TW202102498A - Pyridine-fused imidazole and pyrrole derivatives as ripk2 inhibitors - Google Patents

Abstract

Disclosed are compounds of Formula 1,

, and pharmaceutically acceptable salts thereof, wherein α, β, R² , R³ , R⁴ , R⁵ , R⁸ , R⁹ , X¹ , X⁶ , and X⁷ are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating diseases, disorders, and conditions associated with RIPK2.

Description

Pyridine fused imidazole and pyrrole derivatives as RIPK2 inhibitor

The present invention relates to pyridine-fused imidazole and pyrrole derivatives as selective inhibitors of receptor-interacting protein kinase 2 (RIPK2), pharmaceutical compositions containing them, and their use in the treatment of diseases, disorders and diseases related to RIPK2 Symptoms (including inflammatory bowel disease (IBD)).

Receptor-interacting protein kinase 2 (RIPK2) is a serine/threonine protein kinase, which mediates the pro-inflammatory signal transduction stages involving nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1 and NOD2) United. Cytoplasmic pattern recognition receptors (PPR) NOD1 and NOD2 play a role in the innate immune system by binding to diaminopimelic acid or mural dipeptide (MDP) residues present in bacterial peptidoglycans Detect invasive bacteria. After activation, NOD1 and NOD2 associate with RIPK2, which subsequently undergo autophosphorylation and polyubiquitination via interaction with XIAP and other E3 ligases. The RIPK2-ubiquitin complex activates TAK1 and IKK kinases, which promotes the up-regulation of mitogen-activated protein kinases and NF-κB signaling pathways. For example, see P. Canning, Q. Ruan, T. Schwerd et al., "Inflammatory signaling by NOD-RIPK2 is inhibited by clinically relevant Type II Kinase Inhibitors", Chemistry & Biology 22:1174-84 (2015) and M. Hrdinka , L. Schlicher, B. Dai, etc., "Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling", The EMBO Journal 37: e99372 (2018) and references cited therein.

The dysregulation of the RIPK2-NOD signaling pathway is related to several inflammatory and autoimmune diseases, including IBD . See R. Caruso, N. Warner, N. Inohara and G. Nunez, "NOD1 and NOD2: signaling, host defense, and inflammatory disease", Immunity 41: 898-908 (2014); L. Jostins, S. Ripke, R. Weersma et al., "Hostmicrobe interactions have shaped the genetic architecture of inflammatory bowel disease", Nature 491: 119-24 (2012); and D. Philpott, M. Sorbara, M. Robertson, et al., "NOD proteins: regulators of inflammation in health and disease", Nat. Rev. Immunol. 14: 9-23 (2014). The genetic variation system of NOD2 is a known risk factor for Crohn's disease. See J. Hugot, M. Chamaillard, H. Zouali and others, "Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease", Nature 411: 599-603 (2001) and Y. Ogura, D. Bonen, N . Inohara et al., "A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease", Nature 411: 603-06 (2001). Certain mutations in NOD2 reduce its binding to MDP and can promote excessive inflammatory signaling from other PPRs (including NOD1). See A. Couturier-Maillard, T. Secher, A. Rehman, etc., "NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer", J. Clin. Invest. 123: 700-11 (2013); N. Inohara , Y. Ogura, A. Fontalba and others, "Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease", J. Biol. Chem. 278: 5509-12 (2003). Another mutation disrupts NOD2 inhibition, thereby increasing RIPK2 activation. See M. Sorbara, L. Ellison, M. Ramjeet, et al., "The protein ATG16L1 suppresses inflammatory cytokines induced by the intracellular sensors Nod1 and Nod2 in an autophagy-independent manner", Immunity 39: 858-73 (2013). Excessive RIPK2 activation has also been identified in pediatric patients with Crohn's disease. See A. Negroni, L. Stronati, M. Pierdomenico, et al., "Activation of NOD2-mediated intestinal pathway in a pediatric population with Crohn's disease", Inflamm. Bowel Dis. 15: 1145-54 (2009).

In addition to Crohn’s disease, mutations in the RIPK2-NOD signaling pathway have been associated with other diseases, including Blau Syndrome and early-onset sarcoidosis, which are associated with arthritis, dermatitis, and uveitis And cranial neuropathy is characterized by granulomatous disease in children. Other mutations in the RIPK2-NOD signaling pathway have been associated with allergic airway inflammation, arthritis, and multiple sclerosis. For example, see F. Caso F, Galozzi P, Costa L, et al., "Autoinflammatory granulomatous diseases: from Blau Syndrome and Early-Onset Sarcoidosis to NOD2-mediated disease and Crohn's disease", RMD Open 1: e000097 (2015); J. Jun, F. Cominelli and D. Abbott, "RIP2 activity in inflammatory disease and implications for novel therapeutics." J. Leukoc. Biol. 94: 927-32 (2013); F. Goh, K. Cook, N. Upton, etc. People, "Receptor-interacting protein 2 gene silencing attenuates allergic airway inflammation", J. Immunol. 191: 2691-99 (2013); and P. Shaw, M. Barr, R. Lukens and others, "Signaling via the RIP2 adaptor protein in central nervous system-infiltrating dendritic cells promotes inflammation and autoimmunity", Immunity 34: 75-84 (2011).

It is expected that inhibitors of RIPK2 can be used to treat inflammation and autoimmune diseases, including IBD.

The present invention provides pyridine fused imidazole and pyrrole derivatives and pharmaceutically acceptable salts thereof. The present invention also provides pharmaceutical compositions containing the pyridine-fused imidazole and pyrrole derivatives, and provides methods for treating diseases, disorders, and conditions related to RIPK2 (including IBD and other gastrointestinal diseases, disorders, and conditions) use.

或其醫藥學上可接受之鹽，其中： α係單鍵，β係雙鍵，X¹ 係NR^1N ，且R² 係側氧基；或 α係雙鍵，β係單鍵，X¹ 選自N及CR^1C ，且R² 選自氫、C_1-4 烷基及C_1-4 烷氧基； R^1C 選自氫、鹵基及C_1-6 烷基，該C_1-6 烷基經0至3個獨立地選自以下之視情況存在之取代基取代：鹵基、羥基、氰基、C_1-4 烷氧基及視情況經一或兩個C_1-4 烷基取代之胺基； R^1N 選自C_1-4 烷基、C_3-8 環烷基-(CH₂ )_n 、C_2-8 雜環基-(CH₂ )_n 及C_1-9 雜芳基-(CH₂ )_n ，其中該C_1-4 烷基、該C_3-8 環烷基、該C_2-8 雜環基及該C_1-9 雜芳基部分中之每一者經0至3個獨立地選自以下之視情況存在之取代基取代：鹵基、羥基、氰基、C_1-4 烷基、C_1-4 烷氧基及視情況經一或兩個C_1-4 烷基取代之胺基，且其中視情況存在之該C_1-4 烷基及該C_1-4 烷氧基取代基各自獨立地經0至3個獨立地選自鹵基之視情況存在之取代基取代； n選自0、1、2及3； R³ 係C_1-6 烷基，其經0至3個獨立地選自以下之視情況存在之取代基取代：鹵基、羥基、氰基、視情況經C_1-4 烷氧基取代之C_1-4 烷氧基及視情況經一或兩個C_1-4 烷基取代之胺基，其中R³ 上之一或多個氫原子可視情況係氘； R⁴ 及R⁵ 各自獨立地選自氫、鹵基及C_1-4 烷基； X⁶ 選自N及C(R⁶ )； X⁷ 選自N及C(R⁷ )； R⁶ 及R⁷ 各自獨立地來自氫、鹵基、C_1-4 烷基及C_1-4 烷氧基； R⁸ 選自氫、鹵基、C_1-4 烷基及C_1-4 烷氧基，其中該C_1-4 烷基及該C_1-4 烷氧基取代基經0至3個獨立地選自鹵基之視情況存在之取代基取代；且 R⁹ 選自C_1-6 烷基、C_3-8 環烷基、C_2-8 雜環基及C_1-9 雜芳基，其各自經0至3個獨立地選自以下之視情況存在之取代基取代：鹵基、羥基、氰基、側氧基、C_1-4 烷基、C_1-4 烷氧基及視情況經一或兩個C_1-4 烷基取代之胺基，其中視情況存在之該C_1-4 烷基及該C_1-4 烷氧基取代基各自獨立地經0至3個獨立地選自鹵基之視情況存在之取代基取代；且 其中該雜環基及該雜芳基部分中之每一者獨立地具有1至4個為雜原子之環成員，該等雜原子中之每一者獨立地選自N、O及S。One aspect of the present invention provides a compound of formula 1:

Or a pharmaceutically acceptable salt thereof, wherein: α is a single bond, β is a double bond, X ¹ is NR ^1N , and R ² is a pendant oxy group; or α is a double bond, β is a single bond, and X ^{1 is} selected From N and CR ^1C , and R ^{2 is} selected from hydrogen, C _1-4 alkyl and C _1-4 alkoxy; R ^{1C is} selected from hydrogen, halo and C _1-6 alkyl, the C _1-6 alkane The group is substituted with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, C _1-4 alkoxy and optionally substituted with one or two C _1-4 alkyl groups R ^{1N is} selected from C _1-4 alkyl, C _3-8 cycloalkyl-(CH ₂ ) _n , C _2-8 heterocyclyl-(CH ₂ ) _n and C _1-9 heteroaryl -(CH ₂ ) _n , wherein each of the C _1-4 alkyl group, the C _3-8 cycloalkyl group, the C _2-8 heterocyclic group, and the C _1-9 heteroaryl moiety is controlled by 0 Substitution by up to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy and optionally with one or two C _{1- 4} Alkyl-substituted amine groups, and the C _1-4 alkyl group and the C _1-4 alkoxy substituent which optionally exist are each independently selected from 0 to 3 halo groups as the case may be N is selected from 0, 1, 2 and 3; R ³ is a C _1-6 alkyl group, which is substituted with 0 to 3 substituents independently selected from the following optionally present: halo, hydroxy , Cyano, optionally C _1-4 alkoxy substituted by C _1-4 alkoxy and optionally amine substituted by one or two C _1-4 alkyl groups, wherein one or more of ^{R 3} Each hydrogen atom may be deuterium; R ⁴ and R ⁵ are each independently selected from hydrogen, halo and C _1-4 alkyl; X ^{6 is} selected from N and C(R ⁶ ); X ^{7 is} selected from N and C( R ⁷ ); R ⁶ and R ⁷ are each independently derived from hydrogen, halo, C _1-4 alkyl and C _1-4 alkoxy; R ^{8 is} selected from hydrogen, halo, C _1-4 alkyl and C _1-4 alkoxy, wherein the C _1-4 alkyl and the C _1-4 alkoxy substituent are substituted with 0 to 3 optionally present substituents independently selected from halo; and R ^{9 is} selected From C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocyclyl and C _1-9 heteroaryl, each of which is optionally substituted with 0 to 3 independently selected from the following Substitution: halo, hydroxy, cyano, pendant oxy, C _1-4 alkyl, C _1-4 alkoxy and optionally amine substituted with one or two C _1-4 alkyl groups, where the The C _1-4 alkyl group and the C _1-4 alkoxy substituent that are present are each independently substituted with 0 to 3 optionally present substituents independently selected from halo; and wherein the heterocyclic group And each of the heteroaryl moieties independently has 1 to 4 ring members that are heteroatoms, and each of these heteroatoms is independently selected from N, O, and S.

Another aspect of the present invention provides a compound selected from the group of compounds described in the examples and a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a pharmaceutical composition, which comprises a compound of formula 1 or a pharmaceutically acceptable salt thereof, or any compound or pharmaceutically acceptable salt defined in the preceding paragraph; and pharmaceutically Acceptable excipients.

Another aspect of the present invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof, or any of the compounds described in the examples or a pharmaceutically acceptable salt thereof, for use as a medicament.

Another aspect of the present invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof or any of the compounds described in the examples or a pharmaceutically acceptable salt thereof for use in the treatment of diseases and disorders related to RIPK2 Or symptoms.

Another aspect of the present invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof or any of the compounds described in the examples or a pharmaceutically acceptable salt thereof for use in the treatment of diseases and disorders selected from the following Or symptoms: allergic rhinitis, asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpus, inflammatory bowel disease, Chronic obstructive pulmonary disease, Sjögren's syndrome, joint adhesive spondylitis, Behcet's disease, graft-versus-host disease, pemphigus vulgaris, idiopathic plasma cell lymphadenopathy, arterial Atherosclerosis, myocardial infarction and thrombosis.

Another aspect of the present invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof, or any of the compounds described in the examples or a pharmaceutically acceptable salt thereof, which are used in the manufacture for the treatment of RIPK2 related Medicaments for diseases, illnesses or conditions.

Another aspect of the present invention provides a method for inhibiting RIPK2 in an individual, the method comprising administering to the individual a compound of formula 1 or a pharmaceutically acceptable salt or any one of the compounds described in the examples or the medicine thereof Academically acceptable salt.

Another aspect of the present invention provides a method for treating a disease, disorder or condition associated with RIPK2, the method comprising administering to the individual an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt or instance thereof Any of the compounds described or pharmaceutically acceptable salts thereof.

Another aspect of the present invention provides a method for treating a disease, disorder, or condition in an individual, the method comprising administering to the individual an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt or example as described in Any compound or a pharmaceutically acceptable salt thereof, wherein the disease, disorder or condition is selected from type I hypersensitivity, autoimmune diseases and inflammatory disorders, cancer and non-malignant proliferative disorders.

Another aspect of the present invention provides a method for treating a disease, disorder, or condition in an individual, the method comprising administering to the individual an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt or example as described in Any compound or a pharmaceutically acceptable salt thereof, wherein the disease, disorder or condition is selected from allergic rhinitis, asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Lupus nephritis, psoriasis, immune thrombocytopenic purpura, inflammatory bowel disease, chronic obstructive pulmonary disease, Schrögren’s syndrome, joint adhesive spondylitis, Behcet’s disease, graft-versus-host disease, pemphigus vulgaris , Idiopathic plasma cell lymph node disease, atherosclerosis, myocardial infarction and thrombosis.

Another aspect of the present invention provides a compound of formula 1 or a pharmaceutically acceptable salt thereof or any of the compounds described in the examples or a pharmaceutically acceptable salt thereof; and at least one additional pharmacologically active agent.

Unless otherwise indicated, this disclosure uses the definitions provided below.

When used with regard to a chemical substituent or moiety (e.g. C _1-6 alkyl), "substituted" means that one or more hydrogen atoms of the substituent or moiety have been replaced by one or more non-hydrogen atoms or groups, The premise is to meet the valence requirements and self-substitution produces chemically stable compounds.

When using a measurable numerical variable, "about" or "approximately" refers to the indicated value of the variable and all values of the variable within the experimental error of the indicated value or within ±10% of the indicated value to compare The larger one shall prevail.

"Alkyl" refers to a straight-chain and branched saturated hydrocarbon group usually having a specified number of carbon atoms (for example, C _1-4 alkyl refers to having 1 to 4 (ie 1, 2, 3, or 4) carbons Atom alkyl, C _1-6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, etc.). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pent-1-yl, pent-2-yl, pentyl -3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethylethyl-1-yl, N-hexyl and so on.

"Alkanediyl" refers to a divalent alkyl group, where the alkyl group is defined above and usually has a specified number of carbon atoms (for example, C _1-4 alkanediyl refers to having 1 to 4 (ie 1, 2 , 3 or 4) alkanediyl group with carbon atoms, C _1-6 alkanediyl group refers to an alkanediyl group having 1 to 6 carbon atoms, etc.). Examples of alkanediyl groups include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane- 1,1-diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, butane-1 ,1-diyl, isobutane-1,3-diyl, isobutane-1,1-diyl, isobutane-1,2-diyl and the like.

"Alkenyl" refers to straight and branched chain hydrocarbon groups having one or more carbon-carbon double bonds and usually having a specified number of carbon atoms. Examples of alkenyl groups include vinyl, 1-propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1-propen-1-yl, 2 -Methyl-2-propen-1-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl and the like.

"Alkynyl" refers to a straight or branched chain hydrocarbon group having one or more carbon-carbon triple bonds and usually having a specified number of carbon atoms. Examples of alkynyl groups include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3-butyn-1-yl, 3-butyne-2 -Yl, 2-butyn-1-yl and the like.

"Alkoxy" refers to a linear and branched saturated hydrocarbon group connected via an oxygen atom, which usually has a specified number of carbon atoms (for example, C _1-4 alkoxy refers to having 1 to 4 (that is, 1, 2, 3 or 4) alkoxy of carbon atoms, C _1-6 alkoxy refers to alkoxy having 1 to 6 carbon atoms, etc.). Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, second butoxy, isobutoxy, tertiary butoxy, pentyl-1- Oxy, pent-2-yloxy, pent-3-yloxy, 3-methylbut-1-yloxy, 3-methylbut-2-yloxy, 2-methylbut- 2-yloxy, 2,2,2-trimethyleth-1-yloxy, n-hexyloxy and the like.

"Halo", "halogen" and "halogeno" are used interchangeably and refer to fluoro, chloro, bromo and iodo.

"Haloalkyl", "haloalkenyl" and "haloalkynyl" respectively refer to alkyl, alkenyl and alkynyl groups substituted with one or more halogen atoms and usually having a specified number of carbon atoms, in which alkyl, Alkenyl and alkynyl are defined above. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1- Chloroethyl, 1,1-dichloroethyl, 1-fluoro-1-methylethyl, 1-chloro-1-methylethyl and the like.

"Cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon groups, which usually have a specified number of carbon atoms constituting one or more rings (for example, C _3-8 cycloalkyl refers to having 3 to 8 carbon atoms as Cycloalkyl of ring members). Bicyclic hydrocarbon groups can include isolated rings (two rings that do not share carbon atoms), spiro rings (two rings that share one carbon atom), fused rings (share two carbon atoms and the bond between the two common carbon atoms) The two rings) and bridged rings (two rings that share two carbon atoms, but do not share a common bond). Cycloalkyl groups can be connected via any ring atom (unless the connection would violate the valence requirement), and where indicated, optionally include one or more non-hydrogen substituents (unless such substitution would violate the valence requirement).

Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of fused bicyclic cycloalkyl groups include bicyclo[2.1.0]pentanyl (ie, bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl And bicyclo[2.1.0]pentane-5-yl), bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, two Cyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, bicyclo[4.3.0]nonanyl, bicyclo[4.4.0]decyl and the like. Examples of bridged cycloalkyl groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl , Bicyclo[3.2.1]octyl, bicyclo[4.1.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[3.3. 2]decyl, bicyclo[4.2.2]decyl, bicyclo[4.3.1]decyl, bicyclo[3.3.3]undecyl, bicyclo[4.3.2]undecane Group, bicyclo[4.3.3]dodecyl and the like. Examples of spirocycloalkyl groups include spiro[3.3]heptyl, spiro[2.4]heptyl, spiro[3.4]octyl, spiro[2.5]octyl, spiro[3.5]nonyl, and the like. Examples of isolated bicyclic cycloalkyls include those derived from di(cyclobutane), cyclobutanecyclopentane, di(cyclopentane), cyclobutanecyclohexane, cyclopentanecyclohexane, di(cyclohexane) Alkyl) and other bicyclic cycloalkyl groups.

"Cycloalkanediyl" refers to a divalent cycloalkyl group, where cycloalkyl is defined above and usually has a specified number of carbon atoms (for example, C _3-4 cycloalkane diyl refers to having 3 to 4 (also That is, 3 or 4) cycloalkane diyl groups with carbon atoms, C _3-6 cycloalkane diyl groups refer to cycloalkane diyl groups having 3 to 6 carbon atoms, etc.). Examples of cycloalkane diyl include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl and the like.

"Cycloalkylene" refers to a divalent monocyclic cycloalkyl group, wherein the cycloalkyl group is defined above, which is connected via a single carbon atom of the group, and usually has a specified number of carbon atoms constituting the ring (for example, The C _3-6 cycloalkylene group refers to a cycloalkylene group having 3 to 6 carbon atoms as ring members). Examples include cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.

"Cycloalkenyl" refers to partially unsaturated monocyclic and bicyclic hydrocarbon groups, which usually have a specified number of carbon atoms constituting one or more rings. Just like cycloalkyl, bicyclic cycloalkenyl can include isolated rings, spiro rings, fused rings, or bridged rings. Similarly, a cycloalkenyl group can be attached via any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents, unless such attachment or substitution would violate the valence requirement. Examples of cycloalkenyl groups include the partially unsaturated analogs of cycloalkyl groups described above, such as cyclobutenyl (i.e., cyclobuten-1-yl and cyclobuten-3-yl), cyclopentenyl, Cyclohexenyl, bicyclo[2.2.1]hept-2-enyl and the like.

"Aryl" refers to fully unsaturated monocyclic aromatic hydrocarbons and polycyclic hydrocarbons with at least one aromatic ring. Both monocyclic and polycyclic aryl groups usually have a specified number of carbon atoms constituting their ring members (such as , C _6-14 aryl refers to an aryl group having 6 to 14 carbon atoms as ring members). The group can be connected via any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents, unless such connection or substitution would violate the valence requirement. Examples of aryl groups include phenyl, biphenyl, cyclobutylene, indenyl, naphthyl, benzocycloheptyl, biphenyl, stilbene, and groups derived from cycloheptatriene cations And so on.

"Aryl" refers to a divalent aryl group, wherein the aryl group is defined above. Examples of arylene groups include phenylene (that is, benzene-1,2-diyl).

"Heterocycle" and "heterocyclic group" can be used interchangeably, and refer to a saturated or partially unsaturated monocyclic or bicyclic group having carbon atoms and 1 to 4 independently selected from nitrogen, oxygen and sulfur. A ring atom composed of heteroatoms. Both monocyclic and bicyclic groups usually have a specified number of carbon atoms in one or more of their rings (for example, a C _2-8 heterocyclic group refers to 2 to 8 carbon atoms and 1 to 4 heterocyclic groups). Heterocyclyl with atoms as ring members). Just like bicyclic cycloalkyl, bicyclic heterocyclic groups can include isolated rings, spiro rings, fused rings, and bridged rings, where at least one ring includes one or more heteroatoms. The heterocyclic group can be connected via any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents, unless the connection or substitution would violate the valence requirement or produce a chemically unstable compound. Examples of heterocyclic groups include epoxyethyl, thioethyl, aziridinyl (e.g., aziridin-1-yl and aziridin-2-yl), oxetanyl, thietidine Group, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, hexahydropyridyl, 1,4-dioxanyl, 1,4- Oxylanyl, morpholinyl, 1,4-dithianyl, hexahydropyrazinyl, 1,4-azathianyl, oxepanyl, thiepanyl , Azepanyl, 1,4-dioxepanyl, 1,4-oxathione, 1,4-oxazepanyl, 1,4- Dithiazepanyl, 1,4-thiazepanyl, 1,4-diazepanyl, 3,4-dihydro-2 H -pyranyl, 3,6- Dihydro-2 H -pyranyl, 2 H -pyranyl, 1,2-dihydropyridyl, 1,2,3,4-tetrahydropyridyl, 1,2,5,6-tetrahydropyridine Group, 1,6-dihydropyrimidinyl, 1,2,3,4-tetrahydropyrimidinyl and 1,2-dihydropyrazolo[1,5- d ][1,2,4]triazinyl .

"Heterocyclic-diyl" refers to a heterocyclic group connected via two ring atoms of the group, wherein the heterocyclic group is defined above. It usually has a specified number of carbon atoms in one or more of its rings (for example, C _2-8 heterocyclic-diyl refers to a heterocyclic ring having 2 to 8 carbon atoms and 1 to 4 heteroatoms as ring members -Two bases). Examples of heterocyclic-diyl groups include the multivalent analogues of the heterocyclic groups described above, such as morpholine-3,4-diyl, pyrrolidine-1,2-diyl, 1-pyrrolidinyl-2 -Subunit, 1-pyridyl-2-subunit, 1-( 4H )-pyrazolyl-5-subunit, 1-( 3H )-imidazolyl-2-subunit, 3-oxazolyl -2-ylidene, 1-hexahydropyridinyl-2-ylidene, 1-hexahydropyrazinyl-6-ylidene, and the like.

"Heteroaromatic" and "heteroaryl" can be used interchangeably, and refer to unsaturated monocyclic aromatic groups and polycyclic groups having at least one aromatic ring, each of which has Carbon atoms and 1 to 4 ring atoms independently selected from nitrogen, oxygen and sulfur heteroatoms. Both monocyclic and polycyclic groups usually have a specified number of carbon atoms as ring members (for example, a C _1-9 heteroaryl group refers to having 1 to 9 carbon atoms and 1 to 4 heteroatoms as ring members The heteroaryl group), and may include any bicyclic group in which any of the monocyclic heterocycles listed above are fused to a benzene ring. Heteroaryl groups can be connected via any ring atom (or multiple ring atoms for a fused ring), and where indicated, may optionally include one or more non-hydrogen substituents, unless such connection or substitution would violate valence requirements or produce Chemically unstable compounds. Examples of heteroaryl groups include monocyclic groups such as pyrrolyl (e.g., pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl), furyl, thienyl, pyrazolyl, imidazolyl, iso Oxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl, 1- Oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridyl, thiazinyl, Pyrimidine and pyrazinyl.

Examples of heteroaryl groups also include bicyclic groups such as benzofuranyl, isobenzofuranyl, benzothienyl, benzo[ c ]thienyl, 1 H -indolyl, 3 H -indolyl , Isoindolyl, 1 H -isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, 1 H -indazolyl, 2 H -indazolyl, benzotriazolyl, 1 H -pyrrolo[2,3- b ]pyridyl, 1H -pyrrolo[2,3- c ]pyridyl, 1H -pyrrolo[3,2- c ]pyridyl, 1H -pyrrolo [3,2- b ]pyridyl, 3H -imidazo[4,5- b ]pyridyl, 3H -imidazo[4,5- c ]pyridyl, 1H -pyrazolo[4,3 -b ]pyridyl, 1 H -pyrazolo[4,3- c ]pyridyl, 1H -pyrazolo[3,4- c ]pyridyl, 1H -pyrazolo[3,4- b ]Pyridyl, 7 H -purinyl, indazinyl, imidazo[1,2- a ]pyridyl, imidazo[1,5- a ]pyridyl, pyrazolo[1,5- a ]pyridyl , Pyrrolo[1,2- b ]taazinyl, imidazo[1,2- c ]pyrimidinyl, quinolinyl, isoquinolinyl, quinolinyl, quinazolinyl, quinolinyl, phthalein Azinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl , Pyrido[3,2- d ]pyrimidinyl, pyrido[4,3- d ]pyrimidinyl, pyrido[3,4- d ]pyrimidinyl, pyrido[2,3- d ]pyrimidinyl, pyridine Pyrazino[2,3- b ]pyrazinyl, pyrido[3,4- b ]pyrazinyl, pyrimido[5,4- d ]pyrimidinyl, pyrazino[2,3- b ]pyrazinyl , Pyrimido[4,5- d ]pyrimidinyl, 1,2,3,4-tetrahydropyrido[2,3- b ]pyrazinyl, 2,3-dihydrobenzo[ b ][1, 4] Dioxanyl, 3,4-dihydro-2 H -pyrido[3,2- b ][1,4]oxazinyl, 2,3-dihydro-1 H -benzo [ d ]imidazolyl, benzo[ d ]thiazolyl, 2,3-dihydro-1 H -pyrrolo[2,3- b ]pyridyl, [1,2,4]triazolo[1,5 -a ]pyridyl, 2,3-dihydro-1 H -imidazo[4,5- b ]pyridyl, tetrazolo[1,5- a ]pyridyl, 7 H -pyrrolo[2,3 -d ]pyrimidinyl, pyrazolo[1,5- a ]pyrimidinyl, imidazo[1,2- a ]pyrimidinyl, 4,5-dihydro-1 H -pyrazolo[3,4- d ]Pyrimidinyl, 2,3,6,7-tetrahydro- 1H -purinyl, 5H -pyrrolo[2,3- b ]pyrazinyl, imidazo[1,2- a ]pyrazinyl, Imidazo[1, 2- b ]taazinyl and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl.

