Pentacyclic derivative, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention is a compound represented by formula I, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutical composition of the derivative. The compound represented by formula I or the pharmaceutical composition can be used as a TNF-α inhibitor for treating or preventing a disease or disorder mediated by TNF-α.

Description

A pentacyclic derivative, its preparation method and uses

[0001] Related applications

[0002] This application claims priority to two Chinese invention patent applications filed with the China National Intellectual Property Administration on January 24, 2025, entitled "A Pentylane Derivative Containing Imidazole and Its Preparation Method and Use", application number: 202510118444.3, and filed on April 11, 2025, entitled "A Pentylane Derivative and Its Preparation Method and Use", application number: 202510453921.1, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application belongs to the pharmaceutical field, and specifically relates to a pentacyclic derivative and its pharmaceutically acceptable salt, a method for preparing the derivative and its use as a TNF-α inhibitor, as well as a pharmaceutical composition comprising the derivative. Background Technology

[0004] Tumor necrosis factor-α (TNF-α), discovered in 1975, belongs to the TNF superfamily, which includes more than 50 transmembrane proteins. Membrane-bound TNF-α (mTNF-α) is cleaved by metalloprotease TNF-converting enzyme (TACE) to produce soluble TNF-α (sTNF-α). Both forms of TNF-α are homotrimers. TNF-α signals by binding to two receptors: tumor necrosis factor-α receptor 1 (TNFR1) and tumor necrosis factor-α receptor 2 (TNFR2). The difference lies in that at physiological concentrations, sTNF activates TNFR1 but not TNFR2, while mTNF can activate both receptors.

[0005] The two receptors that bind to TNF-α have different distributions. TNFR1 is widely distributed, present on almost all cells, and mainly promotes TNF-induced inflammatory responses, while TNFR2 is mainly found on immune cells, maintaining local immune homeostasis. mTNF-α is mainly expressed on monocytes and macrophages, inducing cell-cell contact through interactions with other cell surface receptors. sTNF-α binding to TNFR1 can activate the nuclear factor NF-κB and mitogen-activated protein kinase (MAPK) inflammatory pathways or caspase cascades. TNFR2 signals through the non-canonical NF-κB pathway, and its activation is crucial for the proliferation, survival, and development of regulatory T cells (Tregs).

[0006] TNF-α is a pleiotropic cytokine involved in the inflammatory process in the body. Following infection, macrophages release TNF-α and warn other immune cells, triggering inflammation. TNF-α can induce fever, apoptosis, cachexia, and inflammation, inhibit tumorigenesis and viral replication, and respond to inflammation through cells that produce IL-1 and IL-6. TNF-α is dysregulated in autoimmune diseases such as psoriasis, rheumatoid arthritis (RA), ankylosing spondylitis, and inflammatory bowel disease (IBD). Autoimmune diseases can be treated with several TNF-α inhibitors belonging to different classical biotechnology drug classes: monoclonal antibodies (e.g., and ), or receptor fusion proteins that act as decoys competing with the TNF receptor (TNFR) (e.g. (Binding). TNF-α is also upregulated in Alzheimer's disease, cancer, asthma, and major depressive disorder.

[0007] Mounting evidence suggests that the immune system plays a crucial role in Alzheimer's disease (AD) and Parkinson's disease (PD). Abnormal activation of glial cells in patients with neurodegenerative diseases is a hallmark of AD. Modulating the neuroinflammatory response may be a therapeutic strategy for treating neurodegenerative diseases. Specifically, activating TNFR2 signaling by directly targeting TNFR2 with TNFR2 agonists or by blocking TNFR1 signaling with selective TNFR1 antagonists appears to be a promising AD treatment strategy. However, blood-brain barrier (BBB) ​​penetration of the drugs is a prerequisite for their efficacy.

[0008] Antibodies can effectively bind to and antagonize the TNF-α / TNFR interface, as demonstrated by various commercially available antibodies such as infliximab, adalimumab, golimumab, and cetuzumab (pegylated or protein-based etanercept), as well as several recent biosimilars. Biologics are more difficult to manufacture, expensive, can induce immune responses, are not orally bioavailable, cannot cross the blood-brain barrier, are effective only in a small subset of patients, and can even exacerbate disease in some. In contrast, small molecules offer oral bioavailability, are non-immunogenic, can be engineered to enter the brain, and are cost-effective to manufacture, especially for chronic indications. To date, no small-molecule TNF-α inhibitors are marketed; therefore, various companies have begun the challenge of finding small molecules that act as TNF-α inhibitors. Commonly employed strategies involve designing molecules that bind to TNF-α to antagonize its interaction with its receptor.

[0009] SAR441566, developed by UCB (Belgium) and Sanofi (France), has entered Phase I clinical trials. In preclinical mouse CIA models, it demonstrated the same therapeutic efficacy as antibody drugs. In clinical trials, SAR441566 showed good safety and tolerability, with no serious adverse events (SAEs), treatment-associated adverse events (TEAEs), or adverse events of particular concern (AESIs). Regarding efficacy, significant improvements in patient condition and the biomarker IL-17F were observed in the clinical response at week 4.

[0010] In summary, there is an urgent need to develop small molecule oral inhibitors of TNF-α to improve the existing treatment paradigm for autoimmune diseases. Summary of the Invention

[0011] According to one aspect of the invention, an object of the invention is to provide a compound of formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof:

[0012] in:

[0013] R a Selected from hydrogen, deuterium, hydroxyl, amino, cyano, fluorine, chlorine, deuterated methyl, difluoromethyl, trifluoromethyl, vinyl, ethynyl, methylethynyl;

[0014] R b Selected from hydrogen, methyl, deuterated methyl, difluoromethyl, and trifluoromethyl;

[0015] R c R dSelected from hydrogen, deuterium, hydroxyl, methoxy, deuterated methoxy, difluoromethoxy, and trifluoromethoxy;

[0016] Or R c R d Together with the carbon atoms they are attached to, they form a structure. R 1 R 2 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, and trifluoromethyl;

[0017] Ring A is selected from the following groups:

[0018] Among them W 1 W 2 W 3 W 4 W 5 W 6 Each is independently selected from -CH- or -N-;

[0019] Preferably, ring A is selected from the following groups:

[0020] R e Selected from deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, and trifluoromethyl.

[0021] n1 is an integer selected from 0, 1, and 2; when n1 is 2, each R e They can be the same or different.

[0022] Ring B is selected from the following groups:

[0023] in:

[0024] W 7 W 8 W 9 W 10 W 11 W 12 W 13 W 14 W 15 W 16 W 17 W 18 W 19 W 20 W 21 W 22 W 23 W 24 W 25 W 26 W 27 W 28 W 29 W30 W 31 W 32 W 33 W 34 W 35 W 36 W 37 W 38 W 39 W 40 W 41 W 42 Each is independently selected from -CH- or -N-;

[0025] Preferably, ring B is selected from the following groups:

[0026] R f Selected from deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, and trifluoromethyl;

[0027] n2 is selected from integers 0, 1, and 2; when n2 is 2, each R f They can be the same or different;

[0028] R g Selected from the following groups:

[0029] in

[0030] Ring D is selected from C3-C5 cycloalkanes and contains one 4- or 5-membered heterocyclic group selected from nitrogen, oxygen, or sulfur heteroatoms;

[0031] R 5 R 7 Selected from hydrogen, deuterium, hydroxyl, and amino groups;

[0032] R 3 R 4 Selected from hydrogen and hydroxyl groups;

[0033] R 6 Selected from cyano, hydroxy, methyl, deuterated methyl, difluoromethyl, trifluoromethyl, and oxo groups;

[0034] n3 is an integer selected from 0, 1, and 2;

[0035] When R g for When using this method, the following groups are preferred:

[0036] in:

[0037] R 7 Selected from hydrogen, hydroxyl, and amino groups;

[0038] R 6Selected from cyano, hydroxy, methyl, deuterated methyl, fluorinated methyl, and oxo groups;

[0039] n3 is selected from integers 0, 1, and 2; when n3 is 2, each R 6 They can be the same or different;

[0040] Preferably, R g Selected from the following groups:

[0041] According to one embodiment of the present invention, the compound represented by Formula I, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, wherein:

[0042] R a R b R c R d The definition of ring A is the same as the previous definition;

[0043] Ring B is selected from the following groups:

[0044] W 43 W 44 W 45 W 46 W 47 W 48 W 49 W 50 W 51 W 52 W 53 W 54 W 55 W 56 W 57 W 58 W 59 W 60 W 61 W 62 Each is independently selected from -CH- or -N-;

[0045] Preferably, ring B is selected from the following groups:

[0046] R f n is selected from deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, and trifluoromethyl; n2 is selected from integers 0, 1, and 2;

[0047] R g Selected from the following groups:

[0048] Where L 1Selected from the bonded, substituted, or unsubstituted -(CH2) 1-3 - The substitution refers to the substitution of one, two or three hydrogens on a group by the following substituents: deuterium, hydroxyl, amino, methyl, deuterated methyl, difluoromethyl, trifluoromethyl, methoxy, deuterated methoxy, difluorooxymethyl, trifluorooxymethyl;

[0049] Ring E is selected from the following groups:

[0050] in,

[0051] Single or double bond

[0052] W 63 W 66 W 68 W 69 W 70 W 75 W 76 W 77 W 78 W 79 W 80 W 82 W 83 W 84 W 85 W 86 W 87 W 88 W 89 W 90 W 92 W 93 W 94 W 95 W 97 W 99 W 99 W 100 W 101 W 102 W 111 W 113 W 115 Each is independently selected from carbon or nitrogen;

[0053] W 64 W 67 Each is independently selected from carbon, nitrogen, oxygen, sulfur, -CH2O-, -OCH2-, -CH2N(H or CH3)-, -CH(CH3)-, -CH2S-, -SCH2-, -CH2CH2-;

[0054] W 65 W 81 Each is independently selected from carbon, -N (H or CH3)-, and oxygen;

[0055] W71 W 72 W 73 W 74 Each is selected from carbon, W 72 It can be done through L 2 respectively with W 70 W 71 W 73 W 74 The connection forms a bridge ring, W 72 It can also be done through L 3 With W 72 They connect themselves into a loop, where L 2 Selected from -CH2-, -CH2CH2-, L 3 Selected from -CH2-;

[0056] W 91 W 96 W 98 W 114 Selected from oxygen and sulfur;

[0057] W 112 Selected from -(CH2)3, -CH2OCH2-, CH2N(H, methyl, deuterated methyl)CH2-;

[0058] Preferably, ring E is selected from the following groups:

[0059] R 8 Selected from the following groups: deuterium, fluorine, chlorine, hydroxyl, amino, hydroxymethyl, oxo group, where n4 is 0 or 1;

[0060] R 9 Selected from the following groups:

[0061] in:

[0062] L 4 Selected from the bond, -(CH2) 1-6 -、-(CH2) 0-3 CH2=CH2(CH2) 0-3 -、-(CH2) 0-3 CH2≡CH2(CH2) 0-3 -、-(CH2) 0- 3O(CH2) 0-3 -、-(CH2) 0-3 NH(CH2) 0-3 -、-(CH2) 0-3 NHC(=O)(CH2) 0-3 -;

[0063] R 10Selected from hydroxyl, amino, fluorine, cyano, oxo, carboxyl, substituted or unsubstituted C1-C3 alkyl groups, wherein the substitution refers to hydroxyl or amino; n5 is selected from integers 0, 1, and 2; when n5 is 2, the two R groups... 10 The atoms that connect to and are connected together form C3-C6 cycloalkyl groups; when L 2 When R is the key 10 It does not exist;

[0064] L 5 Selected from the bond, -(CH2) 1-6 -、-(CH2) 0-3 O(CH2) 0-3 -、-(CH2) 0-3 NH(CH2) 0-3 -、-(CH2) 0-3 NHC(=O)(CH2) 0- 3-、-(CH2) 0-3 NHC(=O)C(=O)(CH2) 0-3 -、-(CH2) 0-3 OC(=O)(CH2) 0-3 -、;

[0065] R 11 Selected from oxo groups, n6 is selected from 0, 1, 2, 3;

[0066] The ring G is selected from substituted or unsubstituted C3-C6 cycloalkanes, substituted or unsubstituted 1-2 3-6 membered heterocyclic groups selected from N, O, and S heteroatoms, phenyl, and 5-6 membered heteroaryl groups; the substituents are selected from: methyl, oxo, hydroxy, methoxy, -NH (H, methyl, deuterated methyl, cyclopropyl, oxetane, fluorinated C1-C3 alkyl);

[0067] L 6 Selected from the bond, -(CH2) 1-6 -、-(CH2) 0-3 O(CH2) 0-3 -、-(CH2) 0-3 NH(CH2) 0-3 -、-(CH2) 0-3 NHC(=O)(CH2) 0- 3 -;

[0068] R 12 Selected from oxo groups; n7 is selected from integers 0, 1, and 2;

[0069] X is selected from nitrogen and oxygen;

[0070] R 13 Selected from methyl, -NH (H, methyl or deuterated methyl);

[0071] R 14 Selected from hydrogen, methyl, deuterated methyl, and C1-C3 alkyl acids;

[0072] L 7 Selected from bonds, C1-C3 alkyl groups, and -(CH2). 0-3 C(=O)(CH2) 0-3 -;

[0073] R 15 Selected from the following substituents: cyano, C1-C3 alkoxy, -NHR 16 ;

[0074] R 16 Selected from H, methyl, deuterated methyl, and fluorine-substituted C1-C3 alkyl groups;

[0075] R 17 Selected from hydrogen, deuterium, hydroxyl, and amino groups;

[0076] R 18 Selected from fluorine, cyano, hydroxy, methyl, methoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, C1-C6 alkyl, -NH (H or methyl), cyclopropyl;

[0077] L 8 Selected from C1-C3 alkyl groups;

[0078] R 19 Selected from the following substituents: hydroxyl, oxo group; n8 is selected from 0 or 1;

[0079] R 20 R 21 Selected from hydrogen, deuterium, and methyl.

[0080] Preferably, when R 9 for At that time, R 9 Selected from the following groups:

[0081] Preferably, ring G is selected from:

[0082] Preferably, when R 9 for At that time, R 9 Selected from the following groups:

[0083] Preferably, when R 9 for At that time, R 9 Selected from the following groups:

[0084] Preferably, when R9 for At that time, R 9 Selected from the following groups:

[0085] Preferably, when R 9 for At that time, R 9 Selected from the following groups:

[0086] Preferably, when R 9 for At that time, R 9 Selected from the following groups:

[0087] According to one embodiment of the present invention, the compound represented by Formula I or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, is selected from the following compounds:

[0088] According to a second aspect of the invention, another object of the invention is to provide a pharmaceutical composition comprising a compound represented by Formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable excipient.

[0089] According to a third aspect of the invention, another object of the invention is to provide the use of the compound represented by Formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for treating autoimmune diseases and neurological diseases.

[0090] Preferably, the drug for autoimmune diseases and neurological diseases is a TNF-α inhibitor;

[0091] More preferably, the autoimmune disease is selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, systemic lupus erythematosus (lupus), axial spondyloarthritis, polymyositis, pemphigus, multiple sclerosis, neuromyelitis optica, primary cholangitis, autoimmune hepatitis, lupus nephritis, pulmonary hemorrhage-nephritis syndrome, autoimmune oophoritis, or autoimmune orchitis; the neurological disease is selected from sarcoidosis, multiple sclerosis, neurobehçet's disease, chronic inflammatory demyelinating disease, systemic inflammatory vasculitis, traumatic brain injury, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, neuropathic pain, and ischemic stroke.

[0092] According to a fourth aspect of the invention, another object of the invention is to provide a method for treating autoimmune diseases and neurological diseases, the method comprising administering to a subject in need an effective amount of a compound represented by Formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof or a pharmaceutical composition thereof.

[0093] Preferably, the autoimmune disease is selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, systemic lupus erythematosus (lupus), axial spondyloarthritis, polymyositis, pemphigus, multiple sclerosis, neuromyelitis optica, primary cholangitis, autoimmune hepatitis, lupus nephritis, pulmonary hemorrhage-nephritis syndrome, autoimmune oophoritis, or autoimmune orchitis; the neurological disease is selected from sarcoidosis, multiple sclerosis, neurobehçet's disease, chronic inflammatory demyelinating diseases, systemic inflammatory vasculitis, traumatic brain injury, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, neuropathic pain, and ischemic stroke. Detailed Implementation

[0094] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0095] In this document, the terms “comprising,” “including,” “having,” “containing,” or any other similar terms are open-ended conjunctions intended to cover non-exclusive inclusions. For example, a composition or article containing a plurality of elements is not limited to those listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated to the contrary, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as “composed of” and “substantially composed of.”

[0096] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible sub-ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1-8" should be considered as specifically disclosing all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0097] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0098] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.

[0099] In this document, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that subgroups of all elements within a Markush group or option list, or any individual element, can also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it also indicates that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that any combination of subgroups of all elements within a Markush group or option list, or any combination of individual elements, can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," it indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0100] definition

[0101] The compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferably, the isomers can be prepared by asymmetric synthesis. For example, see Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., Notre Dame University Press, Notre Dame, IN 1972). This disclosure further covers the compounds described herein as single isomers substantially free of other isomers, or mixtures of various isomers.

[0102] When listing a series of values, the intention is to cover every value within that range and every subrange. For example, "C 1-6 "Aims to cover C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3- 4. C 4-6 C 4-5 and C 5-6 .

[0103] In some embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-8 aliphatic carbon atoms. In other embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-6 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups used in this disclosure contain 1-4 carbon atoms. Therefore, exemplary aliphatic groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH2-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH2-cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH2-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH2-cyclohexyl moiety, etc., which may further contain one or more substituents. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propynyl), and 1-propynyl.

[0104] The term "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1 to 8 carbon atoms ("C"). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1”). 1-7 Alkyl group (“C”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1”). 1-4 Alkyl group). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise stated, each example of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted by one or more substituents (e.g., a halogen, such as F) (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C1 group. 1-10 Alkyl (e.g., unsubstituted C) 1-6Alkyl group, such as -CH3). In some embodiments, the alkyl group is a substituted C. 1-10 Alkyl (e.g., substituted C) 1-6 Alkyl groups, such as -CF3).

[0105] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds. 2-20 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. The one or more carbon-carbon double bonds can be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group). 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkenyl groups, including pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Unless otherwise stated, each instance of an alkenyl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted by one or more substituents (“substituted alkenyl”). In some embodiments, the alkenyl group is an unsubstituted C5 group. 2-6 Alkenyl. In some embodiments, the alkenyl group is a substituted C. 2-6 Alkenyl. In alkenyl groups, the C=C double bond without a specified stereochemistry (e.g., -CH=CHCH3 or) can be an (E)- or (Z)- double bond.

[0106] "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds. 2-20 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C”). 2- 6-Alynyl group). In some embodiments, the alkynyl group has 2 to 5 carbon atoms (“C6”). 2-5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C”). 2-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2-3The alkynyl group (“C2-alkynyl”) is present in some embodiments. The one or more carbon-carbon triple bonds can be internal (e.g., in the 2-butynyl group) or terminal (e.g., in the 1-butynyl group). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 Examples of alkenyl groups include the C group mentioned above. 2-4 The alkynyl group includes pentynyl (C5), hexynyl (C6), etc. Unless otherwise stated, each instance of the alkynyl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted alkynyl”) or substituted by one or more substituents (“substituted alkynyl”). In some embodiments, the alkynyl group is an unsubstituted C5 group. 2-6 Alkyne group. In some embodiments, the alkynyl group is a substituted C- group. 2-6 Alkyne group.

[0107] "Cycloalkyl" or "carbocyclic" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C"). 3-10 The cycloalkyl group comprises a non-aromatic cycloalkyl group with 3 to 8 carbon atoms (“C”). 3- 8-Cycloalkyl group). In some embodiments, the cycloalkyl group has 3 to 7 cyclic carbon atoms (“C7”). 3-7 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 Cycloalkyl). Exemplary C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). An example C... 3-8 Cycloalkyl groups include, but are not limited to, the above-mentioned C 3-6 Cycloalkyl groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Exemplary C 3-10 Cycloalkyl groups include, but are not limited to, the above-mentioned C 3-8 Cycloalkyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl(C10 As illustrated in the foregoing examples, in some embodiments, the cycloalkyl group is a monocyclic (“monocyclic cycloalkyl”) or contains a fused ring, bridged ring, or spirocyclic system, such as a bicyclic system (“bicyclic cycloalkyl”), and may be saturated or may be partially unsaturated. “Cycloalkyl” also includes ring systems in which the carbon ring as defined above is fused with one or more aryl or heteroaryl groups at the junction point on the carbon ring, and in this case, the carbon number continues to refer to the number of carbons in the carbon ring system. Unless otherwise stated, each instance of a cycloalkyl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C… 3-10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C-shaped group. 3-10 Cycloalkyl.

[0108] In some embodiments, "cycloalkyl" is a monocyclic saturated cycloalkyl group having 3 to 10 ring carbon atoms ("C"). 3-10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). 3-6 Examples of cycloalkyl groups include the aforementioned C14 groups. 5-6 Cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 Cycloalkyl groups, including cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise stated, each instance of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C7 group. 3-10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C-shaped group. 3-10 Cycloalkyl.

[0109] "Heterocyclic group" or "heterocyclic" refers to a group having a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. Heterocyclic bicyclic systems can contain one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems in which the linkage of a heterocycle as defined above with one or more cycloalkyl groups is on the cycloalkyl or heterocycle, or ring systems in which a heterocycle as defined above with one or more aryl or heteroaryl groups is on the heterocycle, and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic system. Unless otherwise stated, each instance of the heterocyclic group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted heterocyclic group”) or substituted by one or more substituents (“substituted heterocyclic group”). In some embodiments, the heterocyclic group is an unsubstituted 3- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3- to 10-membered heterocyclic group.

[0110] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C"). 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups, wherein the groups or linkages are on the aromatic ring, and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise stated, each instance of an aryl is optionally independently substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl is an unsubstituted C 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0111] "Aryl" is a subset of alkyl and aryl and refers to an optionally substituted alkyl group that is optionally substituted with an aryl group. In some embodiments, the aryl group is an optionally substituted benzyl group. In some embodiments, the aryl group is a benzyl group. In some embodiments, the aryl group is an optionally substituted phenethyl group. In some embodiments, the aryl group is a phenethyl group.

[0112] "Heteroaryl" refers to a group having a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows. Heteroaryl bicyclic systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes a ring system in which the heteroaryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups, wherein the linkage is on the heteroaryl ring, and in this case, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the linking point is on an aryl or heteroaryl ring, and in this case, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl (e.g., indolyl, quinolinyl, carbazolyl, etc.) in which one ring does not contain a heteroatom can have its linking point on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0113] In some embodiments, the heteroaryl group is a 5-10-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6-membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6-membered heteroaryl”). In some embodiments, the 5-6-membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6-membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of the heteroaryl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted by one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0114] "Heteroaryl" is a subset of alkyl and heteroaryl, and refers to an alkyl group that is optionally substituted by a heteroaryl group.

[0115] "Unsaturated" or "unsaturated" refers to a group containing at least one double or triple bond. "Partially unsaturated" ring systems are also intended to cover rings with multiple unsaturated sites, but not to include aromatic groups (e.g., aryl or heteroaryl). Similarly, "saturated" refers to a group that contains no double or triple bonds, i.e., all single bonds.

[0116] Unless otherwise expressly stated, atoms, portions, or groups described herein may be unsubstituted or substituted, provided that valence permits. The term "optionally substituted" refers to both substituted and unsubstituted atoms.

[0117] Unless otherwise expressly specified, the group may optionally be substituted. The term "optionally substituted" means substituted or unsubstituted. In some embodiments, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may optionally be substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" cycloalkyl, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). Generally, the term "substituted," regardless of whether it is preceded by the term "optionally," means that at least one hydrogen atom present in the group (e.g., carbon or nitrogen atom) is substituted with a permissible substituent, such that the substituent, upon substitution, forms a stable compound, for example, a compound that does not spontaneously transform (e.g., through rearrangement, cyclization, elimination, or other reactions). Unless otherwise specified, a “substituted” group has substituents at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. The term “substituted” is intended to include substitution with all permissible substituents of an organic compound, any substituent described herein that results in the formation of a stable compound. This disclosure contemplates any and all such combinations to obtain stable compounds. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. In some embodiments, the substituent is a carbon atom substituent. In some embodiments, the substituent is a nitrogen atom substituent. In some embodiments, the substituent is an oxygen atom substituent. In some embodiments, the substituent is a sulfur atom substituent.

