution of dioxane (15 mL). The mixture was stirred at 100 °C under N2 for 16 h. The solution was extracted with ethyl acetate, and the organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (eluting with DCM / CH3OH = 20 / 1) to give the title compound (30 mg, 57.7%) as a yellow solid.

[0996] Step 4: 1-(4-(2-amino-4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 129)

[0997]

[0998] At room temperature, 3 mL of 2N HCl aqueous solution was added to a solution of tert-butyl(2R,5S)-4-(2-(4-(2-(((diphenylmethylene)amino)-4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (30 mg, 0.036 mmol, 1.0 equivalent) in MeOH (3 mL), and the mixture was stirred at 25 °C for 1 h. After concentration, 5 mL of 4N HCl / dioxane was added, and the mixture was stirred at room temperature for 1 h. After evaporating the mixture, an aqueous solution of NH3 / CH3OH was added to the result, the solution was concentrated, and the residue was purified by preparative HPLC to give the title compound as a white solid (1.7 mg, 8.32%).

[0999] 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.53(s,1H),8.29(s,1H),7.06-6.93(m,1H),6.46-6.34(m,1H),6.31-6.21(m,1H) ,5.40(s,2H),4.14-4.10(m,2H),3.92(d,J=10.6Hz,1H),3.80-3.71(m,2H),3.51-3.42(m, 3H),3.24-3.14(m,2H),2.92-2.73(m,5H),2.71-2.60(m,2H),2.41-2.25(m,1H),2.20-2.0 8(m,1H),1.96-1.88(m,1H),1.84-1.74(m,1H),1.59(d,J=18.4Hz,6H),1.00-0.87(m,6H).

[1000] Example 80: 4-(4-fluorobenzyl)-1,8,8-trimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridine-3-carboxynitrile (Compound 130)

[1001]

[1002] Step 1: tert-butyl-4-(4-fluorobenzyl)-3-iodo-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridine-6-carboxylate

[1003]

[1004] Under argon atmosphere, tert-butyl 4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridine-6-carboxylate (0.2 g, 0.488 mmol, 1.0 equivalent) was dissolved in acetonitrile (10 mL) to give a yellow solution. The reaction mixture was cooled to 0 °C in an ice / water bath. NIS (0.110 g, 0.488 mmol, 1.0 equivalent) was added to the reaction mixture in a single addition. The reaction mixture was stirred at room temperature for 1 h. Saturated NaCl (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (0% to 40%) to give a product (0.114 g, 43.6%) as a yellow oil. MS(ESI)m / z536.6[M+H] + .

[1005] Step 2: tert-butyl-3-cyano-4-(4-fluorobenzyl)-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridine-5-carboxylate

[1006]

[1007] Under argon atmosphere, tert-butyl 4-(4-fluorobenzyl)-3-iodo-1,8,8-trimethyl-7,8-dihydro-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyridine-6-carboxylate (0.114 g, 0.213 mmol, 1.0 equivalent) and cuprous cyanide (I) (0.057 g, 0.639 mmol, 3.0 equivalent) were dissolved in DMSO (3 mL) to give a yellow suspension. The reaction mixture was stirred at 135 °C for 6 h. Saturated NaCl (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with ethyl acetate / hexane (0% to 40%) to give a product as a yellow oil (0.023 g, 24.86%). MS(ESI) m / z 435.6 [M+H] + .

[1008] The following steps were performed: Compound 130 (7.8 mg), which was a white solid, was synthesized according to the synthesis of compound 14. 1 H NMR (400MHz, DMSO-d) 6)δ(ppm)7.97(s,1H),7.34-7.25(m,2H),7.22-7.13(m,2H),4.44-4.30(m,2H),4.08(d,J=10. 5Hz,1H),3.90-3.77(m,2H),3.62(d,J=16.4Hz,1H),3.51-3.46(m,2H),3.18(t,J=9.6Hz,1H) ,3.00-2.72(m,8H),2.71-2.58(m,2H),2.48-2.43(m,1H),2.37-2.27(m,1H),2.22-2.10(m,1 H), 1.98-1.88 (m, 1H), 1.77 (d, J = 11.1Hz, 1H), 1.57 (d, J = 18.0Hz, 6H), 0.90 (d, J = 6.0Hz, 6H). MS(ESI)m / z 588.7[M+H] + .