"Heteroaryl" refers to a heteroaryl group connected via two ring atoms of the group, wherein the heteroaryl group is defined above. It usually has a specified number of carbon atoms in one or more of its rings (for example, a C _3-5 heteroaryl group refers to a heteroaryl group having 3 to 5 carbon atoms and 1 to 4 heteroatoms as ring members base). Examples of heteroaryl groups include the polyvalent analogs of the heteroaryl groups described above, such as pyridine-2,3-diyl, pyridine-3,4-diyl, pyrazole-4,5-diyl, pyridine Azole-3,4-diyl and the like.

"Pendant oxygen" refers to double-bonded oxygen (=O).

"Leaving group" refers to any group that leaves the molecule during the fragmentation process, which includes substitution reactions, elimination reactions, and addition-elimination reactions. The leaving group may be nucleated, in which the group detaches with the pair of electrons previously used as the bond between the detaching group and the molecule, or it may be ionized, in which the group does not detach with the electron pair. The ability to break away from the nucleus depends on the strength of its base, and the strongest base is the weakest break away group. Common nucleus leaving groups include nitrogen (for example, from diazonium salts); sulfonate, including alkylsulfonate (for example, methanesulfonate), fluoroalkylsulfonate (for example, triflate (triflate), six Hexaflate, nonaflate and tresylate) and arylsulfonates (e.g. tosylate, bromobenzenesulfonate, chlorobenzenesulfonate and meta-nitrate) Benzenesulfonate). Other nucleus leaving groups include carbonate, halide ion, carboxylate anion, phenate ion and alkoxide. Some relatively strong base (such as NH ₂ ^- and OH ^-) can be treated by the acid of the leaving group becomes better. Common ionization dissociation groups include protons, CO ₂ and metals.

"Anti-mirror isomer" refers to a molecule that is a non-superimposable mirror image of a reference molecule, which can be obtained by reversing all stereo centers of the reference molecule. For example, if the reference molecule has the absolute stereochemical configuration of S , the inverse mirror isomer has the absolute stereochemical configuration of R. Similarly, if the reference molecule has the absolute stereochemical configuration of S and S , the inverse mirror isomer has the stereochemical configuration of R , R , and so on.

The "stereoisomers and stereoisomers" of a compound with a given stereochemical configuration refer to the opposite enantiomers and any diastereoisomers of the compound, including the geometric isomers of the compound ( Z / E ). For example, if a compound has S , R , Z stereochemical configuration, its stereoisomers will include its opposite mirror image isomers with R , S , Z configurations, and its S , S , Z configurations. Shape, R , R , Z configuration, S , R , E configuration, R , S , E configuration, S , S , E configuration and R , R , E configuration of dimirror isomers. If the stereochemical configuration of the compound is not specified, the "stereoisomer" refers to any one of the possible stereochemical configurations of the compound.

"Substantially pure stereoisomers" and their variants mean that the sample contains a compound with a specific stereochemical configuration, and it accounts for at least about 95% of the sample.

"Pure stereoisomers" and their variants mean that the sample contains a compound with a specific stereochemical configuration, and it accounts for at least about 99.5% of the sample.

"Individual" refers to mammals, including humans.

"Pharmaceutically acceptable" substances refer to those substances suitable for administration to an individual.

"Treating" refers to reversing, alleviating, inhibiting or preventing the progression of the disease, disease, or condition to which this term applies, or reversing, alleviating, or inhibiting one or more symptoms of the disease, disease, or condition Or prevent it.

"Treatment" refers to the act of "treating" as defined just above.

"Drug", "API", "active pharmaceutical ingredient" and the like refer to compounds that can be used to treat individuals in need of treatment (for example, compounds of Formula 1, including subgenus compounds and the compounds specifically mentioned in this specification).

The "effective amount" of the drug, the "therapeutically effective amount" of the drug, and the like refer to the amount of the drug that can be used to treat an individual and may especially depend on the weight and age of the individual and the route of administration.

"Excipient" refers to any diluent or vehicle used in medicine.

"Pharmaceutical composition" refers to a combination of one or more APIs and one or more excipients.

"Drug product", "pharmaceutical dosage form", "dosage form", "final dosage form" and the like refer to those suitable for the treatment of individuals in need of treatment and generally can be in the form of tablets, capsules, sachets containing powder or granules, liquid solutions or Pharmaceutical compositions in the form of suspensions, patches, films and the like.

"RIPK2-related conditions" and similar phrases refer to diseases, disorders, or conditions of individuals for which inhibition of RIPK2 can provide therapeutic or preventive benefits.

The following abbreviations can be used in this specification: Ac (acetyl); ACN (acetonitrile); AIBN (azo-bis-isobutyronitrile); API (active pharmaceutical ingredient); aq (aqueous); B ₂ pin ₂ (4 ,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane)); BINAP (2 ,2'-bis(diphenylphosphino)-1,1'-binaphthalene); Boc (third butoxycarbonyl); Cbz (benzyloxycarbonyl); CDI (1,1'-carbonyldiimidazole) ; Dba (dibenzylidene acetone); DAST ( N,N -diethylaminosulfur trifluoride); DCC (1,3-dicyclohexylcarbodiimide); DCE (1,1-dichloro Ethane); DCM (dichloromethane); DIAD (diisopropyl azodicarboxylate); DIPEA ( N , N -diisopropylethylamine, Hünig's Base); DMA ( N , N -dimethylacetamide); DMAP (4-dimethylaminopyridine); DME (1,2-dimethoxyethane); DMF ( N , N -dimethylformamide) ; DMSO (dimethyl sulfide); dppf (1,1'-bis(diphenylphosphino)ferrocene); DTT (dithiothreitol); EC ₅₀ (effective concentration at half-maximum reaction); EDA (ethoxylated dodecyl alcohol, Brj®35); EDC ( N -(3-dimethylaminopropyl) -N ′-ethylcarbodiimide); EDTA (ethylenediamine tetra Acetic acid); ee (mirror isomer excess); eq (equivalent); Et (ethyl); Et ₃ N (triethylamine); EtOAc (ethyl acetate); EtOH (ethanol); HATU (hexafluorophosphoric acid (V ) 2-(3 H -[1,2,3]triazolo[4,5- b ]pyridin-3-yl)-1,1,3,3-tetramethyluronium); HEPES (4- (2-hydroxyethyl)hexahydropyrazine-1-ethanesulfonic acid); HOAc (acetic acid); HOBt (1 H -benzo[ d ][1,2,3]triazol-1-ol); IC ₅₀ (the concentration at 50% inhibition); IPA (isopropyl alcohol); IPAc (isopropyl acetate); IPE (isopropyl ether); KO t- Bu (potassium tertiary butoxide); LDA (diisopropyl Lithium amide); LiHMDS (lithium bis(trimethylsilyl) amide); mCPBA (m-chloroperoxybenzoic acid); Me (methyl); MeOH (methanol); MTBE (methyl tertiary butyl) Ether); mp (melting point); n-BuLi (n-butyllithium); NaO t- Bu (sodium tertiary butoxide); NBS ( N -bromosuccinimide); NCS ( N -chlorosuccinimide) ); NIS ( N -iodosuccinimide); N MM ( N -methylmorpholine); NMP ( N -methyl-pyrrolidone); OTf (trifluoromethanesulfonate); PdCl ₂ (dtbpf) (dichloro[1,1'-bis(di- Tertiary butylphosphino)ferrocene]palladium(II)); PE (petroleum ether); Ph (phenyl); pEC ₅₀ (-log ₁₀ (EC ₅₀ ), where EC ₅₀ is expressed in moles (M) Units are given); pIC ₅₀ (-log ₁₀ (IC ₅₀ ), where IC ₅₀ is given in molar (M) units); Pr (propyl); c -Pr (cyclopropyl); i -Pr ( Isopropyl); PTFE (polytetrafluoroethylene); Rac (racemic); RT (room temperature, about 20°C to 25°C); SEM (2-(trimethylsilyl)ethoxymethyl) ; SEM-Cl ((2-chloromethoxyethyl) trimethylsilane); SFC (supercritical fluid chromatography); T3P (2,4,6-tripropyl-1,3,5,2, 4,6-Trioxatriphosphine 2,4,6-trioxide); TBAF (tetrabutylammonium fluoride); TBS (tertiary butyldimethylsilyl); TBSCl (section Tributylchlorodimethylsilane); TCEP (see (2-carboxyethyl)phosphine); TFA (trifluoroacetic acid); TFAA (2,2,2-trifluoroacetic anhydride); THF (tetrahydrofuran); TLC (Thin layer chromatography); TMEDA (tetramethylethylenediamine); TMS (trimethylsilyl); and Tris buffer (2-amino-2-hydroxymethyl-propane-1,3-diol) Buffer).

As explained below, this disclosure relates to compounds of formula 1 and pharmaceutically acceptable salts thereof. This disclosure also relates to materials and methods for preparing compounds of formula 1, pharmaceutical compositions containing compounds of formula 1, and compounds of formula 1 and pharmaceutically acceptable salts thereof (combined with other pharmacologically active agents as appropriate) For the treatment of diseases, disorders or conditions related to RIPK2.

The compounds of formula 1 include those in the case (1): α is a single bond, β is a double bond, X ¹ is NR ^1N , and R ² is a pendant oxy group; or α is a double bond, β is a single bond, X ^{1 is} selected from N and CR ^1C , and R ^{2 is} selected from hydrogen, C _1-4 alkyl and C _1-4 alkoxy; R ^{1C is} selected from hydrogen, halo and C _1-6 alkyl, the C _{1- 6} Alkyl is substituted with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, C _1-4 alkoxy and optionally with one or two C _1-4 alkane R ^{1N is} selected from C _1-4 alkyl, C _3-8 cycloalkyl-(CH ₂ ) _n , C _2-8 heterocyclyl-(CH ₂ ) _n and C _1-9 hetero Aryl-(CH ₂ ) _n , wherein each of the C _1-4 alkyl group, the C _3-8 cycloalkyl group, the C _2-8 heterocyclic group, and the C _1-9 heteroaryl moiety Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy and optionally with one or two C _{A 1-4} alkyl substituted amino group, and wherein the C _1-4 alkyl group and the C _1-4 alkoxy substituent which optionally exist are each independently selected from the group consisting of 0 to 3 halo groups. Substitution with optional substituents; n is selected from 0, 1, 2 and 3; R ³ is a C _1-6 alkyl group, which is substituted with 0 to 3 optional substituents independently selected from the following: halo , Hydroxy, cyano, optionally C _1-4 alkoxy substituted by C _1-4 alkoxy and optionally amine substituted by one or two C _1-4 alkyl groups, where one of R ³ Or more hydrogen atoms may be deuterium depending on the situation; R ⁴ and R ⁵ are each independently selected from hydrogen, halo and C _1-4 alkyl; X ^{6 is} selected from N and C(R ⁶ ); X ^{7 is} selected from N and C(R ⁷ ); R ⁶ and R ⁷ are each independently derived from hydrogen, halo, C _1-4 alkyl and C _1-4 alkoxy; R ^{8 is} selected from hydrogen, halo, C _1-4 alkyl And a C _1-4 alkoxy group, wherein the C _1-4 alkyl group and the C _1-4 alkoxy substituent are substituted with 0 to 3 optionally present substituents independently selected from halo; and R ^{9 is} selected from a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _2-8 heterocyclic group and a C _1-9 heteroaryl group, each of which is independently selected from 0 to 3 as the case may be Substituent substitution: halo, hydroxyl, cyano, pendant oxy, C _1-4 alkyl, C _1-4 alkoxy and optionally amino substituted with one or two C _1-4 alkyl groups, Wherein the optionally present C _1-4 alkyl group and the C _1-4 alkoxy substituent are each independently substituted with 0 to 3 optionally present substituents independently selected from halo; and wherein the hetero Each of the cyclic group and the heteroaryl moiety independently has 1 to 4 ring members that are heteroatoms, and each of the heteroatoms is independently selected from N, O, and S.

In addition to the embodiment (1) in the preceding paragraph, the compound of formula 1 also includes those compounds in which (2) α is a single bond, β is a double bond, X ¹ is NR ^1N , and R ² is a pendant oxy group.

In addition to the embodiment (2) in the preceding paragraph, the compound of formula 1 also includes those compounds in which R ^{1N is} selected from the following: (3) C _1-4 alkyl, C _3-8 cycloalkyl-(CH ₂ ) _n , C _2-8 heterocyclyl-(CH ₂ ) _n and C _1-5 heteroaryl-(CH ₂ ) _n , wherein the C _1-4 alkyl group, the C _3-8 cycloalkyl group, the C _{Each of the 2-8} heterocyclyl and the C _1-9 heteroaryl moiety is substituted with 0 to 3 substituents as defined in the embodiment (1) as appropriate; (4) C _{1- 4} alkyl, C _3-8 cycloalkyl-(CH ₂ ) _n , C _3-5 heterocyclyl-(CH ₂ ) _n and C _1-5 heteroaryl-(CH ₂ ) _n , wherein the C _{1 -4} alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, the C _3-5 heterocyclic group and the C _1-5 heteroaryl moiety each of 0 to 3 such as Substitution with optional substituents as defined in Example (1); or (5) C _1-4 alkyl, C _3-6 cycloalkyl-(CH ₂ ) _n , C _3-5 heterocyclyl- (CH ₂ ) _n and C _1-5 heteroaryl-(CH ₂ ) _n , wherein the C _1-4 alkyl group, the C _3-6 cycloalkyl group, the C _3-5 heterocyclic group and the C _{1 Each of the -5} heteroaryl moieties is substituted with 0 to 3 optionally present substituents as defined in Example (1).

In addition to any one of Examples (1) to (5) in the preceding paragraph, the compound of formula 1 also includes wherein each of the 0 to 3 optionally present substituents of ^{R 1N is independently selected from the following} The compounds: (6) halo, hydroxy, C _1-4 alkyl, C _1-4 alkoxy and optionally amine substituted with one or two C _1-4 alkyl groups, which optionally exist The C _1-4 alkyl group and the C _1-4 alkoxy substituent are each independently substituted with 0 to 3 optionally present substituents independently selected from halo; (7) halo, hydroxy, C _1-4 alkyl group, C _1-4 alkoxy group and optionally amino group substituted by one or two C _1-4 alkyl groups; (8) fluoro group, chloro group, hydroxyl group, methyl group, methoxy group And optionally amine groups substituted with one or two methyl groups; or (9) fluoro, hydroxyl, methyl, methoxy and optionally amine groups substituted with one or two methyl groups.

In addition to any one of the embodiments (1) and (2), the compound of formula 1 also includes wherein (10) R ^1N is optionally present with 0 to 3 substituents as defined in the embodiment (1) These compounds of substituted C _{1-4 alkyl.}

In addition to the embodiment (10) in the preceding paragraph, the compound of formula 1 also includes compounds in which the C _1-4 ^{alkyl substituent of R 1N} is selected from the following: (11) methyl, ethyl and propyl, They are each substituted with 0 to 3 substituents as defined in Example (1); (12) Methyl and ethyl, which are each substituted with 0 to 3 as defined in Example (1) Or (13) ethyl, which is substituted with 0 to 3 optionally available substituents as defined in Example (1).

In addition to any one of Examples (10) to (13) in the preceding paragraph, the compound of Formula 1 also includes those compounds in which the C _1-4 ^{alkyl substituent of R 1N} is the following: (14) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxy, C _1-4 alkyl, C _1-4 alkoxy and optionally with one or two C _1-4 alkane Group substituted amine group, wherein the optionally present C _1-4 alkyl group and the C _1-4 alkoxy substituent are each independently via 0 to 3 optionally present substituents independently selected from halo Substitution; (15) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxy, C _1-4 alkyl, C _1-4 alkoxy and optionally by one or two A C _1-4 alkyl substituted amino group; (16) Substitution with 0 to 3 optionally present substituents independently selected from the following: fluoro, chloro, hydroxy, methyl, methoxy and optionally Amino groups substituted with one or two methyl groups; (17) Substitution with 0 to 3 optionally present substituents independently selected from fluorine and hydroxyl; (18) Substitution with 0 to 1 substituents selected from fluorine and hydroxyl Substitution of the optionally existing substituents; or (19) Unsubstituted.

In addition to any one of embodiments (1) and (2), the compound of formula 1 also includes those compounds in which (20) R ^1N is C _3-6 cycloalkyl-(CH ₂ ) _n , wherein the C _{The 3-6} cycloalkyl moiety is substituted with 0 to 3 optionally present substituents as defined in Example (1).

In addition to the embodiment (20) in the preceding paragraph, the compound of formula 1 also includes compounds in which the C _3-6 ^{cycloalkyl moiety of R 1N} is selected from the following: (21) cyclopropyl, cyclobutyl and cyclo Pentyl; or (22) cyclopropyl and cyclobutyl.

In addition to any of the embodiments (20) to (22) in the preceding paragraph, the compound of formula 1 also includes the C _3-6 ^{cycloalkyl moiety in which R 1N} is independently selected from the following groups via 0 to 3 These compounds substituted by substituents that exist: (23) Halo, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy and optionally amine substituted with one or two C _{1-4 alkyl} Group, wherein the optionally present C _1-4 alkyl group and the C _1-4 alkoxy substituent are each independently substituted with 0 to 3 optionally present substituents independently selected from halo; (24 ) Halo, hydroxy, C _1-4 alkyl, C _1-4 alkoxy and optionally amine substituted with one or two C _1-4 alkyl; (25) fluoro, chloro, hydroxy, Methyl, methoxy and optionally amino groups substituted with one or two methyl groups; (26) fluorine and methyl; (27) fluoro; or (28) methyl.

In addition to any one of Examples (20) to (22) in the preceding paragraph, the compound of Formula 1 also includes those compounds in which the C _3-6 cycloalkyl moiety of ^{(29) R 1N is unsubstituted.}

In addition to any of the embodiments (1) and (2), the compound of formula 1 also includes those compounds in which (30) R ^1N is C _3-5 heterocyclyl-(CH ₂ ) _n , wherein the C _{The 3-5} heterocyclyl moiety is substituted with 0 to 3 optionally present substituents as defined in Example (1).

In addition to the embodiment (30) in the preceding paragraph, the compound of formula 1 also includes those compounds in which the C _3-5 ^{heterocyclyl moiety of the R 1N} substituent has the following: (31) One or two heteroatoms as a ring Member, each of the heteroatoms is independently selected from N, O, and S; or (32) one or two heteroatoms as ring members, each of the heteroatoms is selected from O.

In addition to any one of the embodiments (30) to (32) in the preceding paragraph, the compound of formula 1 also includes those compounds in which _{the C 3-5} heterocyclyl moiety of the ^{(33) R 1N} substituent is a monocyclic ring .

In addition to the embodiment (30) in the preceding paragraph, the compound of formula 1 also includes compounds in which the C _3-5 ^{heterocyclyl moiety of the R 1N} substituent is selected from the following: (34) oxetanyl, tetrahydrofuran Group, tetrahydro- 2H -pyranyl and 1,4-dioxanyl; or (35) oxetanyl and tetrahydrofuranyl.

In addition to any one of Examples (30) to (35) in the preceding paragraph, the compound of formula 1 also includes those compounds in which the C _3-5 ^{heterocyclyl portion of R 1N} is the following: (36) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxy, C _1-4 alkyl, C _1-4 alkoxy and optionally with one or two C _1-4 alkane Group substituted amine group, wherein the optionally present C _1-4 alkyl group and the C _1-4 alkoxy substituent are each independently via 0 to 3 optionally present substituents independently selected from halo Substitution; (37) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxy, C _1-4 alkyl, C _1-4 alkoxy and optionally by one or two A C _1-4 alkyl substituted amine group; (38) Substitution with 0 to 3 optionally present substituents independently selected from the following: fluoro, chloro, hydroxy, methyl, methoxy and optionally Amino groups substituted by one or two methyl groups; (39) substituted by 0 to 3 optionally present substituents independently selected from fluoro and methyl; (40) substituted by 0 to 3 independently selected Substitution from optionally present substituents of fluoro group; (41) Substitution with 0 to 3 optionally present substituents independently selected from methyl; or (42) Unsubstituted.

In addition to any one of the embodiments (1) and (2), the compound of formula 1 also includes those compounds in which (43) R ^1N is C _1-5 heteroaryl-(CH ₂ ) _n , wherein the C _{The 1-5} heteroaryl moiety is substituted with 0 to 3 optionally present substituents as defined in Example (1).

In addition to the embodiment (43) in the preceding paragraph, the compound of formula 1 also includes those compounds in which (44) _{the C 1-5} heteroaryl moiety of the ^{R 1N} substituent has one or two heteroatoms as ring members, Each of these heteroatoms is independently selected from N, O, and S.

In addition to any one of the embodiments (43) to (44) in the preceding paragraph, the compound of formula 1 also includes those compounds in which _{the C 1-5} heteroaryl moiety of the ^{(45) R 1N} substituent is a monocyclic ring .

In addition to the embodiment (43) in the preceding paragraph, the compound of formula 1 also includes compounds in which _{the C 1-5} heteroaryl moiety of the ^{R 1N} substituent is selected from the following: (46) pyrrolyl, furanyl, thiophene Group, imidazolyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridyl, pyrazinyl, tazinyl and pyrimidinyl; (47) imidazolyl, pyrazolyl, iso Oxazolyl, oxazolyl, isothiazolyl, thiazolyl and pyridyl; or (48) pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl and pyridyl.

In addition to any one of Examples (43) to (48) in the preceding paragraph, the compound of formula 1 also includes those compounds in which the C _1-5 ^{heteroaryl moiety of R 1N} is the following: (49) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxy, C _1-4 alkyl, C _1-4 alkoxy and optionally with one or two C _1-4 alkane Group substituted amine group, wherein the optionally present C _1-4 alkyl group and the C _1-4 alkoxy substituent are each independently via 0 to 3 optionally present substituents independently selected from halo Substitution; (50) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxy, C _1-4 alkyl, C _1-4 alkoxy and optionally with one or two A C _1-4 alkyl substituted amine group; (51) Substitution with 0 to 3 optionally present substituents independently selected from the following: fluoro, chloro, hydroxy, methyl, methoxy and optionally Cases are amino groups substituted with one or two methyl groups; (52) substituted with 0 to 3 optionally present substituents independently selected from methyl groups; or (53) unsubstituted.

In addition to any one of Examples (1) to (53) in the preceding paragraph, the compound of Formula 1 also includes those compounds in the following situations: (54) n is selected from 0, 1 and 2; (55) n is selected from 0 and 1; (56) n is 1; or (57) n is 0.

In addition to embodiment (1), the compound of formula 1 also includes (58) α is a double bond, β is a single bond, X ¹ is N, and R ^{2 is} selected from hydrogen, C _1-4 alkyl and C _1-4 Alkoxy compounds.

In addition to embodiment (1), the compound of formula 1 also includes (59) α-based double bond, β-based single bond, X ¹ is CR ^1C , and R ^{2 is} selected from hydrogen, C _1-4 alkyl and C _{1- 4} Alkoxy compounds.

In addition to the embodiment (59) in the preceding paragraph, the compound of formula 1 also includes those compounds wherein R ^{1C is} selected from the following: (60) hydrogen, halo and C _1-4 alkyl, the C _1-4 alkyl Substituted by 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, C _1-4 alkoxy and optionally substituted by one or two C _1-4 alkyl groups Amino; (61) hydrogen, halo and C _1-4 alkyl, the C _1-4 alkyl is substituted with 0 to 3 substituents independently selected from the following optionally present: halo, hydroxyl, cyano And C _1-4 alkoxy; (62) hydrogen, halo and C _1-4 alkyl, the C _1-4 alkyl is substituted with 0 to 1 optionally present substituent selected from the following: halogen Group, hydroxy group, cyano _{group and C 1-4} alkoxy group; (63) hydrogen, halo group and C _1-4 alkyl group, the C _1-4 alkyl group optionally exists with 0 to 1 selected from hydroxyl group Substituent substitution; (64) hydrogen, halo and C _1-4 alkyl substituted by hydroxy; or (65) hydrogen, halo and unsubstituted C _1-4 alkyl.

In addition to any one of Examples (59) to (65) in the preceding paragraph, the compound of formula 1 also includes those compounds wherein R ^{1C is} selected from the following: (66) hydrogen, halo and C _1-4 alkyl , The C _1-4 alkyl group is selected from methyl, ethyl, propyl and isopropyl, each of which is substituted or unsubstituted; (67) hydrogen, halo and C _1-4 alkyl, the C _{1 -4} alkyl is selected from methyl and ethyl, each of which is substituted or unsubstituted; or (68) hydrogen, halo and C _1-4 alkyl, and the C _1-4 alkyl is selected from methyl and ethyl Group, each of which is unsubstituted.

In addition to embodiment (59), the compound of formula 1 also includes those compounds in which R ^{1C is} selected from the following: (69) hydrogen, fluoro, chloro, methyl, ethyl, propyl, isopropyl, hydroxymethyl Group, hydroxyethyl, hydroxypropyl and hydroxyisopropyl; (70) hydrogen, chloro, methyl, ethyl, isopropyl and hydroxyethyl; (71) hydrogen, methyl and ethyl; or ( 72) Hydrogen.

In addition to any one of Examples (58) to (72) in the preceding paragraph, the compound of formula 1 also includes those compounds wherein R ^{2 is} selected from the following: (73) hydrogen, methyl, ethyl, propyl, Methoxy, ethoxy and propoxy; (74) hydrogen, methyl, ethyl, propyl, methoxy and ethoxy; (75) hydrogen, methyl, ethyl, methoxy and ethyl Oxy; (76) hydrogen, methoxy and ethoxy; or (77) methoxy and ethoxy.

In addition to any of the embodiments (1) to (77) in the preceding paragraph, the compound of formula 1 also includes those compounds in which R ³ is a C _1-4 alkyl group, and the C _1-4 alkyl group: (78 ) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, optionally C _1-4 alkoxy substituted by C _1-4 alkoxy and optionally Amino groups substituted with one or two C _1-4 alkyl groups; (79) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano and optionally C the _1-4 alkoxy substituted with C _1-4 alkoxy; (80) the presence of substituents selected from group substituted with 0-1 of the following optionally independently: halo, hydroxy, cyano and optionally substituted with C the _1-4 alkoxy substituted C _1-4 alkoxy; (81) substituted of unsubstituted C _1-4 alkoxy C _1-4 alkoxy or optionally hydroxylated; or (82) substituted with hydroxy .

In addition to any one of the embodiments (1) to (77) in the preceding paragraph, the compound of formula 1 also includes those compounds in which R ^{3 is} selected from the following: (83) ethyl, isopropyl and tertiary butyl , Each of which is substituted by hydroxy; (84) hydroxy-tertiary butyl; or (85) unsubstituted C _1-4 alkyl.

In addition to any one of embodiments (1) to (85) in the preceding paragraph, the compound of formula 1 also includes those compounds in which R ⁴ and R ⁵ are each independently selected from the following: (86) hydrogen and C _{1- 4} alkyl; (87) hydrogen and methyl; or (88) hydrogen.

In addition to any one of Examples (1) to (88) in the preceding paragraph, the compound of Formula 1 also includes those compounds in the following situations: (89) ^At most one of X 6 and X ⁷ is N; or (90) X ⁶ is C (R ⁶ ) and X ⁷ is C (R ⁷ ).

In addition to any one of the embodiments (1) to (90) in the preceding paragraph, the compound of formula 1 also includes those compounds in which R ⁶ and R ⁷ are each independently selected from the following: (91) hydrogen, halo, Methyl and methoxy; (92) hydrogen, fluoro, chloro, methyl and methoxy; (93) hydrogen and fluoro; or (94) hydrogen.

In addition to any one of Examples (1) to (94) in the preceding paragraph, the compound of formula 1 also includes those compounds in which R ^{8 is} selected from the following: (95) halo and C _1-4 alkyl, which C _1-4 alkyl is substituted with 0 to 3 optionally present substituents independently selected from halo; (96) halo and methyl, where 0 to 3 of the methyl are independently selected from halo Optional substituent substitution; (97) Fluoro group, chloro group and methyl group, the methyl group is substituted with 0 to 3 optional substituent groups independently selected from halo; (98) Fluoro group, chlorine group Group and methyl, fluoromethyl, difluoromethyl and trifluoromethyl; or (99) methyl.