[0118] "Halogen" or "halogen" refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0119] The term "pharmaceutically acceptable salt" refers to those salts that, within reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentylpropionate, diglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohepanoate, glyceryl phosphate, glucuronate, hemisulfate, heptahydrate, hexanoate, hydrogen iodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 - Salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using balancing ions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0120] The term "tautomer" or "tautomerizing" refers to a compound in which two or more interconvertions result from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond becomes a double bond, a triple bond becomes a single bond, or vice versa). The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. Tautomerization reactions (i.e., reactions that provide tautomer pairs) can be catalyzed by acids or bases. Exemplary tautomerization reactions include keto-enol, amide-imide, lactam-lactamimide, enamine-imide, and enamine-(different enamines) tautomerization reactions.

[0121] It should also be understood that compounds with the same molecular formula but different properties, different atomic bonding sequences, or different spatial arrangements of atoms are called "isomers". Isomers with different atomic spatial arrangements are called "stereoisomers".

[0122] Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are not mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, if it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetry center and are described by the R- and S-sequence rules of Cahn and Prelog or by rotating the molecular plane of polarization, and are represented as dextrorotatory or levorotatory (i.e., (+) or (-)- isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0123] The term "prodrug" or "prodrug derivative" refers to a compound having a cleavable group and being converted into the compound described herein by solvent decomposition or under physiological conditions, and which possesses pharmaceutical activity in vivo. Examples of such compounds include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, etc. Other derivatives of the compounds described herein, in both their acid and acid derivative forms, are active, but the acid-sensitive forms often offer advantages in mammalian organisms such as solubility, tissue compatibility, or delayed release (see Bundgard, H., Design of Prodrugs, pp. 7–9, 21–24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives known to those skilled in the art, such as esters prepared by reacting a parent acid with a suitable alcohol, or amides prepared by reacting a parent acid compound with a substituted or unsubstituted amine, or acid anhydrides or mixed acid anhydrides. Simple aliphatic or aromatic esters, amides, and acid anhydrides derived from the acidic side groups of the compounds described herein are specific prodrugs. In some cases, it is necessary to prepare diester-type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. C1-C8 alkyl esters, C2-C8 alkenyl esters, C2-C8 alkynyl esters, aryl esters, and C7-C... of the compounds described herein are likely preferred. 12 Substituted aryl esters and C7-C 12 Arylalkyl esters.

[0124] The term “inhibition” or “inhibitor” refers to the ability of a compound to reduce, slow down, stop, or prevent the activity of a particular biological process (such as the activity of an IDO enzyme in a cell relative to its carrier).

[0125] The terms "abnormal activation" or "abnormal activity" refer to activity that deviates from normal activity. The term "increased activity" refers to activity that is higher than normal activity.

[0126] The terms “composition” and “formulation” are used interchangeably.

[0127] The term "subject" to be administered refers to a person (i.e., a male or female of any age group, such as a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged, or elderly person)). "Patient" refers to a human subject who requires treatment for a disease.

[0128] The term “administration” means the implantation, absorption, ingestion, injection, inhalation or other introduction of the compound or a combination thereof described herein into or onto a subject.

[0129] The term "treatment" refers to reversing, alleviating, delaying the onset of the disease described herein, or inhibiting its development. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to susceptible subjects before the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a pathogen) to delay or prevent the occurrence of the disease. Treatment may also continue after symptoms have subsided, for example, to delay or prevent recurrence.

[0130] The “effective amount” or “therapeutic effective amount” of a compound described herein is an amount sufficient to provide therapeutic benefit in treating a condition or to delay or minimize one or more symptoms associated with said condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in treating the condition. The term “therapeutic effective amount” can include amounts that improve overall treatment, reduce or avoid symptoms, signs, or causes, and / or enhance the therapeutic efficacy of another therapeutic agent.

[0131] Compounds of Formula I of this application can be synthesized using a variety of methods familiar to those skilled in the art of organic synthesis. The following specific examples provide some exemplary methods for synthesizing compounds of Formula I, methods well known in the field of synthetic chemistry. Clearly, by referring to the exemplary schemes in this patent, those skilled in the art can readily design synthetic routes for other compounds of Formula I by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0132] The invention is further illustrated below with reference to specific embodiments; however, these embodiments do not limit the scope of the invention. Unless otherwise stated, all reactants used in the embodiments were obtained commercially; the instruments and equipment used in the synthesis experiments and product analysis were conventional instruments and equipment commonly used in organic synthesis.

[0133] Compounds of Formula I of this application can be synthesized using a variety of methods familiar to those skilled in the art of organic synthesis. The following specific examples provide some exemplary methods for synthesizing compounds of Formula I, methods well known in the field of synthetic chemistry. Clearly, by referring to the exemplary schemes in this patent, those skilled in the art can readily design synthetic routes for other compounds of Formula I by appropriately adjusting the reactants, reaction conditions, and protecting groups.

[0134] The invention is further illustrated below with reference to specific embodiments; however, these embodiments do not limit the scope of the invention. Unless otherwise stated, all reactants used in the embodiments were obtained commercially; the instruments and equipment used in the synthesis experiments and product analysis were conventional instruments and equipment commonly used in organic synthesis.

[0135] In the following embodiments, the structures of the exemplary compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as an internal standard.

[0136] LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph. Thin-layer chromatography used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. Column chromatography generally used Yantai Huanghai 200-300 mesh silica gel as the support. Unless otherwise specified, all reactions in this invention were carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature was expressed in degrees Celsius.

[0137] Furthermore, the abbreviations used in the embodiments have the following meanings:

[0138] EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBt: 1-hydroxybenzotriazole; TiCl4: Titanium tetrachloride; NiCl2: Nickel dichloride; Ti(i-PrO)4: Tetraisopropyl titanate; MnO2: Manganese dioxide; KOAc: Potassium acetate; NH4Cl: Ammonium chloride; NH2OH.HCl: Hydroxylamine hydrochloride; K2CO3: Potassium carbonate; Na2CO3: Sodium carbonate; Ag2CO3: Silver carbonate; Cs₂CO₃: Cesium carbonate; CsF: Cesium fluoride; NaI: Sodium iodide; ZnI₂: Zinc diiodide; SnCl₂: Tin dichloride; KOH: Potassium hydroxide; CH₃MgBr: Magnesium methyl bromide; NaH: Sodium hydride; NaBH₄: Sodium borohydride; DIBAL-H: Diisobutylaluminum hydride; BH₃-THF: Boranetetrahydrofuran complex; DAST: Diethylaminosulfur trifluoride; TMSCN: Trimethylcyanosylsilane; Bredereck's Reagent: tert-butoxydi(dimethylamino)methane; DIB: diacetoxyiodobenzene; CDI: carbamate diimidazole; CSA: camphor sulfonic acid; Pd(OAc)2: palladium acetate; CuI: cuprous iodide; CuCl: cuprous chloride; CuTC: cuprous thiophene-2-carboxylic acid; (BOC)2O: ditert-butyl dicarbonate; PTSA: p-toluenesulfonic acid; MsCl: methanesulfonyl chloride; TsCl: p-toluenesulfonyl chloride; n-BuLi: Lithium n-Butyl; LDA: Lithium diisopropylamino; LHMDS: Lithium hexamethyldisilamide; NaOMe: Sodium methoxide; KOt-Bu: Potassium tert-butoxide; Pd(PPh3)2Cl2: Diphenylphosphine palladium dichloride; Pd2(dba)3: Tridibenzylacetone dipalladium; PCy3.HBF4: Tricyclohexylphosphine tetrafluoroborate; XantPhos: 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene; DPPP: 1,3-bis(diphenylphosphine-9,9-dimethyloxanthracene) (Diphenylphosphine)propane; Xphos-Pd-G4: Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II); BPy: Bipyridine; BPD: Pinacol diborate; BBA: Biboric acid; NaOH: Sodium hydroxide; NH4OH: Ammonia; H2O: Water; EA: Ethyl acetate; PE: Petroleum ether; MeOH: Methanol; EtOH: Ethanol; i-PrOH: Isopropanol; DIPEA: N,N-Diisopropylethylamine; DMSO: Dimethyl sulfoxide; TEA: Triethylamine; DMAP: 4-Dimethylaminopyridine; DMF: N,N-Dimethylformamide; Toluene: Toluene; Et2O: Diethyl ether; 1,4-Dioxane: 1,4-Dioxane; THF: Tetrahydrofuran; DCM: Dichloromethane; TFA: Trifluoroacetic acid; RT: Room temperature.

[0139] Preparation Example:

[0140] Example I-1: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-hydroxy-3,10-diazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 [Tecone-2(3),4(9),5,7,12(13),14,16-heptaen-18-one(I-1)]

[0141] Step A: 2-Bromo-6-[(difluoromethyl)oxy]benzene-1-carboxaldehyde (2)

[0142] Diethyl bromodifluoromethylphosphonate (66.4 g, 248.7 mmol) was dissolved in acetonitrile (500 mL). A solution of potassium hydroxide (13.9 g, 248.7 mmol) in water (500 mL) was added with stirring at 0 °C. Then 2-bromo-6-hydroxybenzaldehyde (compound 1, 50 g, 248.7 mmol) was added. The reaction solution was stirred at 0 °C for 2 hours. The reaction solution was diluted with dichloromethane (500 mL), washed with saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give title compound 2 (30 g, 48%).

[0143] LC-MS (m / z): 251 [M+H] + .

[0144] 1 H NMR (400MHz, CDCl3) δ.10.35 (s, 1H), 7.58 (d, J = 8.0Hz, 1H), 7.41 (t, J = 8.0Hz, 1H), 7.26 (d, J = 8.0Hz, 1H), 6.61 (t, J = 73.6Hz, 1H).

[0145] Step B: (1E)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-N-[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ 4 -Thio]methaneimine (3)

[0146] 2-Bromo-6-[(difluoromethyl)oxy]benzene-1-carboxaldehyde (compound 2, 30 g, 119.5 mmol) was dissolved in dichloromethane (400 mL), and S-tert-butylsulfinamide (17.38 g, 143.4 mmol) and cesium carbonate (46.7 g, 143.4 mmol) were added with stirring. The reaction mixture was stirred for 16 hours, filtered, and the filtrate was washed with saturated sodium chloride (400 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain title compound 3 (30 g, 71%).

[0147] LC-MS (m / z): 354 [M+H] + .

[0148] 1 H NMR (400MHz, CDCl3) δ.8.84(s,1H),7.59-7.57(m,1H),7.35-7.31(m,1H),7.26-7.24(m,1H),6.57(t,J=73.6Hz,1H),1.30(s,9H).

[0149] Step C: (3R)-3-{[(S)-(2-methylpropyl-2-yl)(oxo-ylidene)-λ 4 Ethyl propionate (4) = 3-[2-bromo-6-[(difluoromethyl)oxy]phenyl]propionate

[0150] Zinc powder (5.5 g, 84.7 mmol) was added to a tetrahydrofuran solution (100 mL) of anhydrous cuprous chloride (8.42 g, 84.7 mmol) at room temperature. The mixture was stirred at 70 °C for half an hour and then cooled to room temperature. A tetrahydrofuran solution (100 mL) containing ethyl bromoacetate (28.3 g, 169.4 mmol) was then added dropwise at room temperature. The mixture was stirred at 50 °C for half an hour. The reaction solution was filtered, and (1E)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-N-[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ] was added to the filtrate at 0 °C. 4 A solution of [-thio]methaneimine (compound 3, 30 g, 84.7 mmol) in tetrahydrofuran (50 mL) was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (100 x 3 mL), the organic phases were combined, washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give title compound 4 (29 g, 77%).

[0151] LC-MS (m / z): 442 [M+H] + .

[0152] 1 H NMR (400MHz, CDCl3) δ.7.50-7.42(m,1H),7.23-7.00(m,2H),6.62(t,J=73.2Hz,1H),5.6 8-5.55(m,1H),4.18-4.03(m,2H),3.36-2.92(m,2H),1.22(t,J=7.2Hz,3H),1.16(s,9H).

[0153] Step D: Ethyl (3R)-3-amino-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}propionate (5)

[0154] Ethyl (3R)-3-{[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ4-thio]amino}-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}propionate (compound 4, 29 g, 65.5 mmol) was dissolved in dichloromethane (300 mL), and dioxane hydrochloride solution (4 M, 150 mL) was added with stirring at room temperature. The reaction solution was stirred for 3 hours, and the reaction solution was concentrated to give title compound 5 (28 g, 100%, crude product).

[0155] LC-MS (m / z): 338 [M+H] + .

[0156] Step E: (3R)-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-3-[(5-chloro-2-nitrophenyl)amino]propionate (6)

[0157] Potassium carbonate (26.7 g, 196.5 mmol) was added to acetonitrile (300 mL), and ethyl (3R)-3-amino-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}propionate (compound 5, 28 g, 65.5 mol, crude product) and 4-chloro-2-fluoro-1-nitrobenzene (13.7 g, 78.6 mol) were added with stirring at room temperature. The reaction solution was stirred at 80 °C for 16 hours. After returning to room temperature, the reaction solution was diluted with ethyl acetate (700 mL), the organic phase was washed with saturated sodium chloride aqueous solution (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain title compound 6 (21.5 g, 66%).

[0158] LC-MS (m / z): 493 [M+H] + .

[0159] 1H NMR(400MHz, CDCl3)δ.8.92(d,J=8.8Hz,1H),8.08(d,J=9.2Hz,1H),7.48-7.43(m,1H),7.23–7.11(m,2H),7.11-7.04(m,1H),6.65(t, J=73.2Hz,1H),6.63-6.57(m,1H),5.87-5.77(m,1H),4.18-4.09(m,2H),3.23-3.17(m,1H),3.02-2.85(m,1H),1.22(t,J=7.2Hz,3H).

[0160] Step F: (3R)-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-3-[(5-chloro-2-nitrophenyl)amino]propionaldehyde (7)

[0161] Under nitrogen protection and at -78°C, a tetrahydrofuran solution (1M, 87mL, 87mmol) of diisobutylaluminum hydride was added to a tetrahydrofuran solution of (3R)-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-3-[(5-chloro-2-nitrophenyl)amino]propionate (compound 6, 21.5 g, 43.5 mmol) in 200 mL. The mixture was stirred at -78°C for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution (100 mL), and extracted three times with dichloromethane (200 mL). The organic phases were combined and dried over anhydrous sulfuric acid. After filtration and concentration, column chromatography was used to give product 7 (16 g, 81%).

[0162] LC-MS (m / z): 449 [M+H] + .

[0163] 1 H NMR(400MHz, CDCl3)δ.9.81(s,1H),8.84(d,J=9.2Hz,1H),8.08(d,J=9.2Hz,1H),7.49-7.43(m,1H),7.22-7.14(m,2H), 7.13-7.06(m,1H),6.67(t,J=73.2Hz,1H),6.65-6.60(m,1H),5.97-5.88(m,1H),3.56-3.41(m,1H),3.22-2.93(m,1H).

[0164] Step G: (4R)-4-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butyronitrile (8)

[0165] (3R)-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-3-[(5-chloro-2-nitrophenyl)amino]propanal (compound 7, 16 g, 35.5 mmol) was dissolved in dichloromethane (300 mL). Trimethylcyanosilane (4.2 g, 42.6 mmol), zinc iodide (1.13 g, 3.55 mmol), and triethylamine (1 mL, 7.1 mmol) were added with stirring at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (500 mL). The organic phase was washed with saturated ammonium chloride solution (200 mL) and water (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give title compound 8 (18 g, 92%, crude product).

[0166] LC-MS (m / z): 548 [M+H] + .

[0167] Step H: (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (9)

[0168] (4R)-4-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butyronitrile (compound 8, 18 g, 32.79 mmol) was dissolved in ethanol (100 mL), and stannous chloride (31.2 g, 163.95 mmol) was added with stirring at room temperature. The reaction solution was stirred at 80 °C for 16 hours. The reaction solution was concentrated, and the residue was dissolved in ethyl acetate (200 mL). Saturated sodium carbonate solution was added to adjust the pH of the system to 10. The mixture was filtered, and the filtrate was washed with saturated sodium chloride (100 mL). The organic phase was concentrated, and the mixture was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain title compound 9 (4.4 g, 31%).

[0169] LC-MS (m / z): 429 [M+H] + .

[0170] Step I: (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-one (10)

[0171] (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (compound 9, 1 g, 2.33 mmol) was dissolved in tetrahydrofuran solution (30 mL), and manganese dioxide (870 mg, 10 mmol) was added at room temperature. The reaction solution was stirred at 50 °C for 16 hours. After filtration, the reaction solution was concentrated under vacuum to obtain crude compound 10 (950 mg, 95%).

[0172] LC-MS (m / z): 427 [M+H] + .

[0173] Step J:(1R)-1-{2-acetyl-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[2,1-b]imidazol-3-one (11)

[0174] Compound (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-one (compound 10, 950 mg, 2.22 mmol) was dissolved in toluene (20 mL). Ditriphenylphosphine palladium dichloride (155.84 mg, 0.222 mmol) and tributyl(1-ethoxyenyl)tin (801.42 mg, 2.22 mmol) were added at room temperature. The reaction mixture was heated to 105 °C and stirred for 16 hours under nitrogen protection. The reaction mixture was then quenched with an aqueous potassium fluoride solution (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed once with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The crude compound was dissolved in tetrahydrofuran (50 mL), and p-toluenesulfonic acid (200 mg) and water (5 mL) were added. The mixture was stirred at 45 °C for 5 hours. The reaction solution was poured into ice water, alkalized with sodium bicarbonate aqueous solution (30 mL), and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The crude compound was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain the title compound 11 (720 mg, 83%).

[0175] LC-MS (m / z): 391 [M+H] + .

[0176] Step K: (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19] Twenty-3(4), 5, 7, 9, 14(15), 16, 18-heptaen-13-one(12)

[0177] (1R)-1-{2-acetyl-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[2,1-b]imidazol-3-one (compound 11, 720 mg, 1.84 mmol) was dissolved in tetrahydrofuran (10 mL), and a tetrahydrofuran solution of diisopropylaminolithium (2 M, 0.92 mL, 1.84 mmol) was added at -70 °C, followed by stirring at -70 °C for 2 hours. The reaction mixture was then quenched with saturated ammonium chloride aqueous solution (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The crude compound was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain the title compound 12 (220 mg, 30%).

[0178] LC-MS (m / z): 391 [M+H] + .

[0179] Step L: (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4, 9] Tico-2(3),4(5),6,8,12(13),14,16-heptaen-18-one(13)

[0180] (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19[12, 220 mg, 0.56 mmol] Tico-3(4),5,7,9,14(15),16,18-heptaen-13-one (compound 12, 220 mg, 0.56 mmol), pinacol diborate (285 mg, 1.12 mmol) and potassium acetate (110 mg, 1.12 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction solution was protected with nitrogen. Tris(dibenzylideneacetone)dipalladium (34 mg, 0.04 mmol) and tricyclohexylphosphine tetrafluoroborate (14.72 mg, 0.04 mmol) were added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 140 °C and stirred for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain title compound 13 (180 mg, 66%).

[0181] LC-MS (m / z): 483 [M+H] + .

[0182] Step M: (cyclobutylidene)[(2-methylpropyl-2-yl)(oxo-ylidene)-λ 4 -Thio[amine](16)

[0183] Tetraisopropyl titanate (289 g, 1.02 mol) was added to a tetrahydrofuran solution (1 L) of cyclobutanone (52 g, 713 mmol) and tert-butylsulfinamide (82 g, 679 mmol). The reaction mixture was protected with nitrogen and stirred at 60 °C for 16 hours. The reaction mixture was then diluted with ethyl acetate (1 L) and quenched with saturated sodium bicarbonate solution (1 L). After filtration, the organic phase was separated, washed once with saturated sodium chloride solution (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1-1 / 1) to obtain the title compound 16 (52 g, 44%).

[0184] LC-MS (m / z): 174 [M+H] + .

[0185] 1 H NMR (400MHz, CDCl3) δ.3.59-3.22(m,2H),3.21-3.03(m,2H),2.12(t,J=8.0Hz,2H),1.24(s,9H).

[0186] Step N: 5-bromo-2-({[(2-methylpropyl-2-yl)(oxonyl)-λ) 4 -Thio]amino}cyclobutyl)pyrimidine (17)

[0187] Lithium n-butyl (2.5 M, 106 mL, 265 mmol) was added dropwise to tetrahydrofuran (1.2 L) containing 5-bromo-2-iodopyrimidine (75.5 g, 265 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 30 minutes under nitrogen protection. Then, (cyclobutylene)[(2-methylpropyl-2-yl)(oxoethylenedimethyl)-λ was added at -78 °C. 4 [-thio]amine (compound 16, 46 g, 265 mmol) was reacted in a tetrahydrofuran (300 mL) solution. After the reaction was complete, the solution was quenched in ice water (1 L). The mixture was extracted with ethyl acetate (1 L x 3). The organic phases were combined, washed once with saturated sodium chloride solution (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (PE / EA = 6 / 1-3 / 1) to obtain title compound 17 (30 g, 34%).

[0188] LC-MS (m / z): 332 [M+H] + .

[0189] 1 H NMR (400MHz, CDCl3) δ = 8.77 (s, 2H), 4.78 (s, IH), 2.88-2.78 (m, IH), 2.73-2.55 (m, 2H), 2.54-2.43 (m, IH), 2.14-1.92 (m, 2H), 1.24 (s, 9H).

[0190] Step O: 5-bromo-2-({[(2-methylpropyl-2-yl)(oxonyl)-λ) 4 -Thio]amino}cyclobutyl)pyrimidine (18)

[0191] Add concentrated hydrochloric acid (12M, 30mL) to 5-bromo-2-({[(2-methylpropyl-2-yl)(oxonyl)-λ) at room temperature. 4 [-thio]amino}cyclobutyl)pyrimidine (compound 17, 30 g, 90.3 mmol) was reacted in methanol (300 mL) and stirred at room temperature for 2 hours. The mixture was then directly concentrated under vacuum to obtain crude compound 18 (25 g, 100%).

[0192] LC-MS (m / z): 228 [M+H] + .

[0193] 1 H NMR (400MHz, MeOD-d4) δ = 9.02 (s, 2H), 2.84-2.82 (m, 2H), 2.81-2.78 (m, 2H), 2.60-2.27 (m, 2H).

[0194] Step P: {[(5-bromopyrimidin-2-yl)cyclobutyl]amino}methane-2-methylpropyl-2-yl ester (19)

[0195] 5-bromo-2-({[(2-methylpropyl-2-yl)(oxo-ylidene)-λ) 4 [-thio]amino}cyclobutyl)pyrimidine (compound 18, 25 g, 90.3 mmol) was added to di-tert-butyl dicarbonate (23.6 g, 108.2 mmol) and triethylamine (12 g, 108.2 mmol) in tetrahydrofuran (300 mL) at room temperature. The reaction mixture was stirred at room temperature for half an hour, and then directly concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (PE / EA = 6 / 1-3 / 1) to obtain title compound 19 (25 g, 84%).

[0196] LC-MS (m / z): 328 [M+H] + .

[0197] 1 H NMR (400MHz, CDCl3) δ = 8.78 (s, 2H), 5.80-5.63 (m, 1H), 2.76-2.67 (m, 2H), 2.66-2.53 (m, 2H), 2.21-2.04 (m, 2H), 1.43 (s, 9H).

[0198] Step Q: [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-18-oxoylide-3,10-diazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 [Tecico-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (14)

[0199] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9

[13] 2-(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), {[(5-bromopyrimidin-2-yl)cyclobutyl]amino}methane-2-methylpropyl-2-yl ester (compound 19, 32.8 mg, 0.10 mmol) and potassium carbonate (27.6 mg, 0.20 mmol) were dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was kept under nitrogen atmosphere. Under controlled conditions, methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen, and the mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 14 (25 mg, 41%).