[1009] Example 81: 4-(4-fluorobenzyl)-8,8-dimethyl-6-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-7,8-dihydro-1H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-2(6H)-one (Compound 131)

[1010]

[1011]

[1012] TFA (1.0 mL) was added to a solution of tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzyl)-2-hydroxy-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate in DCM (2.0 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated and the crude product was added to a preparative HPLC column and eluted with water / acetonitrile (5%–45%) to give a product as a white solid. MS: 566.4 (M+H) + ).

[1013] Example 82: 1-(8,8-dimethyl-4-((2-methylthiazolyl-5-yl)methyl)-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (Compound 132)

[1014]

[1015] Step 1: tert-butyl 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

[1016]

[1017] At 25 °C, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-b)pyridine-1-carboxylate (2 g, 6.11 mmol, 1.0 equivalent) (2 g, 6.11 mmol, 1.0 equivalent), PdCl2 (dppf) (0.447 g, 0.611 mmol, 0.1 equivalent), and potassium acetate (1.800 g, 18.34 mmol, 3.0 equivalent) were added to a solution of tert-butyl-6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (2 g, 6.11 mmol, 1.0 equivalent) in dioxane (15 mL). The mixture was stirred at 100 °C under N2 for 16 h. Water and ethyl acetate were added. The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (eluting with PE / EA = 3 / 1) to give the title compound (2.2 g, 96%) as a yellow solid.

[1018] Step 2: tert-butyl 3,3-dimethyl-6-((2-methylthiazolyl-5-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate

[1019]

[1020] At 25 °C, 5-(chloromethyl)-2-methylthiazole (300 mg, 2.032 mmol, 1.0 equivalent), PdCl2 (dppf) (149 mg, 0.203 mmol, 0.1 equivalent), and K2CO3 (843 mg, 6.10 mmol, 3.0 equivalent) were added to a solution of tert-butyl-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (759 mg, 2.032 mmol, 1.0 equivalent) in dioxane (15 mL). The mixture was stirred at 100 °C under N2 for 16 h. Water and ethyl acetate were added. The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (eluting with PE / EA = 3 / 1) to give the title compound (630 mg, 86%) as a yellow solid. MS (ESI) m / z 361.1 [M+H]+.

[1021] The following steps were performed: Following the synthesis of compound 14, compound 132 (22.1 mg) was obtained as a white solid. MS (ESI) m / z 553.7 [M+H] + . 1 H NMR (400MHz, DMSO-d) 6 )δ(ppm)8.53(s,1H),8.45(s,1H),7.52(s,1H),4.49(s,2H),4.20-4.10(m,1H),4.02-3.91( m,1H),3.87-3.76(m,1H),3.73-3.62(m,1H),3.53-3.45(m,2H),3.23-3.12(m,1H),3.06-2.9 6(m,1H),2.95-2.72(m,4H),2.68-2.61(m,2H),2.55-2.52(m,3H),2.38-2.23(m,1H),2.22-2 .10(m,1H),2.03-1.88(m,1H),1.84-1.72(m,1H),1.60(d,J=16.2Hz,6H),0.95-0.85(m,6H).

[1022] Example 83: 1-(4-((S)-(4-fluorophenyl)(hydroxy)methyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetoone

[1023] and

[1024] 1-(4-((R)-(4-fluorophenyl)(hydroxy)methyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acet-1-one (compounds 133 and 134)

[1025]

[1026] Steps 1-4: 1-(5-bromo-6-(4-fluorobenzoyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one

[1027]

[1028] The above intermediate (4.1 g) was obtained as a white solid in a manner similar to that described in compound 166. MS (ESI) m / z 392.2 [M+H]+.