In addition to any one of the embodiments (1) to (99) in the preceding paragraph, the compound of formula 1 also includes those compounds wherein R ^{9 is} selected from the following: (100) C _1-6 alkyl, C _3-8 Cycloalkyl and C _1-9 heteroaryl, each of which is substituted with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, pendant oxy, C _1-4 alkane Group, C _1-4 alkoxy group and optionally amino group substituted with one or two C _1-4 alkyl groups, wherein the C _1-4 alkyl group and the C _1-4 alkoxy group optionally present are substituted The groups are each independently substituted with 0 to 3 optionally present substituents independently selected from halo; (101) C _1-4 alkyl, C _3-6 cycloalkyl, C _3-5 heterocyclyl and C _1-5 heteroaryl groups, each of which is substituted with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxy, cyano, pendant oxy, C _1-4 alkyl, C _{1 -4} Alkoxy and optionally an amino group substituted with one or two C _1-4 alkyl groups; wherein the C _1-4 alkyl group and the C _1-4 alkoxy substituent which optionally exist are each independently Substitution with 0 to 3 optionally present substituents independently selected from halo; or (102) C _1-4 alkyl, C _3-6 cycloalkyl and C _1-5 heteroaryl, each of which is 0 to 3 optionally substituted substituents independently selected from the following: halo, hydroxyl, cyano, pendant oxy, C _1-4 alkyl, C _1-4 alkoxy and optionally with one or Two C _1-4 alkyl substituted amine groups; wherein the C _1-4 alkyl group and the C _1-4 alkoxy substituent which may be present are each independently selected from 0 to 3 halo groups Substitution of the optionally existing substituents.

In addition to any one of the embodiments (100) to (102) in the preceding paragraph, the compound of formula 1 also includes wherein each of the 0 to 3 optional substituents of ^{R 9 is independently selected from the following} The compounds: (103) halo, hydroxy, cyano, pendant oxy, C _1-4 alkyl, C _1-4 alkoxy and optionally substituted by one or two C _{1-4 alkyl} Amino; (104) halo, hydroxyl, cyano, pendant oxy, methyl, methoxy and optionally amine substituted with one or two methyl groups; or (105) halo, hydroxy, pendant oxygen Group, methyl and methoxy.

In addition to any one of the embodiments (100) to (102), the compound of formula 1 also includes those in which each R ⁹ substituent is substituted with 0 to 1 substituents independently selected from the following optionally present Compound: (106) Halo, hydroxyl, pendant oxy, methyl and methoxy; or (107) pendant oxy and methyl.

In addition to any one of Examples (100) to (102), the compound of Formula 1 also includes those compounds in which (108) each R ⁹ substituent is unsubstituted.

In addition to any one of the embodiments (101) to (102), the compound of formula 1 also includes wherein (109) R ⁹ is optionally present with 0 to 3 substituents as defined in the embodiment (1) These compounds of substituted C _{1-4 alkyl.}

In addition to the embodiment (109) in the preceding paragraph, the compound of formula 1 also includes those compounds in which R ⁹ is a C _1-4 alkyl group, and the C _1-4 alkyl group is selected from: (110) methyl, ethyl And propyl, each of which is substituted with 0 to 3 substituents as defined in the embodiment (1); or (111) methyl and ethyl, each of which is substituted with 0 to 3 as in the embodiment ( 1) Substitution with optional substituents as defined in 1).

In addition to any one of Examples (109) to (111) in the preceding paragraph, the compound of formula 1 also includes those compounds in which the C _1-4 ^{alkyl substituent of R 9} is the following: (112) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, pendant oxy, C _1-4 alkoxy and optionally with one or two C _1-4 alkane (113) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, pendant oxy, methoxy and optionally via one or two A methyl-substituted amino group; (114) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, pendant oxy and methoxy; (115) With 0 to 1 One optional substituent selected from the following: halo, hydroxy, pendant oxy and methoxy; (116) unsubstituted or substituted with pendant oxy; or (117) unsubstituted.

In addition to the embodiment (100), the compound of formula 1 also includes a _{C 3-8} cycloalkyl group ^{wherein (118) R 9} is substituted with 0 to 3 substituents as defined in the embodiment (1). The other compounds.

In addition to any one of Examples (101) to (102), the compound of Formula 1 also includes wherein (119) R ⁹ is optionally present with 0 to 3 substituents as defined in Example (1) These compounds of substituted C _{3-6 cycloalkyl.}

In addition to the embodiment (119) in the preceding paragraph, the compound of formula 1 also includes those compounds in which R ⁹ is a C _3-6 cycloalkyl group, and the C _3-6 cycloalkyl group: (120) is selected from cyclopropyl , Cyclobutyl and cyclopentyl, each of which is substituted with 0 to 3 optionally present substituents as defined in Example (1); (121) selected from cyclopropyl and cyclobutyl, each of which is substituted by Substitution with 0 to 3 optional substituents as defined in Example (1); or (122) cyclopropyl, which is substituted with 0 to 3 optional substituents as defined in Example (1) Substituents are substituted.

In addition to any one of Examples (119) to (122) in the preceding paragraph, the compound of formula 1 also includes those compounds in which the C _3-6 ^{cycloalkyl substituent of R 9} is the following: (123) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy and optionally with one or two C _{Amino substituted by 1-4} alkyl; (124) substituted with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, methyl, methoxy and optionally via One or two C _1-4 alkyl substituted amine groups; (125) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxy, methyl and methoxy; ( 126) Substitution with 0 to 1 optionally present substituents independently selected from the following: halo, hydroxy, methyl and methoxy; (127) unsubstituted or substituted with methyl; or (128) unsubstituted Replaced.

In addition to any one of Examples (1) to (99), the compound of Formula 1 also includes wherein (129) R ⁹ is optionally present with 0 to 3 substituents as defined in Example (1) These compounds of substituted C _2-8 heterocyclic group.

In addition to the embodiment (101), the compound of formula 1 also includes a _{C 3-5} heterocyclic group ^{wherein (130) R 9} is substituted with 0 to 3 substituents as defined in the embodiment (1). The other compounds.

In addition to any one of Examples (129) to (130) in the preceding paragraph, the compound of formula 1 also includes those compounds in which ^{the heterocyclyl substituent of R 9} has the following: (131) one or two hetero Atoms are used as ring members, and each of the heteroatoms is independently selected from N, O, and S; or (132) one or two heteroatoms are used as ring members.

In addition to any one of Examples (129) to (132) in the preceding paragraph, the compound of Formula 1 also includes those compounds in which the heterocyclic group substituent of ^{(133) R 9 is a monocyclic ring.}

In addition to any one of Examples (129) to (133) in the preceding paragraph, the compound of Formula 1 also includes those compounds in which ^{the heterocyclyl substituent of R 9} is the following: (134) Through 0 to 3 Substitution with one optionally present substituent independently selected from the following: halo, hydroxy, cyano, C _1-4 alkyl, C _1-4 alkoxy and optionally with one or two C _1-4 alkane (135) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, methyl, methoxy and optionally with one or two C _1-4 alkyl substituted amine group; (136) substituted by 0 to 3 optionally present substituents independently selected from the following: halo, hydroxy, methyl and methoxy; (137) by 0 Substitution to 1 optionally present substituent independently selected from the following: halo, hydroxy, methyl and methoxy; (138) unsubstituted or substituted with methyl; or (139) unsubstituted.

In addition to the embodiment (100), the compound of formula 1 also includes a _{C 1-9} heteroaryl group in ^{which (140) R 9} is substituted with 0 to 3 substituents as defined in the embodiment (1). The other compounds.

In addition to the examples (101) to (102), the compound of formula 1 also includes _{C 1- in} ^{which (141) R 9} is substituted with 0 to 3 substituents as defined in the example (1). ₅ Heteroaryl compounds.

In addition to the examples (140) to (141), the compound of formula 1 also includes those compounds in which ^{the heteroaryl substituent of (142) R 9} has one or two heteroatoms as ring members, and the heteroatoms Each of them is independently selected from N, O, and S.

In addition to Examples (140) to (142), the compounds of Formula 1 also include their compounds (143) in which the heteroaryl substituent of ^{R 9 is a monocyclic ring.}

In addition to the examples (140) to (141), the compound of formula 1 also includes those compounds in which ^{the heteroaryl substituent of R 9} is the following: (144) selected from pyrrolyl, furyl, thienyl, imidazole Group, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridyl, pyrazinyl, tiazinyl and pyrimidinyl; or (145) selected from imidazolyl, pyrazolyl, iso Oxazolyl, oxazolyl, isothiazolyl, thiazolyl and pyridyl.

In addition to the examples (140) to (145), the compounds of formula 1 also include those in which ^{the heteroaryl substituent of R 9} is the following: (146) 0 to 3 independently selected from the following conditions Substituent substitutions that exist: halo, hydroxy, cyano, C _1-4 alkyl, C _1-4 alkoxy and optionally amino substituted with one or two C _1-4 alkyl groups; (147 ) Substitution with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, methyl, methoxy and optionally _{substituted with one or two C 1-4} alkyl groups Amino; (148) substituted with 0 to 3 substituents independently selected from the following optionally present: halo, hydroxy, methyl and methoxy; (149) substituted with 0 to 1 independently selected from the following Substitution with optional substituents: halo, hydroxy, methyl and methoxy; (150) unsubstituted or substituted with methyl; or (151) unsubstituted.

The compound of formula 1 includes all the compounds specifically mentioned in the examples (1) to (151) described in the preceding paragraphs and the examples, and can exist as salts, complexes, solvates, hydrates and liquid crystals. Similarly, the compound of formula 1 which is a salt can exist as a complex, a solvate, a hydrate, and a liquid crystal.

The compound of formula 1 can form pharmaceutically acceptable complexes, salts, solvates and hydrates. Such salts include acid addition salts (including diacids) and basic salts. Pharmaceutically acceptable acid addition salts include salts derived from inorganic acids (such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid), and salts derived from organic acids (such as Aliphatic monocarboxylic and dicarboxylic acids, phenyl substituted alkanoic acid, hydroxyalkanoic acid, alkanedioic acid, aromatic acid, aliphatic and aromatic sulfonic acid, etc.) are non-toxic salts. Such salts include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, Citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, sea benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate Acid salt, methanesulfonate, methyl sulfate, naphthalate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate , Phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and oxalate Naphthate (xinafoate).

Pharmaceutically acceptable basic salts include salts derived from bases, including metal cations, such as alkali metal or alkaline earth metal cations, and amines. Examples of suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum. Examples of suitable amines include arginine, N , N' -dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycerin Amino acid, lysine acid, N -methylglucamine, ethanolamine, 2-amino-2-hydroxymethyl-propane-1,3-diol and procaine. For a discussion of available acid addition salts and basic salts, see SM Berge et al., J. Pharm. Sci. (1977) 66:1-19; see also Stahl and Wermuth, Handbook of Pharmaceutical Salts : Properties, Selection, and Use (2002).

Pharmaceutically acceptable salts can be prepared using various methods. For example, the compound of formula 1 can be reacted with an appropriate acid or base to obtain the desired salt. Alternatively, the precursor of the compound of formula 1 can be reacted with an acid or a base to remove the acid-labile or base-labile protecting group or open the lactone or lactone group of the precursor. In addition, the salt of the compound of formula 1 can be converted into another salt (or free form) by treatment with an appropriate acid or base or by contact with an ion exchange resin. After the reaction, if the salt precipitates from the solution, it can be separated by filtration, or the salt can be recovered by evaporation. The degree of ionization of salt can vary from complete ionization to almost no ionization.

The compound of formula 1 may exist in a continuous solid state ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and can exhibit the physical properties of a solid or liquid depending on the temperature. Generally, these materials do not produce unique X-ray diffraction patterns, and they are more often described as liquids in form when they exhibit solid properties. After heating, a change from solid properties to liquid properties occurs, which is characterized by a state change, usually a second-order change ("glass transition"). The term "crystalline" refers to a solid phase in which the material has a regular and ordered internal structure at the molecular level and has a unique X-ray diffraction pattern with defined peaks. These materials will also exhibit liquid properties when fully heated, but the change from solid to liquid is characterized by a phase change, usually a first-order change ("melting point").

The compound of formula 1 can also exist in unsolvated and solvated forms. The term "solvate" describes a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" refers to a solvate in which the solvent is water. Pharmaceutically acceptable solvates include those in which the solvent can be replaced by an isotope (for example, D ₂ O, acetone- d ₆ , DMSO- d ₆ ).

The currently recognized classification system for solvates and hydrates of organic compounds is a system that distinguishes solvates and hydrates coordinated by isolated sites, channels, and metal ions. For example, see KR Morris (edited by HG Brittain) Polymorphism in Pharmaceutical Solids (1995). Isolation site solvates and hydrates are solvates and hydrates in which solvent (for example, water) molecules are isolated from each other due to intervening molecules of organic compounds without direct contact. In channel solvates, solvent molecules are located in lattice channels, where they are immediately adjacent to other solvent molecules. In metal ion coordinated solvates, solvent molecules are bonded to metal ions.

When the solvent or water is tightly bound, the compound will have a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water or solvent content will depend on humidity and drying conditions. In such situations, non-stoichiometry will generally be observed.

The compound of formula 1 may also exist as a multi-component complex (except salts and solvates), in which the compound (drug) and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include cage compounds (drug-host inclusion complexes) and co-crystals. Co-crystals are usually defined as crystalline complexes of neutral molecular components that are bound together through non-covalent interactions, but they can also be complexes of neutral molecules and salts. Co-crystals can be prepared by melt crystallization, by recrystallization from a solvent, or by physically milling the components together. For example, see O. Almarsson and MJ Zaworotko, Chem. Commun. (2004) 17:1889-1896. For a general review of multi-component complexes, see JK Haleblian, J. Pharm. Sci. (1975) 64(8): 1269-88.

When subjected to suitable conditions, the compound of formula 1 may exist in a mesogenic state (mesophase or liquid crystal). The mesogenic state lies between the real crystalline state and the real liquid (melt or solution). The mesogenic phenomenon derived from temperature changes is described as "thermotropic", and the mesogenic phenomenon derived from the addition of a second component (such as water or another solvent) is described as "lyotropic". The compounds that may form a lyotropic mesophase are described as "amphiphilic" and include polar ionic parts (such as -COOˉNa ⁺ , -COOˉK ⁺ , -SO ₃ ˉNa ⁺ ) or polar nonionic parts (such as -NˉN ⁺ The numerator of (CH ₃ ) _{3 ).} For example, see NH Hartshorne and A. Stuart, Crystals and the Polarizing Microscope (4th edition, 1970).

Each compound of Formula 1 may exist as a polymorph, a stereoisomer, a tautomer, or some combination thereof, may be isotopically labeled, may be produced from the administration of a prodrug, or form a metabolite after administration.

"Prodrug" refers to a compound with little or no pharmacological activity, which can be converted into a compound with the desired pharmacological activity when metabolized in vivo. As explained in, for example, H. Bundgaar, Design of Prodrugs (1985), prodrugs can be prepared by substituting "precursor moieties" for appropriate functional groups present in pharmacologically active compounds. Examples of prodrugs include ester, ether or amide derivatives of the compound of formula 1 having carboxylic acid, hydroxyl or amine functional groups, respectively. For further discussion of prodrugs, see, for example, T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", ACS Symposium Series 14 (1975) and EB Roche editors, Bioreversible Carriers in Drug Design (1987).

"Metabolite" refers to a compound formed in the living body after administration of a pharmacologically active compound. Examples include the hydroxymethyl, hydroxyl, secondary amino, primary amino, phenol and the compound of Formula 1 each having a methyl group, an alkoxy group, a tertiary amino group, a secondary amino group, a phenyl group, and an amide group Carboxylic acid derivatives.

The compounds of formula 1 may exist as stereoisomers, which are generated due to the presence of one or more stereocenters, one or more double bonds, or both. Stereoisomers can be pure, substantially pure or a mixture. These stereoisomers can also be derived from acid addition salts or basic salts in which the counter ion is optically active (for example, when the counter ion is D-lactate or L-lysine).

The compounds of formula 1 may exist as tautomers, which are isomers derived from tautomerization. Tautomerism includes, for example, imine-enamine, keto-enol, oxime-nitroso and amide-imidic acid tautomerism.

The compound of formula 1 can exhibit more than one type of isomerism.

Geometric (cis/trans) isomers can be separated by conventional techniques such as chromatography and segmented crystallization.

Conventional techniques for the preparation or separation of compounds with specific stereochemical configurations include chiral synthesis from suitable optically pure precursors or the use of (for example) chiral high pressure liquid chromatography (HPLC) to resolve racemates (or Salt or derivative racemate). Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound (e.g. alcohol), or in the case where the compound of formula 1 contains an acidic or basic moiety, it can be reacted with such as tartaric acid or 1-phenyl Acid or base reaction of ethylamine. The resulting diastereomer mixture can be separated by chromatography, segmented crystallization, etc., and the appropriate diastereomer can be converted into a compound with the necessary stereochemical configuration. For a further discussion of techniques for separating stereoisomers, see EL Eliel and SH Wilen, Stereochemistry of Organic Compounds (1994).

The compounds of formula 1 may have isotopic variations in which at least one atom is replaced by an atom having the same atomic number but having an atomic mass different from the atomic mass commonly found in nature. Isotopes suitable for inclusion in the compound of formula 1 include, for example, isotopes of hydrogen, such as ² H and ³ H; isotopes of carbon, such as ¹¹ C, ¹³ C, and ¹⁴ C; isotopes of nitrogen, such as ¹³ N and ¹⁵ N; oxygen Isotopes of sulfur, such as ¹⁵ O, ¹⁷ O, and ¹⁸ O; isotopes of sulfur, such as ³⁵ S; isotopes of fluorine, such as ¹⁸ F; isotopes of chlorine, such as ³⁶ Cl; and isotopes of iodine, such as ¹²³ I and ¹²⁵ I. The use of isotopic variants (such as deuterium ² H) can provide certain therapeutic advantages due to greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements. In addition, certain isotopic variations of the disclosed compounds can be incorporated into radioactive isotopes (for example, tritium ³ H or ¹⁴ C), which can be used in drug and/or substrate tissue distribution research. Positron emission isotopes (such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N) can be used to check the occupancy of the substrate in a positron emission tomography (PET) study. Isotopically-labeled compounds can be prepared by similar to those described elsewhere in this disclosure, using appropriate isotope-labeled reagents instead of unlabeled reagents.

The compound of formula 1 can be prepared using the techniques described below. Some schemes and examples can omit the details of common reactions (including oxidation, reduction, etc.), separation techniques (extraction, evaporation, precipitation, chromatography, filtration, grinding, crystallization, and the like) and analysis procedures. These details are familiar with organic chemistry. Known by the skilled person. Details of these reactions and techniques can be found in several papers, including Richard Larock, Comprehensive Organic Transformations (1999), and the multi-volume series Compendium of Organic Synthetic Methods (1974, see below) edited by Michael B. Smith and others. The starting materials and reagents can be obtained from commercially available sources or can be prepared using literature methods. Some reaction schemes may omit secondary products derived from chemical conversion (e.g., alcohol from ester hydrolysis, CO ₂ from diacid decarboxylation, etc.). In addition, in some cases, the reaction intermediate can be used in subsequent steps without isolation or purification (that is, in situ).

In some of the reaction schemes and examples below, certain compounds can be prepared using protecting groups that prevent undesired chemical reactions from occurring at other reactive sites. Protecting groups can also be used to enhance solubility or otherwise improve the physical properties of the compound. Discussion on the strategy of protecting groups, description of materials and methods used to install and remove protecting groups, and summary of available protecting groups for common functional groups (including amines, carboxylic acids, alcohols, ketones, aldehydes, etc.) See TW Greene and PG Wuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

Generally, the chemical transformations described throughout this specification can be carried out using substantially stoichiometric amounts of reactants, but certain reactions may benefit from using an excess of one or more of the reactants. In addition, many reactions disclosed throughout this specification can be carried out at about room temperature (RT) and ambient pressure, but depending on the reaction kinetics, yield, etc., some reactions can be run under elevated pressure or Use a higher temperature (for example, reflux conditions) or a lower temperature (for example, -78°C to 0°C). Regardless of whether any reference to the stoichiometric range, temperature range, pH range, etc. in the present disclosure and the scope of the patent application explicitly uses the term "range", the indicated endpoints are also included.

Many chemical transformations can also use one or more compatible solvents, which can affect the reaction rate and yield. Depending on the nature of the reactants, the one or more solvents can be polar protic solvents (including water), polar aprotic solvents, non-polar solvents, or some combination. Representative solvents include saturated aliphatic hydrocarbons (e.g., n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane); aromatic hydrocarbons (e.g. benzene, toluene, xylene); halogenated Hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride); aliphatic alcohols (e.g. methanol, ethanol, propan-1-ol, propan-2-ol, but-1-ol, 2-methyl-propan-1 -Alcohol, butan-2-ol, 2-methyl-propan-2-ol, pentane-1-ol, 3-methyl-butan-1-ol, hexan-1-ol, 2-methoxy- Ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2-Butoxy-ethoxy)-ethanol); ether (e.g. diethyl ether, diisopropyl ether, dibutyl ether, 1,2-dimethoxy-ethane, 1,2- Diethoxy-ethane, 1-methoxy-2-(2-methoxy-ethoxy)-ethane, 1-ethoxy-2-(2-ethoxy-ethoxy) -Ethane, tetrahydrofuran, 1,4-dioxane); ketones (such as acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (such as methylamide, N , N -Dimethylformamide, acetonitrile, N -methyl-pyrrolidone, pyridine, quinoline, nitrobenzene); sulfur-containing solvents (such as carbon disulfide, dimethyl sulfide, tetrahydro-thiophene-1,1, -Dioxide); and phosphorus-containing solvents (for example, hexamethylphosphatidylamine).

In the scheme below, the substituent identifiers (α, β, n, R ^1C , R ^1N , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X ¹ , X ^6. X ⁷ ) is as defined for Formula 1 above. However, as mentioned before, some starting materials and intermediates may include protecting groups, which are removed before the final product. In these cases, the substituent identifier refers to the part defined in Formula 1 and those parts with appropriate protecting groups (unless explicitly shown). For example, the starting materials or intermediates in the scheme may include X ¹ substituents with potentially reactive hydroxyl groups. In these cases, X ¹ will include moieties with or without, for example, a TBS or Ac group attached to an oxygen atom.

方案ASchemes A and B show general methods for preparing compounds of formula 1. As indicated in Scheme A, the heteroaromatic halide (A-1, where for example X is Cl, Br or I) and the aromatic (or heteroaromatic) boronic acid or ester (A-2, where for example each R ¹⁰ series H or C _1-4 alkyl) in palladium catalyst (such as XPhos Pd G3, Pd(dppf)Cl ₂ , PdCl ₂ (dtbpf), etc.), alkali (such as K ₂ CO ₃ , Na ₂ CO ₃ , KF Etc.) and one or more polar solvents (such as dioxane, DMF, water, etc.) in the presence of the reaction. The palladium-catalyzed cross-coupling reaction is carried out at elevated temperature (for example, 80-130° C.) and directly or indirectly produces the compound of formula 1, for example, after removing the protective group, further purifying the functional group, etc.

Plan A

方案BOr, as shown in Scheme B, the heteroaromatic boronic acid or ester (B-1) and the aromatic (or heteroaromatic) halide (B-2) are used in the palladium catalyst as described in Scheme A above, React in the presence of base and solvent. Like Scheme A, the cross-coupling reaction in Scheme B directly or indirectly produces the compound of formula 1.

Plan B

方案CScheme C shows the general method for preparing heteroaromatic halides (C-1) and heteroaromatic boronic acids or esters (C-2), which have a single bond in α, a double bond in β, X ¹ NR ^1N and When R ² is a pendant oxy group, it corresponds to compounds (A-1) and (B-1), respectively. According to this method, make 2-halo-3-nitropyridine (C-3) and ^{the amine substituted with R 3} (C-4) in the presence of a base (such as DIPEA) and a solvent (such as ACN, DMSO, etc.) The reaction is carried out at elevated temperature (for example, 80°C) to obtain 3-nitropyridin-2-amine (C-5). The amine (C-5) is then reduced (for example, via catalytic hydrogenation, _{treatment with iron metal and NH 4} Cl in EtOH and water, etc.) to provide pyridine-2,3-diamine (C-6). The diamine (C-6) and CDI are reacted in a polar solvent (such as THF) and at elevated temperature (such as 60-75°C) to provide the desired pyrido-fused imidazolidinone (C-7). Treat imidazolidinone (C-7) with a base (such as NaH, K ₂ CO _3, etc.) in a solvent (such as DMF, ACN, etc.), and then make it and halogenated alkane (C-8, R ^1N series as appropriate) substituted The alkyl group, X-based Br, I, etc.) react at elevated temperature (80-130°C) to obtain heteroaromatic halide (C-1). If desired, the halide (C-1) and diboric acid or ester (C-9) can be used in a palladium catalyst (such as Pd(dppf)Cl ₂ , Pd(dppf)Cl ₂ .CH ₂ Cl _2, etc.), alkali (KOAc, potassium phenate, etc.) and a solvent (such as dioxane) are reacted at elevated temperature (such as 80-100°C) to provide heteroaromatic boronic acid or ester (C-2).

Plan C

Scheme D shows the general method for the preparation of heteroaromatic halide (D-1) and heteroaromatic boronic acid or ester (D-2), which are used when α is a double bond, β is a single bond and X ¹ is N. Corresponds to compounds (A-1) and (B-1). According to this method, pyridine-2,3-diamine (C-6) and chloro (D-3, R ² is a C _1-4 alkyl group) in a non-nucleophilic base (such as DIPEA) and a polar solvent ( The reaction is performed under cooling (for example, 0-15°C) in the presence of THF) to obtain N- (pyridin-3-yl)alkylamide (D-4). Then use tetraalkyl orthocarbonate (D-5, each R ¹¹ is (for example) methyl) and C _1-5 alkanoic acid (HOAc, propionic acid, butyric acid, etc.) at elevated temperature (for example, 100-120 The amide (D-4) is treated at ℃) to provide a heteroaromatic halide (D-1, R ² is a C _1-4 alkyl group). Alternatively, pyridine-2,3-diamine (C-6) and tetraalkyl orthocarbonate (D-6, each R ² is C _1-4 alkoxy) and C _1-5 alkanoic acid ( HOAc, propionic acid, butyric acid, etc.) are reacted at elevated temperature (for example, 100-120°C) to provide heteroaromatic halide (D-1, R ² is a C _1-4 alkoxy group). Although not shown, when R ² is H, the diamine (C-6) and orthoester (HC(OR ¹¹ ) ₃ ) can be made to increase the temperature in the presence of _{C 1-5 alkanoic acid (such as HOAc)} (For example, 80°C) to obtain a heteroaromatic halide (D-1, R ² system H). If desired, the halide (D-1) and diboric acid or ester (C-9) can be used in a palladium catalyst (such as Pd(dppf)Cl ₂ , Pd(dppf)Cl ₂ .CH ₂ Cl _2, etc.), alkali (E.g. KOAc, potassium phenate, etc.) and a solvent (e.g. dioxane) are reacted at elevated temperature (e.g. 80-100°C) in the presence of a solvent (e.g. 80-100°C) to provide heteroaromatic boric acid or ester (D-2).

方案DScheme E shows the general method for preparing heteroaromatic halide (E-1) and boronic acid or ester (E-2), which is based on α series double bond, β series single bond, X ¹ series CR ^1C and R ^1C series Hydrogen corresponds to compounds (A-1) and (B-1), respectively. According to this method, the 3-bromo-5-chloro-2-fluoropyridine (E-3) and ^{the amine substituted with R 3} (C-4) are present in a base (such as DIPEA) and a solvent (such as ACN, DMSO, etc.) It reacts at elevated temperature (for example, 80°C) to obtain 3-bromo-5-chloropyridin-2-amine (E-4). Then amine (C-5) and organotinane (E-5, R ¹² series (for example) butyl) in the presence of a palladium catalyst (for example Pd(PPh ₃ ) ₄ ) and a non-polar solvent (for example toluene) The reaction is carried out at an elevated temperature (for example, 100°C). At room temperature or higher (e.g. 60°C), use a strong base (e.g. NaO t -Bu, KO t -Bu, etc.) with the resulting 5-chloro-3-ethynylpyridin-2-amine (E-6) Treated in polar solvent (DMF) to obtain heteroaromatic halide (E-1). If desired, the halide (E-1) and diboronic acid or ester (C-9) can be used in a palladium catalyst (such as Pd(dppf)Cl ₂ , Pd(dppf)Cl ₂ .CH ₂ Cl _2, etc.), alkali (E.g. KOAc, potassium phenate, etc.) and a solvent (e.g. dioxane) are reacted at elevated temperature (e.g. 80-100°C) to provide heteroaromatic boronic acid or ester (E-2).