[0200] LC-MS (m / z): 604 [M+H] + .

[0201] Step R: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-hydroxy-3,10-diazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 [Tecone-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-1)]

[0202] A 4M, 4mL solution of 1,4-dioxane hydrochloric acid was added to [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-18-oxoylide-3,10-diazapentacyclo[9.8.1.0]] at room temperature. 12,17 .0 4,9 .0 2,10 The reaction mixture of 2-(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (compound 14, 25 mg, 0.041 mmol) in 1,4-dioxane (2 mL) was stirred at room temperature for 1 hour, and then directly concentrated under vacuum to obtain the crude compound. The residue was purified by preparative chromatography to obtain the title compound I-1 (5 mg, 24.2%).

[0203] LC-MS (m / z): 504 [M+H] + .

[0204] 1 H NMR (400MHz, MeOD-d4) δ.8.74(s,2H),8.05-7.99(m,2H),7.92(d,J=3.2Hz,1H),7.74(dd,J=8.0,2.0Hz,1H),7.32-7.27(m,1H),7.21(dd,J=8.0,2. 0Hz,1H),6.97(t,J=57.6Hz,1H),6.70-6.67(m,1H),3.89-3.85(m,1H),3. 18-3.15(m,1H),2.80-2.65(m,2H),2.28-2.18(m,4H),1.88-1.80(m,2H).

[0205] The following examples follow the synthetic method steps of Example I-1, where M, N, O, and P are selected to synthesize the corresponding brominated products and to prepare the products by coupling reactions with compound 13 from Example I-1:

[0206] The NMR data of the compounds prepared in the above examples are as follows:

[0207] Example I-81: (1R,11R)-18-[(difluoromethyl)oxy]-11-hydroxy-5-[2-(hydroxycyclobutyl)pyrimidin-5-yl]-2,9-diazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 [I-81] 3(8),4,6,9,14(15),16,18-heptaen-13-one

[0208] Step A: 1-(5-bromopyrimidin-2-yl)cyclobut-1-ol (20)

[0209] Butyllithium (2.5 M, 4 mL, 10 mmol) was added dropwise to anhydrous tetrahydrofuran (50 mL) containing 5-bromo-2-iodopyrimidine (2.85 g, 10 mmol). The reaction mixture was stirred at -78 °C for 30 min under nitrogen protection. Then, a tetrahydrofuran (20 mL) solution containing cyclobutanone (700 mg, 10 mmol) was added at -78 °C. After the reaction was complete, the mixture was quenched in a saturated ammonium chloride aqueous solution (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed once with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The residue was purified by silica gel column chromatography (PE / EA = 4 / 1-3 / 1) to obtain the title compound 20 (1.15 g, 50%).

[0210] LC-MS (m / z): 229 [M+H] + .

[0211] 1 H NMR (400MHz, MeOD-d4) δ = 8.80 (s, 2H), 2.57 (dddd, J = 11.2, 5.2, 4.4, 2.5Hz, 2H), 2.32-2.23 (m, 2H), 1.93-1.76 (m, 2H).

[0212] Step B: (1R,11R)-18-[(difluoromethyl)oxy]-11-hydroxy-5-[2-(hydroxycyclobutyl)pyrimidin-5-yl]-2,9-diazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 [I-81] 3(8),4,6,9,14(15),16,18-heptaen-13-one

[0213] (1R,11R)-13-[(difluoromethyl)oxy]-1-hydroxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 [[Ecto-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 13, 48.2 mg, 0.10 mmol), 1-(5-bromopyrimidin-2-yl)cyclobut-1-ol (compound 20, 22.9 mg, 0.10 mmol) and potassium carbonate (27.6 mg, 0.20 mmol) were dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was kept under nitrogen atmosphere.]] Under controlled conditions, methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen, and the mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound I-81 (15 mg, 29%).

[0214] LC-MS (m / z): 505 [M+H] + .

[0215] 1H NMR(400MHz,MeOD-d4)δ.8.75(s,2H),8.05-7.99(m,2H),7.92(d,J=3.2Hz,1H),7.74(dd,J=8.0,2.0Hz,1H),7.32-7.27(m,1H),7.21(dd,J=8.0,2. 0Hz,1H),6.97(t,J=57.6Hz,1H),6.70-6.67(m,1H),3.89-3.85(m,1H),3. 18-3.15(m,1H),2.80-2.66(m,2H),2.36-2.22(m,4H),1.99-1.89(m,2H).

[0216] The following examples illustrate the synthesis of the corresponding brominated derivatives by selecting appropriate starting materials and reacting them with compound 13 from Examples I-81 via a coupling reaction, following step A of the synthetic method in Examples I-81:

[0217] Example I-231: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,10-diazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 ] Twenty-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-231)

[0218] Step A: (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-fluoro-2,9-diazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 [Tecone-3(4),5,7,9,14(15),16,18-heptaen-13-one(56)]

[0219] (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-hydroxy-2,9-diazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19[12,780 mg, 2 mmol] teico-3(4),5,7,9,14(15),16,18-heptaen-13-one (compound 12,780 mg, 2 mmol) was dissolved in dichloromethane (10 mL), and diethylaminosulfur trifluoride (322 mg, 2 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 16 hours. The reaction solution was then quenched with saturated sodium bicarbonate aqueous solution (10 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the crude compound. The title compound 56 (50 mg, 6%) was purified by silica gel column chromatography (PE / EA = 1 / 1).

[0220] LC-MS (m / z): 393 [M+H] + .

[0221] Step B: (1R,11R)-13-[(difluoromethyl)oxy]-1-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 ] Twenty-2(3),4(5),6,8,12(13),14,16-heptaen-18-one(57)

[0222] (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-fluoro-2,9-diazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 [[Tyro-3(4),5,7,9,14(15),16,18-heptaen-13-one (compound 56, 50 mg, 0.12 mmol), pinacol diboronate (61 mg, 0.24 mmol) and potassium acetate (23.5 mg, 0.24 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction solution was protected with nitrogen. Tris(dibenzylideneacetone)palladium (17 mg, 0.02 mmol) and tricyclohexylphosphine tetrafluoroborate (7.36 mg, 0.02 mmol) were added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 140 °C and stirred for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain title compound 57 (25 mg, 43%).]

[0223] LC-MS (m / z): 485 [M+H] + .

[0224] Step C: [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-fluoro-18-oxoyne-3,10-diazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 [Tecico-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (58)

[0225] (1R,11R)-13-[(difluoromethyl)oxy]-1-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10-diazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 [1,4-Heptaen-18-one (compound 57, 25 mg, 0.05 mmol), {[(5-bromopyrimidin-2-yl)cyclobutyl]amino}methane-2-methylpropyl-2-yl ester (compound 19, 19.7 mg, 0.06 mmol) and potassium carbonate (13.8 mg, 0.10 mmol) were dissolved in a mixed solution of 1,4-dioxane (4 mL) and water (1 mL), and the reaction solution was protected with nitrogen.] Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (8.6 mg, 0.01 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen, and the mixture was heated to 110 °C and stirred for 6 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 58 (12 mg, 39%).

[0226] LC-MS (m / z): 606 [M+H] + .

[0227] Step D: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,10-diazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 ] Twenty-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-231)

[0228] A 4M, 4mL solution of 1,4-dioxane hydrochloric acid was added to [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-fluoro-18-oxoylide-3,10-diazapentacyclo[9.8.1.0]] at room temperature. 12,17 .0 4,9 .0 2,10 The reaction mixture of 2-(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (compound 58, 12 mg, 0.02 mmol) was stirred at room temperature for 1 hour in 1,4-dioxane (2 mL), and then directly concentrated under vacuum to obtain the crude compound. The residue was purified by preparative chromatography to obtain the title compound I-231 (2 mg, 21%).

[0229] LC-MS (m / z): 506 [M+H] + .

[0230] 1 H NMR(400MHz,MeOD-d4)δ.8.73(s,2H),8.04-7.99(m,2H),7.92(d,J=3.2Hz,1H),7.73(dd,J=8.0,2.0Hz,1H),7.32-7.27(m,1H),7.21(dd, J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),6.70-6.67(m,1H),3.81-3.49(m,2H),2.82-2.58(m,2H),2.30-2.21(m,4H),1.88-1.81(m,2H).

[0231] The following examples illustrate the preparation of compounds 57 from Examples I-231 by coupling the corresponding brominated derivatives, methanesulfonates, or alkynates with the synthetic method described in Examples I-231:

[0232] The NMR data of the compounds prepared in the above embodiments are as follows:

[0233] Example I-288: (1R,12R)-16-[2-(aminocyclobutyl)pyrimidin-5-yl]-10-[(difluoromethyl)oxy]-4,13,20-triazahexane[10.9.1.0] 1,4 .0 6,11 .0 13,21 .0 14,19] Twenty-two-6(7),8,10,14(19),15,17,20-heptaen-5-one (I-288)

[0234] Step A: (1R)-3-[(E)-[(R)-(2-methylpropyl-2-yl)(oxonyl)-λ 4 [-Thio]N-Isyl]-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolium (73)

[0235] (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-one (compound 10, 4.27 g, 10.0 mmol), (R)-tert-butylsulfinamide (1.21 g, 10.0 mmol) and tetraisopropyl titanate (5.68 g, 20.0 mmol) were dissolved in tetrahydrofuran (50 mL). The reaction solution was protected with nitrogen and stirred at 60 °C for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain title compound 73 (3.71 g, 70%).

[0236] LC-MS (m / z): 530 [M+H] + .

[0237] Step B: [(1R,3S)-3-{[(R)-(2-methylpropyl-2-yl)(oxo-ylidene)-λ] 4 [-thio]amino}-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl]acetic acid-2-methylpropyl-2-yl ester (74)

[0238] Ethyl bromoacetate (2.94 g, 17.50 mmol), zinc powder (4.55 g, 70 mmol), and cuprous chloride (688.5 mg, 7.0 mmol) were dissolved in tetrahydrofuran (30 mL). The reaction mixture was protected with nitrogen and stirred at 60 °C for half an hour. After cooling to 0 °C, (1R)-3-[(E)-[(R)-(2-methylpropyl-2-yl)(oxonyl)-λ] was added. 4[-thio]azine]-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole (compound 73, 3.71 g, 7.0 mmol) was stirred at 0 °C for 1 hour. The reaction solution was filtered, and the filtrate was diluted with ethyl acetate (100 mL), washed with dilute hydrochloric acid (100 mL) and saturated sodium bicarbonate solution (100 mL), concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to give title compound 74 (2.7 g, 60%).

[0239] LC-MS (m / z): 646 [M+H] + .

[0240] Step C: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,10-diazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 ] Twenty-2(3),4(9),5,7,12(13),14,16-heptaen-18-one(75)

[0241] Add [(1R,3S)-3-{[(R)-(2-methylpropyl-2-yl)(oxonyl)-λ] to a 1,4-dioxane solution of hydrochloric acid (4M, 40 mL) at room temperature. 4 [-thio]amino}-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl]acetic acid-2-methylpropyl-2-yl ester (compound 74, 2.7 g, 4.2 mmol) was reacted in 1,4-dioxane (40 mL) at room temperature for 1 hour, and then directly concentrated under vacuum to obtain the crude compound. The residue was purified by preparative chromatography to obtain the title compound 75 (2 g, 98%).

[0242] LC-MS (m / z): 486 [M+H] + .

[0243] Step D: (1'R,3'S)-1'-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7'-chloro-1',2'-dihydrospiro[azacyclobutane-2,3'-benzo[d]pyrrolo[1,2-a]imidazolium]-4-one (76)

[0244] Methanesulfonyl chloride (563 mg, 4.9 mmol) was added to (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,10-diazapentacyclo[9.8.1.0] 12,17 .0 2,1 0.0 4,9 Compound 76 (1.38 g, 72%) was prepared by reacting 2,4,5,7,12,13,14,16-heptaen-18-one (compound 75, 2 g, 4.1 mmol) and sodium bicarbonate (2.07 g, 24.6 mmol) in acetonitrile (30 mL). The reaction mixture was protected with nitrogen and stirred at 80 °C for 2 hours. The filtrate was diluted with ethyl acetate (120 mL), washed with saturated sodium bicarbonate (100 mL), concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 76.

[0245] LC-MS (m / z): 468 [M+H] + .

[0246] Step E: (1'R,3'R)-1'-{6-bromo-2-[(difluoromethyl)oxy]phenyl}-7'-chloro-1',2'-dihydrospiro[azacyclobutane-2,3'-benzo[d]pyrrolo[2,1-b]imidazole](77)

[0247] A borane tetrahydrofuran complex (4.4 mL, 4.4 mmol) was added to a tetrahydrofuran (30 mL) solution of (1'R,3'S)-1'-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7'-chloro-1',2'-dihydrospiro[azacyclobutane-2,3'-benzo[d]pyrrolo[1,2-a]imidazolium]-4-one (compound 76, 1.39 g, 2.94 mmol). The reaction mixture was protected with nitrogen and stirred at 0 °C for 1 hour. The mixture was quenched with methanol (5 mL), diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (100 mL), concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain the title compound 77 (720 mg, 54%).

[0248] LC-MS (m / z): 454 [M+H] + .

[0249] Step F: (1R,12R)-16-chloro-10-[(difluoromethyl)oxy]-4,13,20-triazahexane[10.9.1.0] 1,4 .0 14,19 .0 13,21 .0 6,11] Twenty-two-6(7),8,10,14(15),16,18,20-heptaen-5-one(78)

[0250] (1'R,3'R)-1'-{6-bromo-2-[(difluoromethyl)oxy]phenyl}-7'-chloro-1',2'-dihydrospiro[azacyclobutane-2,3'-benzo[d]pyrrolo[2,1-b]imidazole] (compound 77, 720 mg, 1.58 mmol), palladium acetate (35.8 mg, 0.16 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (89.2 mg, 0.16 mmol), and potassium carbonate (658 mg, 4.77 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction mixture was stirred at 110 °C for 16 hours under a carbon monoxide pressure of 5 atm. After concentration, the residue was purified by silica gel column chromatography (PE / EA = 1 / 1-0 / 1) to obtain title compound 78 (330 mg, 52%).

[0251] LC-MS (m / z): 402 [M+H] + .

[0252] Step G: [({5-[(1R,12R)-10-[(difluoromethyl)oxy]-5-oxoyne-4,13,20-triazahexane[10.9.1.0] 1,4 .0 6,11 .0 14,19 .0 13,21 ] Twenty-two-6(7),8,10,14(19),15,17,20-heptaen-16-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester(79)

[0253] [({5-[(1R,12R)-10-[(difluoromethyl)oxy]-5-oxoylide-4,13,20-triazahexane[10.9.1.0] 1,4 .0 6,11 .0 14,19 .0 13,21Compound 2-(7), 8, 10, 14 (19), 15, 17, 20-heptaen-16-yl)pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (compound 78, 330 mg, 0.82 mmol), pinacol diboronate (417 mg, 1.64 mmol) and potassium acetate (161 mg, 1.64 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction solution was protected with nitrogen. Methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged with dry nitrogen. The reaction was carried out three times, with the temperature raised to 130°C and microwaved for 1 hour. Then, 5-bromo-2-(5,5-dimethyl-1,4,2-dioxazacyclopenten-3-yl)pyridine (compound 39, 268 mg, 0.82 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17.2 mg, 0.02 mmol), potassium carbonate (226.3 mg, 1.64 mmol), and water (1 mL) were added. The reaction solution was kept under nitrogen protection and stirred at 110°C for 16 hours. The reaction solution was filtered, concentrated, and the residue was purified by preparative chromatography to obtain the title compound 79 (32 mg, 6%).

[0254] LC-MS (m / z): 615 [M+H] + .

[0255] Step H: (1R,12R)-16-[2-(aminocyclobutyl)pyrimidin-5-yl]-10-[(difluoromethyl)oxy]-4,13,20-triazahexane [10.9.1.0] 1,4 .0 6,11 .0 13,21 .0 14,19 ] Twenty-two-6(7),8,10,14(19),15,17,20-heptaen-5-one (I-288)

[0256] A 4M, 4mL solution of 1,4-dioxane in hydrochloric acid was prepared at room temperature [({5-[(1R,12R)-10-[(difluoromethyl)oxy]-5-oxoylide-4,13,20-triazahexane[10.9.1.0]]. 1,4 .0 6,11 .0 14,19 .0 13,21The compound was prepared by stirring 1,4-dioxane (2 mL) of 2-heptaen-16-ylpyrimidin-2-ylcyclobutylaminomethane-2-methylpropyl-2-yl ester (compound 79, 32 mg, 0.128 mmol) at room temperature for 1 hour, and then directly concentrated under vacuum to obtain the crude compound. The residue was purified by preparative chromatography to obtain the title compound I-288 (8 mg, 12%).

[0257] LC-MS (m / z): 504 [M+H] + .

[0258] 1 H NMR(400MHz,MeOD-d4)δ.8.73(s,2H),8.05-7.99(m,2H),7.93(d,J=2.4Hz,1H),7.47(dd,J=8.0,2.0Hz,1H),7.33-7.27(m,1H),7.21(dd, J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),5.06-5.04(m,1H),3.94-3.73(m,2H),2.69-2.39(m,4H),2.26-2.20(m,4H),1.88-1.80(m,2H).

[0259] The following examples illustrate the preparation of compounds by coupling the corresponding brominated derivatives described above with compound 78 from Examples I-288, following the synthetic method of Examples I-288:

[0260] Example I-291: (1R,13R)-19-[2-(aminocyclobutyl)pyrimidin-5-yl]-5,5-difluoro-13-hydroxy-15,22-diaza-4,6-dioxahexane [11.9.1.0] 3,7 .0 2,10 .0 14,22 .0 16,21 ] Twenty-three-2(3),7(8),9,14(15),16(21),17,19-heptaen-11-one (I-291)

[0261] Step A: 5-Bromo-2,2-difluorobenzo[d][1,3]dioxacyclopentene-4-carboxaldehyde (81)

[0262] 5-Bromo-2,2-difluorobenzo[d][1,3]dioxane (compound 80, 237 g, 1 mol) was dissolved in dry tetrahydrofuran (2 L). Diisopropylaminolithium (2 M, 500 mL, 1 mol) was added dropwise with stirring at -78 °C. The mixture was stirred at -78 °C for 1 hour, followed by the addition of N,N-dimethylformamide (87.6 g, 1.2 mol). The reaction mixture was stirred at -78 °C for another 1 hour, and then quenched with saturated ammonium chloride solution (1 L). The mixture was extracted with ethyl acetate (1 L x 3), and the organic phases were combined, washed with saturated sodium chloride solution (1 L), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain the title compound 81 (206.7 g, 78%).

[0263] LC-MS (m / z): 265 [M+H] + .

[0264] 1 H NMR (400MHz, CDCl3) δ.10.31 (s, 1H), 7.48 (d, J = 8.4Hz, 1H), 7.21 (d, J = 8.4Hz, 1H).

[0265] Step B: (1E)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-N-[(S)-(2-methylpropyl-2-yl)(oxonyl)-λ 4 -Thio]methaneimine (82)

[0266] Compound 82 was prepared by using compound 81 as a raw material instead of compound 2, following step B of Example I-1.

[0267] LC-MS (m / z): 368 [M+H] + .

[0268] Step C: (3R)-3-{[(S)-(2-methylpropyl-2-yl)(oxoyl)-λ 4 Ethyl 3-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)propionate (83)

[0269] Compound 83 was prepared by using compound 82 as a raw material instead of compound 3, following step C of Example I-1.

[0270] LC-MS (m / z): 456 [M+H] + .

[0271] Step D: Ethyl (3R)-3-amino-3-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)propionate (84)

[0272] Compound 84 was prepared by using compound 83 as a raw material instead of compound 4, following step D of Example I-1.

[0273] LC-MS (m / z): 352 [M+H] + .

[0274] Step E: (3R)-3-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-3-[(5-chloro-2-nitrophenyl)amino]propionate (85)

[0275] Compound 85 was prepared by using compound 84 as a raw material instead of compound 5, following step E of Example I-1.

[0276] LC-MS (m / z): 507 [M+H] + .

[0277] Step F: (3R)-3-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-3-[(5-chloro-2-nitrophenyl)amino]propionaldehyde (86)

[0278] Compound 86 was prepared by using compound 85 as a raw material instead of compound 6, following step F of Example I-1.

[0279] LC-MS (m / z): 463 [M+H] + .

[0280] Step G: (4R)-4-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-4-[(5-chloro-2-nitrophenyl)amino]-2-[(trimethylsilyl)oxy]butyronitrile (87)

[0281] Compound 87 was prepared by using compound 86 as a raw material instead of compound 7, following step G of Example I-1.

[0282] LC-MS (m / z): 562 [M+H] + .

[0283] Step H: (1R)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (88)

[0284] Compound 88 was prepared by using compound 87 as a raw material instead of compound 8, following step H of Example I-1.

[0285] LC-MS (m / z): 443 [M+H] + .

[0286] Step I: (1R)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-one (89)

[0287] Compound 89 was prepared by using compound 88 as a raw material instead of compound 9, following step I of Example I-1.

[0288] LC-MS (m / z): 441 [M+H] + .

[0289] Step J:(1R)-1-(5-acetyl-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[2,1-b]imidazol-3-one (90)

[0290] Compound 90 was prepared by using compound 89 as a raw material instead of compound 10, following step J of Example I-1.

[0291] LC-MS (m / z): 405 [M+H] + .

[0292] Step K: (1R,13R)-17-chloro-9,9-difluoro-1-hydroxy-14,21-diaza-8,10-dioxane [11.9.1.0] 15, 20 .0 14,22 .0 7,11 .0 4,12 ] Twenty-three-4(12),5,7(11),15(16),17,19,21-heptaen-3-one(91)

[0293] Compound 91 was prepared by using compound 90 as a raw material instead of compound 11, following step K of Example I-1.

[0294] LC-MS (m / z): 405 [M+H] + .

[0295] Step L: (1R,13R)-5,5-difluoro-13-hydroxy-19-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-15,22-diaza-4,6-dioxahexane [11.9.1.0] 3,7 .0 2,10 .0 14,22 .0 16,21] Twenty-three-2(3),7(8),9,14(15),16(17),18,20-heptaen-11-one(92)

[0296] Compound 92 was prepared by using compound 91 as a raw material instead of compound 12, following step L of Example I-1.

[0297] LC-MS (m / z): 497 [M+H] + .

[0298] Step M: [({5-[(1R,13R)-5,5-difluoro-13-hydroxy-11-oxoyl-15,22-diaza-4,6-dioxahexane[11.9.1.0]] 3,7 .0 2,10 .0 14,22 .0 16,21 ]23-2(3),7(8),9,14(15),16(21),17,19-heptaen-19-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester(14)

[0299] Compound 93 was prepared by using compound 92 as a raw material instead of compound 13, following step Q of Example I-1.

[0300] LC-MS (m / z): 618 [M+H] + .

[0301] Step N: (1R,13R)-19-[2-(aminocyclobutyl)pyrimidin-5-yl]-5,5-difluoro-13-hydroxy-15,22-diaza-4,6-dioxahexane [11.9.1.0] 3,7 .0 2,10 .0 14,22 .0 16,21 ] Twenty-three-2(3),7(8),9,14(15),16(21),17,19-heptaen-11-one (I-291)

[0302] Compound I-291 was prepared by using compound 93 as a raw material instead of compound 14, following step R of Example I-1.

[0303] LC-MS (m / z): 518 [M+H] + .

[0304] 1H NMR(400MHz,MeOD-d4)δ.8.73(s,2H),8.05-7.99(m,2H),7.92(d,J=2.4Hz,1H),7.57(d,J=7.6Hz,1H),7.14(d,J=7.6Hz ,1H),5.27-5.23(m,1H),3.89-3.84(m,1H),3.18-3.15(m,1H),2.81-2.65(m,2H),2.28-2.17(m,4H),1.88-1.77(m,2H).