[1029] Step 5: 1-(5-((diphenylmethylene)amino)-6-(4-fluorobenzoyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethyl-1-one

[1030]

[1031] At 25 °C, benzophenone imine (167 mg, 0.920 mmol, 1.2 equivalent), Pd₂(dba)₃ (70.2 mg, 0.077 mmol, 0.1 equivalent), BINAP (47.7 mg, 0.077 mmol, 0.1 equivalent), and Cs₂CO₃ (500 mg, 1.534 mmol, 2.0 equivalent) were added to a solution of 1-(5-bromo-6-(4-fluorobenzoyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one (300 mg, 0.767 mmol, 1.0 equivalent) in dioxane (15 mL). The mixture was stirred at 100 °C under N₂ for 16 h. Water and ethyl acetate were added, and the combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (eluting with PE / EA = 3 / 1) to give the title compound (330 mg, 88%) as a yellow solid. MS (ESI) m / z 492.4 [M+H] + .

[1032] Step 6: 1-(5-amino-6-(4-fluorobenzoyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ethyl-1-one

[1033]

[1034] At 25 °C, 2N HCl (10 mL) was added to a solution of 1-(5-((diphenylmethylene)amino)-6-(4-fluorobenzoyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethyl-1-one (361 mg, 0.734 mmol, 1.0 equivalent) in MeOH (15 mL). The mixture was stirred at 25 °C for 1 h. A saturated aqueous solution of NaHCO3 was added. The solution was extracted with ethyl acetate, and the organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (eluting with PE / EA = 1 / 1) to give the title compound (174 mg, 72.4%) as a yellow solid. MS (ESI) m / z 328.3 [M+H] + .

[1035] Steps 7-11: tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzoyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[1036]

[1037] Following the synthesis of compound 14, the above intermediate (226 mg) was obtained as a white solid. MS (ESI) m / z 665.4 [M+H]+.

[1038] Step 12: tert-butyl(2R,5S)-4-(2-(4-((4-fluorophenyl)(hydroxy)methyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate

[1039]

[1040] At 0 °C, NaBH4 (6.84 mg, 0.181 mmol, 1.2 equivalent) was added to a solution of tert-butyl(2R,5S)-4-(2-(4-(4-fluorobenzoyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (100 mg, 0.151 mmol, 1.0 equivalent) in THF (15 mL) and stirred at room temperature for 3 h (under N2). Saturated aqueous NH4Cl solution and ethyl acetate were added. The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (eluting with DCM / CH3OH = 50 / 1) to give the title compound (37 mg, 36.9%) as a yellow solid. MS (ESI) m / z 667.2 [M+H] + .

[1041] Step 13: 1-(4-((4-fluorophenyl)(hydroxy)methyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorphol...