Plan D

方案E

方案FScheme F shows a general method for preparing aromatic (or heteroaromatic) boronic acid or ester (A-2) or halide (B-2). According to this method, the carboxylic acid (F-1) is treated with thiol chloride in a solvent (for example, DMF) at an elevated temperature (for example, 60-80°C). The obtained chlorine (F-2) and ^{the amine substituted with R 9} (F-3) are reacted in a solvent (for example, DCM) under cooling (0-15° C.) to obtain an aromatic halide (B-2). Alternatively, an amide coupling agent (such as HATU, DCC, EDC hydrochloride, T3P or 2-chloro-1-methylpyridinium iodide) can be used to make carboxylic acid (F-1) and amine (F- 3) React in the presence of a non-nucleophilic base (for example, Et ₃ N, DIPEA) and one or more compatible polar solvents (for example, DCM, DMA, DMF, THF). The amide coupling can be carried out at a temperature ranging from room temperature to about 80°C. HOBt can be used to promote this reaction. If desired, the halide (B-2) and diboronic acid or ester (C-9) can be used in a palladium catalyst (such as Pd(dppf)Cl ₂ , Pd(dppf)Cl ₂ .CH ₂ Cl _2, etc.), alkali (E.g. KOAc, potassium phenate, etc.) and a solvent (e.g. dioxane) are reacted at elevated temperature (e.g. 80-100°C) in the presence of a solvent (e.g. 80-100°C) to provide heteroaromatic boronic acid or ester (A-2).

Plan E

Plan F

The methods depicted in these schemes can be changed as desired. For example, protective groups can be added or removed, and can be cross-coupling reactions catalyzed by, for example, alkylation, acylation, halogenation, hydrolysis, oxidation, reduction, amination, sulfonation, acetylation, and transition metal And so on to further refine the intermediates or products to obtain the desired final product. In addition, any intermediate or final product containing a mixture of stereoisomers may be purified by chiral column chromatography (such as supercritical fluid chromatography) or by derivatization using optically pure reagents as described above, depending on the situation. , To obtain the desired stereoisomer.

In order to select an appropriate dosage form and route of administration, the compounds of formula 1 (including the compounds mentioned above) and their pharmaceutically acceptable complexes, salts, solvates and hydrates should be evaluated for their biomedical properties, such as different Solubility and solution stability at pH, permeability and the like. Compounds intended for medical use can be administered in the form of crystalline or amorphous products, and can be used as solid plugs, powders or membranes, for example, by methods such as precipitation, crystallization, freeze drying, spray drying, evaporative drying, microwave drying or radio frequency drying. Form to obtain.

The compound of formula 1 may be administered alone or in combination with each other or in combination with one or more pharmacologically active compounds different from the compound of formula 1. Generally, one or more of these compounds are administered as a pharmaceutical composition (formulation) in combination with one or more pharmaceutically acceptable excipients. The choice of excipient depends in particular on the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Available pharmaceutical compositions and their preparation methods can be found in, for example, AR Gennaro (Editor), Remington: The Science and Practice of Pharmacy (20th Edition, 2000) .

The compound of formula 1 can be administered orally. Oral administration may involve swallowing, in which case the compound enters the bloodstream via the gastrointestinal tract. Alternatively or additionally, oral administration may involve mucosal administration (e.g., buccal, sublingual, supralingual administration) such that the compound enters the bloodstream through the oral mucosa.

The formulations suitable for oral administration include solid, semi-solid and liquid systems, such as lozenges; soft or hard capsules containing multi- or nano-particles, liquid or powder; rhomboid lozenges that can be filled with liquids; chewables; Gels; quick-dispersing dosage forms; membranes; vaginal suppositories; sprays; and buccal or mucosal adhesive patches. Liquid formulations include suspensions, solutions, syrups and elixirs. These formulations can be used as fillers in soft or hard capsules (for example, made from gelatin or hydroxypropyl methylcellulose) and usually contain a carrier (for example, water, ethanol, polyethylene glycol, propylene glycol, methyl Cellulose or suitable oil) and one or more emulsifiers, suspending agents or both. Liquid formulations can also be prepared by reconstituting solids (for example from small sachets).

The compound of formula 1 can also be used in fast-dissolving, fast-disintegrating dosage forms, such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents (2001) 11(6):981-986.

For the tablet dosage form, depending on the dosage, the active pharmaceutical ingredient (API) may account for about 1 wt% to about 80 wt% of the dosage form, or more usually about 5 wt% to about 60 wt% of the dosage form. In addition to API, lozenges may also include one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, antioxidants, colorants, flavoring agents, preservatives, and taste-masking agents. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose , Microcrystalline cellulose, _{hydroxypropyl cellulose substituted by C 1-6} alkyl group, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from about 1 wt% to about 25 wt% or from about 5 wt% to about 20 wt% of the dosage form.

Binders are generally used to impart adhesive qualities to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and hydrogen phosphate Calcium dihydrate.

Tablets may also include surfactants such as sodium lauryl sulfate and polysorbate 80; and glidants such as silica and talc. When present, the surfactant can comprise from about 0.2 wt% to about 5 wt% of the tablet, and the glidant can comprise from about 0.2 wt% to about 1 wt% of the tablet.

Tablets may also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. The lubricant may comprise about 0.25 wt% to about 10 wt% or about 0.5 wt% to about 3 wt% of the tablet.

The tablet blend can be compressed directly or by rolling to form a tablet. Alternatively, the tablet blend or part of the blend can be wet, dry or melt granulated, melt coagulated or extruded before tableting. If desired, one or more of the components can be sized by sieving or milling or both before blending. The final dosage form may comprise one or more layers and may be coated, uncoated or encapsulated. Exemplary tablets may contain up to about 80 wt% API, about 10 wt% to about 90 wt% binder, about 0 wt% to about 85 wt% diluent, and about 2 wt% to about 10 wt%. Disintegrant and about 0.25 wt% to about 10 wt% lubricant. For a discussion of blending, granulation, milling, screening, tableting, coating, and an explanation of alternative techniques for preparing pharmaceutical products, see AR Gennaro (Editor), Remington: The Science and Practice of Pharmacy (20th Edition) , 2000); HA Lieberman et al (eds.), Pharmaceutical Dosage Forms: Tablets, Vol. 1-3 (2nd Edition, 1990); and DK Parikh and CK Parikh, Handbook of Pharmaceutical Granulation Technology , Vol. 81 (1997) .

A consumable oral film for human or veterinary use, which is easily tortuous, water-soluble or water-swellable film dosage form, which can dissolve quickly or have mucosal adhesion. In addition to API, a typical film also includes one or more film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Other film components may include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulants, coolants, co-solvents (including oils), softeners, build-up agents, defoamers, surfactants, and Taste masking agent. Some components of the formulation can perform more than one function.

In addition to dosing requirements, the amount of API in the membrane may depend on its solubility. If it has water solubility, the API will generally account for about 1 wt% to about 80 wt% of the non-solvent component (solute) in the film or about 20 wt% to about 50 wt% of the solute in the film. APIs with lower solubility can account for a larger proportion of the composition, usually up to about 88 wt% of the non-solvent components in the film.

The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids, and usually accounts for about 0.01 wt% to about 99 wt% or about 30 wt% to about 80 wt% of the film.

The film dosage form is usually prepared by evaporating and drying an aqueous film coated on a peelable backing carrier or paper, which can be in a drying oven or drying tunnel (for example, in a combined coating drying device), in a freeze-drying device, or It is carried out in a vacuum oven.

Usable solid formulations for oral administration can include immediate release formulations and modified release formulations. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release. For a general description of suitable modified release formulations, see U.S. Patent No. 6,106,864. For details on other available release technologies (such as high-energy dispersions and permeability and coated granules), see Verma et al., Pharmaceutical Technology On-line (2001) 25(2):1-14.

The compound of formula 1 can also be directly administered to the bloodstream, muscles or internal organs of the individual. Suitable techniques for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration. Suitable devices for parenteral administration include needle syringes (including micro-needle syringes), needle-free syringes and infusion devices.

Parenteral formulations are generally aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (for example, with a pH of about 3 to about 9). However, in some applications, the compound of Formula 1 may be more suitably formulated as a sterile non-aqueous solution or as a dry form (to be used together with a suitable vehicle (such as sterile pyrogen-free water)). The preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) can be easily accomplished using standard medical techniques.

The solubility of the compound used to prepare the parenteral solution can be increased through appropriate formulation techniques, such as the incorporation of solubility enhancers. The formulations can be formulated for parenteral administration as immediate or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. Therefore, the compound of formula 1 can be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as a reservoir for implantation, thereby providing an improved release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions containing drug-loaded poly(DL -lactic-co-glycolic acid) (PGLA) microspheres.

The compound of formula 1 can also be administered to the skin or mucosa locally, intradermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, spreadable powders, dressings, foams, films, skin patches, wafers, Implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers may include ethanol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. The topical formulations may also include penetration enhancers. For example, see Finnin and Morgan, J. Pharm. Sci. 88(10):955-958 (1999).

Other local administration methods include delivery by electroporation, iontophoresis, sonophoresis, ultrasound introduction, and micro-needle or needle-free (such as Powderject™, Bioject™) injection. The formulations for topical administration can be formulated as immediate or modified release as described above.

The compound of formula 1 can also be administered intranasally or by inhalation, usually in the form of dry powder, aerosol spray or nasal drops. An inhaler can be used to administer dry powders that include API alone, a powder blend of API and diluent (such as lactose), or mixed component particles including API and phospholipids (such as phosphatidylcholine). For intranasal use, the powder may include a bioadhesive such as chitosan or cyclodextrin. A pressurized container, pump, ejector, nebulizer or atomizer can be used to generate an aerosol spray from a solution or suspension that contains API, one or more for dispersing, solubilizing or prolonging the API The release agent (such as EtOH with or without water), one or more solvents used as propellants (such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3, 3-Heptafluoropropane) and optionally surfactants such as sorbitan trioleate, oleic acid or oligolactic acid. The sprayer using electrohydrodynamics can be used to produce fine mist.

Before being used in dry powder or suspension formulations, the drug product is usually pulverized to a particle size suitable for delivery by inhalation (usually 90% of the particles, based on volume, with a maximum size of less than 5 microns). This can be achieved by any suitable size reduction method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid treatment, high pressure homogenization, or spray drying.

Capsules, blisters and cartridges used in inhalers or insufflators (for example, made from gelatin or hydroxypropyl methylcellulose) can be formulated with a powder mixture containing the active compound, a suitable powder base (such as lactose or Starch) and performance modifiers (such as L-leucine, mannitol or magnesium stearate). Lactose can be anhydrous or monohydrate. Other suitable excipients include polydextrose, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation in a sprayer for generating fine mist using electrohydrodynamics may contain 1 μg to about 20 mg API per spray, and the spray volume may vary from about 1 μL to about 100 μL. A typical formulation may include one or more compounds of formula 1, propylene glycol, sterile water, EtOH, and NaCl. Alternative solvents that can be used in place of propylene glycol include glycerin and polyethylene glycol.

Formulations for inhaled administration, intranasal administration, or both can be formulated for immediate release or in a modified manner using, for example, PGLA. Suitable flavoring agents (such as menthol and levomenthol) or sweetening agents (such as saccharin or sodium saccharin) can be added to the formulation intended for inhalation/intranasal administration.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a metered amount. The unit is usually configured to administer a metered dose or "puff" containing about 10 μg to about 1000 μg API. The total daily dose will generally be in the range of about 100 μg to about 10 mg, which can be administered in a single dose or more usually as divided doses administered throughout the day.

The active compound can be administered rectally or vaginally, for example in the form of suppositories, pessaries or enemas. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate. The formulations can be formulated for rectal or vaginal administration as immediate or modified release as described above.

The compound of formula 1 can also be directly administered to the eyes or ears, usually in the form of drops of a micronized suspension or solution in a pH-adjusted isotonic sterile saline. Other formulations suitable for ocular and ear administration include ointments, gels, biodegradable implants (e.g. absorbable gel sponge, collagen), non-biodegradable implants (e.g. polysilicone). Oxygen), glutinous rice paper capsules, lenses and microparticles or vesicular systems (such as non-ionic surfactant niosomes or liposomes). The formulation may include one or more polymers and preservatives (such as benzalkonium chloride). Typical polymers include cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers (such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose) and heteropolysaccharide polymers (such as blue Gum (gelan gum)). These formulations can also be delivered by iontophoresis. The formulations can be formulated for intraocular or transaural administration as immediate or modified release as set forth above.

In order to improve the solubility, dissolution rate, taste masking, bioavailability or stability of the compound of formula 1, the compound of formula 1 can be combined with soluble macromolecular entities (including cyclodextrin and its derivatives and polymer containing polyethylene glycol).物) Combination. For example, API-cyclodextrin complexes can generally be used in most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct compounding with API, cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent or solubilizer. Alpha-cyclodextrin, β-cyclodextrin and γ-cyclodextrin are commonly used for these purposes. For example, see WO 91/11172, WO 94/02518 and WO 98/55148.

As mentioned above, one or more compounds of formula 1 (including the compounds specifically mentioned above) and their pharmaceutically active complexes, salts, solvates and hydrates can be combined with each other or with one or more other active pharmaceutically active compounds To treat various diseases, conditions and illnesses. In such cases, the active compounds may be provided in a single dosage form combination as described above or may be provided in the form of a kit suitable for co-administration of the composition. The kit includes (1) two or more different pharmaceutical compositions, at least one of which contains a compound of formula 1; and (2) a device for separately retaining the two pharmaceutical compositions, such as a separate bottle or separate Style foil package. An example of this set is a common blister pack used to pack tablets or capsules. The kit is suitable for administering different types of dosage forms (for example, oral and parenteral), or for administering different pharmaceutical compositions at separate dosing intervals, or for titrating different pharmaceutical compositions with each other. To facilitate patient compliance, the kit usually includes instructions for administration and may be provided with memory aids.

For administration to human patients, depending on the route of administration, the total daily dose of the claimed and disclosed compound is usually in the range of about 0.1 mg to about 3000 mg. For example, oral administration may require a total daily dose of about 1 mg to about 3000 mg, while an intravenous dose may only require a total daily dose of about 0.1 mg to about 300 mg. The total daily dose can be administered in single or divided doses, and may exceed the typical range given above under the judgment of the physician. Although the doses are based on an average human individual with a mass of about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for patients (e.g., infants) whose mass is outside this weight range.

As mentioned above, the compounds of formula 1 can be used to treat diseases, disorders or conditions in which inhibition of RIPK2 is adapted. These diseases, disorders or conditions are usually related to any unhealthy or abnormal state of the individual, and inhibition of RIPK2 provides therapeutic benefits to the individual. More specifically, these diseases, disorders or conditions may involve the immune system and inflammation, including type I hypersensitivity (allergic) reactions (allergic rhinitis, allergic asthma, and atopic dermatitis); autoimmunity Diseases (rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, lupus nephritis, immune thrombocytopenic purpura, Schrgren’s syndrome, joint adhesive spondylitis, and Besset’s disease); inflammation Intestinal disease; lung inflammation (chronic obstructive pulmonary disease), atherosclerosis, thrombosis, and myocardial infarction. The compound of formula 1 can also be used to treat diseases, disorders or conditions related to abnormal cell growth, including hematological malignancies, such as acute myelogenous leukemia, B-cell chronic lymphocytic leukemia, and B-cell lymphoma (e.g. mantle cell lymphoma) , T-cell lymphoma (for example, peripheral T-cell lymphoma) and multiple myeloma; and epithelial cancers (that is, cancer), such as lung cancer (small cell lung cancer and non-small cell lung cancer), pancreatic cancer and colon cancer.

In addition to the hematological malignancies and epithelial cancers mentioned above, the compound of formula 1 can also be used to treat other types of cancers, including leukemia (chronic myelogenous leukemia and chronic lymphocytic leukemia); breast cancer, genitourinary tract cancer, skin cancer , Bone cancer, prostate cancer and liver cancer; brain cancer; laryngeal cancer, gallbladder cancer, rectal cancer, parathyroid cancer, thyroid cancer, adrenal cancer, nerve tissue cancer, bladder cancer, head cancer, neck cancer, stomach cancer, bronchial cancer and kidney Cancer; basal cell carcinoma, squamous cell carcinoma, metastatic skin cancer, osteosarcoma, Ewing's sarcoma (Ewing's sarcoma), reticular cell sarcoma and Kaposi's sarcoma (Kaposi's sarcoma); myeloma, giant cell tumor, Islet cell tumors, acute and chronic lymphocytic and granular spherical tumors, hair cell tumors, adenomas, medullary carcinomas, pheochromocytomas, mucosal neuromas, enteric gangliocytomas, hyperplastic corneal nerve tumors, Ma Fan Marfanoid habitus tumor, Wilms' tumor, seminoma, ovarian tumor, smooth muscle tumor, cervical dysplasia, neuroblastoma, retinoblastoma, myelodysplastic syndrome , Rhabdomyosarcoma, astrocytoma, non-Hodgkin's lymphoma, malignant hypercalcemia, polycythemia vera, adenocarcinoma, glioblastoma multiforme, glioma, lymphoma Tumor and malignant melanoma.

In addition to cancer, the compound of Formula 1 can also be used to treat other diseases, disorders or conditions related to abnormal cell growth, including non-malignant proliferative diseases, such as benign prostatic hypertrophy, restenosis, hyperplasia, synovial hyperplasia, and idiopathic Plasma cell lymphadenopathy, retinopathy or other neovascular diseases of the eye, etc.

In addition to the diseases, disorders or conditions listed above, the compounds of formula 1 can also be used to treat autoimmune diseases, disorders or conditions. These diseases, disorders or conditions include Crohn's disease, dermatomyositis, type 1 diabetes, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome ), Hashimoto's disease, mixed connective tissue damage, myasthenia gravis, narcolepsy, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, temporal arteritis, ulcerative colon Inflammation, vasculitis and Wegener's granulomatosis.

The compound of formula 1 can be used to treat inflammatory diseases, disorders or conditions, including asthma, chronic inflammation, chronic prostatitis, glomerulonephritis, hypersensitivity, inflammatory bowel disease (ulcerative colitis other than Crohn's disease) , Pelvic inflammatory disease, reperfusion injury, transplant rejection, vasculitis and systemic inflammatory reaction syndrome.

The compounds of formula 1 can also be used to treat specific diseases or conditions that may belong to one or more of the general conditions described above, including arthritis. In addition to rheumatoid arthritis, Schrögren’s syndrome, systemic lupus erythematosus, SLE in children and adolescents, the compound of formula 1 can also be used to treat other arthritic diseases, including joint adhesive spondylitis, vascular necrosis, Bessett’s Disease, bursitis, calcium dihydrogen pyrophosphate crystal deposition disease (pseudogout), carpal tunnel syndrome, Ehlers-Danlos syndrome, fibromyalgia, fifth disease, giant cell arteritis , Gout, juvenile dermatomyositis, juvenile rheumatoid arthritis, juvenile spondyloarthritis, Lyme disease, Marfan syndrome, myositis, osteoarthritis, osteogenesis , Osteoporosis, Paget's disease, psoriatic arthritis, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy syndrome, scleroderma, vertebral stenosis, Steer Still's disease and tendinitis.

The claimed and disclosed compounds can be combined with one or more other pharmacologically active compounds or therapies for the treatment of one or more diseases, disorders or conditions of RIPK2, including those involving the immune system, inflammation, and abnormal cell growth. And other diseases, illnesses or conditions. For example, the compound of formula 1 (including the compounds specifically mentioned in the examples) and its pharmaceutically acceptable complexes, salts, solvates and hydrates can be combined with one or more compounds or therapies to simultaneously, according to Sequential or separate administration for the treatment of arthritis, including rheumatoid arthritis and osteoarthritis, or for the treatment of cancer, including hematological malignancies, such as acute myeloid leukemia, B cell chronic lymphocytic leukemia, B cell Lymphoma, T-cell lymphoma, multiple myeloma, and cancers such as lung cancer, pancreatic cancer, and colon cancer. These combinations can provide significant therapeutic advantages, including fewer side effects, improved ability to treat populations of underserved and underdrugged patients, or synergistic activity.

For example, when used to treat arthritis, the compound of Formula 1 can be combined with one or more non-steroidal anti-inflammatory drugs (NSAID), analgesics, corticosteroids, biological response modifiers, and protein-A immunoadsorption therapy. Alternatively or in addition, when treating rheumatoid arthritis, the compound of formula 1 may be combined with one or more disease-modifying antirheumatic drugs (DMARD), and when treating osteoarthritis, the compound of formula 1 may be combined with one or more osteoporosis Symptom agent combination.

Representative NSAIDs include apazone, aspirin, celecoxib, diclofenac (with and without misoprostol), diflunisal (diflunisal), etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, a Meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, Phenbutazone (phenylbutazone), piroxicam (piroxicam), choline and magnesium salicylate, salsalate and sulindac. Representative analgesics include acetaminophen and morphine sulfate, as well as codeine, hydrocodone, oxycodone, propoxyphene and tramadol, all of which are With or without acetaminophen. Representative corticosteroids include betamethasone, cortisone acetate, dexamethasone, hydrocortisone, methylprednisolone, and praisolone And prednisone. Representative biological response modifiers include TNF-α inhibitors, such as adalimumab, etanercept, and infliximab; selective B cell inhibitors, such as rituximab Anti (rituximab); IL-1 inhibitors, such as anakinra; and selective costimulation modulators, such as abatacept.

Representative DMARDs include auranofin (oral gold), azathioprine, chlorambucil, cyclophosphamide, cyclosporine, sodium gold thiomalate (injectable gold), hydroxychloroquine, leflunomide Leflunomide, methotrexate, minocycline, myophenolate mofetil, penicillamine, sulfasalazine, and JAK3 inhibitor ( For example tofacitinib (tofacitinib)). Representative osteoporosis agents include bisphosphonates such as alendronate, ibandronate, risedronate and zoledronic acid; select Sex estrogen receptor modulators, such as droloxifene, lasofoxifene and raloxifene; hormones such as calcitonin, estrogen and parathyroid hormone ; And immunosuppressive agents, such as azathioprine, cyclosporine and rapamycin.

Particularly useful combinations for the treatment of rheumatoid arthritis include a compound of formula 1 and methotrexate; a compound of formula 1 and one or more biological response modifiers, such as leflunomide, etanercept, adalimumab And infliximab; or a compound of formula 1, methotrexate and one or more biological response modifiers, such as leflunomide, etanercept, adalimumab and infliximab.

To treat thrombosis and restenosis, the compound of formula 1 can be combined with one or more cardiovascular agents, such as calcium channel blockers, statins, fibric acid, β-blockers, ACE inhibitors and platelet aggregation inhibitors.

The compound of formula 1 can also be combined with one or more compounds or therapies used to treat cancer. Such compounds or therapies include chemotherapeutic agents (ie, cytotoxic or anti-tumor agents), such as alkylating agents, antibiotics, antimetabolites, botanical agents, and topoisomerase inhibitors, and participate in tumor growth by interference Molecular targeted drugs that block the growth and spread of cancer with specific molecules that are progressing. Molecular targeted drugs include both small molecules and biological agents.

Representative alkylating agents include dichloroethylamine (chlorambucil, such as chlorambucil, cyclophosphamide, ifosphamide, methyl bis (chloroethyl) amine, melphalan (melphalan) and Uracil mustard); aziridine (e.g. thiotepa); alkyl ketone sulfonate (e.g. busulfan); nitrosourea (e.g. carmustine, Luo Lomustine and streptozocin); non-classical alkylating agents (such as altretamine, dacarbazine and procarbazine); and platinum compounds ( For example, carboplatin, cisplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate.

Representative antibiotic agents include anthracyclines (e.g., aclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin, ida Idarubicin, pirarubicin, valrubicin, and zorubicin); anthracenediones (such as mitoxantrone and pixantrone) ); and Streptomyces (such as actinomycin, bleomycin, actinomycin D, mitomycin C and plicamycin).

Representative antimetabolites include dihydrofolate reductase inhibitors (such as methotrexate, methotrexate, and pemetrexed); thymidylate synthase inhibitors (such as raltitrexed) and Pemetrexed); aldofolic acid (e.g. tetrahydrofolate); adenosine deaminase inhibitors (e.g., pentostatin); halogenated/ribonucleotide reductase inhibitors (e.g., cladribine ( cladribine), clofarabine and fludarabine); thiopurine (such as thioguanine and mercaptopurine); thymidylate synthase inhibitors (such as fluorouracil, capecitabine), Tegafur, carmofur, and fluorouridine); DNA polymerase inhibitors (e.g., cytarabine); ribonucleotide reductase inhibitors (e.g., gemcitabine) ; Hypomethylating agents (such as azacitidine and decitabine); and ribonucleotide reductase inhibitors (such as hydroxyurea); and aspartame depleting agents (such as Asdinase).

Representative botanical agents include vinca alkaloid (e.g., vincristine, vinblastine, vindesine, vinzolidine, and vinorelbine) , Podophyllotoxin (e.g. etoposide and teniposide) and taxanes (e.g. docetaxel, larotaxel, otaxel) ortataxel), paclitaxel (paclitaxel) and tesetaxel (tesetaxel).

Representative type I topoisomerase inhibitors include camptothecins, such as belotecan, irinotecan, rubitecan, and topotecan. Representative type II topoisomerase inhibitors include amsacrine, etoposide, etoposide phosphate, and teniposide, which are derivatives of epipodophyllotoxin.

Molecular targeted therapies include biological agents, such as cytokines and other immunomodulators. Available cytokines include interleukin-2 (IL-2, aldesleukin), interleukin 4 (IL-4), interleukin 12 (IL-12) and interferon, which include More than 23 related subtypes. Other cytokines include granulosphere community stimulating factor (CSF) (e.g. filgrastim) and granulosphere macrophage community stimulating factor (GM-CSF or CSF2) (e.g., sargramostim, that Namilumab). Other immunomodulators include bacillus Calmette-Guerin, levamisole and octreotide; monoclonal antibodies against tumor antigens, such as trastuzumab and rituximab; and cancer Vaccine, which induces an immune response against tumors.

In addition, molecular targeted drugs that interfere with specific molecules involved in tumor growth and progression include the following inhibitors: epidermal growth factor (EGF), transforming growth factor-α (TGF _α ), TGF _β , heregulin, insulin-like Growth factor (IGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), community stimulating factor (CSF), erythropoietin (EPO), interleukin-2 (IL-2), nerve Growth factor (NGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), angiogenin, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), HER4, insulin-like growth factor 1 receptor (IGF1R), IGF2R, fibroblast growth factor 1 receptor (FGF1R), FGF2R, FGF3R, FGF4R, vascular endothelial growth factor receptor (VEGFR), with immunoglobulin Protein-like and epidermal growth factor-like domain of tyrosine kinase 2 (Tie-2), platelet-derived growth factor receptor (PDGFR), Abl, Bcr-Abl, Raf, FMS-like tyrosine kinase 3 (FLT3), c-Kit, Src, protein kinase c (PKC), tropomyosin receptor kinase (Trk), Ret, mammalian target of rapamycin (mTOR), aurora kinase (Aurora kinase), polo-like kinase (PLK) ), mitogen-activated protein kinase (MAPK), mesenchymal-epithelial transition factor (c-MET), cyclin-dependent kinase (CDK), Akt, extracellular signal-regulated kinase (ERK), poly (ADP) Ribose polymerase (PARP) and the like.