[0305] The following examples illustrate the synthesis of the corresponding brominated derivatives using the same starting materials as in Example I-291, and the preparation of the brominated derivatives via coupling reactions with compound 92 from Example I-291:

[0306] The NMR data of the compounds prepared in the above embodiments are as follows:

[0307] Example I-346: (1R,11S)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,4-diazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 ] Twenty-2(3),5,7,9(10),12(13),14,16-heptaen-18-one (I-346)

[0308] Step A: (2E)-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}prop-2-enoic acid ethyl ester (115)

[0309] Diethyl (2-ethoxy-2-oxomethylene)phosphonate (11.2 g, 50.0 mmol) was dissolved in tetrahydrofuran (500 mL), and sodium hydride (2 g, 50.0 mmol) was added at 0 °C. The mixture was stirred for half an hour, and then 2-bromo-6-[(difluoromethyl)oxy]benzene-1-carboxaldehyde (compound 2, 12.5 g, 50.0 mmol) was added at -0 °C. The reaction mixture was stirred at room temperature for 16 hours, and the reaction mixture was quenched with saturated ammonium chloride solution (500 mL). The mixture was extracted with ethyl acetate (300 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to column chromatography to give the title compound 115 (12.8 g, 80%).

[0310] LC-MS (m / z): 321 [M+H] + .

[0311] Step B: 1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-8-chloro-2,3-dihydro-1H-cyclopentano[1',2':3,4]pyrazolo[1,5-a]pyridin-3-one (117)

[0312] Ethyl (2E)-3-{2-bromo-6-[(difluoromethyl)oxy]phenyl}prop-2-enoate (compound 115, 6.4 g, 20 mmol) was dissolved in 1,2-dichloroethane (50 mL). 5-chloropyrazolo[1,5-a]pyridine (compound 116, 3.05 g, 20.0 mmol) and trifluoromethanesulfonic acid (9.05 g, 60.0 mmol) were added at room temperature. The reaction mixture was stirred at 80 °C for 16 hours and quenched with saturated sodium bicarbonate solution (500 mL). The mixture was extracted with dichloromethane (300 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to column chromatography to give the title compound 117 (600 mg, 7%).

[0313] LC-MS (m / z): 427 [M+H] + .

[0314] Step C: 8-chloro-1-{6-[(difluoromethyl)oxy]-2-(1-ethoxyvinyl)phenyl}-2,3-dihydro-1H-cyclopentano[1',2':3,4]pyrazolo[1,5-a]pyridin-3-one (118)

[0315] Using compound 117 as a raw material instead of compound 10, and following step J of Example I-1, compound 118 was prepared without the need for acid hydrolysis.

[0316] LC-MS (m / z): 419 [M+H] + .

[0317] Step D: 5-Chloro-18-[(difluoromethyl)oxy]-11-hydroxy-8,9-diazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] 2-(3), 4, 6, 9, 14(15), 16, 18-heptaen-13-one(119)

[0318] Compound 119 was prepared by using compound 118 as a raw material instead of compound 63, following step A of Example I-285.

[0319] LC-MS (m / z): 391 [M+H] + .

[0320] Step E: 5-Chloro-18-[(difluoromethyl)oxy]-11-fluoro-8,9-diazapentacyclo[9.8.1.0] 3,8.0 2,10 .0 14,19 ] Twenty-2(3), 4, 6, 9, 14(15), 16, 18-heptaen-13-one(120)

[0321] Compound 120 was prepared by using compound 119 as a raw material instead of compound 12, following step A of Example I-231.

[0322] LC-MS (m / z): 393 [M+H] + .

[0323] Step F: (1S,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-fluoro-8,9-diazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] Twenty-2(3), 4, 6, 9, 14(15), 16, 18-heptaen-13-one(121)

[0324] Compound 121 was prepared by SFC resolution of compound 120.

[0325] LC-MS (m / z): 393 [M+H] + .

[0326] Step G: [({5-[(1R,11S)-13-[(difluoromethyl)oxy]-1-fluoro-18-oxoyne-3,4-diazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 [Tecico-2(3),5,7,9(10),12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (122)

[0327] Compound 122 was prepared by replacing compound 19 with compound 121 and replacing compound 13 with compound ({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrimidin-2-yl]cyclobutyl}amino)methane-2-methylpropyl-2-yl ester), referring to step Q of Example I-1.

[0328] LC-MS (m / z): 606 [M+H] + .

[0329] Step H: (1R,11S)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,4-diazapentacyclo[9.8.1.0] 12,17 .0 4,9 .02,10 ] Twenty-2(3),5,7,9(10),12(13),14,16-heptaen-18-one (I-346)

[0330] Compound I-346 was prepared by using compound 122 as a raw material instead of compound 14, following step R of Example I-1.

[0331] LC-MS (m / z): 506 [M+H] + .

[0332] 1 H NMR (400MHz, MeOD-d4) δ.8.74(s,2H),8.66(d,J=5.6Hz,1H),7.98(d,J=1.6Hz,1H),7.92(dd,J=5.6,1.2Hz,1H),7.68(dd,J=8.0,2.0Hz,1H),7.3 1-7.29(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),4.2 4-4.19(m,1H),3.78-3.48(m,2H),2.43-2.17(m,6H),1.89-1.81(m,2H).

[0333] The following examples illustrate the synthesis of corresponding brominated derivatives using the same starting materials as in Examples I-346, and the preparation of the brominated derivatives via coupling reactions with compound 121 from Examples I-346:

[0334] The NMR data of the compounds prepared in the above embodiments are as follows:

[0335] Example I-357: (1R,11S)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-hydroxy-3,4-diazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 ] Twenty-2(3),5,7,9(10),12(13),14,16-heptaen-18-one (I-357)

[0336] Step A: ({[5-(1-{2-[(difluoromethyl)oxy]-6-(1-ethoxyvinyl)phenyl}-3-oxoylide-2,3-dihydro-1H-cyclopentano[1',2':3,4]pyrazolo[1,5-a]pyridin-8-yl)pyrimidin-2-yl]cyclobutyl}amino)methane-2-methylpropyl-2-yl ester (123)

[0337] Compound 123 was prepared by replacing compound 19 with compound 118 and replacing compound 13 with compound ({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrimidin-2-yl]cyclobutyl}amino)methane-2-methylpropyl-2-yl ester), referring to step Q of Example I-1.

[0338] LC-MS (m / z): 632 [M+H] + .

[0339] Step B: {[(5-{13-[(difluoromethyl)oxy]-1-hydroxy-18-oxoylide-3,4-diazapentacyclo[9.8.1.0]} 12,17 .0 4,9 .0 2,10

[124] 2-(3),5,7,9(10),12(13),14,16-heptaen-7-ylpyrimidin-2-yl)cyclobutyl]aminomethane-2-methylpropyl-2-yl ester (124)

[0340] Compound 124 was prepared by using compound 123 as a raw material instead of compound 63, following step A of Example I-285.

[0341] LC-MS (m / z): 604 [M+H] + .

[0342] Step C: (1R,11S)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-hydroxy-3,4-diazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 ] Twenty-2(3),5,7,9(10),12(13),14,16-heptaen-18-one (I-357)

[0343] Using compound 124 as the raw material instead of compound 14, and referring to step R of Example I-1, compound I-357 was finally prepared by chiral resolution.

[0344] LC-MS (m / z): 504 [M+H] + .

[0345] 1H NMR(400MHz,MeOD-d4)δ.8.73(s,2H),8.66(d,J=5.6Hz,1H),7.98(d,J=1.6H z,1H),7.91(dd,J=5.6,1.2Hz,1H),7.68(dd,J=8.0,2.0Hz,1H),7.31-7.29(m ,1H),7.21(dd,J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),4.20-4.15(m,1H) ,3.89-3.84(m,1H),3.15-3.11(m,1H),2.48-2.21(m,6H),1.89-1.78(m,2H).

[0346] Example I-358: (1R,11S)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,4-diazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 ] Twenty-2(3),5,7,9(10),12(13),14,16-heptaen-18-one (I-358)

[0347] Step A: 5-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-3-chloro-6,7-dihydro-5H-cyclopentano[1',2':3,4]pyrazolo[5,1-f]pyrimidin-7-one (127)

[0348] Compound 127 was prepared by using compound 126 as a raw material instead of compound 116, following step B of Example I-346.

[0349] LC-MS (m / z): 428 [M+H] + .

[0350] Step B: 3-Chloro-5-{6-[(difluoromethyl)oxy]-2-(1-ethoxyvinyl)phenyl}-6,7-dihydro-5H-cyclopentano[1',2':3,4]pyrazolo[5,1-f]pyrimidin-7-one (128)

[0351] Using compound 127 as a raw material instead of compound 10, and following step J of Example I-1, compound 128 was prepared without the need for acid hydrolysis.

[0352] LC-MS (m / z): 420 [M+H] + .

[0353] Step C: 5-Chloro-18-[(difluoromethyl)oxy]-11-hydroxy-6,8,9-triazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] Twenty-2(3), 4, 6, 9, 14(15), 16, 18-heptaen-13-one(129)

[0354] Compound 129 was prepared by using compound 128 as a raw material instead of compound 63, following step A of Example I-285.

[0355] LC-MS (m / z): 392 [M+H] + .

[0356] Step D: 5-Chloro-18-[(difluoromethyl)oxy]-11-fluoro-6,8,9-triazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] Twenty-2(3), 4, 6, 9, 14(15), 16, 18-heptaen-13-one(130)

[0357] Compound 130 was prepared by using compound 129 as a raw material instead of compound 12, following step A of Example I-231.

[0358] LC-MS (m / z): 394 [M+H] + .

[0359] Step E: (1S,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-fluoro-6,8,9-triazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] Twenty-2(3), 4, 6, 9, 14(15), 16, 18-heptaen-13-one(131)

[0360] Compound 131 was prepared by SFC resolution of compound 130.

[0361] LC-MS (m / z): 394 [M+H] + .

[0362] Step F: [({5-[(1R,11S)-13-[(difluoromethyl)oxy]-1-fluoro-18-oxoyne-3,4,6-triazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10[Tecico-2(3),5,7,9(10),12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (132)

[0363] Compound 132 was prepared by replacing compound 19 with compound 131 and replacing compound 13 with compound ({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrimidin-2-yl]cyclobutyl}amino)methane-2-methylpropyl-2-yl ester), referring to step Q of Example I-1.

[0364] LC-MS (m / z): 607 [M+H] + .

[0365] Step G: (1R,11S)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,4-diazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 ] Twenty-2(3),5,7,9(10),12(13),14,16-heptaen-18-one (I-358)

[0366] Compound I-358 was prepared by using compound 132 as a raw material instead of compound 14, following step R of Example I-1.

[0367] LC-MS (m / z): 507 [M+H] + .

[0368] 1 H NMR(400MHz,MeOD-d4)δ.9.55(s,1H),8.83(s,2H),7.81(s,1H),7.69(dd,J=8.0,2.0Hz,1H),7.31-7.29(m,1H),7.21(dd ,J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),4.24-4.19(m,1H),3.78-3.48(m,2H),2.43-2.18(m,6H),1.90-1.81(m,2H).

[0369] The following examples illustrate the synthesis of corresponding brominated derivatives using the same starting materials as in Examples I-358, and the preparation of the brominated derivatives via coupling reactions with compound 131 from Examples I-358:

[0370] The NMR data of the compounds prepared in the above embodiments are as follows:

[0371] Example I-367: (1R,11S)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,4,8-triazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 ] Twenty-2(3),5,7,9(10),12(13),14,16-heptaen-18-one (I-367)

[0372] Step A: 9-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-2-chloro-8,9-dihydro-7H-cyclopentano[1',2':3,4]pyrazolo[1,5-a]pyrimidin-7-one (143)

[0373] Compound 143 was prepared by using compound 142 as a raw material instead of compound 116, following step B of Example I-346.

[0374] LC-MS (m / z): 428 [M+H] + .

[0375] Step B: 2-Chloro-9-{6-[(difluoromethyl)oxy]-2-(1-ethoxyvinyl)phenyl}-8,9-dihydro-7H-cyclopentano[1',2':3,4]pyrazolo[1,5-a]pyrimidin-7-one (144)

[0376] Using compound 143 as a raw material instead of compound 10, and following step J of Example I-1, compound 144 was prepared without acid hydrolysis.

[0377] LC-MS (m / z): 420 [M+H] + .

[0378] Step C: 5-Chloro-18-[(difluoromethyl)oxy]-11-hydroxy-4,8,9-triazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] 2-(3), 4, 6, 9, 14(15), 16, 18-heptaen-13-one(145)

[0379] Compound 145 was prepared by using compound 144 as a raw material instead of compound 63, following step A of Example I-285.

[0380] LC-MS (m / z): 392 [M+H] + .

[0381] Step D: 5-Chloro-18-[(difluoromethyl)oxy]-11-fluoro-4,8,9-triazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] 2-(3), 4, 6, 9, 14(15), 16, 18-heptaen-13-one(146)

[0382] Compound 146 was prepared by using compound 145 as a raw material instead of compound 12, following step A of Example I-231.

[0383] LC-MS (m / z): 394 [M+H] + .

[0384] Step E: (1S,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-fluoro-4,8,9-triazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] Twenty-2(3), 4, 6, 9, 14(15), 16, 18-heptaen-13-one(147)

[0385] Compound 147 was prepared by SFC resolution of compound 146.

[0386] LC-MS (m / z): 394 [M+H] + .

[0387] Step F: [({5-[(1R,11S)-13-[(difluoromethyl)oxy]-1-fluoro-18-oxoyne-3,4,8-triazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 [Tecico-2(3),5,7,9(10),12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (148)

[0388] Compound 148 was prepared by replacing compound 19 with compound 147 and replacing compound 13 with compound ({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrimidin-2-yl]cyclobutyl}amino)methane-2-methylpropyl-2-yl ester), referring to step Q of Example I-1.

[0389] LC-MS (m / z): 607 [M+H] + .

[0390] Step G: (1R,11S)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,4,8-triazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 ] Twenty-2(3),5,7,9(10),12(13),14,16-heptaen-18-one (I-367)

[0391] Compound I-367 was prepared by using compound 148 as a raw material instead of compound 14, following step R of Example I-1.

[0392] LC-MS (m / z): 507 [M+H] + .

[0393] 1 H NMR(400MHz,MeOD-d4)δ.8.84(s,2H),8.72(d,J=5.6Hz,1H),7.68(dd,J=8.0,2.0Hz,1H),7.59(d,J=5.6Hz,1H),7.31-7.29(m,1H) ,7.21(dd,J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),5.23-5.17(m,1H),3.80-3.50(m,2H),2.44-2.18(m,6H),1.87-1.79(m,2H).

[0394] The following examples illustrate the synthesis of the corresponding brominated derivatives using the same starting materials as in Examples I-367, and their preparation by coupling reaction with compound 147 from Examples I-367:

[0395] Example I-371: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,9-diazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 [Tecone-2(10),3,5,7,12(13),14,16-heptaen-18-one (I-371)]

[0396] Step A: 1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-cyclopentano[1',2':4,5]imidazo[3,2-a]pyridin-3-one (150)

[0397] Compound 150 was prepared by using compound 149 as a raw material instead of compound 116, following step B of Example I-346.

[0398] LC-MS (m / z): 427 [M+H] + .

[0399] Step B: 7-Chloro-1-{6-[(difluoromethyl)oxy]-2-(1-ethoxyvinyl)phenyl}-2,3-dihydro-1H-cyclopentano[1',2':4,5]imidazo[3,2-a]pyridin-3-one (151)

[0400] Using compound 150 as a raw material instead of compound 10, and following step J of Example I-1, compound 151 was prepared without the need for acid hydrolysis.

[0401] LC-MS (m / z): 419 [M+H] + .

[0402] Step C: 5-Chloro-18-[(difluoromethyl)oxy]-11-hydroxy-3,9-diazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] Twenty-2(10), 4, 6, 8(9), 14(15), 16, 18-heptaen-13-one(152)

[0403] Compound 152 was prepared by using compound 151 as a raw material instead of compound 63, following step A of Example I-285.

[0404] LC-MS (m / z): 391 [M+H] + .

[0405] Step D: 5-Chloro-18-[(difluoromethyl)oxy]-11-fluoro-3,9-diazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] Twenty-2(10), 4, 6, 8(9), 14(15), 16, 18-heptaen-13-one(153)

[0406] Compound 153 was prepared by using compound 152 as a raw material instead of compound 12, following step A of Example I-231.

[0407] LC-MS (m / z): 393 [M+H] + .

[0408] Step E: (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-fluoro-3,9-diazapentacyclo[9.8.1.0]3,8 .0 2,10 .0 14,19 ] 2-(10), 4, 6, 8 (9), 14 (15), 16, 18-heptaen-13-one (154)

[0409] Compound 154 was prepared by SFC resolution of compound 153.

[0410] LC-MS (m / z): 394 [M+H] + .

[0411] Step F: [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-fluoro-18-oxoyne-3,9-diazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 [Tecico-2(10),3,5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (155)

[0412] Compound 155 was prepared by replacing compound 19 with compound 154 and replacing compound 13 with compound ({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrimidin-2-yl]cyclobutyl}amino)methane-2-methylpropyl-2-yl ester), referring to step Q of Example I-1.

[0413] LC-MS (m / z): 606 [M+H] + .

[0414] Step G: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,9-diazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 [Tecone-2(10),3,5,7,12(13),14,16-heptaen-18-one (I-371)]

[0415] Compound I-371 was prepared by using compound 155 as a raw material instead of compound 14, following step R of Example I-1.

[0416] LC-MS (m / z): 506 [M+H] + .

[0417] 1H NMR (400MHz, MeOD-d4) δ.8.71(s,2H),8.51(d,J=1.2Hz,1H),8.02(dd,J=5.6,1.2Hz,1H),7.70(dd,J=8.0,2.0Hz,1H),7.37(d,J=5.6Hz,1H),7.3 1-7.29(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.98(t,J=57.6Hz,1H),5.3 5-5.31(m,1H),3.81-3.49(m,2H),2.44-2.18(m,6H),1.87-1.79(m,2H).

[0418] The following examples illustrate the synthesis of corresponding brominated derivatives using the same starting materials as in Examples I-371, and the preparation of the brominated derivatives via coupling reactions with compound 154 from Examples I-371:

[0419] Example I-376: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,8,9-triazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 ] 2-(10),3,5,7,12(13),14,16-heptaen-18-one (I-376)

[0420] Step A: 8-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-2-chloro-7,8-dihydro-6H-cyclopentazo[1',2':4,5]imidazo[2,3-f]pyridazin-6-one (159)

[0421] Compound 159 was prepared by using compound 158 as a raw material instead of compound 116, following step B of Example I-346.

[0422] LC-MS (m / z): 428 [M+H] + .

[0423] Step B: 2-Chloro-8-{6-[(difluoromethyl)oxy]-2-(1-ethoxyvinyl)phenyl}-7,8-dihydro-6H-cyclopentazo[1',2':4,5]imidazo[2,3-f]pyridazin-6-one (160)

[0424] Using compound 159 as a raw material instead of compound 10, and following step J of Example I-1, compound 160 was prepared without acid hydrolysis.

[0425] LC-MS (m / z): 420 [M+H] + .

[0426] Step C: 5-Chloro-18-[(difluoromethyl)oxy]-11-hydroxy-3,4,9-triazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] 2-(10), 4, 6, 8 (9), 14 (15), 16, 18-heptaen-13-one (161)

[0427] Compound 161 was prepared by using compound 160 as a raw material instead of compound 63, following step A of Example I-285.

[0428] LC-MS (m / z): 392 [M+H] + .

[0429] Step D: 5-Chloro-18-[(difluoromethyl)oxy]-11-fluoro-3,4,9-triazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] 2-2(10), 4, 6, 8(9), 14(15), 16, 18-heptaen-13-one(162)

[0430] Compound 162 was prepared by using compound 161 as a raw material instead of compound 12, following step A of Example I-231.

[0431] LC-MS (m / z): 394 [M+H] + .

[0432] Step E: (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-11-fluoro-3,4,9-triazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] 2-(10), 4, 6, 8 (9), 14 (15), 16, 18-heptaen-13-one (163)

[0433] Compound 163 was prepared by SFC resolution of compound 162.

[0434] LC-MS (m / z): 394 [M+H] + .

[0435] Step F: [({5-[(1R,11R)-13-[(difluoromethyl)oxy]-1-fluoro-18-oxoyne-3,8,9-triazapentacyclo[9.8.1.0] 12,17 .04,9 .0 2,10 [Tecico-2(10),3,5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester (164)

[0436] Compound 164 was prepared by replacing compound 19 with compound 163 and replacing compound 13 with compound ({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrimidin-2-yl]cyclobutyl}amino)methane-2-methylpropyl-2-yl ester), referring to step Q of Example I-1.

[0437] LC-MS (m / z): 607 [M+H] + .

[0438] Step G: (1R,11R)-7-[2-(aminocyclobutyl)pyrimidin-5-yl]-13-[(difluoromethyl)oxy]-1-fluoro-3,8,9-triazapentacyclo[9.8.1.0] 12,17 .0 4,9 .0 2,10 ] 2-(10),3,5,7,12(13),14,16-heptaen-18-one (I-376)

[0439] Compound I-376 was prepared by using compound 164 as a raw material instead of compound 14, following step R of Example I-1.

[0440] LC-MS (m / z): 507 [M+H] + .

[0441] 1 H NMR(400MHz,MeOD-d4)δ.8.82(s,2H),8.20(d,J=8.8Hz,1H),7.70(dd,J=8.0,2.0Hz,1H),7.47(d,J=8.8Hz,1H),7.31-7.29(m,1H) ,7.21(dd,J=8.0,2.0Hz,1H),6.98(t,J=57.6Hz,1H),5.57-5.47(m,1H),3.91-3.46(m,2H),2.50-2.18(m,6H),1.88-1.79(m,2H).

[0442] The following examples illustrate the synthesis of corresponding brominated derivatives using the same starting materials as in Examples I-376, and the preparation of the brominated derivatives via coupling reactions with compound 163 from Examples I-376:

[0443] Example I-862: (1R,13R)-17-[2-(aminocyclobutyl)pyrimidin-5-yl]-9,9-difluoro-2-methyl-8,10-dioxa-2,15,21-triazahexane[11.9.1.0] 15,20 .0 4,12 .0 14,22 .0 7,11 ] Twenty-three-4(5),6,11(12),14(22),16,18,20(21)-heptaen-3-one(I-862)

[0444] Step A: (1R)-3-[(E)-[(R)-(2-methylpropyl-2-yl)(oxonyl)-λ 4 [-thio]nidiyl]-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-7-chloro-2,3-dihydro-1H-cyclopenta[1',2':4,5]imidazo[3,2-a]pyridine(224)

[0445] Compound 224 was prepared using compound (1R)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-7-chloro-2,3-dihydro-1H-cyclopenta[1',2':4,5]imidazo[3,2-a]pyridin-3-one as a starting material, following the synthesis method of intermediate 70 in patent WO2016050975.

[0446] LC-MS (m / z): 544 [M+H] + .

[0447] Step B: (1R,3R)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-4-yl)-7-chloro-2,3-dihydro-1H-cyclopenta[1',2':4,5]imidazo[3,2-a]pyridine-3-amine (225)

[0448] Compound 225 was prepared using compound 224 as a raw material, following the synthesis method of intermediate 71 in patent WO2016050975.

[0449] LC-MS (m / z): 442 [M+H] + .

[0450] Step C: (1R,13R)-17-chloro-9,9-difluoro-8,10-dioxa-2,15,21-triazahexane [11.9.1.0] 15,20 .0 14,22 .0 7,11 .0 4,12] Twenty-three-4(12),5,7(11),14(22),16,18,20(21)-heptaen-3-one(226)

[0451] Compound 226 was prepared using compound 225 as a raw material, following the synthesis method described in Example 36 of patent WO2016050975.

[0452] LC-MS (m / z): 390 [M+H] + .

[0453] Step D: (1R,13R)-17-chloro-9,9-difluoro-2-methyl-8,10-dioxa-2,15,21-triazahexane [11.9.1.0] 15,20 .0 14,22 .0 7,11 .0 4,12 ] Twenty-three-4(5),6,11(12),14(22),16,18,20(21)-heptaen-3-one(227)

[0454] Compound 227 was prepared using compound 226 as a raw material, following the synthesis method of intermediate 149 in patent WO2016050975.

[0455] LC-MS (m / z): 404 [M+H] + .