Claims

1. A compound having formula I: I， in: W represents O, S, S(O)2, and NR. a -C (=O) or CR a R b , where R a and R b Each is independently selected from H, halogenated, C1-C6 alkyl, OH, or C3-C6 cycloalkyl; X and Y are each independently C or N; ------ indicates a single or double bond; R1 is selected from the following groups: ;or R1 can be selected from the following groups: ;or R1 can be selected from the following groups: ； R2 and R3 are each independently selected from H or C1-C6 alkyl; or R2 and R3 together with the carbon atoms to which they are attached form C3-C6 cycloalkyl or C3-C6 heterocyclic groups; R4 is selected from one or more R4s. 4a Substituted phenyl, C2-C6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, or C1-C6 alkyl or -C1-C6 alkyl-C3-C6 cycloalkyl; and R 4a Selected from CN, halogenated, OH, NH2, oxo, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; optionally, R a and R 4a Together with the atoms to which they are attached, they can form 5-6 membered carbocyclic groups, 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups, which may optionally be substituted by one or more of halogen, C1-C6 alkyl, or OH; R5 and R6 are each independently selected from H or C1-C6 alkyl groups; R7 is selected from C1-C6 alkyl groups; Ring A is selected from 5-6-membered heteroaryl groups, which are optionally substituted by one or more groups selected from R8; and R8 is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 haloalkyl-OH, C1-C6 alkoxy, C1-C6 alkyl(C1-C6 alkoxy)-C1-C6 alkoxy, C3-C6 cycloalkyl, -C1-C6 alkyl-C3-C6 cycloalkyl, oxo, 4-7-membered heterocyclic group, -NH-4-7-membered heterocyclic group, -C1-C6 alkyl -4-7 membered heterocyclic group, -C1-C6 alkyl(OH)-4-7 membered heterocyclic group, CN, -C1-C6 alkyl-CN, -COOH, -OH, amino, halogenated, -NH-S(O)2-C1-C6 alkyl, -N(S(O)2-C1-C6 alkyl)2, -C1-C6 alkyl-OH, -C1-C6 haloalkyl-OH, -C1-C6 alkyl(OH)-OH, -S(O)2-C1-C6 alkyl, -C1-C6 alkyl-S(O)2-C1-C 6-alkyl, -P(O)-(C1-C6 alkyl)2, -C1-C6 alkyl-N(C1-C6 alkyl)2, -C(=O)-NH2, -C1-C6 alkyl-C(=O)-NH2, -C(=O)-NH-C1-C6 alkyl, -C(=O)-NH-C3-C6 cycloalkyl, -C(=O)-NH-(deuterated C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, -C(=O)-O-C1-C6 alkyl, -C(=O)- C1-C6 alkyl, -NH-C(=O)-C1-C6 alkyl, -NH-C(=O)-H, -N(C1-C6 alkyl)-C(=O)-H, -NH-C(=O)-O-C1-C6 alkyl, -N(C1-C6 alkyl)-C(=O)-C1-C6 alkyl, 5-6 heteroaryl, -C1-C6 alkyl-(5-6 heteroaryl), or phenyl, wherein the C3-C6 cycloalkyl, 4-7 heterocyclic, 5-6 heteroaryl, or phenyl is optionally separated by one or more R 8a Replace, and R 8a Selected from halogenated, -OH, C1-C6 alkyl, or oxo-substituted compounds; Or its pharmaceutically acceptable salt.

2. A compound having formula I: I， in: W represents O, S, S(O)2, and NR. a -C (=O) or CR a R b , where R a and R b Each is independently selected from H, halogenated, C1-C6 alkyl, OH, or C3-C6 cycloalkyl; X and Y are each independently C or N; ------ indicates a single or double bond; R1 is selected from the following groups: It may optionally be substituted with one or more groups selected from the following: CN, halogen, OH, -COOH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -C(=O)-C1-C6 alkyl, -C1-C6 alkyl-OC1-C6 alkyl, -C1-C6 alkyl-OH, and -C1-C6 alkyl-NH2; R2 and R3 are each independently selected from H or C1-C6 alkyl; or R2 and R3 together with the carbon atoms to which they are attached form C3-C6 cycloalkyl or C3-C6 heterocyclic groups; R4 is selected from one or more R4s. 4a Substituted phenyl, C2-C6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, or C1-C6 alkyl or -C1-C6 alkyl-C3-C6 cycloalkyl; and R 4a Selected from CN, halogenated, OH, NH2, oxo, COOH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; optionally, R a and R 4a Together with the atoms to which they are attached, they can form 5-6 membered carbocyclic groups, 5-6 membered heterocyclic groups or 5-6 membered heteroaryl groups, which may optionally be substituted by one or more of halogen, C1-C6 alkyl, or OH; R5 and R6 are each independently selected from H or C1-C6 alkyl groups; R7 is selected from C1-C6 alkyl groups; Ring A is selected from 5-6-membered heteroaryl groups, which are optionally substituted by one or more groups selected from R8; and R8 is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 haloalkyl, -C1-C6 haloalkyl-OH, C1-C6 alkoxy, C1-C6 alkyl(C1-C6 alkoxy)-C1-C6 alkoxy, C3-C6 cycloalkyl, -C1-C6 alkyl-C3-C6 cycloalkyl, oxo, 4-7-membered heterocyclic group, -NH-4-7-membered heterocyclic group, -C1-C6 alkyl -4-7 membered heterocyclic group, -C1-C6 alkyl(OH)-4-7 membered heterocyclic group, CN, -C1-C6 alkyl-CN, -COOH, -OH, amino, halogenated, -NH-S(O)2-C1-C6 alkyl, -N(S(O)2-C1-C6 alkyl)2, -C1-C6 alkyl-OH, -C1-C6 haloalkyl-OH, -C1-C6 alkyl(OH)-OH, -S(O)2-C1-C6 alkyl, -C1-C6 alkyl-S(O)2-C1-C 6-alkyl, -P(O)-(C1-C6 alkyl)2, -C1-C6 alkyl-N(C1-C6 alkyl)2, -C(=O)-NH2, -C1-C6 alkyl-C(=O)-NH2, -C(=O)-NH-C1-C6 alkyl, -C(=O)-NH-C3-C6 cycloalkyl, -C(=O)-NH-(deuterated C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, -C(=O)-O-C1-C6 alkyl, -C(=O)- C1-C6 alkyl, -NH-C(=O)-C1-C6 alkyl, -NH-C(=O)-H, -N(C1-C6 alkyl)-C(=O)-H, -NH-C(=O)-O-C1-C6 alkyl, -N(C1-C6 alkyl)-C(=O)-C1-C6 alkyl, 5-6 heteroaryl, -C1-C6 alkyl-(5-6 heteroaryl), or phenyl, wherein the C3-C6 cycloalkyl, 4-7 heterocyclic, 5-6 heteroaryl, or phenyl is optionally separated by one or more R 8a Replace, and R 8a Selected from halogenated, -OH, C1-C6 alkyl, or oxo-substituted compounds; Or its pharmaceutically acceptable salt.