Specific molecularly targeted drugs include selective estrogen receptor modulators, such as tamoxifen, toremifene, fulvestrant and raloxifene; antiandrogens, Such as bicalutamide, nilutamide, megestrol and flutamide; and aromatase inhibitors such as exemestane, anastrozole (anastrozole) and letrozole (letrozole). Other specific molecularly targeted drugs include agents that inhibit signal transduction, such as imatinib, dasatinib, nilotinib, trastuzumab, and gefitinib ( gefitinib, erlotinib, cetuximab, lapatinib, panitumumab and temsirolimus; it induces apoptosis Agents, such as bortezomib (bortezomib); agents that block angiogenesis, such as bevacizumab, sorafenib and sunitinib; one of which helps the immune system destroy cancer cells Agents, such as rituximab and alemtuzumab; and monoclonal antibodies that deliver toxic molecules to cancer cells, such as gemtuzumab ozogamicin, tositumomab (tositumomab), 131I-tositumomab and ibritumomab tiuxetan. Biological activity

Various methods (including in vitro and in vivo methods) can be used to determine the activity of the compound of formula 1. The LanthaScreen® Eu kinase binding assay (Invitrogen®) was optimized to screen for compounds of formula 1 that inhibit RIPK2. LanthaScreen® Eu kinase binding analysis is based on the binding and replacement of related kinases by a proprietary ATP-competitive kinase inhibitor backbone (kinase-199 tracer). In this case, using a europium-labeled anti-tag antibody that binds to RIPK2 kinase, the assay detects the binding of the kinase tracer-199 labeled with Alexa Fluor® 647 to RIPK2. The simultaneous binding of both the tracer and the antibody to RIPK2 results in a highly fluorescent resonance energy transfer (FRET) from the europium (Eu) donor fluorophore to the Alexa Fluor® 647 acceptor fluorophore on the kinase tracer. The binding of the test compound to RIPK2 competes with the binding of the tracer, which results in loss of FRET.

Compound screening analysis using complete binding assay buffer: 50 mM HEPES, 100 mM NaCl, 1 mM DTT, 10 mM MgCl ₂ , 1.15 mM CHEGA11, 0.1 mg/mL BSA, 2 nM RIPK2, 50 nM Kinase Tracer-199 And 2 nM Eu-anti-His antibody, pH 7.3. Eu-anti-His antibody and kinase tracer-199 were purchased from Invitrogen, and human RIPK2 protein (8-317 aa, N-terminal His tag, R171C, 38.3 KDa) can be obtained as described below.

The RIPK2 DNA encoding human protein residues 8-317 was cloned into the pFastBac vector (Invitrogen®), which incorporates a 6 histidine tag at the N-terminus, followed by the rTEV cleavage site. The R171C mutant was generated by site-directed mutagenesis. Using the Bac-to-Bac system (Invitrogen®), a recombinant baculovirus incorporated into the RIPK2 construct was generated by transposition. By infecting Spodoptera frugiperda (Spodoptera frugiperda) Sf9 cells to produce high titer virus stock; by infecting Spodoptera frugiperda Sf9 (Invitrogen®) for 48 hours to perform recombinant protein expression.

Recombinant RIPK2 protein was isolated from cell extracts by combining with Probond nickel resin (Life Technology®). Wash the resin with a buffer containing 25 mM HEPES pH 7.6, 0.5 M NaCl, and 20 mM imidazole, and then use the elution buffer 50 mM HEPES pH 7.6, 250 mM imidazole, 150 mM NaCl, 5% glycerol, and 0.5 mM TCEP. Dissolve. The partially purified protein was then dephosphorylated by adding 0.05 mM MnCl ₂ and λ-phosphatase and incubating at room temperature for 4 hours. Purify and dephosphorylate through Superdex 75 column in a buffer containing 10 mM HEPES pH 7.5, 150 mM NaCl, 5% glycerol, 2 mM DTT, 1 mM TCEP, 5 mM L-Arg and 5 mM L-Glu RIPK2 protein. Store the protein in small aliquots at -80°C.

The compounds of formula 1 were tested for RIPK2 inhibition as follows. Prepare the test compound in 100% DMSO and distribute it to individual wells of the multiwell plate in duplicate, starting at 10 µM, and perform 2.5 × serial dilutions. Next, use the Multidrop™ Combi reagent dispenser to add 10 µL of fully bound assay buffer to each test compound. Cover each well with an aluminum sealer, shake at 900 rpm for 2 minutes, spin down at 1000 rpm for 10 seconds, incubate at room temperature for 60 minutes, shake at 900 rpm for 2 minutes and spin down at 1000 rpm for 10 seconds, and then take a reading. Read the sample on an instrument capable of measuring fluorescence polarization. The PHERAstar plate reader was used to determine the ratio of 665 nM/620 nM. The test compound inhibition is expressed as the percentage inhibition (%) of the internal analysis control. For concentration response experiments, normalized data were fitted and pIC50 was determined using conventional techniques. Average the pIC50 to determine the average of at least two experiments. Instance

The following examples are intended to be illustrative and non-limiting, and represent specific embodiments of the invention.

In the following examples, ¹ H nuclear magnetic resonance (NMR) spectra of many compounds were obtained. The characteristic chemical shift (δ) is given in parts per million from the low-field region of tetramethylsilane. Use conventional abbreviations to designate the main peaks, including s (single peak), d (doublet), t (triplet) , Q (quartet), m (multiple peak) and br (broad peak). The following abbreviations are used for common solvents: CDCl ₃ (deuterated chloroform), DMSO- d ₆ (deuterated dimethyl sulfide), CD ₃ OD (deuterated methanol), CD ₃ CN (deuterated acetonitrile), and THF- d ₈ (Deuterated tetrahydrofuran). Use electrospray ionization (ESI-MS) or atmospheric pressure chemical ionization (APCI-MS) mass spectrometry to record mass spectra (m/z ^{for [M+H] +).}

Where indicated, the products of certain preparations and examples were purified by mass-triggered HPLC, flash chromatography, preparative TLC or SFC. Reversed phase chromatography is usually used on a column (eg Gemini™ 5μm C18 110Å, Axia™, 30 × 75 mm, 5 μm) under acidic conditions ("acid mode") containing 0.035% and 0.05% trifluoroacetic acid, respectively (TFA) ACN and water mobile phase to dissolve, or under alkaline conditions ("alkaline mode") water and 20/80 (v/v) water/acetonitrile mobile phase (both contain 10 mM NH ₄ HCO ₃ ) Perform elution. Preparative TLC is usually implemented on a silicone 60 F ₂₅₄ board. These preparations and examples can use SFC to separate the spiegelmers. After separation by chromatography, the solvent is removed and the product is obtained by drying in a centrifugal evaporator (eg GeneVac™), rotary evaporator, vacuum flask, etc. The reaction in an inert (for example, nitrogen) or reactive (for example, H ₂ ) atmosphere is usually carried out at a pressure of about 1 atmosphere (14.7 psi). Preparation 1: 5-Bromo-2-fluoro-4-methylbenzoic acid

To a solution of 2-fluoro-4-methylbenzoic acid (50 g, 324.38 mmol) in H ₂ SO ₄ (300 mL) was added NBS (63.51 g, 356.82 mmol). The mixture was stirred at 0°C for 2 hours, and then poured into ice water and filtered. The filter cake was dried under reduced pressure to obtain the title compound (140 g, crude) as a white solid. ESI-MS m/z [M+H] ⁺ = 234.1. Preparation 2: 5-Bromo-2-fluoro-4-methylbenzyl chloride

To a solution of 5-bromo-2-fluoro-4-methylbenzoic acid (70 g, 300.39 mmol) in toluene (300 mL) was added SOCl ₂ (108.95 mL, 1.50 mol) and DMF (2.31 mL, 30.04 mmol) . The resulting mixture was stirred at 70°C for 5 hours and then concentrated under reduced pressure to give the title compound (70 g, crude) as a yellow oil. Preparation 3: 5-Bromo- N -cyclopropyl-2-fluoro-4-methylbenzamide

To a solution of cyclopropylamine (20.16 g, 353.1 mmol) in DCM (300 mL) was added Et ₃ N (163.83 mL, 1.18 mol). The mixture was stirred at 0°C for 0.5 hour. A solution of 5-bromo-2-fluoro-4-methylbenzyl chloride (74 g, 294.26 mmol) in DCM (200 mL) was added dropwise, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was then diluted with DCM, washed with water and brine, dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure. The crude product was triturated with ethyl acetate (15%) in petroleum ether to give the title compound (80 g, 100%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.46-0.59 (m, 2 H) 0.64-0.75 (m, 2 H) 2.37 (s, 3 H) 2.76-2.89 (m, 1 H) 7.35 ( d, J =11.2 Hz, 1 H) 7.71 (d, J =11.2 Hz, 1 H) 8.38 (s, 1 H). Preparation 4: N -Cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Benzamide

步驟1：2-((5-溴-3-硝基吡啶-2-基)胺基)-2-甲基丙-1-醇

To a solution of 5-bromo- N -cyclopropyl-2-fluoro-4-methylbenzamide (67 g, 246.22 mmol) in dioxane (500 mL) was added 4,4,4',4 ',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (65.65 g, 258.53 mmol), KOAc (72.49 g , 738.66 mmol) and Pd(dppf)Cl ₂ (1.80 g, 2.46 mmol). The mixture was degassed and _{purged with N 2} (3×), and then stirred at 90° C. for 12 hours and filtered. The filtrate was poured into water and extracted with EtOAc. Dried organic layer was washed with brine Na ₂ SO _4, and concentrated under reduced pressure. The crude product was triturated with EtOAc (10%) in petroleum ether to give the title compound (41 g, 52%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.51-0.58 (m, 2 H) 0.65-0.74 (m, 2 H) 1.31 (s 12 H) 2.49 (s, 3 H) 2.60-2.82 (m , 1 H) 7.10 (d, J =12.0 Hz, 1 H) 7.82 (d, J =8.4 Hz, 1 H) 8.25 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 320.3 . Preparation 5: 5-Bromo- N ² -(1-((tert-butyldimethylsilyl)oxy)-2-methylprop-2-yl)pyridine-2,3-diamine

Step 1: 2-((5-Bromo-3-nitropyridin-2-yl)amino)-2-methylpropan-1-ol

Combine 5-bromo-2-chloro-3-nitropyridine (25 g, 105.29 mmol), 2-amino-2-methylpropan-1-ol (18.77 g, 210.6 mmol) and DIPEA (40.82 g, 315.87). A solution of mmol) in acetonitrile (500 mL) was stirred at 80°C for 12 hours under nitrogen. Then the mixture was concentrated. Water was added and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, and concentrated under reduced pressure. The concentrate was extracted with 1 M aqueous HCl. The organic layer was _{dried over Na 2} SO ₄ and concentrated to give the title compound (30 g, crude) as a yellow oil. Step 2: 2-((3-Amino-5-bromopyridin-2-yl)amino)-2-methylpropan-1-ol

Combine 2-((5-bromo-3-nitropyridin-2-yl)amino)-2-methylpropan-1-ol (30 g, 103.41 mmol), Fe (28.87 g, 517.04 mmol) and NH _{A mixture of 4} Cl (22.13 g, 413.63 mmol) in EtOH (300 mL) and water (50 mL) was stirred at 80°C for 1 hour. The mixture was filtered, and the filtrate was concentrated. Water was added and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to give the title compound (25 g, crude) as a black oil. Step 3: 5-Bromo- N ² -(1-((tert-butyldimethylsilyl)oxy)-2-methylprop-2-yl)pyridine-2,3-diamine

步驟1：2-((5-溴-3-硝基吡啶-2-基)胺基)-2-甲基丙-1-醇

Combine 2-((3-amino-5-bromopyridin-2-yl)amino)-2-methylpropan-1-ol (50 g, 192.21 mmol), imidazole (26.17 g, 384.4 mmol) and TBSCl A mixture of (43.46 g, 288.32 mmol) in DCM (500 mL) was stirred under nitrogen at 15°C for 12 hours. The mixture was extracted with water. The organic layer was washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (48 g, 67%) as a purple oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.17 (s, 6 H) 0.73 (s, 9 H) 1.27 (s, 6 H) 3.10 (s, 2 H) 3.52 (s, 2 H) 4.42 (s , 1 H) 6.91 (d, J = 2.40 Hz, 1 H) 7.73 (d, J = 2.40 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 376.2. Preparation 6: Acetic acid 2-((3-amino-5-bromopyridin-2-yl)amino)-2-methylpropyl ester

Step 1: 2-((5-Bromo-3-nitropyridin-2-yl)amino)-2-methylpropan-1-ol

To 5-bromo-2-chloro-3-nitropyridine (3 g, 12.63 mmol) and 2-amino-2-methylpropan-1-ol (2.41 mL, 25.27 mmol) in acetonitrile (20 mL) Add DIPEA (11.00 mL, 63.17 mmol) to the solution. The reaction mixture was stirred at 80°C for 16 hours and then quenched by the addition of water. The aqueous phase was separated and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 3%-30% EtOAc in petroleum ether to purify the residue to obtain the title compound (3 g, 82%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.42 (s, 6 H) 3.50 (d, J =5.6 Hz, 2 H) 5.25 (s, 1 H) 8.53 (s, 1 H) 8.54 -8.59 (m, 2 H); ESI-MS m/z [M+H] ⁺ = 291.9. Step 2: Acetic acid 2-((5-bromo-3-nitropyridin-2-yl)amino)-2-methylpropyl ester

To a solution of 2-((5-bromo-3-nitropyridin-2-yl)amino)-2-methylpropan-1-ol (1.5 g, 5.2 mmol) in pyridine (15 mL) was added ethyl Acid anhydride (0.969 mL, 10.34 mmol). The mixture was stirred at 80°C for 4 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0%-3% EtOAc in petroleum ether to purify the residue to obtain the title compound (1.6 g, 93%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.08 (s, 3 H) 4.41 (s, 2 H) 8.31 (s, 1 H) 8.42 (d, J =2.4 Hz, 1 H) 8.55 (d, J =2.4 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 334.0. Step 3: Acetic acid 2-((3-amino-5-bromopyridin-2-yl)amino)-2-methylpropyl ester

To acetic acid 2-((5-bromo-3-nitropyridin-2-yl)amino)-2-methylpropyl ester (1.6 g, 4.82 mmol) in EtOH (20 mL) and water (2 mL) Add Fe (1.35 g, 24.09 mmol) and NH ₄ Cl (2.58 g, 48.17 mmol) to the solution in the solution. The reaction mixture was stirred at 80°C for 2 hours and then filtered. The filtrate was concentrated in vacuo. Water was added and the aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 3%-10% EtOAc in petroleum ether to purify the residue to obtain the title compound (1.2 g, 82%) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.47 (s, 6 H) 2.08 (s, 3 H) 3.22 (s, 2 H) 4.19 (s, 1 H) 4.37 (s, 2 H) 6.95 (d , J =2.0 Hz, 1 H) 7.72 (d, J =2.0 Hz, 1 H). Preparation 7: Acetic acid 2-(6-bromo-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl acetate

Combine 2-((3-amino-5-bromopyridin-2-yl)amino)-2-methylpropyl acetate (0.5 g, 1.65 mmol) and CDI (402.46 mg, 2.48 mmol) in THF ( The mixture in 60 mL) was stirred at 70°C for 16 hours, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 3%-20% EtOAc in petroleum ether to purify the residue to obtain the title compound (400 mg, 73.7%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.60 (s, 3 H) 1.86 (s, 6 H) 1.99 (s, 3 H) 4.71 (s, 2 H) 7.39 (d, J =2.0 Hz, 1 H) 8.06 (d, J =2.0 Hz, 1 H) 9.37 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 330.0. Preparation 8: 5-Bromo- N ² -(1-((tertiary butyldimethylsilyl)oxy)prop-2-yl)pyridine-2,3-diamine

The title compound was prepared as in Preparation 5, starting with 2-aminopropan-1-ol (379.60 mg, 5.05 mmol, 1.2 equivalents) instead of 2-amino-2-methylpropan-1-ol, and passing through the middle Body 2-((5-bromo-3-nitropyridin-2-yl)amino)-1-propanol and 2-((3-amino-5-bromopyridin-2-yl)amino)propane -1-ol continues. The title compound (1 g, 76% step 3) was obtained as a black oil. ESI-MS m/z [M+H] ⁺ = 362.1. Preparation 9: 5-Bromo- N ² -(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridine-2,3-diamine

The title compound was prepared as in Preparation 5, starting with 2-aminoethanol (282.98 mg, 4.63 mmol, 1.1 equivalents) instead of 2-amino-2-methylpropan-1-ol, and via intermediate 2-( (5-Bromo-3-nitropyridin-2-yl)amino)ethan-1-ol and 2-((3-amino-5-bromopyridin-2-yl)amino)ethan-1-ol keep going. The title compound (600 mg, 50.3% step 3) was obtained as a purple solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.00 (s, 6H) -0.08-0.06 (m, 1 H) 0.84 (s, 9 H) 3.39 -3.39 (m, 3 H) 3.35-3.47 ( m, 1 H) 3.68 (t, J = 6.4 Hz, 2 H) 5.01 (s, 2 H) 5.78 (br t, J = 5.6 Hz, 1 H) 6.78 (d, J = 2.0 Hz, 1 H) 7.35 (d, J= 2.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 346.1. Preparation 10: 6-Bromo-3-(1-hydroxy-2-methylpropan-2-yl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridin-2-one

To acetic acid 2-(6-bromo-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (38 g, 115.80 mmol) in MeOH (200 mL) was added K ₂ CO ₃ (48.01 g, 347.39). The reaction mixture was stirred at 65°C for 3 hours, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with EtOAc, then triturated with EtOAc/petroleum ether (1:5, 60 mL) and filtered to obtain the title compound (16 g, 47%) as an off-white solid ). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.65 (s, 6H) 3.84 (d, J = 6.0 Hz, 2H) 4.85 (t, J = 6.0 Hz, 1H) 7.41 (d, J = 2.0 Hz, 1H) 8.00 (d, J= 2.0Hz, 1H) 11.21 (s, 1H); ESI-MS m/z [M+H] ⁺ = 288.0 [M+2] ⁺ . Preparation 11: Acetic acid 2-(6-bromo-2-methyl- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

To 5-bromo- N ² -(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)pyridine-2,3-diamine (500 mg, 1.34 mmol) in HOAc (5 mL) was added tetramethoxymethane (181.82 mg, 1.34 mmol). The reaction mixture was heated to 120°C and stirred under nitrogen for 12 hours. The mixture was then concentrated in vacuo to remove HOAc. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 6%-20% EtOAc in petroleum ether to obtain the title compound (61 mg, 14%) as a pale yellow oil . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.92 (s, 6 H) 1.94 (s, 3 H) 2.81 (s, 3 H) 4.77 (s, 2 H) 8.01 (d, J = 2.00 Hz, 1 H) 8.31 (d, J= 2.40 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 326.1. Preparation 12: 6-Bromo-3-(1-((tertiary butyldimethylsilyl)oxy)-2-methylprop-2-yl)-2-methoxy- 3H -imidazo [4,5- b ]pyridine

步驟1：2-(((苄基氧基)羰基)胺基)-2-甲基丙酸甲基酯

Make 5-bromo- N ² -(1-((tertiary butyldimethylsilyl)oxy)-2-methylprop-2-yl)pyridine-2,3-diamine (200 mg, 534 µmol), a mixture of tetramethoxymethane (218.19 mg, 1.60 mmol) and propionic acid (118.72 mg, 1.60 mmol) was degassed and _{purged with N 2} (3 ×), and then at 100° C. under a _{N 2 atmosphere} Stir for 6 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO ₂ ) using a gradient of 0%-5% EtOAc in petroleum ether to obtain the title as a light blue oil Compound (130 mg, 58.7%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.20 (d, J =2.8 Hz, 6 H) 0.73 (t, J =2.8 Hz, 9 H) 1.80 (s, 6 H) 4.01 (s, 2 H) 4.14 (s, 3 H) 7.81 (d, J =2.0 Hz, 1 H) 8.15 (d, J =2.4 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 416.2. Preparation 13: Acetic acid 2-(6-bromo-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl- 1,1- d ₂ ester

Step 1: 2-(((Benzyloxy)carbonyl)amino)-2-methylpropionic acid methyl ester

To a stirred solution of 2-amino-2-methyl-propionic acid methyl ester (1 g, 8.54 mmol, HCl) in water (15 mL) at 10°C was added Na ₂ CO ₃ (3.17 g, 29.88 mmol ), then add a solution of benzyl chloroformate (1.53 g, 8.96 mmol) in dioxane (20 mL). The resulting white suspension was stirred at 25°C for 2 hours under nitrogen. The mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-30% EtOAc in petroleum ether to obtain the title compound (860 mg, 40.1%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.35 (s, 6H) 3.58 (s, 3H) 5.00 (s, 2H) 7.28-7.42 (m, 5H) 7.73 (s, 1H); ESI-MS m/z [M+H] ⁺ = 252.1. Step 2: (1-Hydroxy-2-methylprop-2-yl-1,1- d ₂ ) benzyl carbamate

To a solution of LiAlD ₄ (151.05 mg, 3.98 mmol) in THF (10 mL) was added 2-(((benzyloxy)carbonyl)amino)-2-methylpropionic acid methyl ester (500 mg, 1.99 mmol), and the resulting mixture was stirred at 10°C for 1 hour under nitrogen. The reaction mixture was quenched with saturated _{aqueous NH 4} Cl and water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 10%-30% EtOAc in petroleum ether to obtain the title compound (340 mg, 75.9%) as a white oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.16 (s, 6 H) 4.65 (s, 1 H) 4.97 (s, 2 H) 6.69 (s, 1 H) 7.31-7.36 (m, 5 H) ). Step 3: 2-Amino-2-methylpropan-1,1- d ₂ -1-ol

Combine (1-hydroxy-2-methylprop-2-yl-1,1- d ₂ ) benzyl carbamate (340 mg, 1.51 mmol) and Pd/C (50 mg, 10% purity) in MeOH The mixture in (5 mL) was stirred under H ₂ (15 psi) at 15°C for 2 hours. The mixture was filtered and the filtrate was concentrated to give the title compound (150 mg, crude) as a white oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.946 (s, 6H). Step 4: 2-((5-Bromo-3-nitropyridin-2-yl)amino)-2-methylpropan-1,1- d ₂ -1-ol

Combine 2-amino-2-methylpropan-1,1- d ₂ -1-ol (138.20 mg, 1.52 mmol), 5-bromo-2-chloro-3-nitro-pyridine (300 mg, 1.26 mmol) ) And a solution of DIPEA (326.59 mg, 2.53 mmol, 440.14 µL) in acetonitrile (5 mL) under nitrogen at 80°C for 12 hours. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ ) using a 5%-20% EtOAc gradient in petroleum ether to obtain the title compound (160 mg, 43.3%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.48 (s, 6 H) 4.19 (s, 1 H) 8.37-8.47 (m, 2 H) 8.60 (d, J= 2.4 Hz, 1 H). Step 5: Acetic acid 2-((5-bromo-3-nitropyridin-2-yl)amino)-2-methylpropyl-1,1- d ₂ ester

Combine 2-((5-bromo-3-nitropyridin-2-yl)amino)-2-methylpropan-1,1- d ₂ -1-ol (160 mg, 547.71 µmol) and acetic anhydride ( A solution of 111.83 mg, 1.10 mmol) in pyridine (3 mL) was stirred under nitrogen at 80°C for 3 hours. The mixture was concentrated, and the resulting residue was washed with 1 M HCl. The organic layer was evaporated to give the title compound (200 mg, crude) as a yellow solid. ESI-MS m/z [M+H] ⁺ = 333.9. Step 6: Acetic acid 2-((3-amino-5-bromopyridin-2-yl)amino)-2-methylpropyl-1,1- d ₂ ester

Acetic acid 2-((5-bromo-3-nitropyridin-2-yl)amino)-2-methylpropyl-1,1- d ₂ ester (183 mg, 548 µmol), Fe (152.91 mg , 2.74 mmol) and NH ₄ Cl (117.18 mg, 2.19 mmol) in EtOH (2 mL) and water (0.5 mL) were stirred at 80°C for 1 hour under nitrogen. The mixture was filtered, and the filtrate was concentrated. The resulting residue was dispersed in water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to give the title compound (160 mg, crude) as a brown solid. ESI-MS m/z [M+H] ⁺ = 304.0. Step 7: Acetic acid [2-(6-bromo-2-oxo-1H-imidazo[4,5-b]pyridin-3-yl)-1,1-dideutero-2-methyl-propyl ]ester

步驟1：5-溴-2-((1-羥基-2-甲基丙-2-基)胺基)菸鹼甲腈

Acetic acid 2-((3-amino-5-bromopyridin-2-yl)amino)-2-methylpropyl-1,1- d ₂ ester (160 mg, 526.01 µmol) and CDI (127.94 mg , 789.01 µmol) in THF (3 mL) was stirred at 70°C for 5 hours under nitrogen. The mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO ₂ ) using a gradient of 0%-30% EtOAc in petroleum to obtain the title compound (130 mg, 74.9%) as a yellow solid. ESI-MS m/z [M+H] ⁺ = 330.1. Preparation 14: 2-(5-Bromo-1 H -pyrrolo[2,3- b ]pyridin-1-yl)-2-methylpropan-1-ol

Step 1: 5-Bromo-2-((1-hydroxy-2-methylprop-2-yl)amino)nicotine carbonitrile

To 5-bromo-2-chloronicotine carbonitrile (5 g, 22.99 mmol) and 2-amino-2-methylpropan-1-ol (4.10 g, 45.99 mmol, 4.39 mL) in acetonitrile (50 mL) _{Add Cs 2} CO ₃ (14.98 g, 45.99 mmol) to the solution in the solution. The mixture was stirred at 85°C for 15 hours, and then quenched by the addition of water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 9%-17% EtOAc in petroleum ether to obtain the title compound (2 g, 32%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.42 (s, 6 H) 3.66 (s, 2 H) 7.92 (d, J = 2.40 Hz, 1 H) 8.29 (d, J = 2.40 Hz, 1 H ); ESI-MS m/z [M+H] ⁺ = 271.0. Step 2: 5-Bromo-2-((1-hydroxy-2-methylprop-2-yl)amino)nicotinaldehyde

To 5-bromo-2-((1-hydroxy-2-methylprop-2-yl)amino)nicotine carbonitrile (2 g, 7.40 mmol) in pyridine (20 mL), water (10 mL) and Add Raney-Ni (2.22 g, 25.91 mmol) and NaH ₂ PO ₂ (3.18 g, 37.02 mmol) to the solution in HOAc (10 mL). The mixture was stirred under nitrogen at 25°C for 12 hours, then filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ ) using a gradient of 4%-5% EtOAc in petroleum ether to obtain the title compound (750 mg, 35.2%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.43 (s, 6 H) 3.68 (s, 2 H) 5.73 (s, 1 H) 7.86 (d, J =2.40 Hz, 1 H) 8.25 (d, J =2.40 Hz, 1 H) 8.63 (s, 1 H) 9.74 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 274.0. Step 3: 2-((5-Bromo-3-ethynylpyridin-2-yl)amino)-2-methylpropan-1-ol

To 5-bromo-2-((1-hydroxy-2-methylprop-2-yl)amino)nicotinic aldehyde (750 mg, 2.75 mmol) and (1-diazo-2-oxypropyl) _{Add K 2} CO ₃ (760.13 mg, 5.50 mmol) to a solution of dimethyl phosphonate (633.96 mg, 3.30 mmol) in MeOH (10 mL). The mixture was stirred at 25°C for 15 hours, and then concentrated under reduced pressure. The concentrate was adjusted to pH=8 using saturated aqueous NaHCO _{3 and then extracted with EtOAc.} The organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated. By column chromatography (SiO ₂ ), elution was performed using a 4%-6% EtOAc gradient in petroleum ether and then the resulting residue was purified by preparative HPLC to give the title compound (510 mg, crude). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.38 (s, 6 H) 3.52 (s, 1 H) 3.65 (s, 2 H) 4.02 (s, 1 H) 5.36 (s, 1 H) 6.20 (s , 1 H) 7.64 (d, J= 2.40 Hz, 1 H) 8.02 (d, J= 2.40 Hz, 1 H); ESI-MS m/z [M+Na] ⁺ = 291.0. Step 4: 2-(5-Bromo- 1H -pyrrolo[2,3- b ]pyridin-1-yl)-2-methylpropan-1-ol

步驟1：2-((3-溴-5-氯吡啶-2-基)胺基)-2-甲基丙-1-醇

To a solution of 2-((5-bromo-3-ethynylpyridin-2-yl)amino)-2-methylpropan-1-ol (510 mg, 1.89 mmol) in DMF (5 mL) was added KO t -Bu (425.27 mg, 3.79 mmol). The reaction mixture was stirred at 25°C for 15 hours, and then quenched by the addition of water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-5% EtOAc in petroleum ether to obtain the title compound (360 mg, 70.6%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.66 (s, 6 H) 4.03 (s, 2 H) 6.13 (s, 1 H) 6.43 (d, J = 4.00 Hz, 1 H) 7.40 (d, J = 3.60 Hz, 1 H) 8.05 (d, J= 2.00 Hz, 1 H) 8.27 (d, J= 2.00 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 269.0. Preparation 15: 2-(5-Chloro-2-methyl- 1H -pyrrolo[2,3- b ]pyridin-1-yl)-2-methylpropan-1-ol