[0456] Step E: [({5-[(1R,13R)-5,5-difluoro-12-methyl-11-oxoylide-4,6-dioxa-12,15,21-triazahexane[11.9.1.0]] 2,10 .0 16,21 .0 3,7 .0 14,22 ]23-2(3),7(8),9,14(22),15,17,19-heptaen-19-yl]pyrimidin-2-yl}cyclobutyl)amino]methane-2-methylpropyl-2-yl ester(228)

[0457] Compound 228 was prepared by replacing compound 19 with compound 227 and replacing compound 13 with compound ({[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)pyrimidin-2-yl]cyclobutyl}amino)methane-2-methylpropyl-2-yl ester), referring to step Q of Example I-1.

[0458] LC-MS (m / z): 617 [M+H] + .

[0459] Step F: (1R,13R)-17-[2-(aminocyclobutyl)pyrimidin-5-yl]-9,9-difluoro-2-methyl-8,10-dioxa-2,15,21-triazahexane[11.9.1.0] 15,20 .0 4,12 .0 14,22 .0 7,11 ] Twenty-three-4(5),6,11(12),14(22),16,18,20(21)-heptaen-3-one(I-862)

[0460] Compound I-862 was prepared by using compound 228 as a starting material instead of compound 14, following step R of Example I-1.

[0461] LC-MS (m / z): 517 [M+H] + .

[0462] 1 H NMR (400MHz, MeOD-d4) δ.8.69(s,2H),8.54(d,J=1.6Hz,1H),8.02(dd,J=8.0,2.0Hz,1H),7.31(d,J=8.0Hz,1H),7.23(d,J= 8.0Hz,1H),7.11(d,J=8.0Hz,1H),5.51-5.48(m,1H),5.20-5.16(m,1H),3.07(s,3H),2.35-1.95(m,6H),1.90-1.79(m,2H).

[0463] The following examples show the preparation of the materials according to the synthesis method of Example I-862:

[0464] The NMR data of the compounds prepared in the above embodiments are as follows:

[0465] Example I-883: (1R,11R)-18-[(difluoromethyl)oxy]-5-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-883)]

[0466] Step A: (1R)-3-azido-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[2,1-b]imidazolium (229)

[0467] (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (compound 9, 10 g, 23.3 mmol) was dissolved in toluene solution (80 mL), and diphenyl azidophosphate (6.4 g, 23.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (7.05 g, 46.4 mmol) were added. The reaction solution was stirred at 45 °C for 16 hours. The reaction solution was diluted with ethyl acetate (500 mL), and the organic phase was washed with saturated ammonium chloride solution (200 mL) and water (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to give title compound 229 (6.2 g, 58%).

[0468] LC-MS (m / z): 454 [M+H] + .

[0469] 1 H NMR (400MHz, Methanol-d4) δ7.70(d,J=7.8Hz,1H),7.63(d,J=2.3Hz,1H),7.41(dd,J=8.4,1.4Hz,1H),7.30-7.21(m, 2H),7.06(dd,J=8.7,1.3Hz,1H),5.59-5.74(m,1H),4.88-4.77(m,2H),2.85-2.55(m,1H),2.41-2.37(m,J=12.6,1H).

[0470] Step B: (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine (230)

[0471] (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol (compound 229, 6.2 g, 13.6 mmol) was dissolved in a mixture of toluene (30 mL) and tetrahydrofuran (30 mL), and triphenylphosphine (3.56 g, 13.6 mmol) and water (490 mg, 27.2 mmol) were added. The reaction mixture was stirred at 45 °C for 5 hours. The reaction mixture was diluted with ethyl acetate (200 mL), the organic phase was washed with water (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to column chromatography to give the title compound 230 (4.5 g, 79%).

[0472] LC-MS (m / z): 428 [M+H] + .

[0473] 1 H NMR (400MHz, Methanol-d4) δ7.73-7.67(m,1H),7.63(d,J=2.2Hz,1H),7.41(dd,J=8.3,1.1Hz,1H),7.30-7.21(m, 2H),7.06(dd,J=8.6,1.2Hz,1H),6.84-6.79(m,1H),5.08(d,J=4.5Hz,2H),4.84-4.80(m,1H),3.21-3.20(m,1H).

[0474] Step C: (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] Twenty-3(4), 5, 7, 9, 14(15), 16, 18-heptaen-13-one(231)

[0475] (1R)-1-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine (compound 230, 8.5 g, 19.8 mmol) was dissolved in 1,4-dioxane (80 mL), and palladium acetate (225 mg, 1.00 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (579 mg, 1.00 mmol), and potassium carbonate (2.72 g, 20.00 mmol) were added. The mixture was stirred at 100 °C for 16 hours under carbon monoxide pressure. The reaction mixture was then diluted with water (40 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to give the title compound 231 (1.5 g, 20%).

[0476] LC-MS (m / z): 376 [M+H] + .

[0477] Step D: (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] Twenty-3(4), 5, 7, 9, 14(15), 16, 18-heptaen-13-one(232)

[0478] (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 [[Icero-3(4),5,7,9,14(15),16,18-heptaen-13-one (compound 231, 1.5 g, 4.00 mmol) was dissolved in tetrahydrofuran (40 mL). The reaction solution was protected with nitrogen. Bis(trimethylsilyl)amino potassium (5 mL, 1 M, 5.00 mmol) and iodomethane (705 mg, 5.00 mmol) were added at -78 °C. The reaction solution was stirred from -78 °C to 0 °C for 2 hours. The reaction solution was then diluted with water (40 mL) and extracted with ethyl acetate (70 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to give the title compound 232 (860 mg, 55%).]

[0479] LC-MS (m / z): 390 [M+H] + .

[0480] Step E: (1R,11R)-13-[(difluoromethyl)oxy]-19-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 ] 20-2(3),4(5),6,8,12(13),14,16-heptaen-18-one(233)

[0481] (1R,11R)-5-chloro-18-[(difluoromethyl)oxy]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 [Tecone-3(4),5,7,9,14(15),16,18-heptaen-13-one (compound 232, 120 mg, 0.30 mol) was dissolved in 1,4-dioxane (10 mL), and pinacol diboronic acid ester (101.6 mg, 0.40 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-diphenyl-2'-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl- ...1'-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'-biphenyl-2'-dicyclohexylphosphino-2',1'-dicyclohexylphosphino-2',4',6'-tris-isopropyl-1,1'- '-Biphenyl-2-yl)palladium(II) (34.42 mg, 0.04 mmol) and potassium acetate (59 mg, 0.60 mmol) were reacted under nitrogen protection in a microwave environment at 125 °C for 2 hours. The reaction solution was then diluted with ethyl acetate (100 mL) and washed with water (30 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to column chromatography to give the title compound 233 (120 mg, 83%).

[0482] LC-MS (m / z): 482 [M+H] + .

[0483] 1 H NMR (400MHz, Methanol-d4) δ7.79-7.72(m,2H),7.68-7.55(m,2H),7.33(t,J=8.7Hz,1H),7.16(dd,J=8.8 ,1.8Hz,1H),5.89(dd,J=6.2,4.3Hz,1H),3.13(s,3H),2.83–2.73(m,1H),2.51-2.44(m,2H),1.28(s,9H).

[0484] Step F: 2-(imidazo[1,2-a]pyridin-8-yl)prop-2-ol (235)

[0485] Magnesium methyl bromide (1.0 M, 6.78 mL, 6.78 mmol) was added dropwise to tetrahydrofuran (10 mL) containing methyl imidazo[1,2-a]pyridine-8-carboxylate (compound 234, 400 mg, 2.26 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with saturated ammonium chloride (40 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to give the title compound 235 (80 mg, 20%).

[0486] LC-MS (m / z): 177 [M+H] + .

[0487] 1 H NMR (400MHz, Methanol-d4) δ8.58 (dd, J=7.7, 1.7Hz, 1H), 8.10 (d, J=4.5Hz, 1H), 7.7 3(d,J=4.6Hz,1H),7.41(dd,J=8.1,1.3Hz,1H),6.94(t,J=7.9Hz,1H),1.49(s,6H).

[0488] Step G: 2-(3-Iodoimidazole[1,2-a]pyridin-8-yl)prop-2-ol (236)

[0489] N-iodosuccinimide (101 mg, 0.45 mmol) was added to N,N-dimethylformamide (5 mL) of 2-(imidazo[1,2-a]pyridin-8-yl)prop-2-ol (compound 235, 80 mg, 0.45 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with saturated ammonium chloride (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to give the title compound 236 (80 mg, 59%).

[0490] LC-MS (m / z): 303 [M+H] + .

[0491] 1 H NMR (400MHz, Methanol-d4) δ8.15(dd,J=7.3,1.3Hz,1H),7.86(s,1H),7.41(dd,J=8.1,1.3Hz,1H),6.89(dd,J=8.2,7.4Hz,1H),1.49(s,6H).

[0492] Step H: (1R,11R)-18-[(difluoromethyl)oxy]-5-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-883)]

[0493] (1R,11R)-13-[(difluoromethyl)oxy]-19-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 [1,4-Heptaen-18-one (compound 233, 48.2 mg, 0.10 mmol), 2-(3-iodoimidazolo[1,2-a]pyridin-8-yl)prop-2-ol (compound 236, 30.2 mg, 0.10 mmol) and potassium phosphate (42.4 mg, 0.20 mmol) were dissolved in a mixed solution of 1,4-dioxane (8 mL) and water (2 mL). The reaction solution was protected with nitrogen. 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (14.6 mg, 0.02 mmol) was added with stirring at room temperature. The reaction solution was purged three times with dry nitrogen. The mixture was heated to 100 °C and stirred for 4 hours. The reaction solution was filtered, concentrated, and the residue was purified by chromatography to obtain the title compound I-883 (5 mg, 9%).

[0494] LC-MS (m / z): 604 [M+H] + .

[0495] 1 H NMR (400MHz, Methanol-d4) δ9.03 (dd, J=7.6, 1.2Hz, 1H), 8.03-7.93 (m, 2H), 7.83 (d ,J=2.2Hz,1H),7.66-7.55(m,2H),7.41(dd,J=8.1,1.3Hz,1H),7.33(t,J=8.7Hz,1H ),7.16(dd,J=8.8,1.7Hz,1H),7.03-6.90(m,1H),6.97(t,J=57.6Hz,1H),5.80(dd, J=6.2,4.5Hz,1H),3.13(s,3H),2.90-2.76(m,1H),2.53-2.42(m,2H),1.49(s,6H).

[0496] Example I-884: (1R,11R)-18-[(difluoromethyl)oxy]-5-[7-(2-hydroxypropyl-2-yl)pyrazolo[1,5-a]pyridin-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] Twenty-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-884)

[0497] Step A: 2-(pyrazolo[1,5-a]pyridin-7-yl)prop-2-ol (238)

[0498] Compound 238 was prepared by using compound 237 as a raw material instead of compound 234, following step F of Example I-883.

[0499] LC-MS (m / z): 177 [M+H] + .

[0500] 1 H NMR (400MHz, Methanol-d4) δ8.33 (d, J = 3.7Hz, 1H), 7.81-7.79 (m, 1H), 7.43 (dd, J=8.6,7.1Hz,1H),7.31(dd,J=7.2,1.4Hz,1H),7.20-7.15(m,1H),1.51(s,6H).

[0501] Step B: 2-(3-iodopyrazolo[1,5-a]pyridin-7-yl)prop-2-ol (239)

[0502] Compound 239 was prepared by using compound 238 as a raw material instead of compound 235, following step G of Example I-1.

[0503] LC-MS (m / z): 303 [M+H] + .

[0504] 1 H NMR (400MHz, Methanol-d4) δ8.01(s,1H),7.94(dd,J=8.5,1.4Hz,1H),7.42(dd,J=8.4,7.2Hz,1H),7.29(dd,J=7.2,1.4Hz,1H),1.51(s,6H).

[0505] Step C: (1R,11R)-18-[(difluoromethyl)oxy]-5-[7-(2-hydroxypropyl-2-yl)pyrazolo[1,5-a]pyridin-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] Twenty-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-884)

[0506] Compound I-884 was prepared by using compound 239 as a raw material instead of compound 236, following step H of Example I-1.

[0507] LC-MS (m / z): 530 [M+H] + .

[0508] 1 H NMR(400MHz, Methanol-d4)δ9.03(dd,J=7.6,1.2Hz,1H),8.03-7.93(m,2H),7.83(d ,J=2.2Hz,1H),7.66-7.55(m,2H),7.41(dd,J=8.1,1.3Hz,1H),7.33(t,J=8.7Hz,1H ),7.16(dd,J=8.8,1.7Hz,1H),7.03-6.90(m,1H),6.97(t,J=57.6Hz,1H),5.80(dd, J=6.2,4.5Hz,1H),3.13(s,3H),2.81-2.77(m,1H),2.53-2.42(m,2H),1.49(s,6H).

[0509] Example I-885: (1R,11R)-18-[(difluoromethyl)oxy]-5-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyrazin-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] Twenty-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-885)

[0510] Compound I-885 was prepared by using compound 240 as a raw material instead of compound 234, following steps F, G, and H of Example I-883.

[0511] LC-MS (m / z): 531 [M+H] + .

[0512] 1 H NMR (400MHz, Methanol-d4) δ8.49 (d, J=6.1Hz, 1H), 8.04-7.93 (m, 2H), 7.85 (d, J= 2.3Hz,1H),7.69(s,1H),7.59(dd,J=8.6,1.9Hz,1H),7.33(t,J=8.7Hz,1H),7.28 (d,J=6.1Hz,1H),7.16(dd,J=8.8,1.8Hz,1H),6.97(t,J=57.6Hz,1H),5.80(dd,J =6.2,4.5Hz,1H),3.13(s,3H),2.81-2.76(m,1H),2.53-2.42(m,2H),1.58(s,6H).

[0513] Example I-886: (1R,11R)-18-[(difluoromethyl)oxy]-5-[8-(2-hydroxypropyl-2-yl)imidazo[2,1-f]pyrimidin-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-886)]

[0514] Compound I-886 was prepared by using compound 243 as a raw material instead of compound 234, following steps F, G, and H of Example I-883.

[0515] LC-MS (m / z): 531 [M+H] + .

[0516] 1 H NMR(400MHz, Methanol-d4)δ9.02(d,J=1.2Hz,1H),8.43(d,J=1.2Hz,1H),8.06- 7.97(m,2H),7.86(d,J=2.0Hz,1H),7.69(s,1H),7.59(dd,J=8.6,1.9Hz,1H),7.3 8-7.29(m,1H),7.16(dd,J=8.8,1.7Hz,1H),6.97(t,J=57.6Hz,1H),5.80(dd,J= 6.2,4.5Hz,1H),3.13(s,3H),2.81-2.76(m,1H),2.53-2.42(m,2H),1.52(s,6H).

[0517] Example I-887: (1R,11R)-18-[(difluoromethyl)oxy]-5-[8-(2-hydroxypropyl-2-yl)imidazo[2,1-f]pyridazin-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] Twenty-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-887)

[0518] Compound I-887 was prepared by using compound 246 as a raw material instead of compound 234, following steps F, G, and H of Example I-883.

[0519] LC-MS (m / z): 531 [M+H] + .

[0520] 1 H NMR (400MHz, Methanol-d4) δ8.29(d,J=5.3Hz,1H),8.10(dd,J=6.8,2.1Hz,1H),8.02(d,J =6.7Hz,1H),7.86(d,J=2.3Hz,1H),7.59(dd,J=8.6,1.9Hz,1H),7.53(d,J=5.5Hz,1H),7. 42(s,1H),7.33(t,J=8.7Hz,1H),7.16(dd,J=8.8,1.8Hz,1H),6.97(t,J=57.6Hz,1H),5.8 0(dd,J=6.2,4.5Hz,1H),3.13(s,3H),2.81-2.75(m,1H),2.53-2.42(m,2H),1.49(s,6H).

[0521] Example I-888: (1R,11R)-18-[(difluoromethyl)oxy]-5-[8-(2-hydroxypropyl-2-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] 10-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-888)

[0522] Compound I-888 was prepared by using compound 249 as a raw material instead of compound 234, following steps F, G, and H of Example I-883.

[0523] LC-MS (m / z): 531 [M+H]+ .

[0524] 1 H NMR (400MHz, Methanol-d4) δ8.74(dd,J=8.6,1.4Hz,1H),8.24(dd,J=7.8,2.1Hz,1H),8.13(d,J=2.1Hz,1H),8.04(d,J=7.9Hz,1H),7.62-7.52(m,2H),7.3 3(t,J=8.7Hz,1H),7.20-7.06(m,2H),6.97(t,J=57.6Hz,1H),5.80(dd,J=6.2 ,4.5Hz,1H),3.13(s,3H),2.81-2.76(m,1H),2.53-2.42(m,2H),1.49(s,6H).

[0525] Example I-889: (1R,11R)-18-[(difluoromethyl)oxy]-5-[7-(2-hydroxypropyl-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-889)]

[0526] Compound I-889 was prepared by using compound 252 as a raw material instead of compound 234, following steps F, G, and H of Example I-883.

[0527] LC-MS (m / z): 531 [M+H] + .

[0528] 1 H NMR (400MHz, Methanol-d4) δ8.65 (s, 1H), 8.48 (d, J = 6.2Hz, 1H), 8.11-8.00 (m, 2H), 7.92-7.87 (m, 1H), 7.59 (dd, J = 8.6, 1.9Hz, 1H), 7.33 (t, J = 8. 7Hz,1H),7.21-7.12(m,2H),6.97(t,J=57.6Hz,1H),5.80(dd,J=6.2,4.5 Hz,1H),3.13(s,3H),2.81-2.76(m,1H),2.53-2.42(m,2H),1.52(s,6H).

[0529] Example I-890: (1R,11R)-18-[(difluoromethyl)oxy]-5-[7-(2-hydroxypropyl-2-yl)[1,2,3]triazolo[1,5-a]pyridin-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-890)]

[0530] Compound I-890 was prepared by using compound 255 as a raw material instead of compound 234, following steps F, G, and H of Example I-883.

[0531] LC-MS (m / z): 531 [M+H] + .

[0532] 1 H NMR (400MHz, Methanol-d4) δ8.14(dd,J=8.4,2.1Hz,1H),8.06(d,J=8.2Hz,1H),8.00-7.93(m,2H),7.62-7.48(m,3H),7.33(t,J=8.7Hz,1H),7. 16(dd,J=8.8,1.8Hz,1H),6.97(t,J=57.6Hz,1H),5.80(dd,J=6.2,4.5Hz,1H),3.13(s,3H),2.81-2.75(m,1H),2.53-2.42(m,2H),1.51(s,6H).

[0533] Example I-891: (1R,11R)-18-[(difluoromethyl)oxy]-5-[7-(2-hydroxypropyl-2-yl)-1-benzofuran-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-891)]

[0534] Compound I-891 was prepared by using compound 258 as a raw material instead of compound 234, following steps F, G, and H of Example I-883.

[0535] LC-MS (m / z): 530 [M+H] + .

[0536] 1H NMR (400MHz, Methanol-d4) δ8.03 (ddd, J=17.5, 8.2, 1.6Hz, 2H), 7.92 (d, J=7.5Hz, 1H), 7.87 (s,1H),7.78(d,J=2.1Hz,1H),7.59(dd,J=8.6,1.9Hz,1H),7.44(dd,J=9.2,1.2Hz,1H),7.33 (t,J=8.7Hz,1H),7.24(t,J=9.0Hz,1H),7.16(dd,J=8.8,1.7Hz,1H),6.97(t,J=57.6Hz,1H), 5.80(dd,J=6.2,4.5Hz,1H),3.13(s,3H),2.82-2.75(m,1H),2.53-2.42(m,2H),1.47(s,6H).

[0537] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Examples I-891:

[0538] Example I-900: (1R,11R)-18-[(difluoromethyl)oxy]-5-[6-fluoro-7-(2-hydroxypropyl-2-yl)-1-benzofuran-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecico-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-900) Step A: 2-(6-fluoro-1-benzofuran-7-yl)prop-2-ol (262)]

[0539] Butyllithium (2.5 M, 4.0 mL, 10.0 mmol) was added dropwise to tetrahydrofuran (30 mL) of 7-bromo-6-fluoro-1-benzofuran (compound 261, 2.15 g, 10.0 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for half an hour, then acetone (870 mg, 15.0 mmol) was added, and the reaction mixture was stirred at -78 °C for another 2 hours until room temperature. The mixture was diluted with saturated ammonium chloride (40 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to column chromatography to give the title compound 262 (737 mg, 38%).

[0540] LC-MS (m / z): 195 [M+H] + .

[0541] 1 H NMR (400MHz, Methanol-d4) δ7.84-7.76 (m, 1H), 7.72 (s, 1H), 7.15 (dd, J = 10.1, 7.3Hz, 1H), 6.97 (s, 1H), 1.52 (s, 6H).

[0542] Step B: 2-(3-iodo-6-fluoro-1-benzofuran-7-yl)prop-2-ol (263)

[0543] Compound 263 was prepared by using compound 262 as a raw material instead of compound 235, following step G of Example I-883.

[0544] LC-MS (m / z): 321 [M+H] + .

[0545] 1 H NMR (400MHz, Methanol-d4) δ8.29(s,1H),7.88(dd,J=7.2,5.1Hz,1H),7.12(dd,J=10.2,7.2Hz,1H),1.52(s,6H).

[0546] Step C: (1R,11R)-18-[(difluoromethyl)oxy]-5-[6-fluoro-7-(2-hydroxypropyl-2-yl)-1-benzofuran-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] Twenty-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-900)

[0547] Compound I-900 was prepared by using compound 263 as a raw material instead of compound 236, following step H of Example I-883.

[0548] LC-MS (m / z): 548 [M+H] + .

[0549] 1H NMR (400MHz, Methanol-d4) δ8.05(dd,J=7.6,2.1Hz,1H),7.95-7.84(m,3H),7.79(d,J=2.2Hz,1H),7.59(dd,J=8.6,1.9Hz,1H),7.33(t,J=8.7H z,1H),7.20-7.10(m,2H),6.97(t,J=57.6Hz,1H),5.80(dd,J=6.2,4.5H z,1H),3.13(s,3H),2.82-2.76(m,1H),2.53-2.42(m,2H),1.52(s,6H).

[0550] Example I-901: (1R,11R)-18-[(difluoromethyl)oxy]-5-[6-fluoro-7-(2-hydroxypropyl-2-yl)-1-benzofuran-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] Twenty-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-901) Step A: 2-(6-Fluoropyrazolo[1,5-a]pyridin-7-yl)prop-2-ol (265)

[0551] Butyllithium (2.5 M, 4.0 mL, 10.0 mmol) was added dropwise to tetrahydrofuran (30 mL) containing 6-fluoropyrazole[1,5-a]pyridine (compound 264, 1.36 g, 10.0 mmol). The reaction mixture was stirred at -78 °C for half an hour, then acetone (870 mg, 15.0 mmol) was added, and the mixture was stirred at -78 °C for another 2 hours until room temperature. The mixture was diluted with saturated ammonium chloride (40 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to column chromatography to give the title compound 265 (1 g, 52%).

[0552] LC-MS (m / z): 195 [M+H] + .

[0553] 1 H NMR (400MHz, Methanol-d4) δ8.31 (d, J = 3.7Hz, 1H), 7.94-7.86 (m, 1H), 7.32-7.23 (m, 1H), 7.26-7.20 (m, 1H), 1.56 (s, 6H).

[0554] Step B: 2-(3-iodo-6-flupyrazolo[1,5-a]pyridin-7-yl)prop-2-ol (266)

[0555] Compound 266 was prepared by using compound 265 as a raw material instead of compound 235, following step G of Example I-883.

[0556] LC-MS (m / z): 321 [M+H] + .

[0557] 1 H NMR (400MHz, Methanol-d4) δ8.27(s,1H),7.96(dd,J=8.3,4.7Hz,1H),7.33(dd,J=23.0,8.2Hz,1H),1.56(s,6H).

[0558] Step C: (1R,11R)-18-[(difluoromethyl)oxy]-5-[6-fluoro-7-(2-hydroxypropyl-2-yl)-1-benzofuran-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-901)]

[0559] Compound I-901 was prepared by using compound 266 as a raw material instead of compound 236, following step H of Example I-883.