3. A compound having formula I: I， in: W represents O, S, NR a , or CR a R b , where R a and R b Each is independently selected from H, halogenated, C1-C6 alkyl, OH, or C3-C6 cycloalkyl; X and Y are each independently C or N; ------ indicates a single or double bond; R1 is selected from the following groups: ;or R1 can be selected from the following groups: ;or R1 can be selected from the following groups: ； R2 and R3 are each independently selected from H or C1-C6 alkyl; or R2 and R3 together with the carbon atoms to which they are attached form C3-C6 cycloalkyl; R4 is selected from one or more R4s. 4a Substituted phenyl or pyridyl, or C1-C6 alkyl or -C1-C6 alkyl-C3-C6 cycloalkyl; and R 4a Selected from CN, halogenated, OH, NH2, COOH, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy groups; R5 and R6 are each independently selected from H or C1-C6 alkyl groups; R7 is selected from C1-C6 alkyl groups; Ring A is selected from 5-6-membered heteroaryl groups, which are optionally substituted by one or more groups selected from R8; and R8 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5 or 6-membered heterocyclic groups containing one or more heteroatoms selected from N, O and S, CN, -COOH, -OH, amino, halogen, -NH-S(O)2-C1-C6 alkyl, -N(S(O)2-C1-C6 alkyl)2, -C1-C6 alkyl-OH, -C(=O)-NH2, -C(=O)-NH-C1-C6 alkyl, -C(=O)-O-C1-C6 alkyl, -NH-C(=O)-C1-C6 alkyl, phenyl, which are optionally substituted by one or more halogens; Or its pharmaceutically acceptable salt.

4. A compound having formula I: I， in: W represents O, S, NR a , or CR a R b , where R a and R b Each is independently selected from H, halogenated, C1-C6 alkyl, OH, or C3-C6 cycloalkyl; X and Y are each independently C or N; ------ indicates a single or double bond; R1 is selected from the following groups: It may optionally be substituted with one or more groups selected from the following: CN, halogen, OH, -COOH, NH2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, -C(=O)-C1-C6 alkyl, -C1-C6 alkyl-OC1-C6 alkyl, -C1-C6 alkyl-OH, and -C1-C6 alkyl-NH2; R2 and R3 are each independently selected from H or C1-C6 alkyl; or R2 and R3 together with the carbon atoms to which they are attached form C3-C6 cycloalkyl; R4 is selected from one or more R4s. 4a Substituted phenyl or pyridyl, or C1-C6 alkyl or -C1-C6 alkyl-C3-C6 cycloalkyl; and R 4a Selected from CN, halogenated, OH, NH2, COOH, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy groups; R5 and R6 are each independently selected from H or C1-C6 alkyl groups; R7 is selected from C1-C6 alkyl groups; Ring A is selected from 5-6-membered heteroaryl groups, which are optionally substituted by one or more groups selected from R8; and R8 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5 or 6-membered heterocyclic groups containing one or more heteroatoms selected from N, O and S, CN, -COOH, -OH, amino, halogen, -NH-S(O)2-C1-C6 alkyl, -N(S(O)2-C1-C6 alkyl)2, -C1-C6 alkyl-OH, -C(=O)-NH2, -C(=O)-NH-C1-C6 alkyl, -C(=O)-O-C1-C6 alkyl, -NH-C(=O)-C1-C6 alkyl, phenyl, which are optionally substituted by one or more halogens; Or its pharmaceutically acceptable salt.