Step 1: 2-((3-Bromo-5-chloropyridin-2-yl)amino)-2-methylpropan-1-ol

To 3-bromo-5-chloro-2-fluoropyridine (5 g, 24 mmol) and 2-amino-2-methylpropan-1-ol (3.18 g, 35.6 mmol, 3.40 mL) under _{N 2} Add DIPEA (6.14 g, 47.52 mmol) to the mixture in DMSO (50 mL) all at once. The reaction mixture was stirred at 150 °C for 6 hours, then quenched with water (50 mL) and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ ) using a 5%-20% EtOAc gradient in petroleum ether to obtain the title compound (2.8 g, 41%) as a colorless oil. ESI-MS m/z [M+H] ⁺ = 281.0. Step 2: Acetic acid 2-((3-bromo-5-chloropyridin-2-yl)amino)-2-methylpropyl ester

Add ₂ -((3-bromo-5-chloropyridin-2-yl)amino)-2-methylpropan-1-ol (2.8 g, 9.7 mmol) in pyridine (10 mL) under N 2 Acetic anhydride (1.98 g, 19.4 mmol, 1.82 mL) was added to the mixture in one portion. The reaction mixture was stirred at 80°C for 3 hours, then diluted with water, and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-5% EtOAc in petroleum ether to obtain the title compound (3.0 g, 95%) as a colorless oil. ESI-MS m/z [M+H] ⁺ = 323.0. Step 3: Acetic acid 2-((5-chloro-3-(prop-1-yn-1-yl)pyridin-2-yl)amino)-2-methylpropyl ester

Under N ₂ to the acetic acid 2 - ((3-bromo-5-chloro-pyridin-2-yl) amino) -2-methyl-propyl ester (1 g, 3.07 mmol) and tributyl (prop-l _{Add Pd(PPh 3} ) ₄ (177.32 mg, 153.45 µmol) to a mixture of alkyn-1-yl)stannane (1.21 g, 3.68 mmol) in toluene (10 mL) in one portion. The reaction mixture was stirred at 100°C for 12 hours, and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-20% EtOAc in petroleum ether to obtain the title compound (600 mg, 67.6%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.46 (s, 6 H) 2.08 (s, 3 H) 2.13 (s, 3 H) 4.36 (s, 2 H) 5.25 (s, 1 H) 7.35 (d , J= 2.6 Hz, 1 H) 7.91 (d, J= 2.6 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 281.1. Step 4: 2-(5-Chloro-2-methyl-1 H -pyrrolo[2,3- b ]pyridin-1-yl)-2-methylpropan-1-ol

Under N ₂ to the acetic acid 2 - ((5-chloro-3- (prop-1-yn-1-yl) pyridin-2-yl) amino) -2-methyl-propyl ester (500 mg, 1.73 mmol ) Add NaO t- Bu (498.56 mg, 5.19 mmol) to the mixture in DMF (10 mL) in one portion. The reaction mixture was stirred at 60°C for 12 hours, then diluted with water, and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 2%-10% EtOAc in petroleum ether to obtain the title compound (250 mg, 60.0%) as a pale yellow oil . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.65 (s, 6 H) 2.68 (s, 3 H) 4.17 (s, 2 H) 6.23 (s, 1 H) 6.34 (s, 1 H) 7.73 (d , J= 2.4 Hz, 1 H) 8.08 (d, J= 2.4 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 239.1. Preparation 16: 6-Bromo-3-(1-((tert-butyldimethylsilyl)oxy)-2-methylprop-2-yl)-2-ethoxy- 3H -imidazo [4,5- b ]pyridine

Make tetraethoxymethane (2.57 g, 13.35 mmol), propionic acid (593.59 mg, 8.01 mmol) and 5-bromo- N ² -(1-((tertiary butyldimethylsilyl)oxy)- The mixture of 2-methylpropan-2-yl)pyridine-2,3-diamine (2 g, 5.34 mmol) was degassed and _{purged with N 2} (3 ×), followed by stirring at 100°C under nitrogen 6 Hours and concentrated. The crude product was purified by column chromatography using a gradient of 0%-20% EtOAc in petroleum ether to obtain the title compound (1.2 g, 52%) as a purple oil. ESI-MS m/z [M+H] ⁺ = 430.1. Preparation 17: 6-Bromo-3-(1-((tertiary butyldimethylsilyl)oxy)prop-2-yl)-2-methoxy- 3H -imidazo[4,5- b ]pyridine

To 5-bromo- N ² -(1-((tert-butyldimethylsilyl)oxy)prop-2-yl)pyridine-2,3-diamine (400 mg, 1.11 mmol) in propionic acid Add tetramethoxymethane (377.80 mg, 2.77 mmol) to the solution in (123.34 mg, 1.66 mmol). The reaction mixture was stirred at 100°C for 5 hours, then concentrated under reduced pressure and diluted with EtOAc and water. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-40% EtOAc in petroleum ether to obtain the title compound (300 mg, 67.5%) as a yellow oil. ESI-MS m/z [M+H] ⁺ = 402.0. Preparation 18: 6-Bromo-3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methoxy- 3H -imidazo[4,5- b ]pyridine

To 5-bromo- N ² -(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridine-2,3-diamine (300 mg, 866.21 µmol) in propionic acid (96.25 mg , 1.30 mmol, 96.93 µL) add tetramethoxymethane (294.83 mg, 2.17 mmol). The reaction mixture was stirred at 100°C for 7 hours, then poured into water and extracted with EtOAc. The organic layer was washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ ) with a gradient of 8%-30% EtOAc in petroleum ether to obtain the title compound (200 mg, 59.8%) as a yellow oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.23 (s, 6 H) 0.68 (s, 9 H) 3.89-3.93 (m, 2 H) 4.13 (s, 3 H) 4.14-4.16 (m, 2 H) 8.04 (d, J= 2.0 Hz, 1 H) 8.21 (d, J= 2.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 388.0. Preparation 19: Acetic acid 2-(6-bromo-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

步驟1：3-溴-N -環丙基-4-甲基苯甲醯胺

To a solution of 2-((3-amino-5-bromopyridin-2-yl)amino)-2-methylpropyl acetate (2.8 g, 9.27 mmol) in HOAc (10 mL) was added triethyl Oxymethane (6.87 g, 46.33 mmol). The reaction mixture was stirred at 80°C for 15 hours, then concentrated under reduced pressure, and _{purified by column chromatography (SiO 2} ) using a gradient of 15%-25% EtOAc in petroleum ether to elute to obtain The title compound (2.4 g, 83%) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.84 (s, 6 H) 1.94 (s, 3 H) 4.69 (s, 2 H) 8.10 (s, 1 H) 8.19 (d, J = 1.6 Hz, 1 H) 8.41 (d, J= 2.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 311.8. Preparation 20: N -cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl Amide

Step 1: 3-Bromo- N -cyclopropyl-4-methylbenzamide

To a solution of 3-bromo-4-methylbenzoic acid (3.6 g, 16.74 mmol) and cyclopropylamine (955.80 mg, 16.74 mmol) in DMF (20 mL) was added HATU (7.00 g, 18.41 mmol) and Et ₃ N (5.08 g, 50.22 mmol). The reaction mixture was stirred at 30°C for 16 hours, and then diluted with water (40 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 10%-30% EtOAc in petroleum ether to purify the resulting residue to obtain the title compound (4.7 g, 99%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.63 (dd, J= 1.6, 3.6 Hz, 2 H) 0.85 (dd, J= 1.6, 3.6 Hz, 2 H) 2.43 (s, 3 H) 2.86-2.92 (m, 1 H) 6.23 (s, 1 H) 7.27 (s, 1 H) 7.58 (dd, J= 1.6, 8.0 Hz, 1 H) 7.90 (d, J= 1.6 Hz, 1 H). Step 2: N -Cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl Amide

步驟1：2-(5-溴-1H -吡咯并[2,3-b ]吡啶-1-基)乙酸

Make 3-bromo- N -cyclopropyl-4-methylbenzamide (4.8 g, 18.89 mmol), 4,4,4',4',5,5,5',5'-octamethyl -2,2'-bis(1,3,2-dioxaborolane) (5.04 g, 19.83 mmol), KOAc (5.56 g, 56.67 mmol), Pd(dppf)Cl ₂ (829.26 mg, A mixture of 1.13 mmol) in dioxane (80 mL) was degassed and _{purged with N 2} (3×). The mixture _{was stirred at 80°C for 1 hour under an N 2} atmosphere, and then diluted with water (40 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 10%-30% EtOAc in petroleum ether to purify the resulting residue, followed by trituration with 10% EtOAc in petroleum ether (30 mL) and filtration to obtain The title compound (5.5 g, 97%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.55-0.70 (m, 2 H) 0.73-0.94 (m, 2 H), 1.28-1.43 (m, 12 H) 2.51-2.60 (m, 3 H) 2.87 (td, J= 3.6, 7.2 Hz, 1 H) 6.31-6.55 (m, 1 H) 7.17-7.24 (m, 1 H) 7.77-7.85 (m, 1 H) 7.98 (s, 1 H). Preparation 21: 2-(5-Bromo-1 H -pyrrolo[2,3- b ]pyridin-1-yl)ethan-1-ol

Step 1: 2-(5-Bromo-1 H -pyrrolo[2,3- b ]pyridin-1-yl)acetic acid

To a solution of 5-bromo- 1H -pyrrolo[2,3- b ]pyridine (500 mg, 2.54 mmol) in DMF (5 mL) was added methyl 2-bromoacetate (465.84 mg, 3.05 mmol) and Cs ₂ CO ₃ (4.13 g, 12.69 mmol). The reaction mixture was stirred at 80°C for 16 hours, then poured into water and adjusted to pH 3 with aqueous HCl (1 M). The acidified mixture was extracted with EtOAc, and the organic layer was washed with brine and dried _{over Na 2} SO _4. The crude product was dried under reduced pressure to obtain a yellow solid, which was triturated with petroleum ether/EtOAc (10:1) and separated by filtration. The filter cake was dried under reduced pressure to obtain the title compound (500 mg, 74.9%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 5.03 (s, 2 H) 6.50 (d, J = 3.6 Hz, 1 H) 7.62 (d, J = 3.6 Hz, 1 H) 8.24 (d, J = 2.0 Hz, 1 H) 8.30 (d, J= 2.0 Hz, 1 H) 12.64-13.48 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 256.9. Step 2: 2-(5-Bromo-1 H -pyrrolo[2,3- b ]pyridin-1-yl)ethan-1-ol

_{Add BH 3 to a} solution of 2-(5-bromo-1 H -pyrrolo[2,3- b ]pyridin-1-yl)acetic acid (100 mg, 392.05 µmol) in DCM (10 mL) at 0°C -Me ₂ S (10 M, 196.03 µL). The reaction mixture was stirred at 20°C for 12 hours, then poured into water and extracted with DCM. Dried organic layer was washed with brine Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by preparative TLC (SiO ₂ ) and eluted with 50% EtOAc in petroleum ether to obtain the title compound (50 mg, 53%) as a yellow oil. ESI-MS m/z [M+H] ⁺ = 243.0. Preparation 22: 2-((3-Amino-5-bromopyridin-2-yl)amino)ethyl acetate

The title compound was prepared as in Preparation 6, starting with 2-aminoethanol (257.26 mg, 4.21 mmol, 2 equivalents) instead of 2-amino-2-methylpropan-1-ol, and via intermediate 2-( (5-Bromo-3-nitropyridin-2-yl)amino)ethan-1-ol and 2-((5-bromo-3-nitropyridin-2-yl)amino)ethyl acetate continue get on. The title compound (430 mg, crude) was obtained as a red solid. ESI-MS m/z [M+H] ⁺ = 276.1. Preparation 23: 2-(6-Bromo- 3H -imidazo[4,5- b ]pyridin-3-yl)ethyl acetate

To a solution of 2-((3-amino-5-bromopyridin-2-yl)amino)ethyl acetate (200 mg, 729.62 µmol) and HOAc (3 mL) was added trimethoxymethane (193.57 mg, 1.82 mmol). The mixture was stirred at 80°C for 2 hours, and then concentrated under reduced pressure to remove HOAc. The residue was dissolved in EtOAc, and the mixture was washed with water. The organic layer was dried, concentrated, and purified by preparative TLC using EtOAc to obtain the title compound (178 mg, 85.8% yield) as a brown solid. ESI-MS m/z [M+H] ⁺ = 286.0. Preparation 24: Acetic acid 2-(6-bromo-2-methoxy- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl acetate

步驟1：2-((5-溴-4-甲基-3-硝基吡啶-2-基)胺基)-2-甲基丙-1-醇

To acetic acid 2-((3-amino-5-bromopyridin-2-yl)amino)-2-methylpropyl ester (150 mg, 496.41 µmol) in tetramethoxymethane (405.51 mg, 2.98 mmol) Add propionic acid (36.77 mg, 496.41 µmol) to the solution in ). The reaction mixture was stirred at 100°C for 2 hours. Acetonitrile (1 mL) was added, and the mixture was stirred at 90 °C for 16 hours, at which time additional propionic acid (147.09 mg, 1.99 mmol) was added. The reaction mixture was stirred at 100°C for 48 hours, then concentrated in vacuo, and purified by silica gel column chromatography using a 5%-30% petroleum ether gradient in EtOAc to obtain a blue solid The title compound (165 mg, 97.1%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.85 (s, 6 H) 1.96 (s, 3 H) 4.20 (s, 3 H) 4.67 (s, 2 H) 7.85 (d, J = 2.0 Hz , 1 H) 8.17 (d, J= 2.0 Hz, 1 H). Preparation 25: Acetic acid 2-((3-amino-5-bromo-4-methylpyridin-2-yl)amino)-2-methylpropyl ester

Step 1: 2-((5-Bromo-4-methyl-3-nitropyridin-2-yl)amino)-2-methylpropan-1-ol

Under N ₂ 5-bromo-2-chloro-4-methyl-3-nitropyridine (3 g, 11.9 mmol) in 2-amino-2-methylpropan-1-ol (11.4 mL, 119 The solution in mmol) was heated to 100°C for 2 hours, then diluted with water and extracted with EtOAc. The organic phase was separated, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ ) using a 5%-20% EtOAc gradient in petroleum ether to obtain the title compound (2.5 g, 67%) as an orange solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.39 (s, 6 H) 2.48 (s, 3 H) 3.68 (d, J = 6.0 Hz, 2 H) 4.81-4.85 (m, 1 H) 6.63 (s , 1 H) 8.29 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 304.2. Step 2: Acetic acid 2-((5-bromo-4-methyl-3-nitropyridin-2-yl)amino)-2-methylpropyl ester

To 2-((5-bromo-4-methyl-3-nitropyridin-2-yl)amino)-2-methylpropan-1-ol (1 g, 3.19 mmol) in pyridine (10 mL) Add acetic anhydride (0.597 mL, 6.38 mmol) to the solution in the solution. The reaction mixture was stirred at 90°C for 4 hours, and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) and eluted with 10% EtOAc in petroleum ether to obtain the title compound (1.1 g, crude) as an orange oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.10 (s, 6 H) 2.68 (s, 3 H) 3.10 (s, 3 H) 4.98 (s, 2 H) 7.99 (s, 1 H) 8.92 (s , 1 H); ESI-MS m/z [M+H] ⁺ = 346.1. Step 3: Acetic acid 2-((3-amino-5-bromo-4-methylpyridin-2-yl)amino)-2-methylpropyl ester

To acetic acid 2-((5-bromo-4-methyl-3-nitropyridin-2-yl)amino)-2-methylpropyl ester (1.1 g, 3.18 mmol) in EtOH (15 mL) and Add Fe (887 mg, 15.9 mmol) and NH ₄ Cl (1.70 g, 31.8 mmol) to the solution in water (1.5 mL). The reaction mixture was stirred at 80°C for 2 hours, and then concentrated under reduced pressure. The concentrate was diluted with water and extracted with EtOAc (40 mL). The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to give the title compound (0.8 g, crude) of a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.45 (s, 6 H) 2.06 (s, 3 H) 2.24 (s, 3 H) 3.28 (s, 2 H) 4.36 (s, 2 H) 7.79 (s , 1 H); ESI-MS m/z [M+H] ⁺ = 318.2. Preparation 26: Acetic acid 2-((3-amino-5-bromo-6-methylpyridin-2-yl)amino)-2-methylpropyl ester

The title compound was prepared as in Preparation 25, replacing 5-bromo-2-chloro-4-methyl with 3-bromo-6-chloro-2-methyl-5-nitropyridine (1.5 g, 5.97 mmol, 1 equivalent) Started with 3-nitropyridine and via the intermediate 2-((5-bromo-6-methyl-3-nitropyridin-2-yl)amino)-2-methylpropan-1-ol (2.11 g, crude) and 2-((5-bromo-6-methyl-3-nitropyridin-2-yl)amino)-2-methylpropyl acetate (2.4 g, 85%) continue get on. The title compound (0.98 g, 82%) was obtained as a yellow liquid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.47 (s, 6 H) 1.87 (s, 3 H) 2.06 (s, 3 H) 3.06 (s, 2 H) 4.40 (s, 2 H) 6.96 (s , 1 H); ESI-MS m/z [M+H] ⁺ = 316.2. Preparation 27: Acetic acid 2-(6-bromo-7-methyl-2-oxo-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2- Methyl propyl ester

To acetic acid 2-((3-amino-5-bromo-4-methylpyridin-2-yl)amino)-2-methylpropyl ester (0.5 g, 1.58 mmol) in THF (60 mL) Add CDI (385 mg, 2.37 mmol) to the solution. The mixture was stirred at 70°C for 16 hours. Add additional CDI (0.2 g) and THF (20 mL). The reaction mixture was stirred at 75°C for 3 hours, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2) using a 10%-50% EtOAc gradient in petroleum ether to obtain the title compound (0.35 g, 65%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.85 (s, 6 H) 1.98 (s, 3 H) 2.41 (s, 3 H) 4.71 (s, 2 H) 8.09 (s, 1 H) 10.69 (s , 1 H); ESI-MS m/z [M+Na] ⁺ = 364.2. Preparation 28: Acetic acid 2-(6-bromo-5-methyl-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2- Methyl propyl ester

步驟1：2-胺基-2-(甲基-d ₃ )丙腈-3,3,3-d ₃

To acetic acid 2-((3-amino-5-bromo-6-methylpyridin-2-yl)amino)-2-methylpropyl ester (0.98 g, 2.85 mmol) in THF (120 mL) Add CDI (693 mg, 4.27 mmol) to the solution. The mixture was stirred at 75°C for 19 hours, then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO _4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of 30%-50% EtOAc in petroleum ether to purify the resulting residue to obtain the title compound (1 g, 92%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.85 (s, 6 H) 2.00 (s, 3 H) 2.58 (s, 3 H) 4.73 (s, 2 H) 7.37 (s, 1 H) 8.95 (s , 1 H); ESI-MS m/z [M+H] ⁺ = 342.2. Preparation 29: 2-Amino-2-(methyl- d ₃ )propan-3,3,3- d ₃ -1-ol

Step 1: 2-Amino-2-(methyl- d ₃ )propionitrile-3,3,3- d ₃

To a solution of NH ₄ Cl (11.01 g, 205.88 mmol) and NaCN (10.09 g, 205.88 mmol) in DCM (60 mL) and water (120 mL) was added propan-2-one- d ₆ (11 g, 171.56 mmol). The reaction mixture was stirred in a sealed container at 15°C for 24 hours, followed by extraction with DCM. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to give the title compound (11.5 g, crude) as a yellow oil. Step 2: 2-Amino-2-(methyl- d ₃ )propionic acid-3,3,3- d ₃

To the 2-amino-2-(methyl- d ₃ )propionitrile-3,3,3- d ₃ solution (11.5 g, 90.82 mmol, HCl) was added aqueous HCl solution (12 M, 70 mL). The mixture was stirred at 100°C for 4 hours, and then concentrated in vacuo. Ethanol was added, and the mixture was filtered through a Buchner funnel. The crude product was purified by recrystallization from THF to obtain the HCl salt of the title compound (12 g, 91%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.61 (d, J =6.4 Hz, 1 H) 8.61 (s, 2 H). Step 3: 3-Amino-3-(methyl- d ₃ )butyric acid-4,4,4- d ₃ methyl ester

To a solution of SOCl ₂ (24.60 g, 206.77 mmol) in MeOH (80 mL) at 0°C was added 2-amino-2-(methyl- d ₃ )propionic acid-3,3,3- at 0°C A solution of d ₃ (12 g, 97.42 mmol, HCl) in MeOH (40 mL). The reaction mixture was stirred under N ₂ at 70 ℃ 3 h and then concentrated in vacuo to afford the HCl salt of the title compound of yellow solid (15.1 g, crude). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.73 (s, 2 H) 4.56 (s, 3 H) 8.82 (s, 2 H); ESI-MS m/z [M+H] ⁺ = 174.1 . Step 4: 3-(((Benzyloxy)carbonyl)amino)-3-(methyl- d ₃ )butyric acid-4,4,4- d ₃ methyl ester

Add 3-amino-3-(methyl- d ₃ )butyric acid-4,4,4- d ₃ methyl ester (5.1 g, 29.37 mmol, HCl) and Na ₂ CO ₃ (9.34 g , 88.10 mmol) in water (30 mL) and dioxane (85 mL) was added dropwise to benzyl chloroformate (6.01 g, 35.24 mmol) in dioxane (15 mL). The reaction mixture was stirred at 15°C for 3 hours, then diluted with EtOAc and water. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-20% EtOAc in petroleum ether to obtain the title compound (2 g, 25%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.59 (s, 3 H) 5.01 (s, 2 H) 7.32-7.40 (m, 5 H) 7.72 (s, 1 H). Step 5: (2-(Hydroxymethyl)prop-2-yl-1,1,1,3,3,3- d ₆ )benzyl carbamate

_{To a mixture of LiAlH 4} (590.01 mg, 15.55 mmol) in THF (30 mL) was added dropwise 3-(((benzyloxy)carbonyl in THF (15 mL) during a 5-minute period at 15°C )Amino)-3-(methyl- d ₃ )butyric acid-4,4,4- d ₃ methyl ester (2 g, 7.77 mmol). The reaction mixture was stirred at 15°C for 2 hours, and then adjusted to pH 7 _{with saturated aqueous NH 4 Cl.} The aqueous phase was extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to give the title compound as a yellow solid (1.2 g, 67%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.18 (t, J =7.2 Hz, 1 H) 2.00 (s, 1 H) 4.01-4.07 (m, 1 H) 4.70 (t, J = 6.0 Hz , 1 H) 5.00 (s, 2 H) 6.70 (s, 1 H) 7.29-7.33 (m, 1 H) 7.36 (s, 2 H) 7.37 (d, J =2.8 Hz, 1 H). Step 6: 2-Amino-2-(methyl- d ₃ )propan-3,3,3- d ₃ -1-ol

步驟1：2-((5-溴-3-硝基吡啶-2-基)胺基)-2-(甲基-d ₃ )丙-3,3,3-d ₃ -1-醇

Make (2-(hydroxymethyl)prop-2-yl-1,1,1,3,3,3- d ₆ ) benzyl carbamate (1.2 g, 5.23 mmol), Pd/C (300 mg , 10% purity) in MeOH (20 mL) was degassed and _{purged with H 2} (3×). The reaction mixture _{was stirred at 15°C for 2 hours under an atmosphere of H 2} (15 psi), then poured into MeOH and filtered through a pad of Celite®. The filtrate was concentrated in vacuo to give the title compound (480 mg, crude) as a white oil. ESI-MS m/z [M+H] ⁺ = 96.1. Preparation 30: Acetic acid 2-(6-bromo-2-oxo-1,2-dihydro- 3H -imidazo[4,5-b]pyridin-3-yl)-2-(methyl- d ₃ ) Propyl-3,3,3- d ₃ ester

Step 1: 2-((5-Bromo-3-nitropyridin-2-yl)amino)-2-(methyl- d ₃ )prop-3,3,3- d ₃ -1-ol

Make 2-amino-2-(methyl- d ₃ )propan-3,3,3- d ₃ -1-ol (480 mg, 5.04 mmol), 5-bromo-2-chloro-3-nitro- A mixture of pyridine (1.09 g, 4.58 mmol) and DIPEA (1.19 g, 9.17 mmol) in acetonitrile (10 mL) was degassed and _{purged with N 2} (3×). The reaction mixture was stirred at 80°C for 12 hours under an _{N 2 atmosphere, and then diluted with EtOAc and water.} The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-20% EtOAc in petroleum ether to obtain the title compound (850 mg, 62.6%) as a yellow solid. Step 2: Acetic acid 2-((5-bromo-3-nitropyridin-2-yl)amino)-2-(methyl- d ₃ )propyl-3,3,3- d ₃ ester

To 2-((5-bromo-3-nitropyridin-2-yl)amino)-2-(methyl- d ₃ )prop-3,3,3- d ₃ -1-ol (850 mg, Add acetic anhydride (586.02 mg, 5.74 mmol) to a solution of 2.87 mmol) in pyridine (10 mL). The reaction mixture was stirred at 80°C for 3 hours, then diluted with EtOAc and water. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to give the title compound (950 mg, crude) of a yellow solid. Step 3: Acetic acid 2-((3-amino-5-bromopyridin-2-yl)amino)-2-(methyl- d ₃ )propyl-3,3,3- d ₃ ester

Make acetic acid 2-((5-bromo-3-nitropyridin-2-yl)amino)-2-(methyl- d ₃ )propyl-3,3,3- d ₃ ester (950 mg, 2.81 A mixture of Fe (784.37 mg, 14.05 mmol) and NH ₄ Cl (601.05 mg, 11.24 mmol) in EtOH (10 mL) and water (2 mL) was degassed and _{purged with N 2} (3×). The reaction mixture _{was stirred at 80°C for 1 hour under a N 2} atmosphere, then poured into EtOH and filtered through a pad of Celite®. The filtrate was concentrated in vacuo to give the title compound (800 mg, crude) as a black oil. Step 4: Acetic acid 2-(6-bromo-2-oxo-1,2-dihydro- 3H -imidazo[4,5-b]pyridin-3-yl)-2-(methyl- d ₃ ) Propyl-3,3,3- d ₃ ester

Acetic acid 2-((3-amino-5-bromopyridin-2-yl)amino)-2-(methyl- d ₃ )propyl-3,3,3- d ₃ ester (800 mg, 2.60 A solution of CDI (631.33 mg, 3.89 mmol) in THF (10 mL) was stirred at 70°C for 5 hours under _{N 2.} Add ethyl acetate and water. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-30% EtOAc in petroleum ether to purify the resulting residue to obtain the title compound (800 mg, 92.2%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.00 (s, 3 H) 4.72 (s, 2 H) 7.42 (d, J =2.0 Hz, 1 H) 8.08 (d, J =2.0 Hz, 1 H) . Preparation 31: 3-Bromo-4-methylbenzyl chloride

步驟1：3-溴-N ,4-二甲基苯甲醯胺

To a solution of 3-bromo-4-methyl-benzoic acid (2 g, 9.30 mmol) in toluene (20 mL) was added SOCl ₂ (3.32 g, 27.90 mmol) and DMF (6.80 mg, 93.00 µmol). The mixture was stirred at 70°C for 3 hours and then concentrated under reduced pressure to give the title compound (2.1 g, 96.7%) as a yellow solid. Preparation 32: N ,4-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Step 1: 3-Bromo- N ,4-dimethylbenzamide

To a solution of methylamine (2 M, 12.85 mL) and DIPEA (3.71 g, 28.71 mmol) at 0°C was slowly added 3-bromo-4-methylbenzyl chloride (2 g, 8.57 mmol). The reaction mixture was stirred at 15°C for 1.5 hours, and then diluted with water. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, _{dried over Na 2} SO ₄ and concentrated to give the title compound (1.8 g, crude) as a white solid. Step 2: N ,4-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Make 3-bromo- N ,4-dimethylbenzamide (1 g, 4.38 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2, 2'-bis(1,3,2-dioxaborolane) (1.34 g, 5.26 mmol), KOAc (1.29 g, 13.15 mmol) and Pd(dppf)Cl ₂ (192.48 mg, 263.06 µmol) The mixture in dioxane (20 mL) was degassed and _{purged with N 2} (3×). The reaction mixture was stirred at 90°C for 16 hours under an _{N 2 atmosphere, and then diluted with water.} The aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 10%-30% EtOAc in petroleum ether to purify the resulting residue to obtain the title compound (600 mg, 49.7%) as a white solid. ESI-MS m/z [M+H] ⁺ = 276.2. Preparation 33: Acetic acid 2-(6-bromo-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridine-3- Yl)-2-methyl propyl ester