[0560] LC-MS (m / z): 548 [M+H] + .

[0561] 1 H NMR (400MHz, Methanol-d4) δ8.51(s,1H),8.06(dd,J=7.6,2.2Hz,1H),8.03-7.94(m,2H),7.89(d,J=2.2Hz,1H),7.59(dd,J=8.6,1.9Hz,1H),7.38-7.22( m,2H),7.16(dd,J=8.8,1.8Hz,1H),6.97(t,J=57.6Hz,1H),5.80(dd,J=6.2, 4.5Hz,1H),3.13(s,3H),2.83-2.75(m,1H),2.53-2.42(m,2H),1.56(s,6H).

[0562] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-901:

[0563] Example I-905: (1R,11R)-18-[(difluoromethyl)oxy]-5-[4-(2-hydroxypropyl-2-yl)benzo[d]imidazol-1-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-905)]

[0564] Step A: 2-(1H-benzo[d]imidazol-4-yl)prop-2-ol (268)

[0565] Magnesium methyl bromide (1.0 M, 9.09 mL, 9.09 mmol) was added dropwise to methyl 1H-benzo[d]imidazolium-4-carboxylate (compound 267, 400 mg, 2.27 mmol) in tetrahydrofuran (10 mL) at 0 °C. The reaction mixture was stirred from 0 °C to room temperature for 2 hours. The reaction mixture was then diluted with saturated ammonium chloride (40 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to column chromatography to give the title compound 268 (160 mg, 40%).

[0566] LC-MS (m / z): 177 [M+H] + .

[0567] 1 H NMR (400MHz, Methanol-d4) δ9.75 (d, J = 6.1 Hz, 1H), 8.06 (d, J = 5.9 Hz, 1H), 7.48-7.43 (m, 2H), 7.32-7.23 (m, 1H), 1.68 (s, 6H).

[0568] Step B: (1R,11R)-18-[(difluoromethyl)oxy]-5-[4-(2-hydroxypropyl-2-yl)benzo[d]imidazol-1-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-905)]

[0569] (1R,11R)-13-[(difluoromethyl)oxy]-19-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 [10 mL] 2-(1H-benzo[d]imidazol-4-yl)prop-2-ol (268, 30.2 mg, 0.10 mmol) and triethylamine (50.5 mg, 0.50 mmol) were dissolved in acetonitrile (10 mL) solution, and copper acetate (16.4 mg, 0.30 mmol) was added. The reaction solution was heated to 50 °C and stirred for 16 hours under an oxygen atmosphere. The reaction solution was filtered, concentrated, and the residue was purified by chromatography to obtain the title compound I-905 (8.2 mg, 15%).

[0570] LC-MS (m / z): 530 [M+H] + .

[0571] 1 H NMR(400MHz, Methanol-d4)δ8.44(s,1H),8.15(dd,J=7.0,1.2Hz,1H),7.93–7.82(m ,2H),7.68(d,J=2.3Hz,1H),7.59(dd,J=8.6,1.9Hz,1H),7.49(dd,J=8.3,1.3Hz,1H ),7.41-7.29(m,2H),7.16(dd,J=8.8,1.8Hz,1H),6.97(t,J=57.6Hz,1H),5.80(dd, J=6.2,4.5Hz,1H),3.13(s,3H),2.83-2.76(m,1H),2.53-2.42(m,2H),1.68(s,6H).

[0572] Example I-906: (1R,11R)-18-[(difluoromethyl)oxy]-5-[4-(2-hydroxypropyl-2-yl)benzo[d][1,2,3]triazol-1-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-906)]

[0573] Compound I-906 was prepared by using compound 269 as a raw material instead of compound 267, following steps A and B of Example I-905.

[0574] LC-MS (m / z): 531 [M+H] + .

[0575] 1 H NMR (400MHz, Methanol-d4) δ8.10 (dd, J = 7.2, 2.1Hz, 1H), 7.93-7.85 (m, 3H), 7. 83(d,J=2.3Hz,1H),7.59(dd,J=8.6,1.9Hz,1H),7.42(t,J=8.0Hz,1H),7.33(t, J=8.7Hz,1H),7.16(dd,J=8.8,1.8Hz,1H),6.97(t,J=57.6Hz,1H),5.80(dd,J=6 .2,4.5Hz,1H),3.13(s,3H),2.83-2.76(m,1H),2.53-2.42(m,2H),1.68(s,6H).

[0576] Example I-907: (1R,11R)-18-[(difluoromethyl)oxy]-5-[4-(2-hydroxypropyl-2-yl)imidazo[4,5-c]pyridin-1-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-907)]

[0577] Compound I-907 was prepared using compound 271 instead of compound 267, following steps A and B of Example I-905. LC-MS (m / z): 531 [M+H] + .

[0578] 1H NMR (400MHz, Methanol-d4) δ8.51(s,1H),8.33(d,J=3.9Hz,1H),7.91(dd,J=6.2,2 .1Hz,1H),7.88-7.80(m,2H),7.71(d,J=2.1Hz,1H),7.59(dd,J=8.6,1.9Hz,1H),7. 33(t,J=8.7Hz,1H),7.16(dd,J=8.8,1.8Hz,1H),6.97(t,J=57.6Hz,1H),5.80(dd, J=6.2,4.5Hz,1H),3.13(s,3H),2.83-2.76(m,1H),2.53-2.42(m,2H),1.81(s,6H).

[0579] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-907:

[0580] Example I-917: (1R,11R)-5-[7-(aminocyclobutyl)pyrazolo[1,5-a]pyridin-3-yl]-18-[(difluoromethyl)oxy]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] Twenty-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-917) Step A: 7-({[(2-methylpropyl-2-yl)(oxonyl)-λ 4 -Thio[amino]cyclobutyl)pyrazolo[1,5-a]pyridine (274)

[0581] Lithium n-butyl (2.5 M, 4.0 mL, 10.0 mmol) was added dropwise to tetrahydrofuran (30 mL) containing 7-bromopyrazolo[1,5-a]pyridine (compound 273, 1.96 g, 10.0 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for half an hour, and then (cyclobutylene)[(2-methylpropyl-2-yl)(oxoene)-λ was added. 4 [-thio]amine (compound 16, 2.61 g, 15.0 mmol), reaction solution was stirred at -78 °C for 2 hours until room temperature, diluted with saturated ammonium chloride (40 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), dried with anhydrous sodium sulfate, filtered, concentrated and column chromatography to give title compound 274 (1.22 g, 42%).

[0582] LC-MS (m / z): 292 [M+H] + .

[0583] 1 H NMR(400MHz, Methanol-d4)δ8.31(d,J=3.6Hz,1H),7.82-7.75(m,1H),7.44(dd,J=8.4,7.1Hz,1H),7.36(dd, J=7.2,1.4Hz,1H),7.24-7.18(m,1H),2.59-2.53(m,2H),2.34-2.28(m,2H),1.71-1.65(m,2H),1.26(s,9H).

[0584] Step B: 1-(3-bromopyrazolo[1,5-a]pyridin-7-yl)cyclobut-1-amine (275)

[0585] Compound 275 was prepared by using compound 274 as a starting material instead of compound 235, and N-bromosuccinimide as a starting material instead of compound N-iodosuccinimide, following step G of Example I-883.

[0586] LC-MS (m / z): 266 [M+H] + .

[0587] 1 H NMR (400MHz, Methanol-d4) δ8.08(s,1H),7.87(dd,J=8.5,1.5Hz,1H),7.48(dd,J=6.8,1.4H z,1H),7.37(dd,J=8.4,6.8Hz,1H),2.37-2.30(m,2H),2.11-2.05(m,2H),1.78-1.71m,2H).

[0588] Step C: (1R,11R)-5-[7-(aminocyclobutyl)pyrazolo[1,5-a]pyridin-3-yl]-18-[(difluoromethyl)oxy]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-917)]

[0589] Compound I-917 was prepared by using compound 275 as a raw material instead of compound 236, following step H of Example I-883.

[0590] LC-MS (m / z): 541 [M+H] + .

[0591] 1 H NMR (400MHz, Methanol-d4) δ8.56 (s, 1H), 8.06 (dd, J = 7.6, 2.1Hz, 1H), 8.00-7.93 (m, 2H), 7.84 (d,J=2.3Hz,1H),7.59(dd,J=8.6,1.9Hz,1H),7.48(dd,J=6.8,1.4Hz,1H),7.43-7.29(m,2H), 7.16(dd,J=8.8,1.7Hz,1H),6.97(t,J=57.6Hz,1H),5.80(dd,J=6.2,4.5Hz,1H),3.13(s,3H), 2.81-2.76(m,1H),2.51-2.44(m,1H),2.37-2.30(m,2H),2.22-2.05(m,4H),1.78-1.71(m,2H).

[0592] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Examples I-917:

[0593] Example I-924: (1R,11R)-5-[8-(aminocyclobutyl)imidazo[1,2-a]pyridin-3-yl]-18-[(difluoromethyl)oxy]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-924)]

[0594] Compound I-924 was prepared by using compound 276 as a raw material instead of compound 273, following steps A, B, and C of Example I-917.

[0595] LC-MS (m / z): 541 [M+H] + .

[0596] 1H NMR(400MHz, Methanol-d4)δ8.80(dd,J=7.7,1.3Hz,1H),8.03-7.93(m,2H),7.83(d,J=2.2Hz ,1H),7.66-7.55(m,2H),7.48(dd,J=7.7,1.3Hz,1H),7.38-7.29(m,1H),7.16(dd,J=8.8,1.7H z,1H),7.03-6.90(m,1H),6.97(t,J=57.6Hz,1H),5.80(dd,J=6.2,4.5Hz,1H),3.13(s,3H),2 .85-2.76(m,1H),2.53-2.42(m,2H),2.36-2.24(m,2H),2.08-2.01(m,2H),1.82-1.70(m,2H).

[0597] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Examples I-924:

[0598] Example I-931: (1R,11R)-5-[7-(aminocyclobutyl)-6-fluoropyrazolo[1,5-a]pyridin-3-yl]-18-[(difluoromethyl)oxy]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-931)]

[0599] Step A: 6-Fluoro-7-({[(2-methylpropyl-2-yl)(oxonyl)-λ) 4 -Thio[amino]cyclobutyl)pyrazolo[1,5-a]pyridine (279)

[0600] Compound 279 was prepared by using compound 264 as a raw material instead of compound 273, following step A of Example I-917.

[0601] LC-MS (m / z): 310 [M+H] + .

[0602] 1H NMR (400MHz, Methanol-d4) δ8.32 (d, J = 3.6Hz, 1H), 7.92-7.84 (m, 1H), 7.31-7.1 8(m,2H),2.63-2.54(m,2H),2.35-2.29(m,2H),1.78-1.70(m,2H),1.26(s,9H).

[0603] Step B: 1-(3-bromoimidazolo[1,2-a]pyridin-8-yl)cyclobut-1-amine (280)

[0604] Compound 280 was prepared by using compound 279 as a starting material instead of compound 235, and N-bromosuccinimide as a starting material instead of N-iodosuccinimide, following step G of Example I-883.

[0605] LC-MS (m / z): 284 [M+H] + .

[0606] 1 H NMR (400MHz, Methanol-d4) δ8.16 (s, 1H), 7.86 (dd, J = 8.5, 4.8Hz, 1H), 7.18-7.05 (m, 1H), 2.45-2.38 (m, 2H), 2.19-2.13 (m, 2H), 1.82-1.76 (m, 2H).

[0607] Step C: (1R,11R)-5-[7-(aminocyclobutyl)-6-fluoropyrazolo[1,5-a]pyridin-3-yl]-18-[(difluoromethyl)oxy]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-931)]

[0608] Compound I-931 was prepared by using compound 280 as a raw material instead of compound 236, following step H of Example I-883.

[0609] LC-MS (m / z): 559 [M+H] + .

[0610] 1H NMR (400MHz, Methanol-d4) δ8.50 (s, 1H), 8.06 (dd, J = 7.6, 2.1Hz, 1H), 8.00–7.87 (m ,3H),7.59(dd,J=8.6,1.9Hz,1H),7.38-7.29(m,1H),7.21-7.14(m,1H),7.17-7.09( m,1H),6.97(t,J=57.6Hz,1H),5.80(dd,J=6.2,4.5Hz,1H),3.13(s,3H),2.85-2.76( m,1H),2.53-2.42(m,2H),2.45-2.38(m,2H),2.18-2.14(m,2H),1.80-1.75(m,2H)..

[0611] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-931:

[0612] Example I-956: (1R,11R)-5-[7-(aminocyclobutyl)-1-benzofuran-3-yl]-18-[(difluoromethyl)oxy]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(4),5,7,9,14(15),16,18-heptaen-13-one (I-956)]

[0613] Compound I-956 was prepared by using compound 281 as a raw material instead of compound 273, following steps A, B, and C of Example I-917.

[0614] LC-MS (m / z): 541 [M+H] + .

[0615] 1H NMR (400MHz, Methanol-d4) δ8.09-7.97(m,2H),7.95-7.85(m,2H),7.78(d,J=2. 1Hz,1H),7.59(dd,J=8.6,1.9Hz,1H),7.39-7.29(m,2H),7.29–7.20(m,1H),7.1 6(dd,J=8.8,1.8Hz,1H),6.97(t,J=57.6Hz,1H),5.85(dd,J=6.2,4.5Hz,1H),3. 13(s,3H),2.85-2.76(m,1H),2.53-2.40(m,2H),2.46-2.38(m,2H),1.36(s,2H).

[0616] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-956:

[0617] Example I-1020: (1R,11R)-5-[4-(aminocyclobutyl)benzo[d]imidazol-1-yl]-18-[(difluoromethyl)oxy]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] Twenty-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-1020)

[0618] Step A: 4-({[(2-methylpropyl-2-yl)(oxonyl)-λ) 4 -Thio[amino}cyclobutyl)-1H-benzo[d]imidazolium(285)

[0619] Magnesium methyl bromide (1.0 M, 10.0 mL, 10.0 mmol) and n-butyllithium (2.5 M, 4.0 mL, 10.0 mmol) were added dropwise to tetrahydrofuran (30 mL) of 4-bromo-1H-benzo[d]imidazole (compound 284, 1.96 g, 10.0 mmol). The reaction mixture was stirred at -78 °C for half an hour, and then (cyclobutylidene)[(2-methylpropyl-2-yl)(oxonyl)-λ was added. 4[-thio]amine (compound 16, 2.61 g, 15.0 mmol), reaction solution was stirred at -78 °C for 2 hours until room temperature, diluted with saturated ammonium chloride (40 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), dried with anhydrous sodium sulfate, filtered, concentrated and column chromatography to give title compound 285 (436 mg, 15%).

[0620] LC-MS (m / z): 292 [M+H] + .

[0621] 1 H NMR (400MHz, CDCl3) δ = 8.77 (s, 2H), 4.78 (s, 1H), 2.88-2.78 (m, 1H), 2.73-2.55 (m, 2H), 2.54-2.43 (m, IH), 2.14-1.92 (m, 2H), 1.24 (s, 9H).

[0622] Step B: (1R,11R)-18-[(difluoromethyl)oxy]-12-methyl-5-[4-({[(2-methylpropyl-2-yl)(oxonyl)-λ 4 [-thio]amino}cyclobutyl)benzo[d]imidazol-1-yl]-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] Twenty-3(8), 4, 6, 9, 14(15), 16, 18-heptaen-13-one(286)

[0623] (1R,11R)-13-[(difluoromethyl)oxy]-19-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 [Tecone-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (compound 233, 48.2 mg, 0.10 mmol), 4-({[(2-methylpropyl-2-yl)(oxonyl)-λ 4[-thio]amino}cyclobutyl)-1H-benzo[d]imidazole (compound 285, 29.2 mg, 0.10 mmol) and triethylamine (50.5 mg, 0.50 mmol) were dissolved in acetonitrile (10 mL) solution, and copper acetate (16.4 mg, 0.30 mmol) was added. The reaction solution was heated to 50 °C and stirred for 16 hours under an oxygen atmosphere. The reaction solution was filtered, concentrated, and the residue was purified by column chromatography to obtain the title compound 286 (15.5 mg, 24%).

[0624] LC-MS (m / z): 645 [M+H] + .

[0625] Step C: (1R,11R)-5-[4-(aminocyclobutyl)benzo[d]imidazol-1-yl]-18-[(difluoromethyl)oxy]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] Twenty-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-1020)

[0626] Compound I-1020 was prepared by using compound 286 as a raw material instead of compound 14, following step R of Example I-1.

[0627] LC-MS (m / z): 541 [M+H] + .

[0628] 1 H NMR (400MHz, MeOD-d4) δ.8.74(s,2H),8.05-7.99(m,2H),7.92(d,J=3.2Hz,1H),7.74(dd,J=8.0,2.0Hz,1H),7.32-7.27(m,1H),7.21(dd,J=8.0,2. 0Hz,1H),6.97(t,J=57.6Hz,1H),6.70-6.67(m,1H),3.89-3.85(m,1H),3. 18-3.15(m,1H),2.80-2.65(m,2H),2.28-2.18(m,4H),1.88-1.80(m,2H).

[0629] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1020:

[0630] Example I-1066: (1R,13R)-9,9-difluoro-17-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-2-methyl-8,10-dioxa-2,14,21-triazahexane[11.9.1.0] 15,20 .0 7,11 .0 4,12 .0 14,22 ] Twenty-three-4(5),6,11(12),15(20),16,18,21-heptaen-3-one (I-1066)

[0631] Step A: (1R)-3-azido-1-(6-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[2,1-b]imidazolium (287)

[0632] Compound 287 was prepared by using compound 88 as a raw material instead of compound 9, following step A of Example I-883.

[0633] LC-MS (m / z): 468 [M+H] + .

[0634] Step B: (1R)-1-(6-bromo-2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine (288)

[0635] Compound 288 was prepared by using compound 287 as a raw material instead of compound 229, following step B of Example I-883.

[0636] LC-MS (m / z): 442 [M+H] + .

[0637] Step C: (1R,13R)-17-chloro-9,9-difluoro-8,10-dioxa-2,14,21-triazahexane [11.9.1.0] 15,20 .0 14,22 .0 7,11 .0 4,12 ] Twenty-three-4(12),5,7(11),15(16),17,19,21-heptaen-3-one(289)

[0638] Compound 289 was prepared by using compound 288 as a raw material instead of compound 230, following step C of Example I-883.

[0639] LC-MS (m / z): 390 [M+H] + .

[0640] Step D: (1R,13R)-17-chloro-9,9-difluoro-2-methyl-8,10-dioxa-2,14,21-triazahexane [11.9.1.0] 15,20 .0 14,22 .0 7,11 .0 4,12 ] Twenty-three-4(5),6,11(12),15(16),17,19,21-heptaen-3-one(290)

[0641] Compound 290 was prepared by using compound 289 as a raw material instead of compound 231, following step D of Example I-883.

[0642] LC-MS (m / z): 404 [M+H] + .

[0643] 1 H NMR (400MHz, MeOD-d4) δ = 9.02 (s, 2H), 2.84-2.82 (m, 2H), 2.81-2.78 (m, 2H), 2.60-2.27 (m, 2H).

[0644] Step E: (1R,13R)-9,9-difluoro-2-methyl-17-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-8,10-dioxa-2,14,21-triazahexane [11.9.1.0] 15,20 .0 14,22 .0 7,11 .0 4,12 ] Twenty-three-4(5),6,11(12),15(16),17,19,21-heptaen-3-one(291)

[0645] Compound 291 was prepared by using compound 290 as a raw material instead of compound 232, following step E of Example I-883.

[0646] LC-MS (m / z): 496 [M+H] + .

[0647] Step F: (1R,13R)-9,9-difluoro-17-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-2-methyl-8,10-dioxa-2,14,21-triazahexane[11.9.1.0] 15,20 .0 7,11 .0 4,12 .0 14,22 ] Twenty-three-4(5),6,11(12),15(20),16,18,21-heptaen-3-one (I-1066)

[0648] Compound I-1066 was prepared by using compound 291 as a raw material instead of compound 233, following step H of Example I-883.

[0649] LC-MS (m / z): 544 [M+H] + .

[0650] 1 H NMR(400MHz,MeOD-d4)δ.8.41(dd,J=6.4,2.0Hz,1H),8.02(dd,J=6.4,2.0Hz,1H),7.92 (d,J=6.4Hz,1H),7.86(d,J=2.4Hz,1H),7.64(s,1H),7.37(dd,J=6.4,2.0Hz,1H),7.15 (d,J=8.0Hz,1H),7.11(d,J=8.0Hz,1H),6.94-6.90(m,1H),5.31-5.25(m,1H),5.13-5. 05(m,1H),3.04(s,3H),2.67-2.61(m,2H),2.48-2.41(m,4H),1.48(s,3H),1.43(s,3H).

[0651] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1066:

[0652] The NMR data of the compounds prepared in the above embodiments are as follows:

[0653] Example I-1148: (1R,11R)-18-[(difluoromethyl)oxy]-5-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-12-methyl-2,6,9,12-tetraazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-1148)]

[0654] Step A: (6R)-8-azido-6-{2-bromo-6-[(difluoromethyl)oxy]phenyl}-3-chloro-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[5,4-c]pyridine (292)

[0655] Compound I-1148 was prepared by using compound 195 as a raw material instead of compound 273, following steps A, B, C, D, E, and H of Example I-883.

[0656] LC-MS (m / z): 531 [M+H] + .

[0657] 1 H NMR (400MHz, MeOD-d4) δ.9.19(s,1H),8.53(d,J=2.0Hz,1H),7.85(d,J=6.4Hz,1H),7.39-7.31(m,2H),7.21(dd,J=8.0,2.0Hz,1H),6.97(t,J=57 .6Hz,1H),6.95-6.91(m,1H),6.24-6.17(m,1H),5.33-5.24(m,1H),3.05 (s,3H),2.67-2.61(m,1H),2.38-2.31(m,1H),1.48(s,3H),1.43(s,3H).

[0658] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1148:

[0659] The NMR data of the compounds prepared in the above embodiments are as follows:

[0660] Example I-1185: (1R,11R)-18-[(difluoromethyl)oxy]-6-fluoro-5-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-12-methyl-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tecone-3(8),4,6,9,14(15),16,18-heptaen-13-one (I-1185)]

[0661] Compound I-1185 was prepared by using compound 204 as a raw material instead of compound 273, following steps A, B, C, D, E, and H of Example I-883.

[0662] LC-MS (m / z): 548 [M+H] + .

[0663] 1H NMR (400MHz, MeOD-d4) δ.8.44(dd,J=6.4,2.0Hz,1H),7.91(d,J=6.4Hz,1H),7.66-7.58(m,3H),7.40-7.31(m,2H),7.21(dd,J=8.0,2.0Hz,1H),6.97(t ,J=57.6Hz,1H),6.95-6.91(m,1H),6.22-6.15(m,1H),5.35-5.30(m,1H),3 .04(s,3H),2.67-2.61(m,1H),2.38-2.31(m,1H),1.48(s,3H),1.43(s,3H).

[0664] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1185:

[0665] The NMR data of the compounds prepared in the above embodiments are as follows:

[0666] Example I-1216: (1S,11R)-18-[(difluoromethyl)oxy]-5-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-12-methyl-8,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] 2, 4, 6, 9, 14 (15), 16, 18-heptaen-13-one (I-1216)

[0667] Compound I-1216 was prepared by using compound 117 as a raw material instead of compound 273, following steps A, B, C, D, E, and H of Example I-883.

[0668] LC-MS (m / z): 530 [M+H] + .

[0669] 1H NMR(400MHz,MeOD-d4)δ.8.66(d,J=6.4Hz,1H),8.42(dd,J=6.4,2.0Hz,1H),7.98(d,J=3.2 Hz,1H),7.92(dd,J=6.4,2.0Hz,1H),7.77(s,1H),7.58(dd,J=6.4,2.0Hz,1H),7.39-7.31( m,2H),7.21(dd,J=8.0,2.0Hz,1H),6.98(t,J=57.6Hz,1H),6.95-6.92(m,1H),5.52-5.45( m,1H),4.92-4.85(m,1H),2.36-2.31(m,1H),2.08-2.00(m,1H),1.48(s,3H),1.43(s,3H).