5. The compound according to any one of claims 1 to 4, wherein the compound has formula II: II, Or its pharmaceutically acceptable salt.

6. The compound according to any one of claims 1 to 4, wherein the compound has the formula II-A, II-B or II-C; Or its pharmaceutically acceptable salt.

7. The compound according to any one of claims 1 to 4, wherein ring A contains 1, 2 or 3 nitrogen atoms.

8. The compound according to any one of claims 1 to 4, wherein X is N, Y is C, and the Selected from: or It is optionally substituted with one or more groups selected from R8.

9. The compound according to any one of claims 1 to 4, wherein X is N, Y is C, and the Selected from: or It is optionally substituted with one or more groups selected from R8.

10. The compound according to any one of claims 1 to 4, wherein X is C, Y is N, and the Selected from: or It is optionally substituted with one or more groups selected from R8.

11. The compound according to any one of claims 1 to 4, wherein X is C, Y is C, and the Selected from: or It is optionally substituted with one or more groups selected from R8.

12. The compound according to any one of claims 1 to 4, wherein Choose from the following groups: 。 13. The compound according to any one of claims 1 to 4, wherein Choose from the following groups: 。 14. The compound according to any one of claims 1 to 4, wherein R2 and R3 are both methyl groups.

15. The compound according to any one of claims 1 to 4, wherein W is CR a R b And R a and R b Each is independently selected from H, halogenated, C1-C6 alkyl, OH, or C3-C6 cycloalkyl.

16. The compound according to any one of claims 1 to 4, wherein R4 is selected from the group consisting of: and .

17. The compound according to any one of claims 1 to 4, wherein R4 is selected from the group consisting of: and .

18. The compound according to any one of claims 1 to 4, wherein -W-R4 is selected from the group consisting of: 。 19. The compound according to any one of claims 1 to 4, wherein R5 and R6 are both hydrogen.

20. The compound according to any one of claims 1 to 4, wherein the halogen is selected from F or Cl; and / or the C1-C6 alkyl is selected from C1-C4 alkyl.

21. A compound selected from: Or its pharmaceutically acceptable salt.

22. A compound selected from: Or its pharmaceutically acceptable salt.

23. A pharmaceutical composition comprising a compound as described in any one of claims 1-22 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

24. Use of the compound of any one of claims 1-22 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 23, in the manufacture of a medicament for treating a disease or condition in which inhibition of the IAP protein provides a benefit.

25. The use as described in claim 24, wherein the disease or condition is cancer.

26. The use as described in claim 24, wherein the disease or condition is selected from the group consisting of: T-cell and B-cell mediated autoimmune diseases; inflammatory diseases; infections; proliferative disorders; AIDS; degenerative diseases; and vascular diseases.

27. The use as described in claim 24, wherein the disease or condition is selected from the group consisting of: HBV, autoimmune hemolytic anemia, autoimmune hepatitis, Bergey's disease or IgA nephropathy, stomatitis, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft-versus-host disease, Graves' disease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, and vitiligo.

28. The use as described in claim 24, wherein the IAP is selected from cIAP1, cIAP2 and XIAP.

29. A kit comprising the compound as described in any one of claims 1-22 and instructions for administering the compound or a pharmaceutically acceptable salt thereof to a subject, wherein inhibition of the IAP protein provides a benefit to the subject.

30. The kit of claim 29, wherein the IAP is selected from cIAP1, cIAP2 and XIAP.

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