To acetic acid 2-(6-bromo-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropane at 15℃ Add 1-bromo-2-fluoroethane (7.31 g, 57.6 mmol) and K ₂ CO ₃ (5.31 g, 38.4 mmol) to a solution of methyl ester (6.3 g, 19 mmol) in acetonitrile (50 mL). The mixture was stirred at 80°C for 12 hours, and then filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography using a gradient of 3%-30% EtOAc in petroleum ether to obtain the title compound (6.6 g) as a purple solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.84 (s, 9 H) 1.98 (s, 3 H) 4.07-4.15 (m, 2 H) 4.64 (t, J =4.4 Hz 1 H) 4.69 (s, 2 H) 4.76 (t, J =4.4 Hz, 1 H) 7.36 (t, J =1.6 Hz, 1 H) 8.04 (t, J =6.0 Hz, 1 H); ESI-MS m/z [M+H ] ⁺ = 374.0. Preparation 34: Acetic acid 2-(1-(2-fluoroethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborole heterocycle Pentan-2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

Make acetic acid 2-(6-bromo-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl) -2-methylpropyl ester (5 g, 12.4 mmol), KOAc (3.67 g, 37.4 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2 ,2'-bis(1,3,2-dioxaborolane) (3.31 g, 13.0 mmol) and Pd(dppf)Cl ₂ (980 mg, 1.34 mmol) in dioxane (40 mL) The mixture was degassed and _{purged with N 2} (3×), and stirred at 90° C. for 5 hours under a _{N 2 atmosphere.} The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography using a gradient of 0.3%-20% EtOAc in petroleum ether to obtain the title compound (5.5 g, crude) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.31 (s, 12 H) 1.78 (s, 6 H) 1.88 (s, 3 H) 4.10-4.30 (m, 2 H) 4.55-4.65 (m, 3 H) 4.72 (m, J = 3.6 Hz 1 H) 7.63 (s, 1 H) 8.20 (s, 1 H). ESI-MS m/z [M+H] ⁺ = 422.2. Preparation 35: 3-Bromo-4-chloro- N -cyclopropylbenzamide

To a solution of 3-bromo-4-chlorobenzoic acid (500 mg, 2.12 mmol) in DCM (6 mL) was added HATU (888 mg, 2.34 mmol) and DIPEA (1.11 mL, 6.37 mmol). The mixture was stirred at 10°C for 30 minutes. Cyclopropylamine (0.147 mL, 2.12 mmol) was added, and the reaction mixture was stirred at 30 °C for 16 hours, then diluted with water and extracted with EtOAc. The organic layers were combined, washed with water, _{dried over Na 2} SO ₄ , concentrated in vacuo, and purified by column chromatography using a gradient of 0%-2.5% EtOAc in petroleum ether to obtain a yellowish color. The title compound (473 mg, 77.1%) as an oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.58-0.64 (m, 2 H) 0.86-0.92 (m, 2 H) 2.86-2.92 (m, 1 H) 6.28 (s, 1 H) 7.51 (d, J =8.4 Hz, 1 H) 7.8 (d, J =2.8 Hz, 1 H) 8.22 (dd, J ₁ =2.0 Hz, J ₂ =6.4 Hz, 1 H); ESI-MS m/z [M+H ] ⁺ = 276.0. Preparation 36: 3-Bromo- N -cyclopropyl-4-fluorobenzamide

To a solution of 3-bromo-4-fluorobenzoic acid (500 mg, 2.28 mmol) and Et ₃ N (0.953 mL, 6.85 mmol) in DMF (3 mL) was added HATU (868 mg, 2.28 mmol). The mixture was stirred at 10°C for 30 minutes. Add cyclopropylamine (0.158 mL, 2.28 mmol). The reaction mixture was stirred at 10°C for 14 hours, and then water (20 mL) was added, forming a precipitate. The solids were separated by filtration. The filter cake was triturated with a mixture of petroleum ether (5 mL) and EtOAc (50 mL) to obtain the title compound (550 mg, 93.3%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.61-0.65 (m, 2 H) 0.84-0.91 (m, 2 H) 2.87-2.91 (m, 1 H) 6.33 (d, J = 72.8 Hz, 1 H ) 7.14-7.27 (m, 1 H) 7.71-7.68 (m, 1 H) 7.95-7.98 (m, 1 H). Preparation 37: 4-Bromo- N -cyclopropyl-5-methylpyridinium

To a solution of 4-bromo-5-methylpicolinic acid (100 mg, 0.463 mmol) and cyclopropylamine (0.032 mL, 0.463 mmol) in DCM (5 mL) was added HATU (194 mg, 0.509 mmol) and Et ₃ N (0.193 mL, 1.39 mmol). The reaction mixture was stirred at 15°C for 2 hours, then concentrated and _{purified by preparative TLC (SiO 2} ) using 50% EtOAc in petroleum ether to elute to obtain the title compound (100 mg, 78.8%). ESI-MS m/z [M+H] ⁺ = 255.0. Preparation 38: 3-Bromo- N -cyclobutyl-4-methylbenzamide

To a solution of cyclobutylamine (85.99 mg, 1.21 mmol) in DCM (5 mL) at 0°C was added Et ₃ N (282.33 mg, 2.79 mmol). Next add 3-bromo-4-methylbenzyl chloride (217.16 mg, 930.04 µmol) in DCM (4 mL) dropwise. The reaction mixture was stirred at 15°C for 15 minutes, then poured into water and extracted with DCM. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo to give the title compound as a white solid (230 mg, 92.2%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.60-1.74 (m, 2 H) 1.98-2.13 (m, 2 H) 2.15-2.26 (m, 2 H) 2.38 (s, 3 H) 4.39 ( t, J = 8.0 Hz, 1 H) 7.44 (d, J = 8.0 Hz, 1 H) 7.76 (dd, J ₁ = 8.0, J ₁ = 1.6 Hz, 1 H) 8.06 (d, J = 1.6 Hz, 1 H) 8.65 (d, J= 7.2 Hz, 1 H). Preparation 39: 3-Bromo- N -cyclopropyl-5-fluoro-4-methylbenzamide

步驟1：3-氯-5-碘-4-甲基苯甲酸

To a solution of 3-bromo-5-fluoro-4-methylbenzoic acid (0.20 g, 0.858 mmol) in DCM (1 mL) at 15°C was added HATU (359 mg, 0.944 mmol) and DIPEA (0.45 mL, 2.57 mmol). The mixture was stirred at 15°C for 30 minutes, after which cyclopropylamine (49 mg, 0.858 mmol) was added. The reaction mixture was stirred at 30°C for 12 hours, then diluted with water and extracted with DCM. The organic layer was concentrated under reduced pressure, and the _{resulting residue was purified by column chromatography (SiO 2} ) using a gradient of 1%-1.25% EtOAc in petroleum ether to obtain the title compound (200 mg, 79.8%). ESI-MS m/z [M+H] ⁺ = 272.0. Preparation 40: 3-Chloro- N -cyclopropyl-5-iodo-4-methylbenzamide

Step 1: 3-Chloro-5-iodo-4-methylbenzoic acid

To a solution of 3-chloro-4-methylbenzoic acid (0.2 g, 1.17 mmol) in H ₂ SO ₄ (4 mL) at 0° C. was added NIS (290.14 mg, 1.29 mmol). The reaction mixture was stirred at 15°C for 1 hour, and then added to ice water (10 mL), forming a solid precipitate. The mixture was filtered to separate the precipitate, which was washed with n-hexane and dried under reduced pressure to obtain the title compound (130 mg, 37.4%) as a pale pink solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.57 (s, 3 H) 7.89 (d, J =1.2 Hz, 1 H) 8.26 (s, 1 H); ESI-MS m/z [M+ H] ⁺ = 297.0. Step 2: 3-Chloro-5-iodo-4-methylbenzyl chloride

To a solution of 3-chloro-5-iodo-4-methylbenzoic acid (76 mg, 0.256 mmol) in THF (2 mL) at 0°C was added SOCl ₂ (0.056 mL, 0.769 mmol), and then DMF ( 1.52 mL, 19.8 mmol). The reaction mixture was stirred at 15°C for 1 hour and then concentrated under reduced pressure to obtain the title compound (80.7 mg, 100%) as a yellow solid. Step 3: 3-Chloro- N -cyclopropyl-5-iodo-4-methylbenzamide

To a solution of cyclopropylamine (0.018 mL, 0.256 mmol) and Et ₃ N (0.107 mL, 769.02 µmol) in THF (1 mL) _{under N 2 at 0°C, add 3-chloro in THF (1 mL)} -5-iodo-4-methylbenzyl chloride (80.7 mg, 0.256 µmol). The reaction mixture was stirred at 15°C for 3 hours, then diluted with water (15 mL) and extracted with EtOAc. The organic layer was washed with 1 M HCl (3 mL) and concentrated under reduced pressure to give the title compound (86 mg, 96%) as a yellow solid. ESI-MS m/z [M+H] ⁺ = 336.0. Preparation 41: 5-Bromo- N -cyclopropyl-6-methylnicotinamide

Add HATU (704 mg, 1.85 mmol) and DIPEA (0.968 mL, 5.55 mmol) to a solution of 5-bromo-6-methylnicotinic acid (400 mg, 1.85 mmol) in DMF (3 mL) at 30°C . The mixture was stirred for 30 minutes, at which time cyclopropylamine (0.128 mL, 1.85 mmol) was added. The reaction mixture was stirred at 30°C for 4 hours, then diluted with water and extracted with DCM. The organic layers were combined, washed with water, dried over Na ₂ SO _4, and concentrated in vacuo. The crude product was triturated with EtOAc (10 mL) at 8°C for 30 minutes to give the title compound (400 mg, 81%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.63-0.69 (m, 2 H) 0.85-0.92 (m, 2 H) 2.70 (s, 3 H) 2.88-2.94 (m, 1 H) 6.50 (s, 1 H) 8.22 (d, J =2.0 Hz, 1 H) 8.73 (d, J =1.6 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 256.8. Preparation 42: 3-Bromo-4-methyl- N- (1-methylcyclopropyl)benzamide

步驟1：3-硝基-1-((2-(三甲基矽基)乙氧基)甲基)-1H -吡唑

To a solution of 1-methylcycloprop-1-amine (110.58 mg, 1.03 mmol, HCl) in Et ₃ N (2 mL) at 0°C was added 3-bromo-4-methylbenzyl chloride (200 mg, 856.57 µmol) in DCM (2 mL). The reaction mixture was stirred at 15°C for 2 hours, and then diluted with water. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude product was purified by preparative TLC using a mixture of petroleum ether and EtOAc (3:1) to obtain the title compound (196 mg, 85.3%) as a white solid. ESI-MS m/z [M+H] ⁺ = 269.2. Preparation 43: 3-Bromo-4-methyl- N -(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazol-3-yl)benzamide

Step 1: 3-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole

To a solution of 3-nitro-1 H -pyrazole (1 g, 8.84 mmol) in DMF (5 mL) was added SEM-Cl (1.77 g, 10.61 mmol) and Cs ₂ CO ₃ (8.64 g, 26.53 mmol) . The reaction mixture was stirred at 15°C for 3 hours, and then poured into water. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO ₂ ) using a 5%-10% EtOAc gradient in petroleum ether to obtain the title compound (1.35 g, 62.7%) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δppm 0.00-0.03 (m, 9 H), 0.95-0.90 (m, 2 H), 3.67-3.58 (m, 2 H), 5.50 (s, 2 H), 6.98 (d, J= 2.4 Hz, 1 H) 7.68-7.65 (m, 1 H). Step 2: 1-((2-(Trimethylsilyl)ethoxy)methyl)-1 H -pyrazol-3-amine

Add Pd to a solution of 3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole (1.35 g, 5.55 mmol) in MeOH (10 mL) /C (102 mg, 5.55 mmol). The reaction mixture was stirred under H ₂ at 15° C. for 3 hours and then filtered. The filtrate was concentrated to obtain the title compound (1.0 g, 84%) as a brown oil. ESI-MS m/z [M+H] ⁺ = 214.1. Step 3: 3-Bromo-4-methyl- N -(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazol-3-yl)benzamide

Add 1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazol-3-amine (164.47 mg, 770.91 µmol) in pyridine (2 mL) at 0℃ The solution was added with a mixture of 3-bromo-4-methylbenzyl chloride (150 mg, 642.43 µmol) in DCM (2 mL). The reaction mixture was stirred at 15°C for 3 hours, and then diluted with water. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ ) with a gradient of 6%-10% EtOAc in petroleum ether to obtain the title compound (230 mg, 87.2%) as a yellow oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.00-0.02 (m, 9 H) 0.88-0.97 (m, 2 H) 2.46 (s, 3 H) 3.50-3.60 (m, 2 H) 5.32 ( s, 2 H) 6.92 (d, J =2.4 Hz, 1 H) 7.34 (d, J =8.0 Hz, 1 H) 7.50 (d, J =2.4 Hz, 1 H) 7.70 (dd, J ₁ =1.6 Hz , J ₂ =7.6 Hz, 1 H) 8.07 (d, J =1.6 Hz, 1 H) 8.35 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 411.2. Preparation 44: 5-Bromo-2-fluoro- N ,4-dimethylbenzamide

Combine 5-bromo-2-fluoro-4-methylbenzoic acid (500 mg, 2.15 mmol), EDCI (616.98 mg, 3.22 mmol), HOBt (289.92 mg, 2.15 mmol) and DIPEA (693.26 mg, 2.15 mmol) at 20°C A mixture of 5.36 mmol) in DMF (10 mL) was stirred for 30 minutes. Methylamine hydrochloride (173.84 mg, 2.57 mmol) was added, and the reaction mixture was stirred at 20°C under N ₂ for 15 hours. Ethyl acetate (50 mL) and water (50 mL) were added, and the aqueous layer and the organic layer were separated. The aqueous layer was extracted with EtOAc, and the organic layers were combined, washed successively with 1 N HCl, saturated aqueous NaHCO ₃ and brine, _{dried over Na 2} SO ₄ , filtered and concentrated in vacuo to give the title compound as a white solid (480 mg , 81%). ESI-MS m/z [M] ⁺ = 246.1.

步驟1：3-硝基-1-(四氫-2H -吡喃-2-基)-1H -吡唑

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.42 (s, 3 H), 3.02-3.03 (m, 3 H), 6.69 (s, 1 H) , 7.01 (d, J = 12.34 Hz, 1 H) , 8.26 (d, J= 7.46 Hz, 1 H). Preparation 45: 1- (tetrahydro -2 H - pyran-2-yl) -1 H - pyrazol-3-amine

Step 1: 3-nitro-1- (tetrahydro -2 H - pyran-2-yl) -1 H - pyrazol

To a solution of 3-nitro-1 H -pyrazole (0.6 g, 5.31 mmol) in THF (5 mL) was added 3,4-dihydro-2 H -pyran (669.51 mg, 7.96 mmol) and p-toluene Sulfonic acid (91.37 mg, 530.62 µmol). The reaction mixture was stirred at 65°C for 5 hours, and then poured into water. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 4%-6% EtOAc in petroleum ether to obtain the title compound (935 mg, 89.4%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.62-1.71 (m, 3 H) 1.95-2.08 (m, 2 H) 2.11-2.22 (m, 1 H) 3.67-3.76 (m, 1 H) 4.02- 4.09 (m, 1 H) 5.45 (dd, J ₁ =2.80 Hz, J ₂ =8.80 Hz, 1 H) 6.92 (d, J =2.80 Hz, 1 H) 7.70 (d, J =2.40 Hz, 1 H) . Step 2: 1- (tetrahydro -2 H - pyran-2-yl) -1 H - pyrazol-3-amine

To a solution of 3-nitro-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazole (600 mg, 3.04 mmol) in MeOH (6 mL) at 20℃ Add Pd/C (60 mg, 3.04 mmol, 10% purity). The suspension was degassed under vacuum and _{purged with H 2} four times. The reaction mixture was stirred for 5 hours at 20 ℃ under H ₂ (15 psi) and then filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (450 mg, crude) as a pale yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.52-1.67 (m, 4 H) 1.97-2.03 (m, 2 H) 3.66 (dd, J ₁ =2.40 Hz, J ₂ =8.00 Hz, 1 H) 4.03 -4.07 (m, 1 H) 5.11 (dd, J ₁ =2.40 Hz, J ₂ = 8.00 Hz, 1 H) 5.65 (d, J =2.40 Hz, 1 H) 7.32 (d, J =2.40 Hz, 1 H ). Preparation 46: 5-Bromo-2-fluoro-4-methyl - N - (1- (tetrahydro -2 H - pyran-2-yl) -1 H - pyrazol-3-yl) benzoyl amine

To a solution of 5-bromo-2-fluoro-4-methylbenzoic acid (250 mg, 1.07 mmol) in DMF (5 mL) at 20°C was added EDCI (308.49 mg, 1.61 mmol), HOBt (217.44 mg, 1.61 mmol) and DIPEA (554.61 mg, 4.29 mmol). The mixture was degassed under vacuum and purged with nitrogen (3×), and then stirred at 20°C for 30 minutes under nitrogen. Intermediate l- at 20 ℃ (tetrahydro -2 H - pyran-2-yl) -1 H - pyrazol-3-amine (233.20 mg, 1.39 mmol). The reaction mixture was degassed under vacuum and purged with nitrogen (3×), and then stirred under nitrogen at 20° C. for another 12 hours. The mixture was then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated under reduced pressure and _{purified by column chromatography (SiO 2} ) using a gradient of 9%-11% EtOAc in petroleum ether to obtain the title compound ( 227 mg, 47.3%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.59-1.74 (m, 4 H) 2.05 (s, 2 H) 2.45 (s, 3 H) 4.01-4.19 (m, 2 H) 5.27 (d, J= 9.60 Hz, 1 H) 6.90 (s, 1 H) 7.54 (s, 1 H) 8.33 (d, J= 7.20 Hz, 1 H) 8.90 (d, J= 14.80 Hz, 1 H); ESI-MS m/ z [M+Na] ⁺ = 404.9. Preparation 47: 5-Bromo-2-fluoro-4-methyl- N -(1-methyl-1 H -pyrazol-3-yl)benzamide

步驟1：2-氯-5-碘-4-甲基苯甲酸

Make 5-bromo-2-fluoro-4-methylbenzoic acid (1.25 g, 4.29 mmol), 1-methyl-1 H -pyrazol-3-amine (458.3 mg, 4.72 mmol), EDCI (1.23 g, A mixture of 6.44 mmol), HOBt (869.52 mg, 6.44 mmol) and DIPEA (2.99 mL, 17.16 mmol) in DMF (15 mL) was degassed and _{purged with N 2} (3×). The reaction mixture was stirred at 15°C for 2 hours under an _{N 2 atmosphere, and then diluted with EtOAc and water.} The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ ) using a gradient of 20%-30% EtOAc in petroleum ether to obtain the title compound (850 mg, 63.5%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.46 (s, 3 H) 3.85 (s, 3 H) 6.82 (d, J =2.0 Hz, 1 H) 7.09 (d, J =12.0 Hz, 1 H) 7.31 (d, J =2.4 Hz, 1 H) 8.34 (d, J =7.6 Hz, 1 H) 8.85 (d, J =14.4 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 312.1. Preparation 48: 2-Chloro- N -cyclopropyl-5-iodo-4-methylbenzamide

Step 1: 2-Chloro-5-iodo-4-methylbenzoic acid

To a solution of 2-chloro-4-methylbenzoic acid (500 mg, 2.93 mmol) in DCM (20 mL) at 0°C during a 10-minute period, H ₂ SO ₄ (6.49 mL, 123 mmol) was added portionwise And NIS (692.39 mg, 3.08 mmol). The reaction mixture was stirred at 20°C for 30 minutes, then quenched with ice and water, and extracted with EtOAc. The aqueous and organic layers were separated, and the aqueous layer was washed with EtOAc. The organic layers were combined, washed with _{aqueous Na 2} SO ₃ (10%), dried over MgSO ₄ and concentrated in vacuo to give the title compound (800 mg, 92%) as a brown solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.39 (s, 3 H) 7.54 (s, 1 H) 8.17 (s, 1 H) 13.44 (s, 3 H). Step 2: 2-Chloro- N -cyclopropyl-5-iodo-4-methylbenzamide

To a mixture of cyclopropylamine (0.10 mL, 1.48 mmol) and 2-chloro-5-iodo-4-methylbenzoic acid (400 mg, 1.35 mmol) in DMF (6 mL) was added EDCI (310 mg, 1.62 mmol) , HOBt (219 mg, 1.62 mmol) and Et ₃ N (0.28 mL, 2.02 mmol). The reaction mixture was stirred at 20°C for 13 hours, then diluted with water and extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure. The crude product was triturated with petroleum ether to obtain the title compound (300 mg, 66.3%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.51-0.54 (m, 2 H) 0.65-0.69 (m, 2 H) 2.36 (s, 3 H) 2.75-2.80 (m, 1 H) 7.47 ( s, 1 H) 7.77 (s, 1 H) 8.45 (d, J = 3.6 Hz, 1 H). Preparation 49: 3-Bromo-4-methyl- N -((1 S ,2 S )-2-methylcyclopropyl)benzamide

To 3-bromo-4-methylbenzoic acid (149.92 mg, 697.15 µmol) and (1 S , 2 S )-2-methylcycloprop-1-amine (49.58 mg, 697.15 µmol, HCl) in DMF (3 Add EDCI (200.47 mg, 1.05 mmol), HOBt (141.30 mg, 1.05 mmol) and DIPEA (540.61 mg, 4.18 mmol) to the solution in mL). The reaction mixture was stirred overnight, then diluted with water and extracted with EtOAc. The organic layer was dried over Na ₂ SO _4, filtered and concentrated. The residue was purified by preparative TLC (SiO ₂ ) and eluted with 10% EtOAc in petroleum ether to obtain the title compound (135 mg, 72.2%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.64-0.66 (m, 1 H), 0.74-0.75 (m, 1 H), 0.76-0.78 (m, 1 H), 0.98-1.16 (m, 3 H ), 2.43 (s, 3 H), 2.58-2.60 (m, 1 H), 6.14 (s, 1 H), 7.26-7.27 (m, 1 H) , 7.58 (d, J = 8.00 Hz, 1 H) , 7.89 (d, J= 2.0 Hz, 1 H) ; ESI-MS m/z [M] ⁺ = 268.1. Preparation 50: 5-Bromo- N -cyclopropyl-2,4-difluorobenzamide

To a solution of 5-bromo-2,4-difluorobenzoic acid (500 mg, 2.11 mmol) in DMF (5 mL) was added cyclopropylamine (180.68 mg, 3.16 mmol, 219.27 µL), EDCI (606.66 mg, 3.16 mmol) ), HOBt (313.58 mg, 2.32 mmol) and DIPEA (1.09 g, 8.44 mmol, 1.47 mL). The reaction mixture was stirred at 15°C for 12 hours, then poured into water and extracted with EtOAc. Dried organic layer was washed with brine Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ ) with a gradient of 10%-80% EtOAc in petroleum ether to obtain the title compound (350 mg, 60.1%) as a white solid. ESI-MS m/z [M+H] ⁺ = 276.1. Preparation 51: 3-Bromo- N -cyclopropyl-4-(trifluoromethyl)benzamide

步驟1：5-溴-2-甲氧基-4-甲基苯甲醯氯

To a solution of 3-bromo-4-(trifluoromethyl)benzoic acid (200 mg, 743.45 µmol) in DMF (3 mL) was added HOBt (120.55 mg, 892.14 µmol), EDCI (213.78 mg, 1.12 mmol), DIPEA (384.34 mg, 2.97 mmol, 517.98 µL) and cyclopropylamine (63.67 mg, 1.12 mmol, 77.27 µL). The reaction mixture was stirred at 15°C for 12 hours, then poured into water and extracted with EtOAc. Dried organic layer was washed with brine Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ ) with a gradient of 10%-80% EtOAc in petroleum ether to obtain the title compound (80 mg, 35%) as a yellow solid. ESI-MS m/z [M+H] ⁺ = 308.1. Preparation 52: 5-Bromo- N -cyclopropyl-2-methoxy-4-methylbenzamide

Step 1: 5-Bromo-2-methoxy-4-methylbenzyl chloride

To a solution of 5-bromo-2-methoxy-4-methylbenzoic acid (100 mg, 408.05 µmol) in toluene (1 mL) was added SOCl ₂ (242.73 mg, 2.04 mmol) and DMF (1.49 mg, 20.40 µmol). The reaction mixture was stirred at 70°C for 2 hours and then dried in vacuo to give the title compound (100 mg, 93%) as a yellow solid. Step 2: 5-Bromo- N -cyclopropyl-2-methoxy-4-methylbenzamide

To a solution of cyclopropylamine (21.67 mg, 379.48 µmol) in DCM (1 mL) was added Et ₃ N (192.00 mg, 1.90 mmol). The mixture was stirred at 0°C for 30 minutes. Add a solution of 5-bromo-2-methoxy-4-methylbenzyl chloride (100 mg, 379.48 µmol) in DCM (1 mL). The reaction mixture was stirred at 0°C for 1 hour, then poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, and concentrated under reduced pressure to give the title compound as a yellow solid (100 mg, 93%). ESI-MS m/z [M+H] ⁺ = 284.0. Preparation 53: N -(Bicyclo[1.1.1]pentan-2-yl)-3-bromo-4-methylbenzamide

步驟1：3-溴-4-(氟甲基)苯甲酸

To a solution of 3-bromo-4-methylbenzyl chloride (150 mg, 1.25 mmol, HCl) in pyridine (494.38 mg, 6.25 mmol) was added dropwise the bicyclic ring (1.1. 1] Pentane-2-amine (291.86 mg, 1.25 mmol). The mixture was stirred at 0°C for 2 hours, and then concentrated under reduced pressure. The resulting residue was diluted with 1 M HCl and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to give an off-white solid of the title compound (240 mg, 69%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.21 (s, 6 H), 2.45 (s, 3 H), 6.46 (s, 1 H), 7.28 (s, 2 H), 7.60 (dd, J ₁ =1.6, J ₂ = 8.0 Hz, 1 H), 7.93-7.90 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 281.9. Preparation 54: 3-Bromo- N -cyclopropyl-4-(fluoromethyl)benzamide

Step 1: 3-Bromo-4-(fluoromethyl)benzoic acid

To 3-bromo-4-methylbenzoic acid (322.57 mg, 1.5 mmol), sodium peroxodisulfate (178.58 mg, 750 µmol) and Selectfluor® (1.59 g, 4.50 mmol) under nitrogen at -78℃ _{Add AgNO 3} (25.48 mg, 150 µmol) to the mixture of acetonitrile (0.75 mL) and water (0.75 mL). The reaction mixture was heated to 80°C for 5 hours, and then filtered through a pad of Celite®. Adjust the filtrate to pH 4 with HCl (1 M). The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to obtain the title compound (50 mg, 14%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 5.44-5.69 (m, 2 H) 7.66 (d, J =8.0 Hz, 1 H) 7.99 (d, J =8.0 Hz, 1 H) 8.12 ( s, 1 H) 13.38 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 234.1. Step 2: 3-Bromo- N -cyclopropyl-4-(fluoromethyl)benzamide

To a solution of 3-bromo-4-(fluoromethyl)benzoic acid (30.00 mg, 128.74 µmol) and cyclopropylamine (8.82 mg, 154.48 µmol) in DMF (2 mL), add HATU (73.42 mg, 193.10 µmol) and DIPEA (49.91 mg, 386.21 µmol). The reaction mixture was stirred at 15°C for 2 hours, and then diluted with water. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo to give the title compound (30 mg, crude). ESI-MS m/z [M+H] ⁺ = 273.0. Preparation 55: 3-Bromo-4-methyl- N -((1 S ,2 R )-2-methylcyclopropyl)benzamide