[0670] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1216:

[0671] The NMR data of the compounds prepared in the above embodiments are as follows:

[0672] Example I-1235: (1S,11R)-18-[(difluoromethyl)oxy]-5-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-12-methyl-6,8,9,12-tetraazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] Twenty-2(3),4,6,9,14(15),16,18-heptaen-13-one (I-1235)

[0673] Compound I-1235 was prepared by using compound 127 as a raw material instead of compound 273, following steps A, B, C, D, E, and H of Example I-883.

[0674] LC-MS (m / z): 531 [M+H] + .

[0675] 1H NMR(400MHz,MeOD-d4)δ.9.42(s,1H),8.57-8.52(m,2H),7.78(s,1H),7.58( dd,J=8.0,2.0Hz,1H),7.40-7.35(m,2H),7.21(dd,J=8.0,2.0Hz,1H),6.97( t,J=57.6Hz,1H),6.95-6.91(m,1H),5.54-5.45(m,1H),4.81-4.65(m,1H),3 .05(s,3H),2.37-2.31(m,1H),2.12-2.05(m,1H),1.48(s,3H),1.43(s,3H).

[0676] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Examples I-1235:

[0677] The NMR data of the compounds prepared in the above embodiments are as follows:

[0678] Example I-1242: (1S,11R)-18-[(difluoromethyl)oxy]-6-fluoro-5-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-12-methyl-8,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] Twenty-2(3),4,6,9,14(15),16,18-heptaen-13-one (I-1242)

[0679] Compound I-1242 was prepared by using compound 136 as a raw material instead of compound 273, following steps A, B, C, D, E, and H of Example I-883.

[0680] LC-MS (m / z): 548 [M+H] + .

[0681] 1H NMR(400MHz,MeOD-d4)δ.8.62(d,J=8.0Hz,1H),8.51(d,J=6.4Hz,1H),8.44(dd,J=6.4,2 .0Hz,1H),8.12(d,J=6.4Hz,1H),7.57(dd,J=8.0,2.0Hz,1H),7.40-7.35(m,2H),7.21(dd ,J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),6.95-6.91(m,1H),5.54-5.51(m,1H),4.95-4 .88(m,1H),3.05(s,3H),2.35-2.31(m,1H),2.02-1.88(m,1H),1.48(s,3H),1.43(s,3H).

[0682] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1242:

[0683] The NMR data of the compounds prepared in the above embodiments are as follows:

[0684] Example I-1249: (1S,11R)-18-[(difluoromethyl)oxy]-5-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-12-methyl-4,8,9,12-tetraazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 ] Twenty-2(3),4,6,9,14(15),16,18-heptaen-13-one (I-1249)

[0685] Compound I-1249 was prepared by using compound 143 as a raw material instead of compound 273, following steps A, B, C, D, E, and H of Example I-883.

[0686] LC-MS (m / z): 531 [M+H] + .

[0687] 1H NMR (400MHz, MeOD-d4) δ.8.76 (d, J = 6.4 Hz, 1H), 8.55-8.52 (m, 2H), 7.57 (dd, J = 8. 0,2.0Hz,1H),7.43(d,J=6.4Hz,1H),7.39-7.35(m,2H),7.21(dd,J=8.0,2.0Hz,1 H),6.98(t,J=57.6Hz,1H),6.69-6.62(m,1H),5.64-5.56(m,1H),5.08-5.02(m,1 H),3.06(s,3H),2.40-2.35(m,1H),2.00-1.88(m,1H),1.48(s,3H),1.43(s,3H).

[0688] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1249:

[0689] The NMR data of the compounds prepared in the above embodiments are as follows:

[0690] Example I-1256: (1R,11R)-18-[(difluoromethyl)oxy]-5-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-12-methyl-3,4,9,12-tetraazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] Twenty-2(10),4,6,8(9),14(15),16,18-heptaen-13-one (I-1256)

[0691] Compound I-1256 was prepared by using compound 159 as a raw material instead of compound 273, following steps A, B, C, D, E, and H of Example I-883.

[0692] LC-MS (m / z): 531 [M+H] + .

[0693] 1H NMR(400MHz,MeOD-d4)δ.8.56(dd,J=6.4,2.0Hz,1H),8.51(s,1H),8.13(d,J=6.4Hz ,1H),7.57(dd,J=8.0,2.0Hz,1H),7.39-7.32(m,2H),7.33(d,J=6.4Hz,1H),7.20(d d,J=8.0,2.0Hz,1H),6.98(t,J=57.6Hz,1H),6.95-6.91(m,1H),5.63-5.59(m,1H), 5.29-5.22(m,1H),2.36-2.31(m,1H),2.02-1.88(m,1H),1.47(s,3H),1.43(s.3H)..

[0694] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1256:

[0695] The NMR data of the compounds prepared in the above embodiments are as follows:

[0696] Example I-1263: (1R,11R)-18-[(difluoromethyl)oxy]-5-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-12-methyl-3,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] Twenty-2(10),4,6,8(9),14(15),16,18-heptaen-13-one (I-1263)

[0697] Compound I-1263 was prepared by using compound 150 as a raw material instead of compound 273, following steps A, B, C, D, E, and H of Example I-883.

[0698] LC-MS (m / z): 530 [M+H] + .

[0699] 1H NMR(400MHz,MeOD-d4)δ.8.52(s,1H),8.43(dd,J=6.4,2.0Hz,1H),8.00(dd,J=6.4, 2.0Hz,1H),7.75(s,1H),7.57(dd,J=6.4,2.0Hz,1H),7.40-7.35(m,2H),7.24-7.19 (m,2H),6.98(t,J=57.6Hz,1H),6.95-6.91(m,1H),5.52-5.47(m,1H),5.19-5.15(m ,1H),3.06(s,3H),2.31-2.27(m,1H),1.99-1.85(m,1H),1.48(s,3H),1.43(s,3H).

[0700] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1263:

[0701] The NMR data of the compounds prepared in the above embodiments are as follows:

[0702] Example I-1270: (1R,11R)-18-[(difluoromethyl)oxy]-5-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-12-methyl-3,6,9,12-tetraazapentacyclo[9.8.1.0] 3,8 .0 2,10 .0 14,19 ] Twenty-2(10),4,6,8(9),14(15),16,18-heptaen-13-one (I-1270)

[0703] Compound I-1270 was prepared by using compound 168 as a raw material instead of compound 273, following steps A, B, C, D, E, and H of Example I-883.

[0704] LC-MS (m / z): 531 [M+H] + .

[0705] 1H NMR(400MHz,MeOD-d4)δ.8.86(s,1H),8.68(s,1H),8.64(s,1H),8.55(dd,J=6.4,2.0Hz ,1H),7.57(dd,J=6.4,2.0Hz,1H),7.39-7.35(m,2H),7.21(dd,J=8.0,2.0Hz,1H),7.08( d,J=8.0Hz,1H),6.98(t,J=57.6Hz,1H),6.95-6.91(m,1H),5.52-5.47(m,1H),5.19-5. 15(m,1H),3.06(s,3H),2.31-2.27(m,1H),2.00-1.85(m,1H),1.48(s,3H),1.43(s,3H).

[0706] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1270:

[0707] Example I-1277: (1R,13R)-5,5-difluoro-19-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-12-methyl-4,6-dioxa-12,15,21-triazahexane[11.9.1.0] 2,10 .0 16,21 .0 3,7 .0 14,22 ] Twenty-three-2(3),7(8),9,14(22),15,17,19-heptaen-11-one (I-1277)

[0708] Step A: (1R,13R)-9,9-difluoro-2-methyl-17-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-8,10-dioxa-2,15,21-triazahexane [11.9.1.0] 15,20 .0 14,22 .0 7,11 .0 4,12 ] Twenty-three-4(5),6,11(12),14(22),16,18,20(21)-heptaen-3-one(337)

[0709] Compound 337 was prepared by using compound 227 as a raw material instead of compound 232, following step E of Example I-883.

[0710] LC-MS (m / z): 496 [M+H] + .

[0711] Step B: (1R,13R)-5,5-difluoro-19-[8-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-3-yl]-12-methyl-4,6-dioxa-12,15,21-triazahexane[11.9.1.0] 2,10 .0 16,21 .0 3,7 .0 14,22 ] Twenty-three-2(3),7(8),9,14(22),15,17,19-heptaen-11-one (I-1277)

[0712] Compound I-1277 was prepared by using compound 337 as a raw material instead of compound 233, following step H of Example I-883.

[0713] LC-MS (m / z): 544 [M+H] + .

[0714] 1 H NMR(400MHz,MeOD-d4)δ.8.52(s,1H),8.42(dd,J=8.0,2.0Hz,1H),8.08(dd,J =8.0,2.0Hz,1H),7.57(s,1H),7.37(dd,J=8.0,2.0Hz,1H),7.24-7.20(m,2H), 7.11(d,J=8.0Hz,1H),6.95-6.91(m,1H),5.52-5.45(m,1H),5.37-5.31(m,1H) ,3.05(s,3H),2.38-2.31(m,4H),2.07-2.02(m,1H),1.47(s,3H),1.43(s,3H).

[0715] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1277:

[0716] The NMR data of the compounds prepared in the above embodiments are as follows:

[0717] Example I-1410: (1R,11R)-7-{2-[(3R)-4-(2-hydroxyacetyl)-3-methylpiperazin-1-yl]pyrimidin-5-yl}-13-[(difluoromethyl)oxy]-19-methyl-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .04,9 ] Twenty-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-1410)

[0718] Step A: (1R,13R)-9,9-difluoro-2-methyl-17-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)-8,10-dioxa-2,15,21-triazahexane [11.9.1.0] 15,20 .0 14,22 .0 7,11 .0 4,12 ] Twenty-three-4(5),6,11(12),14(22),16,18,20(21)-heptaen-3-one(340)

[0719] 5-Bromo-2-chloropyrimidine (compound 338, 1.92 g, 10.00 mmol) was dissolved in ethanol (20 mL), and triethylamine (2.02 g, 20.00 mmol) and (2R)-2-methylpiperazine (compound 339, 1.01 g, 10.00 mmol) were added. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was then diluted with water (40 mL) and extracted with ethyl acetate (70 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography to give the title compound 340 (1.28 g, 50%).

[0720] LC-MS (m / z): 257 [M+H] + .

[0721] 1 H NMR (400MHz, MeOD-d4) δ = 8.27 (s, 2H), 3.87-3.68 (m, 3H), 3.40-3.33 (m, 1H), 3.11-3.01 (m, 3H), 3.13 (d, J = 8.0Hz, 3H).

[0722] Step B: (1R,11R)-7-{2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-5-yl}-13-[(difluoromethyl)oxy]-19-methyl-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 ] Twenty-2(3),4(9),5,7,12(13),14,16-heptaen-18-one(341)

[0723] Compound 341 was prepared by using compound 340 as a raw material instead of compound 236, following step H of Example I-883.

[0724] LC-MS (m / z): 532 [M+H] + .

[0725] Step C: (1R,11R)-7-{2-[(3R)-4-(2-hydroxyacetyl)-3-methylpiperazin-1-yl]pyrimidin-5-yl}-13-[(difluoromethyl)oxy]-19-methyl-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 ] Twenty-2(3),4(9),5,7,12(13),14,16-heptaen-18-one (I-1410)

[0726] (1R,11R)-7-{2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-5-yl}-13-[(difluoromethyl)oxy]-19-methyl-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 [2,3),4,5,7,12,13,14,16-heptaen-18-one (compound 341, 53.1 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (5 mL), and triethylamine (30.3 mg, 0.30 mmol) and glycolic acid (compound 342, 9.1 mg, 0.12 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographically prepared to give the title compound I-1410 (16.5 mg, 28%).

[0727] LC-MS (m / z): 590 [M+H] + .

[0728] 1H NMR(400MHz,MeOD-d4)δ.8.60(s,2H),8.03-7.99(m,2H),7.88(d,J=2.0Hz,1H ),7.64(dd,J=8.0,2.0Hz,1H),7.37-7.31(m,1H),7.21(dd,J=8.0,2.0Hz,1H) ,6.97(t,J=57.6Hz,1H),6.23-6.18(m,1H),5.31-5.24(m,1H),4.21-3.53(m, 9H),3.04(s,3H),2.64-2.61(m,1H),2.38-2.31(m,1H),1.22(d,J=8.0Hz,3H).

[0729] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1410:

[0730] The NMR data of the compounds prepared in the above embodiments are as follows:

[0731] Example I-1465: 2-[(2R)-4-{5-[(1R,11R)-13-[(difluoromethyl)oxy]-19-methyl-18-oxoyne-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 [Tecone-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}-2-methylpiperazin-1-yl]-N-methyl-2-oxomethyleneacetamide (I-1465)

[0732] (1R,11R)-7-{2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-5-yl}-13-[(difluoromethyl)oxy]-19-methyl-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9[[2,3),4,9,5,7,12,13,14,16-heptaen-18-one (compound 341, 53.1 mg, 0.10 mmol) was dissolved in acetonitrile (5 mL), and triethylamine (30.3 mg, 0.30 mmol) and ethyl 2-(methylamino)-2-oxonyl acetate (compound 343, 19.6 mg, 0.15 mmol) were added. The reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographically prepared to give the title compound I-1465 (16.5 mg, 43%).]

[0733] LC-MS (m / z): 617 [M+H] + .

[0734] 1 H NMR (400MHz, MeOD-d4) δ.8.61 (s, 2H), 8.02-7.99 (m, 2H), 7.86 (d, J = 2.0Hz, 1H), 7.64 (dd ,J=8.0,2.0Hz,1H),7.37-7.32(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.98(t,J=57.6Hz,1 H),6.23-6.18(m,1H),5.33-5.28(m,1H),4.18-3.73(m,6H),3.57-3.52(m,1H),3.04(s, 3H),2.85(d,J=5.6Hz,3H),2.64-2.58(m,1H),2.37-2.31(m,1H),1.21(d,J=8.0Hz,2H).

[0735] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1465:

[0736] The NMR data of the compounds prepared in the above embodiments are as follows:

[0737] Example I-1478: 4-[(2R)-4-{5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-methyl-13-oxoyne-2,9,12-triazapentacyclo[9.8.1.0] 2,10 .0 3,8 .0 14,19[Tecone-3(8),4,6,9,14(15),16,18-heptaen-5-yl]pyrimidin-2-yl}-2-methylpiperazin-1-yl]-3-(methylamino)cyclobut-3-ene-1,2-dione (I-1478)

[0738] (1R,11R)-7-{2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-5-yl}-13-[(difluoromethyl)oxy]-19-methyl-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 [[2,3),4,5,7,12,13,14,16-heptaen-18-one (compound 341, 53.1 mg, 0.10 mmol)] was dissolved in ethanol (5 mL), and triethylamine (30.3 mg, 0.30 mmol) and 3-methoxy-4-(methylamino)cyclobut-3-ene-1,2-dione (compound 344, 21.3 mg, 0.15 mmol) were added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographically prepared to give the title compound I-1465 (22.4 mg, 35%).

[0739] LC-MS (m / z): 641 [M+H] + .

[0740] 1 H NMR(400MHz,MeOD-d4)δ.8.62(s,2H),8.03-7.99(m,2H),7.86(d,J=2.0Hz,1H),7.64(dd ,J=8.0,2.0Hz,1H),7.37-7.32(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.98(t,J=57.6Hz,1 H),6.23-6.18(m,1H),5.33-5.28(m,1H),4.20-3.78(m,5H),3.58-3.55(m,1H),3.04(s, 3H),2.89(d,J=5.6Hz,3H),2.64-2.58(m,1H),2.37-2.31(m,1H),1.22(d,J=8.0Hz,2H).

[0741] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1478:

[0742] The NMR data of the compounds prepared in the above embodiments are as follows:

[0743] Example I-1491: (2R)-4-{5-[(1R,11R)-13-[(difluoromethyl)oxy]-19-methyl-18-oxoyne-3,10,19-triazapentacyclo[9.8.1.0]} 12,17 .0 2,10 .0 4,9 [Tecico-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}-2,N-dimethylpiperazin-1-carboxamide (I-1491)

[0744] (1R,11R)-7-{2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-5-yl}-13-[(difluoromethyl)oxy]-19-methyl-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 [[2,3),4,5,7,12,13,14,16-heptaen-18-one (compound 341, 53.1 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (30.3 mg, 0.30 mmol) and methyl aziridine formyl chloride (compound 345, 13.8 mg, 0.15 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water (10 mL) and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographically prepared to give the title compound I-1491 (21.7 mg, 37%).]

[0745] LC-MS (m / z): 589 [M+H] + .

[0746] 1H NMR(400MHz,MeOD-d4)δ.8.62(s,2H),8.04-7.99(m,2H),7.88(d,J=3.2Hz,1H),7.64(dd,J=8 .0,2.0Hz,1H),7.36-7.30(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.98(t,J=57.6Hz,1H),6.23- 6.17(m,1H),5.33-5.27(m,1H),4.12-3.89(m,3H),3.82-3.69(m,3H),3.58-3.53(m,1H),3.0 5(s,3H),2.71(d,J=5.6Hz,3H),2.66-2.56(m,1H),2.37-2.31(m,1H),1.21(d,J=8.0Hz,3H).

[0747] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1491:

[0748] The NMR data of the compounds prepared in the above embodiments are as follows:

[0749] Example I-1501: (2R)-4-{5-[(1R,11R)-13-[(difluoromethyl)oxy]-19-methyl-18-oxoyne-3,10,19-triazapentacyclo[9.8.1.0]} 12,17 .0 2,10 .0 4,9 [Tecone-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}-2,N-dimethylpiperazine-1-sulfonamide (I-1501)

[0750] (1R,11R)-7-{2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-5-yl}-13-[(difluoromethyl)oxy]-19-methyl-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9[[2,3),4,5,7,12,13,14,16-heptaen-18-one (compound 341, 53.1 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (30.3 mg, 0.30 mmol) and methyl aziran sulfonyl chloride (compound 346, 19.4 mg, 0.15 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water (10 mL) and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographically prepared to give the title compound I-1501 (11.2 mg, 18%).]

[0751] LC-MS (m / z): 625 [M+H] + .

[0752] 1 H NMR(400MHz,MeOD-d4)δ.8.62(s,2H),8.04-7.99(m,2H),7.88(d,J=3.2Hz,1H),7.64(d d,J=8.0,2.0Hz,1H),7.36-7.30(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.98(t,J=57.6Hz ,1H),6.23-6.17(m,1H),5.33-5.27(m,1H),4.16-4.12(m,1H),3.97-3.76(m,3H),3.70 -3.49(m,2H),3.04(s,3H),2.66-2.56(m,4H),2.37-2.18(m,1H),1.18(d,J=8.0Hz,3H).

[0753] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1501:

[0754] The NMR data of the compounds prepared in the above embodiments are as follows:

[0755] Example I-1511: [(2R)-4-{5-[(1R,11R)-13-[(difluoromethyl)oxy]-19-methyl-18-oxoyne-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9[1-2(3),4(9),5,7,12(13),14,16-heptaen-7-yl]pyrimidin-2-yl}-2-methylpiperazin-1-yl]acetic acid (I-1511)

[0756] (1R,11R)-7-{2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-5-yl}-13-[(difluoromethyl)oxy]-19-methyl-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 [[2,3),4,5,7,12,13,14,16-heptaen-18-one (compound 341, 53.1 mg, 0.10 mmol) was dissolved in isopropanol (5 mL), and triethylamine (30.3 mg, 0.30 mmol) and bromoacetic acid (compound 347, 20.7 mg, 0.15 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water (10 mL) and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed once with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographically prepared to give the title compound I-1511 (12.9 mg, 22%).]

[0757] LC-MS (m / z): 590 [M+H] + .

[0758] 1 H NMR(400MHz,MeOD-d4)δ.8.62(s,2H),8.04-7.99(m,2H),7.87(d,J=3.2Hz,1H),7.64(dd,J= 8.0,2.0Hz,1H),7.37-7.33(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.98(t,J=57.6Hz,1H),6.2 4-6.21(m,1H),5.31-5.28(m,1H),4.05-4.01(m,1H),3.85-3.71(m,2H),3.48-3.35(m,3H), 3.07-2.88(m,3H),3.04(s,3H),2.66-2.58(m,1H),2.37-2.31(m,1H),1.11(d,J=8.0Hz,3H).

[0759] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1511:

[0760] The NMR data of the compounds prepared in the above embodiments are as follows:

[0761] Example I-1652: (1-{5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-methyl-13-oxoyne-2,9,12-triazapentacyclo[9.8.1.0]) 3,8 .0 14,19 .0 2,10 [Tyro-3(8),4,6,9,14(15),16,18-heptaen-5-yl]pyrimidin-2-yl}hexahydropyridin-4-yl)acetic acid (I-1652)

[0762] Step A: [1-(5-bromopyrimidin-2-yl)hexahydropyridin-4-yl]acetic acid (355)

[0763] Compound 355 was prepared by using compound 354 as a raw material instead of compound 339, following step A of Example I-1410.

[0764] LC-MS (m / z): 300 [M+H] + .

[0765] 1 H NMR (400MHz, DMSO-d6) δ.11.91(s,1H),8.25(s,2H),4.32-4.25(m,2H),3.90-3.83(m,2H),2.31-2.15(m,2H),2.16-1.98(m,5H).

[0766] Step B: (1-{5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-methyl-13-oxoyne-2,9,12-triazapentacyclo[9.8.1.0]) 3,8 .0 14,19 .0 2,10 [Tyro-3(8),4,6,9,14(15),16,18-heptaen-5-yl]pyrimidin-2-yl}hexahydropyridin-4-yl)acetic acid (I-1652)

[0767] Compound I-1652 was prepared by using compound 355 as a raw material instead of compound 236, following step H of Example I-883.

[0768] LC-MS (m / z): 575 [M+H] + .

[0769] 1H NMR(400MHz,MeOD-d4)δ.8.62(s,2H),8.04-7.97(m,2H),7.86(d,J=1.62Hz, 1H),7.64(dd,J=8.0,2.0Hz,1H),7.37-7.32(m,1H),7.21(dd,J=8.0,2.0Hz,1 H),6.97(t,J=57.6Hz,1H),6.23-6.20(m,1H),5.34-5.28(m,1H),4.32-4.25( m,2H),3.90-3.83(m,2H),3.04(s,3H),2.65-2.61(m,1H),2.38-1.98(m,8H).

[0770] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1652:

[0771] The NMR data of the compounds prepared in the above embodiments are as follows:

[0772] Example I-1749: 1-[(2S)-2-{5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-methyl-13-oxoyne-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tyro-3(4),5,7,9,14(15),16,18-heptaen-5-yl]pyrimidin-2-yl]-2-hydroxyethyl]hexahydropyridine-4-carboxylic acid (I-1749)

[0773] Step A: 1-[2-(5-bromopyrimidin-2-yl)-2-hydroxyethyl]hexahydropyridine-4-carboxylic acid (358)

[0774] Hexahydropyridine-4-carboxylic acid (compound 356, 1.29 g, 10.0 mmol) was dissolved in ethanol (10 mL), and 5-bromo-2-(oxacycloprop-2-yl)pyrimidine (compound 357, 2.00 g, 10.0 mmol) was added. The reaction mixture was stirred in a microwave at 120 °C for 1 hour. The reaction mixture was then directly concentrated and subjected to column chromatography to obtain the title compound 358 (987 mg, 33%).

[0775] LC-MS (m / z): 330 [M+H] + .

[0776] 1 H NMR(400MHz,MeOD-d4)δ.9.01(s,2H),5.10-5.05(m,1H),3.15-2.99(m,4H),2.87-2.82(m,2H),2.51-2.47(m,1H),1.94-1.79(m,4H).

[0777] Step B: 1-[(2S)-2-{5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-methyl-13-oxoyne-2,9,12-triazapentacyclo[9.8.1.0] 3,8 .0 14,19 .0 2,10 [Tyro-3(4),5,7,9,14(15),16,18-heptaen-5-yl]pyrimidin-2-yl]-2-hydroxyethyl]hexahydropyridine-4-carboxylic acid (I-1749)

[0778] Compound I-1749 was prepared by using compound 358 as a starting material instead of compound 236, following step H of Example I-883.

[0779] LC-MS (m / z): 605 [M+H] + .

[0780] 1 H NMR(400MHz,MeOD-d4)δ.9.10(s,2H),8.05-7.99(m,2H),7.88(d,J=3.2Hz,1H),7.74( dd,J=8.0,2.0Hz,1H),7.32-7.27(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.97(t,J=57.6H z,1H),6.23-6.19(m,1H),5.34-5.30(m,1H),5.16-5.12(m,1H),3.18-3.15(m,2H),3. 04(s,3H),3.04-2.98(m,2H),2.86-2.80(m,2H),2.65-2.33(m,3H),1.97-1.82(m,4H).

[0781] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1749:

[0782] The NMR data of the compounds prepared in the above embodiments are as follows:

[0783] Example I-1799: (4-{5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-methyl-13-oxoyne-2,9,12-triazapentacyclo[9.8.1.0]) 3,8 .0 14,19 .0 2,10 [Tecone-3(4),5,7,9,14(15),16,18-heptaen-5-yl]pyrimidin-2-yl}hexahydropyridin-1-yl)acetic acid (I-1799)

[0784] Step A: [4-(5-bromopyrimidin-2-yl)-1,2,3,6-tetrahydropyridin-1-yl]acetic acid (361)

[0785] Compound 361 was prepared by using compound 360 as a raw material instead of compound 236, following step H of Example I-883.

[0786] LC-MS (m / z): 298 [M+H] + .

[0787] 1 H NMR (400MHz, MeOD-d4) δ.8.49 (s, 2H), 6.59-6.48 (m, 1H), 3.49-3.40 (m, 2H), 3.36 (d, J = 4.0Hz, 2H), 3.19-3.11 (m, 2H), 3.05-3.00 (m, 2H).

[0788] Step B: (4-{5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-methyl-13-oxoyne-2,9,12-triazapentacyclo[9.8.1.0]) 3,8 .0 14,19 .0 2,10

[1798] 2-3(4),5,7,9,14(15),16,18-heptaen-5-yl]pyrimidin-2-yl}-1,2,3,6-tetrahydropyridin-1-yl)acetic acid (I-1798)

[0789] Compound I-1798 was prepared by using compound 361 as a raw material instead of compound 236, following step H of Example I-883.

[0790] LC-MS (m / z): 573 [M+H] + .

[0791] 1H NMR(400MHz,MeOD-d4)δ.9.13(s,2H),8.06-7.97(m,2H),7.93(d,J=3.2Hz,1H),7.64(dd,J= 8.0,2.0Hz,1H),7.35-7.30(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),6.5 2-6.50(m,1H),6.23-6.22(m,1H),5.23-5.20(m,1H),3.49-3.40(m,2H),3.36(d,J=4.0Hz,2 H),3.18-3.11(m,2H),3.05-3.00(m,2H),3.04(s,3H),2.64-2.57(m,1H),2.36-2.31(m,1H).

[0792] Step C: (4-{5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-methyl-13-oxoyne-2,9,12-triazapentacyclo[9.8.1.0]) 3,8 .0 14,19 .0 2,10 [Tecone-3(4),5,7,9,14(15),16,18-heptaen-5-yl]pyrimidin-2-yl}hexahydropyridin-1-yl)acetic acid (I-1799)

[0793] (4-{5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-methyl-13-oxoyne-2,9,12-triazapentacyclo[9.8.1.0]) 3,8 .0 14,19 .0 2,10 [[I-1798, 57.2 mg, 0.1 mmol]]-3(4),5,7,9,14(15),16,18-heptaen-5-yl]pyrimidin-2-yl}-1,2,3,6-tetrahydropyridin-1-yl)acetic acid (compound I-1798, 57.2 mg, 0.1 mmol) was dissolved in methanol (5 mL), and palladium on carbon (50 mg) was added. The reaction solution was stirred at room temperature under hydrogen pressure for 1 hour. The reaction solution was then filtered and concentrated, and preparative chromatography was used to obtain the title compound I-1799 (14.4 mg, 25%).

[0794] LC-MS (m / z): 575 [M+H] + .

[0795] 1H NMR (400MHz, MeOD-d4) δ.8.93 (s, 2H), 8.06-7.97 (m, 2H), 7.89 (d, J = 3.2Hz, 1H), 7.64 (dd,J=8.0,2.0Hz,1H),7.35-7.31(m,1H),7.21(dd,J=8.0,2.0Hz,1H),6.97(t,J=57 .6Hz,1H),6.23-6.22(m,1H),5.32-5.28(m,1H),3.36(s,2H),3.19-3.13(m,1H),3.0 5(s,3H),2.97-2.82(m,4H),2.64-2.57(m,1H),2.37-2.31(m,1H),2.17-2.02(m,4H).

[0796] The following examples are synthesized using the appropriate initial raw materials, following the synthesis methods of Examples I-1798 and I-1799:

[0797] The NMR data of the compounds prepared in the above embodiments are as follows:

[0798] Example I-1809: (4-{5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-methyl-13-oxoyne-2,9,12-triazapentacyclo[9.8.1.0]) 3,8 .0 14,19 .0 2,10

[1809] 2-3(4),5,7,9,14(15),16,18-heptaen-5-yl]pyrimidin-2-yl}-4-hydroxycyclohexyl)acetic acid (I-1809)

[0799] Step A: [4-(5-bromopyrimidin-2-yl)-4-hydroxycyclohexyl]acetic acid (363)

[0800] Compound 363 was prepared using compound 362 instead of compound 15, following step A of Example I-81. LC-MS (m / z): 315 [M+H] + .

[0801] 1 H NMR(400MHz,MeOD-d4)δ.8.46(s,2H),2.33-1.68(m,11H).

[0802] Step B: (4-{5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-methyl-13-oxoyne-2,9,12-triazapentacyclo[9.8.1.0]) 3,8.0 14,19 .0 2,10

[1809] 2-3(4),5,7,9,14(15),16,18-heptaen-5-yl]pyrimidin-2-yl}-4-hydroxycyclohexyl)acetic acid (I-1809)

[0803] Compound I-1809 was prepared by using compound 363 as a raw material instead of compound 236, following step H of Example I-883.

[0804] LC-MS (m / z): 590 [M+H] + .

[0805] 1 H NMR(400MHz,MeOD-d4)δ.8.71(s,2H),8.05-7.98(m,2H),7.92(d,J=3.2Hz,1H),7.64(dd,J=8.0,2.0Hz,1H),7.32-7.27(m,1H ),7.21(dd,J=8.0,2.0Hz,1H),6.97(t,J=57.6Hz,1H),6.22-6.18(m,1H),5.32-5.25(m,1H),3.04(s,3H),2.64-1.69(m,11H).

[0806] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1809:

[0807] The NMR data of the compounds prepared in the above embodiments are as follows:

[0808] Example I-1819: (1R,11R)-13-[(difluoromethyl)oxy]-7-[1-(2-hydroxypropyl-2-yl)bicyclo[1.1.1]pentan-3-yl]-19-methyl-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 [Ecto-2(3),4(5),6,8,12(13),14,16-heptaen-18-one (I-1819) Step A: 3-[(1R,11R)-13-[(difluoromethyl)oxy]-19-methyl-18-oxoyne-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 [Tecico-2(3),4(5),6,8,12(13),14,16-heptaen-7-yl]bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (365)

[0809] Compound 365 was prepared by using compound 364 as a raw material instead of compound 236, following step H of Example I-883.

[0810] LC-MS (m / z): 480 [M+H] + .

[0811] 1 H NMR(400MHz,MeOD-d4)δ.7.64(dd,J=8.0,2.0Hz,1H),7.51(d,J=8.0Hz,1H),7.36-7.32(m,2H),7.27(dd,J=8.0,2.0Hz,1H),7.21(dd,J=8.0 ,2.0Hz,1H),6.97(t,J=57.6Hz,1H),6.22-6.19(m,1H),5.32-5.26(m,1H),3.57(s,3H),3.05(s,3H),2.67-2.61(m,1H),2.43-2.28(m,7H).

[0812] Step B: (1R,11R)-13-[(difluoromethyl)oxy]-7-[1-(2-hydroxypropyl-2-yl)bicyclo[1.1.1]pentan-3-yl]-19-methyl-3,10,19-triazapentacyclo[9.8.1.0] 12,17 .0 2,10 .0 4,9 ] 2, 4, 6, 8, 12, 13, 14, 16-heptaen-18-one (I-1819)

[0813] Compound I-1819 was prepared by using compound 363 as a raw material instead of compound 236, following step H of Example I-883.

[0814] LC-MS (m / z): 480 [M+H] + .

[0815] 1H NMR(400MHz,MeOD-d4)δ.7.63(dd,J=8.0,2.0Hz,1H),7.51(d,J=8.0Hz,1H),7.36-7.32(m,2H),7.27(dd,J=8.0,2.0Hz,1H),7.21(dd,J=8.0 ,2.0Hz,1H),6.98(t,J=57.6Hz,1H),6.22-6.19(m,1H),5.32-5.26(m,1H),3.07(s,3H),2.65-2.61(m,1H),2.37-2.31(m,1H),1.96(s,6H).

[0816] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1819:

[0817] Example I-1822: 2-({5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-methyl-13-oxoyne-2,9,12-triazapentacyclo[9.8.1.0]) 3,8 .0 14,19 .0 2,10 [Tecico-3(4),5,7,9,14(15),16,18-heptaen-5-yl]pyridin-2-yl}methyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (I-1822)

[0818] Step A: 2-[(5-bromopyridin-2-yl)methyl]-2-azaspiro[3.3]heptane-6-carboxylic acid (368)

[0819] 2-azaspiro[3.3]heptane-6-carboxylic acid (compound 366, 1.41 g, 10.0 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium cyanoborohydride (1.25 g, 20.0 mmol) and 5-bromopyridine-2-carboxaldehyde (compound 367, 1.84 g, 10.0 mmol) were added. The reaction mixture was stirred at room temperature (60 °C) for 1 hour. The reaction mixture was then diluted with water (40 mL), extracted with dichloromethane (50 mL x 3), and the organic phases were combined, washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography was performed to give the title compound 368 (1.02 g, 33%).

[0820] LC-MS (m / z): 311 [M+H] + .

[0821] 1H NMR(400MHz,MeOD-d4)δ.8.45(d,J=2.0Hz,1H),7.81(dd,J=8.0,2.0Hz,1H),7.42(d,J=8.0Hz,1H) ,3.65(s,2H),3.19(s,2H),3.00(s,2H),2.46-2.39(m,1H),1.97-1.95(m,2H),1.83-1.80(m,2H).

[0822] Step B: 2-({5-[(1R,11R)-18-[(difluoromethyl)oxy]-12-methyl-13-oxoyne-2,9,12-triazapentacyclo[9.8.1.0 3,8 .0 14,19 .0 2,10 [Tecico-3(4),5,7,9,14(15),16,18-heptaen-5-yl]pyridin-2-yl}methyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (I-1822)

[0823] Compound I-1822 was prepared by using compound 368 as a raw material instead of compound 236, following step H of Example I-883.

[0824] LC-MS (m / z): 586 [M+H] + .

[0825] 1 H NMR (400MHz, MeOD-d4) δ.8.72 (d, J = 2.0 Hz, 1H), 7.92-7.90 (m, 2H), 7.79-7.78 (m, 1H), 7.74 (dd, J = 8. 0,2.0Hz,1H),7.64(dd,J=8.0,2.0Hz,1H),7.42(d,J=8.0Hz,1H),7.36-7.33(m,1H),7.21(dd,J=8.0, 2.0Hz,1H),6.97(t,J=57.6Hz,1H),6.23-6.20(m,1H),5.31-5.26(m,1H),3.65(s,2H),3.18(s,2H),3 .04(s,3H),3.00(s,2H),2.64-2.61(m,1H),2.47-2.31(m,2H),1.99-1.92(m,2H),1.83-1.79(m,2H).

[0826] The following examples illustrate the synthesis of materials using the appropriate initial raw materials, following the synthesis method described in Example I-1822:

[0827] The NMR data of the compounds prepared in the above embodiments are as follows:

[0828] Biological evaluation

[0829] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0830] The HEK-Blue TNF-α reporter assay for hTNF-α uses the following methods: HEK-Blue TNF-α cells were used; recombinant human TNF-α was used as the stimulant; and the Quanti-Blue™ assay was used as the detection conditions. The HEK Blue TNF-α protocol is as follows: Cells were cultured and prepared for detection according to the manufacturer's instructions. HEK Blue TNF-α cells were detected during the exponential growth phase. Growth medium was aspirated, and cells were washed twice with PBS to remove phenol red. Cells were then resuspended in the test medium to an appropriate concentration. Only cells with a viability greater than 90% were used for assay; 25 μL of compound dilution was transferred to a 384-well plate; 5 μL of TNF-α protein solution was added to a 384-well plate; the plates were centrifuged at 1000 rpm for 1 minute and incubated at 37°C for 1 hour; 20 μL of HEK Blue TNF-α cells were seeded into a 384-well plate; the cells were incubated at 37°C under a 5% CO2 atmosphere for 20 hours; 5 μL of cell supernatant was transferred to each well of a 384-well assay plate; 20 μL of QUANTI blue solution was added to each well; the plates were incubated at 37°C for 1 hour; SEAP levels were measured at 620 nm using a spectrophotometer; the experimental data were processed using a graph pad nonlinear fitting of compound concentration and corresponding inhibition rate to calculate the half-maximal inhibitory concentration (IC50). 50 .

[0831] Table 1, IC50 of example compounds 50 Note: A represents IC 50 Values ​​less than 20 nM, B indicates IC 50 Values ​​between 20 nM and 100 nM, where C represents IC. 50 Value greater than 100 nM

[0832] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A compound of Formula I or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof. in: R a Selected from hydrogen, deuterium, hydroxyl, amino, cyano, fluorine, chlorine, deuterated methyl, difluoromethyl, trifluoromethyl, vinyl, ethynyl, methylethynyl; R b Selected from hydrogen, methyl, deuterated methyl, difluoromethyl, and trifluoromethyl; R c R d Selected from hydrogen, deuterium, hydroxyl, methoxy, deuterated methoxy, difluoromethoxy, and trifluoromethoxy; Or R c R d Together with the carbon atoms they are attached to, they form a structure. R 1 R 2 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, and trifluoromethyl; Ring A is selected from the following groups: Among them W 1 W 2 W 3 W 4 W 5 W 6 Each is independently selected from -CH- or -N-; Preferably, ring A is selected from the following groups: R e Selected from deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, and trifluoromethyl. n1 is an integer selected from 0, 1, and 2; when n1 is 2, each R e They can be the same or different; Ring B is selected from the following groups: in: W 7 、W 8 、W 9 、W 10 、W 11 、W 12 、W 13 、W 14 、W 15 、W 16 、W 17 、W 18 、W 19 、W 20 、W 21 、W 22 、W 23 、W 24 、W 25 、W 26 、W 27 、W 28 、W 29 、W 30 、W 31 、W 32 、W 33 、W 34 、W 35 、W 36 、W 37 、W 38 、W 39 、W 40 、W 41 、W 42 are each independently selected from -CH- or -N-; Preferably, ring B is selected from the following groups: R f Selected from deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, and trifluoromethyl; n2 is selected from integers 0, 1, and 2; when n2 is 2, each R f They can be the same or different; R g Selected from the following groups: in Ring D is selected from C3-C5 cycloalkanes and contains one 4- or 5-membered heterocyclic group selected from nitrogen, oxygen, or sulfur heteroatoms; R 5 R 7 Selected from hydrogen, deuterium, hydroxyl, and amino groups; R 3 R 4 Selected from hydrogen and hydroxyl groups; R 6 Selected from cyano, hydroxy, methyl, deuterated methyl, difluoromethyl, trifluoromethyl, and oxo groups; n3 is an integer selected from 0, 1, and 2; When R g for When using this method, the following groups are preferred: in: R 7 Selected from hydrogen, hydroxyl, and amino groups; R 6 Selected from cyano, hydroxy, methyl, deuterated methyl, fluorinated methyl, and oxo groups; n3 is selected from integers 0, 1, and 2; when n3 is 2, each R 6 They can be the same or different; Preferably, R g Selected from the following groups:

2. The compound of Formula I according to claim 1, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, characterized in that, in: R a R b R c R d The definition of ring A is the same as in claim 1; Ring B is selected from the following groups: W 43 、W 44 、W 45 、W 46 、W 47 、W 48 、W 49 、W 50 、W 51 、W 52 、W 53 、W 54 、W 55 、W 56 、W 57 、W 58 、W 59 、W 60 、W 61 、W 62 are each independently selected from -CH- or -N-; Preferably, ring B is selected from the following groups: R f n is selected from deuterium, fluorine, chlorine, methyl, deuterated methyl, difluoromethyl, and trifluoromethyl; n2 is selected from integers 0, 1, and 2; R g Selected from the following groups: Where L 1 Selected from the bonded, substituted, or unsubstituted -(CH2) 1-3 - The substitution refers to the substitution of one, two or three hydrogens on a group by the following substituents: deuterium, hydroxyl, amino, methyl, deuterated methyl, difluoromethyl, trifluoromethyl, methoxy, deuterated methoxy, difluorooxymethyl, trifluorooxymethyl; Ring E is selected from the following groups: in, Single or double bond W 63 、W 66 、W 68 、W 69 、W 70 、W 75 、W 76 、W 77 、W 78 、W 79 、W 80 、W 82 、W<000用 83 、W 84 、W 85 、W 86 、W 87 、W 88 、W 89 、W 90 、W 92 、W 93 、W 94 、W 95 、W 97 、W 99 、W 99 、W 100 、W 101 、W 102 、W 111 、W 113 、W 115 are each independently selected from carbon or nitrogen; W 64 W 67 Each is independently selected from carbon, nitrogen, oxygen, sulfur, -CH2O-, -OCH2-, -CH2N(H or CH3)-, -CH(CH3)-, -CH2S-, -SCH2-, -CH2CH2-; W 65 W 81 Each is independently selected from carbon, -N (H or CH3)-, and oxygen; W 71 W 72 W 73 W 74 Each is selected from carbon, W 72 Through L 2 respectively with W 70 W 71 W 73 W 74 The connection forms a bridge ring, W 72 It can also be done through L 3 With W 72 They connect themselves into a loop, where L 2 Selected from -CH2-, -CH2CH2-, L 3 Selected from -CH2-; W 91 W 96 W 98 W 114 Selected from oxygen and sulfur; W 112 Selected from -(CH2)3, -CH2OCH2-, CH2N(H, methyl, deuterated methyl)CH2-; Preferably, ring E is selected from the following groups: R 8 Selected from the following groups: deuterium, fluorine, chlorine, hydroxyl, amino, hydroxymethyl, oxo group, where n4 is 0 or 1; R 9 Selected from the following groups: in: L 4 Selected from the bond, -(CH2) 1-6 -、-(CH2) 0-3 CH2=CH2(CH2) 0-3 -、-(CH2) 0-3 CH2≡CH2(CH2) 0-3 -、-(CH2) 0- 3O(CH2) 0-3 -、-(CH2) 0-3 NH(CH2) 0-3 -、-(CH2) 0-3 NHC(=O)(CH2) 0-3 -; R 10 Selected from hydroxyl, amino, fluorine, cyano, oxo, carboxyl, substituted or unsubstituted C1-C3 alkyl groups, wherein the substitution refers to hydroxyl or amino; n5 is selected from integers 0, 1, and 2; when n5 is 2, the two R groups... 10 The atoms that connect to and are connected together form C3-C6 cycloalkyl groups; when L 2 When R is the key 10 It does not exist; L 5 Selected from the bond, -(CH2) 1-6 -、-(CH2) 0-3 O(CH2) 0-3 -、-(CH2) 0-3 NH(CH2) 0-3 -、-(CH2) 0-3 NHC(=O)(CH2) 0- 3-、-(CH2) 0-3 NHC(=O)C(=O)(CH2) 0-3 -、-(CH2) 0-3 OC(=O)(CH2) 0-3 -、; R 11 Selected from oxo groups, n6 is selected from 0, 1, 2, 3; The ring G is selected from substituted or unsubstituted C3-C6 cycloalkanes, substituted or unsubstituted 1-2 3-6 membered heterocyclic groups selected from N, O, and S heteroatoms, phenyl, and 5-6 membered heteroaryl groups; the substituents are selected from: methyl, oxo, hydroxy, methoxy, -NH (H, methyl, deuterated methyl, cyclopropyl, oxetane, fluorinated C1-C3 alkyl); L 6 Selected from the bond, -(CH2) 1-6 -、-(CH2) 0-3 O(CH2) 0-3 -、-(CH2) 0-3 NH(CH2) 0-3 -、-(CH2) 0-3 NHC(=O)(CH2) 0- 3 -; R 12 Selected from oxo groups; n7 is selected from integers 0, 1, and 2; X is selected from nitrogen and oxygen; R 13 Selected from methyl, -NH (H, methyl or deuterated methyl); R 14 Selected from hydrogen, methyl, deuterated methyl, and C1-C3 alkyl acids; L 7 Selected from bonds, C1-C3 alkyl groups, and -(CH2). 0-3 C(=O)(CH2) 0-3 -; R 15 Selected from the following substituents: cyano, C1-C3 alkoxy, -NHR 16 ; R 16 Selected from H, methyl, deuterated methyl, and fluorine-substituted C1-C3 alkyl groups; R 17 Selected from hydrogen, deuterium, hydroxyl, and amino groups; R 18 Selected from fluorine, cyano, hydroxy, methyl, methoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, C1-C6 alkyl, -NH (H or methyl), cyclopropyl; L 8 Selected from C1-C3 alkyl groups; R 19 Selected from the following substituents: hydroxyl, oxo group; n8 is selected from 0 or 1; R 20 R 21 Selected from hydrogen, deuterium, and methyl; Preferably, when R 9 for At that time, R 9 Selected from the following groups: Preferably, ring G is selected from: Preferably, when R 9 for At that time, R 9 Selected from the following groups: Preferably, when R 9 for At that time, R 9 Selected from the following groups: Preferably, when R 9 for At that time, R 9 Selected from the following groups: Preferably, when R 9 for At that time, R 9 Selected from the following groups: Preferably, when R 9 for At that time, R 9 Selected from the following groups:

3. The compound of formula I according to claim 1 or 2, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer, or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, characterized in that, It is selected from the following compounds:

4. A pharmaceutical composition comprising a compound of Formula I as claimed in any one of claims 1 to 3, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable excipient.

5. Use of the compound represented by Formula I according to any one of claims 1 to 3, or its isotopically labeled compound, or its optical isomer, geometric isomer, tautomer or mixture of isomers, or its pharmaceutically acceptable salt, or its prodrug, or its metabolite, or the pharmaceutical composition according to claim 4, in the preparation of a medicament for treating autoimmune diseases and neurological diseases; Preferably, the drug for autoimmune diseases and neurological diseases is a TNF-α inhibitor; Preferably, the autoimmune disease is selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, systemic lupus erythematosus (lupus), axial spondyloarthritis, polymyositis, pemphigus, multiple sclerosis, neuromyelitis optica, primary cholangitis, autoimmune hepatitis, lupus nephritis, pulmonary hemorrhage-nephritis syndrome, autoimmune oophoritis, or autoimmune orchitis; the neurological disease is selected from sarcoidosis, multiple sclerosis, neurobehçet's disease, chronic inflammatory demyelinating diseases, systemic inflammatory vasculitis, traumatic brain injury, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, neuropathic pain, and ischemic stroke.

6. A method for treating autoimmune diseases and neurological diseases, the method comprising administering to a subject in need an effective amount of a compound represented by Formula I according to any one of claims 1 to 3, or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer, or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, or a pharmaceutical composition according to claim 4; preferably, the autoimmune disease is selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, infection Sexual shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, systemic lupus erythematosus (lupus), axial spondyloarthritis, polymyositis, pemphigus, multiple sclerosis, neuromyelitis optica, primary cholangitis, autoimmune hepatitis, lupus nephritis, pulmonary hemorrhage-nephritis syndrome, autoimmune oophoritis or autoimmune orchitis; the neurological diseases mentioned are selected from sarcoidosis, multiple sclerosis, neuroBehçet's disease, chronic inflammatory demyelinating diseases, systemic inflammatory vasculitis, traumatic brain injury, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, neuropathic pain, and ischemic stroke.

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