步驟1：3-溴-N -環丙基-4-甲醯基苯甲醯胺

To a solution of 2-methylcycloprop-1-amine (1 g, 14.06 mmol) and Et ₃ N (4.27 g, 42.18 mmol) in DCM (20 mL) was added 3-bromo-4-methylbenzamide A solution of chlorine (3.28 g, 14.06 mmol) in DCM (10 mL). The reaction mixture was stirred at 0-15°C for 1 hour, then diluted with EtOAc, washed with water and brine, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated under reduced pressure, and purified by reverse-phase HPLC and preparative TLC (SiO ₂ ) using 15% EtOAc in petroleum ether to elute to obtain the title compound (80 mg , 2%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.41 (q, J = 4.8 Hz, 1 H) 0.94-1.03 (m, 1 H) 1.03-1.11 (m, 4 H) 3.46 (s, 3 H) 2.79-2.85 (m, 1 H) 7.40 (d, J =8.0 Hz, 1 H) 7.72 (dd, J =1.6, 8.0 Hz, 1 H) 8.03 (d, J =1.6 Hz, 1 H); ESI- MS m/z [M+H] ⁺ = 270.0. Preparation 56: 3-Bromo- N -cyclopropyl-4-(difluoromethyl)benzamide

Step 1: 3-Bromo- N -cyclopropyl-4-methanylbenzamide

To a solution of 3-bromo-4-methanoic acid (500 mg, 2.18 mmol) and cyclopropylamine (162.04 mg, 2.84 mmol) in DMF (3 mL) was added EDCI (627.77 mg, 3.27 mmol), HOBt ( 294.99 mg, 2.18 mmol) and DIPEA (846.47 mg, 6.55 mmol). The reaction mixture was stirred at 15°C for 3 hours, then poured into water and extracted with EtOAc. The organic phase was dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a 5%-33% EtOAc gradient in petroleum ether to obtain the title compound (325 mg, 55.5%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.56-0.63 (m, 2 H) 0.69-0.75 (m, 2 H) 2.81-2.93 (m, 1 H) 7.89-7.97 (m, 2 H) 8.16 (d, J= 1.2 Hz, 1 H) 8.63-8.80 (m, 1 H) 10.24 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 268.0. Step 2: 3-Bromo- N -cyclopropyl-4-(difluoromethyl)benzamide

Add DAST (240.49 mg, 1.49 mmol) to a solution of 3-bromo- N -cyclopropyl-4-methanoylbenzamide (100 mg, 372.99 µmol) in DCM (10 mL) at -40°C , Then add EtOH (2 mg, 43.41 µmol). The reaction mixture was warmed to 10°C and stirred for 2 hours, then poured into water (20 mL) and extracted with DCM (20 mL). The organic phase was dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO ₂ ) and eluted with 60% EtOAc in petroleum ether to obtain the title compound (27 mg, 25%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.56-0.61 (m, 2 H), 0.68-0.74 (m, 2 H), 2.86 (d, J ₁ =4.0, J ₂ =8.0 Hz, 1 H), 7.01-7.33 (m, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.91-7.98 (m, 1 H), 8.11-8.17 (m, 1 H), 8.68 (d, J= 3.6 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 292.0. Preparation 57: 3-Bromo-4-methyl- N- (pyridin-2-yl)benzamide

To a solution of pyridine-2-amine (120.92 mg, 1.28 mmol) in pyridine (2 mL) at 0°C was added 3-bromo-4-methylbenzyl chloride (300 mg) in DCM (1 mL) , 1.28 mmol). The reaction mixture was stirred at 20°C for 1 hour and then concentrated. The resulting residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-30% EtOAc in petroleum ether to obtain the title compound (248 mg, 60.5%) as a pale yellow solid. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.40-2.48 (m, 3 H), 7.15-7.19 (m, 1 H), 7.39-7.47 (m, 1 H), 7.81 -7.91 (m, 2 H), 8.14-8.20 (m, 2 H), 8.35 (dd, J1=0.8 Hz and J2=4.8 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 291.01. Preparation 58: 3-Bromo-4-methylbenzamide

Make 3-bromo-4-methylbenzoic acid (1 g, 4.65 mmol), NH ₄ Cl (298.50 mg, 5.58 mmol), DIPEA (1.80 g, 13.95 mmol), EDCI (1.34 g, 6.98 mmol) and HOBt ( A mixture of 628.35 mg, 4.65 mmol) in DMF (4 mL) was degassed and _{purged with N 2} (3×). The reaction mixture was stirred at 20°C for 2 hours under an _{N 2 atmosphere, then poured into water and filtered.} The filter cake was dried in vacuum to give the title compound (700 mg, 70%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.46 (s, 3 H) 5.67-5.97 (m, 2 H) 7.32 (d, J =8.0 Hz, 1 H) 7.65 (d, J =7.6 Hz, 1 H) 8.00 (s, 1 H). Preparation 59: Acetic acid 2-(6-(5-aminocarboxyl-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo-1,2-dihydro-3 H -Imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

Make 3-bromo-4-methylbenzamide (300 mg, 1.40 mmol), 2-(1-(2-fluoroethyl)-2-oxo-6-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl )-2-methylpropyl ester (648.76 mg, 1.54 mmol), Na ₂ CO ₃ (445.15 mg, 4.20 mmol) and Pd(dppf)Cl ₂ (102.44 mg, 140.00 µmol) in dioxane (10 mL) The mixture in water and water (1 mL) was degassed and _{purged with N 2} (3×). The reaction mixture _{was stirred at 90°C under N 2} atmosphere for 5 hours, then concentrated in vacuo, and eluted by column chromatography (SiO ₂ ) using a gradient of 33%-50% EtOAc in petroleum ether For purification, the title compound (550 mg, 92%) was obtained as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.91 (s, 6 H) 2.01 (s, 3 H) 2.34 (s, 3 H) 4.10-4.20 (m, 2 H) 4.76 (s, 2 H) 4.65 -4.79 (m, 2 H) 5.84-6.17 (m, 2 H) 7.21 (s, 1 H) 7.37 (d, J = 7.6 Hz, 1 H) 7.70-7.74 (m, 2 H) 7.95 (d, J = 2.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 429.1. Preparation 60: Methyl 3-bromo-4-methylbenzoate

步驟1：3-溴-N -(異噁唑-3-基)-4-甲基苯甲醯胺

To a solution of 3-bromo-4-methylbenzoic acid (300 mg, 1.40 mmol) in MeOH (5 mL) was added H ₂ SO ₄ (13.68 mg, 139.51 µmol). The reaction mixture was stirred at 60°C for 1 hour under _{N 2 and then concentrated.} The resulting residue was diluted with water and extracted with EtOAc. The organic layers were combined, concentrated, and purified by column chromatography using a gradient of 0%-50% EtOAc in petroleum ether to obtain the title compound (310 mg, 95%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.4 (s, 3 H) 3.86 (s, 3 H) 7.23 (d, J = 10.40 Hz, 1 H) 7.82 (dd, J ₁ =1.6 Hz and J ₂ =8.0 Hz, 1 H) 8.15 (d, J =1.6 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 228.98. Preparation 61: N -(isoxazol-3-yl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzamide

Step 1: 3-Bromo- N- (isoxazol-3-yl)-4-methylbenzamide

To a mixture of isoxazol-3-amine (327.35 mg, 3.89 mmol) in pyridine (8 mL) at 0°C was added 3-bromo-4-methylbenzyl chloride ( 1.0 g, 4.28 mmol). The reaction mixture was stirred at 15°C for 1 hour, and then concentrated under reduced pressure. The resulting residue was dissolved in EtOAc, washed with water, dried and concentrated. The concentrate was triturated with EtOAc: petroleum ether (5:1, 15 mL) and filtered to give the title compound (800 mg, 73%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.42 (s, 3H) 7.03 (d, J =1.6 Hz, 1H) 7.52 (d, J =8.0 Hz, 1H) 7.94 (dd, J ₁ =1.6 Hz, J ₂ =8.0 Hz, 1H) 8.25 (d, J =1.6 Hz, 1H) 8.86 (d, J =1.6 Hz, 1H) 11.50 (s, 1H). Step 2: N -(isoxazol-3-yl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)benzamide

步驟1：5-溴-2,4-二甲基苯甲酸

To 3-bromo- N- (isoxazol-3-yl)-4-methylbenzamide (1.2 g, 4.27 mmol) and 4,4,4',4',5,5,5', A solution of 5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.30 g, 5.12 mmol) in dioxane (5 mL) add potassium acetate (1.26 g, 12.81 mmol) and Pd(dppf)Cl ₂ (312.36 mg, 426.89 µmol). The reaction mixture _{was stirred at 90°C under N 2} for 3 hours, and then diluted with water. The aqueous phase was extracted with EtOAc and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ ) using a 10%-20% EtOAc gradient in petroleum ether to purify the crude product, then triturated with petroleum ether and EtOAc (10:1, 15mL) and filtered to obtain The title compound (1.15 g, 82.1%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.32 (s, 12 H) 2.53 (s, 3 H) 7.03 (d, J =1.6 Hz, 1 H) 7.33 (d, J =8.0 Hz, 1 H) 7.99 (dd, J ₁ =2.0 Hz, J ₂ =8.0 Hz, 1 H) 8.25 (d, J =2.0 Hz, 1 H) 8.84 (d, J =1.6 Hz, 1 H) 11.44 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 329.1. Preparation 62: 5-Bromo- N -cyclopropyl-2,4-dimethylbenzamide

Step 1: 5-Bromo-2,4-dimethylbenzoic acid

To a solution of 2,4-dimethylbenzoic acid (0.8 g, 5.33 mmol) in TFA (16.00 mL, 216 mmol) at 10°C was added NBS (1.42 g, 7.99 mmol). The reaction mixture was stirred at 50°C for 12 hours, and then concentrated in vacuo. The residue was purified by column chromatography with a gradient of 0%-2% EtOAc in petroleum ether to obtain the title compound (0.6 g, 47%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.43 (s, 3 H) 2.58 (s, 3 H) 7.15 (s, 1 H) 8.24 (s, 1 H). Step 2: 5-Bromo- N -cyclopropyl-2,4-dimethylbenzamide

To a solution of cyclopropylamine (0.172 mL, 2.49 mmol) in DCM (20 mL) at 10° C. was added HATU (1.04 g, 2.74 mmol) and DIPEA (1.30 mL, 7.46 mmol) during a period of 30 minutes. Next, 5-bromo-2,4-dimethylbenzoic acid (600 mg, 2.49 mmol) was added. The reaction mixture was stirred at 30°C for 16 hours, and then washed with water. The organic layers were combined, dried over Na ₂ SO _4, and concentrated in vacuo. The product was triturated with EtOAc (20 mL) at 10°C for 30 minutes to give the title compound (500 mg, 75%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.60-0.63 (m, 2 H) 0.85-0.88 (m, 2 H) 2.36 (s, 6 H) 2.84-2.91 (m, 1 H) 5.87 (s, 1 H) 7.08 (s, 1 H) 7.45 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 269.8. Preparation 63: Acetic acid 2-(6-bromo-1-ethyl-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2- Methyl propyl ester

Make acetic acid 2-(6-bromo-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (50 mg, 152.36 µmol), ethyl iodide (47.53 mg, 304.73 µmol) and K ₂ CO ₃ (42.12 mg, 304.73 µmol) in DMF (2 mL) were degassed and _{purged with N 2} (3 ×). The reaction mixture was stirred at 90°C for 16 hours under an _{N 2 atmosphere, and then diluted with water.} The aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (SiO ₂ ) and eluted with 60% EtOAc in petroleum ether to obtain the title compound (50 mg, 92%) as a yellow oil. ESI-MS m/z [M+H] ⁺ = 356.1. Preparation 64: Acetic acid 2-(1-ethyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

To acetic acid 2-(6-bromo-1-ethyl-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methyl Propyl ester (2.17 g, 6.09 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxide Heteroborolane) (1.70 g, 6.70 mmol) in dioxane (30 mL) was added potassium acetate (1.49 g, 15.23 mmol) and Pd(dppf)Cl ₂ (222.87 mg, 304.59 µmol). The reaction mixture was stirred for 3 hours at 80 deg.] C to 90 deg.] C under N _2, and then concentrated in vacuo. The resulting residue was purified by column chromatography using a gradient of 10%-30% EtOAc in petroleum ether to obtain the title compound (2.55 g, crude) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.30-1.34 (m, 3 H) 1.36 (s, 12 H) 1.86 (s, 6 H) 1.96 (s, 3 H) 3.86 -3.92 (m, 2 H ) 4.74 (s, 2 H) 7.45 (s, 1 H) 8.38 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 404.2. Preparation 65: 3-Bromo-4-methyl - N - (1- (tetrahydro -2 H - pyran-2-yl) -1 H - pyrazol-3-yl) benzoyl amine

To a solution of 3-bromo-4-methylbenzoic acid (100 mg, 465.02 µmol) in DMF (3 mL) at 20°C was added EDCI (133.72 mg, 697.53 µmol), HOBt (94.25 mg, 697.53 µmol) and DIPEA (240.40 mg, 1.86 mmol). The mixture was degassed under vacuum and purged with nitrogen (3×), and stirred at 20°C for 30 minutes under nitrogen. Next, add 1- (tetrahydro -2 H - pyran-2-yl) -1 H - pyrazol-3-amine (101.08 mg, 604.53 μmol). The mixture was degassed under vacuum and purged with nitrogen (3×), and stirred at 20° C. for another 12 hours under nitrogen. The mixture was then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated under reduced pressure and the _{resulting residue was purified by preparative TLC (SiO 2} ) using 67% EtOAc in petroleum ether to obtain the title compound (119 mg, 62.3) as a yellow oil %). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.56-1.75 (m, 6 H) 2.47 (s, 3 H) 4.10-4.15 (m, 2 H) 5.25 (dd, J ₁ =2.00 Hz, J ₂ = 8.00 Hz, 1 H) 6.90 (d, J = 2.40 Hz, 1 H) 7.32-7.36 (m, 1 H) 7.53-7.55 (m, 1 H) 7.69 (dd, J ₁ =2.00 Hz, J ₂ =8.00 Hz, 1 H) 8.07 (d, J= 2.40 Hz, 1 H) 8.40 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 365.0. Preparation 66: 3-Bromo-4-methyl- N -(1-methyl-1 H -pyrazol-3-yl)benzamide

To a solution of 3-bromo-4-methylbenzoic acid (1 g, 4.65 mmol) in DMF (15 mL) was added EDCI (1.34 g, 6.98 mmol), HOBt (942.53 mg, 6.98 mmol) and DIPEA (3.61 g , 27.90 mmol), followed by 1-methyl- 1H -pyrazol-3-amine (496.78 mg, 5.12 mmol). The reaction mixture was stirred at 15°C for 12 hours, then washed with water and extracted with EtOAc. The organic layer was dried over Na ₂ SO _4, filtered and concentrated. The resulting residue was purified by column chromatography (SiO ₂ ) using a gradient of 10%-50% EtOAc in petroleum ether to obtain the title compound (1.22 g, 89.2%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.46 (s, 3 H) 3.77 (s, 3 H) 6.83 (d, J = 2.0 Hz, 1 H) 7.30 (d, J = 2.0 Hz, 1 H) 7.33 (d, J= 8.4 Hz, 1 H) 7.68-7.71 (m, 1 H) 8.06 (s, 1 H) 8.73 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 294.1 . Preparation 67: 3-Bromo-4-methyl- N -(1-methyl-1 H -pyrazol-5-yl)benzamide

To the mixture of 3-bromo-4-methylbenzoic acid (0.1 g, 0.465 mmol) and 1-methyl-1 H -pyrazol-5-amine (45.2 mg, 0.465 mmol) in DMF (3 mL) HOBt (75.4 mg, 0.558 mmol), EDCI (134 mg, 0.698 mmol) and DIPEA (0.243 mL, 1.40 mmol). The reaction mixture was stirred at 25°C for 12 hours, and then concentrated under reduced pressure. The residue was purified by preparative TLC and eluted with 60% EtOAc in petroleum ether to obtain the title compound as a pale yellow solid. ESI-MS m/z [M+H] ⁺ = 294.0. Preparation 68: 5-Bromo-2-fluoro- N -(isoxazol-3-yl)-4-methylbenzamide

步驟1：乙酸2-(6-溴-1-甲基-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

To a mixture of isoxazol-3-amine (303.93 mg, 3.61 mmol) in pyridine (5 mL) was added 5-bromo-2-fluoro-4-methylbenzyl chloride ( 1 g, 3.98 mmol). The reaction mixture was stirred at 20°C for 1 hour, and then EtOAc and water were added. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ ) using a 5%-25% EtOAc gradient in petroleum ether to elute. The fractions containing the product were combined and dried under reduced pressure to obtain the title compound (900 mg, 83.2%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.37 (s, 1 H) 2.40 (s, 3 H) 7.00 (s, 1 H) 7.41-7.43 (d, J =10.8 Hz, 1 H) 7.88 -7.90 (d, J =6.8 Hz, 1 H) 8.86 (s, 1 H) 11.52 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 300.9. Preparation 69: Acetic acid 2-methyl-2-(1-methyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborole Pentan-2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)propyl ester

Step 1: Acetic acid 2-(6-bromo-1-methyl-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2- Methyl propyl ester

To acetic acid 2-(6-bromo-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (200 mg, 609.46 µmol) and methyl iodide (173.01 mg, 1.22 mmol) in DMF (2 mL) add K ₂ CO ₃ (168.46 mg, 1.22 mmol). The reaction mixture was stirred at 15°C for 16 hours and then filtered. The organic layer was concentrated in vacuo and _{purified by column chromatography (SiO 2} ) using a gradient of 5%-20% EtOAc in petroleum ether to obtain the title compound (240 mg , Crude). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.83 (s, 6 H) 1.98 (s, 3 H) 3.35 (s, 3 H) 4.70 (s, 2 H) 7.24 (d, J =2.0 Hz, 1 H) 8.04 (d, J = 2.4 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 344.0. Step 2: Acetic acid 2-methyl-2-(1-methyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborole Pentan-2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)propyl ester

To acetic acid 2-(6-bromo-1-methyl-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methyl Propyl ester (208.5 mg, 609.31 µmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxide) Heteroborolane) (170.20 mg, 670.25 µmol) in dioxane (8 mL) was added with Pd(dppf)Cl ₂ (22.29 mg, 30.47 µmol) and potassium acetate (149.50 mg, 1.52 mmol). The reaction mixture was stirred for 3 hours at 80 deg.] C to 90 deg.] C under N _2, and then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO ₂ ) using a 5%-20% EtOAc gradient in petroleum ether to obtain the title compound (150 mg, 63.2%) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.36 (s, 12 H) 1.86 (s, 6 H) 1.97 (s, 3 H) 3.37 (s, 3 H) 4.75 (s, 2 H) 7.45 (d , J =1.6 Hz, 1 H) 8.40 (d, J =1.6 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 390.2. Preparation 70: Acetic acid 2-(6-bromo-1-(2,2-difluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridine -3-yl)-2-methylpropyl ester

Make acetic acid 2-(6-bromo-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (150 mg, 457.09 µmol), 1,1-difluoro-2-iodoethane (96.51 mg, 502.80 µmol) and K ₂ CO ₃ (75.81 mg, 548.51 µmol) in DMF (2 mL) were degassed and used N ₂ purge (3×). The reaction mixture was stirred at 15°C for 16 hours under an _{N 2 atmosphere, and then diluted with water.} The aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude product was purified by preparative TLC and eluted with EtOAc: petroleum ether (1:2) to obtain the title compound (75 mg, crude) as a yellow oil. ESI-MS m/z [M+H] ⁺ = 392.2. Preparation 71: 2-Fluoro- N ,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Formamide

Combine 5-bromo-2-fluoro- N ,4-dimethylbenzamide (250 mg, 904.19 µmol), 4,4,4',4',5,5,5',5'-octamethyl -2,2'-bis(1,3,2-dioxaborolane) (252.57 mg, 994.61 µmol), potassium acetate (221.85 mg, 2.26 mmol) and Pd(dppf)Cl ₂ (66.16 A mixture of mg, 90.42 µmol) in dioxane (10 mL) was heated to 100°C and _{stirred under N 2} for 15 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel using a gradient of 20%-100% EtOAc in petroleum ether. The title compound (110 mg, 34%) was obtained as a white solid. ESI-MS m/z [M+H] ⁺ = 294.2. Preparation 72: Acetic acid 2-(6-bromo-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridine-3- Yl)-2-methylpropyl-1,1- d ₂ ester

To acetic acid 2-(6-bromo-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1, A solution of 1- d ₂ ester (130 mg, 393.73 µmol) and 1-bromo-2-fluoroethane (74.98 mg, 590.60 µmol) in DMF (2 mL) with K ₂ CO ₃ (108.83 mg, 787.46 µmol) . The reaction mixture was stirred under nitrogen at 15°C for 12 hours, and then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-30% EtOAc in petroleum ether to obtain the title compound (110 mg, 74.3%) as a brown oil. ESI-MS m/z [M+H] ⁺ = 376.0. Preparation 73: 2-Fluoro- N -(isoxazol-3-yl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborole Cyclopentane-2-yl)benzamide

Make 5-bromo-2-fluoro- N -(isoxazol-3-yl)-4-methylbenzamide (0.2 g, 668.68 µmol), 4,4,4',4',5,5 ,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (203.76 mg, 802.42 µmol), potassium acetate (131.25 mg, 1.34 mmol) A mixture of Pd(dppf)Cl ₂ (48.93 mg, 66.87 µmol) in dioxane (5 mL) was degassed and _{purged with N 2} (3×). The reaction mixture was stirred at 90°C for 6 hours under an _{N 2 atmosphere, and then concentrated under reduced pressure.} The residue was purified by column chromatography (SiO ₂ ) using a gradient of 2%-20% EtOAc in petroleum ether to obtain the title compound (0.11 g, 48%) as a white solid. ESI-MS m/z [M+H] ⁺ = 347.1. Preparation 74: Acetic acid 2-(1-(2-fluoroethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborole heterocycle Pentan-2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester

Make acetic acid 2-(6-bromo-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl) -2-methylpropyl-1,1- d ₂ ester (500 mg, 1.33 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2 '-Bis(1,3,2-dioxaborolane) (371.24 mg, 1.46 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (54.27 mg, 66.45 µmol) and potassium acetate (391.29 The mixture of mg, 3.99 mmol) in dioxane (10 mL) was degassed and _{purged with N 2} (3×). The reaction mixture was stirred at 80°C for 2 hours under _{N 2 atmosphere, then diluted with EtOAc and water.} The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-40% EtOAc in petroleum ether to obtain the title compound (460 mg, 81.8%) as a white oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.30 (s, 12 H) 1.78 (s, 6 H) 1.88 (s, 3 H) 4.14-4.24 (m, 2 H) 4.58-4.72 (m, 2 H) 7.63 (s, 1 H) 8.21 (d, J = 1.2 Hz, 1 H). Preparation 75: 3-Bromo- N -(isothiazol-3-yl)-4-methylbenzamide

步驟1：5-溴-2-氟-4-甲基苯甲醯胺

To a solution of 3-bromo-4-methylbenzamide (78.30 mg, 365.80 µmol) in dioxane (2 mL) was added 3-bromoisothiazole (50 mg, 304.83 µmol), CuI (11.61 mg, 60.97 µmol), (1 R , 2 R )-cyclohexane-1,2-diamine (6.96 mg, 60.97 µmol) and K ₂ CO ₃ (84.26 mg, 609.67 µmol). The reaction mixture was stirred at 120°C for 12 hours, then poured into water and extracted with EtOAc. Dried organic layer was washed with brine Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ ) using a 5%-10% EtOAc gradient in petroleum ether to purify the crude product to obtain the title compound (40 mg, 44%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.43 (s, 3 H) 7.51 (d, J = 8.0 Hz, 1 H) 7.87 (d, J = 4.8 Hz, 1 H) 7.96 (dd, J ₁ = 8.0, J ₂ = 2.0 Hz, 1 H) 8.18-8.38 (m, 1 H) 9.07 (d, J= 4.8 Hz, 1 H) 11.55 (s, 1 H); ESI-MS m/z [M +H] ⁺ = 297.0. Preparation 76: 5-Bromo-2-fluoro- N -(isothiazol-3-yl)-4-methylbenzamide

Step 1: 5-Bromo-2-fluoro-4-methylbenzamide

Make 5-bromo-2-fluoro-4-methylbenzoic acid (1 g, 4.29 mmol), NH ₄ Cl (275.45 mg, 5.15 mmol), DIPEA (1.66 g, 12.87 mmol), EDCI (1.23 g, 6.44 mmol) A mixture of) and HOBt (579.83 mg, 4.29 mmol) in DMF (10 mL) was degassed and _{purged with N 2} (3×). The reaction mixture was stirred at 15°C for 16 hours under an _{N 2 atmosphere, and then poured into water and filtered.} The filter cake was collected and dried under reduced pressure to obtain the title compound (860 mg, 86.4%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.35 (s, 3 H) 7.26-7.39 (m, 1 H) 7.69 (d, J =12.4 Hz, 2 H) 7.80 (d, 6.8 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 231.7. Step 2: 5-Bromo-2-fluoro- N -(isothiazol-3-yl)-4-methylbenzamide

步驟1：3-(5-溴-2-氟-4-甲基苯甲醯胺基)-1H -吡唑-1-甲酸第三丁基酯

Make 5-bromo-2-fluoro-4-methylbenzamide (300 mg, 1.29 mmol), 3-bromoisothiazole (212.05 mg, 1.29 mmol), CuI (49.24 mg, 258.57 µmol), K ₂ CO ₃ (357.35 mg, 2.59 mmol) and (1 R , 2 R )-cyclohexane-1,2-diamine (29.53 mg, 258.57 µmol) in dioxane (4 mL) was degassed and degassed with N ₂ Purge (3 ×). The reaction mixture _{was stirred at 120°C for 16 hours under an N 2} atmosphere, and then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-20% EtOAc in petroleum ether to obtain the title compound (150 mg, 37%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.47 (s, 3 H) 7.12 (d, J =12.4 Hz, 1 H) 8.03 (d, J =4.8 Hz, 1 H) 8.34 (d, J =7.6 Hz, 1 H) 8.67 (d, J =4.8 Hz, 1 H) 9.32 (d, J =13.6 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 314.8. Preparation 77: 3-(2-Fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Carboxamido)-1 H -pyrazole-1-carboxylic acid tert-butyl ester

Step 1: 3-(5-Bromo-2-fluoro-4-methylbenzamide)-1 H -pyrazole-1-carboxylic acid tertiary butyl ester

To a mixture of 3-amino-1 H -pyrazole-1-carboxylic acid tert-butyl ester (728.52 mg, 3.98 mmol) in pyridine (3 mL) at 0°C was added 5 in DCM (1.5 mL) -Bromo-2-fluoro-4-methylbenzyl chloride (1.0 g, 3.98 mmol). The reaction mixture was stirred at 20°C for 2 hours, and then diluted with water. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated in vacuo and _{purified by column chromatography (SiO 2} ) using a gradient of 0%-5% EtOAc in petroleum ether to elute to obtain the title compound (1.06 g, 66.9%) as a white solid ). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.57 (s, 9 H) 2.39 (s, 3 H) 6.93 (s, 1 H) 7.40 (d, J =11.0 Hz, 1 H) 7.85 (d , J =6.7 Hz, 1 H) 8.23 (d, J =2.4 Hz, 1 H) 11.44 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 398.1. Step 2: 3-(2-Fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Carboxamido)-1 H -pyrazole-1-carboxylic acid tert-butyl ester

To 3-(5-bromo-2-fluoro-4-methylbenzamide)-1 H -pyrazole-1-carboxylic acid tert-butyl ester (1.05 g, 2.64 mmol) and 4,4,4 ',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (803.47 mg, 3.16 mmol) in two Add potassium acetate (776.31 mg, 7.91 mmol) and Pd(dppf)Cl ₂ (192.93 mg, 263.67 µmol) to the solution in oxane (10 mL). The reaction mixture _{was stirred at 90°C under N 2} for 3 hours, and then diluted with water. The aqueous phase was extracted with ethyl acetate, and the organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated in vacuo and _{purified by column chromatography (SiO 2} ) using a gradient of 10%-30% EtOAc in petroleum ether to obtain the title compound (1.0 g, 85 %). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.33 (s, 12 H) 1.65 (s, 9 H) 2.58 (s, 3 H) 6.97 (d, J =13.2 Hz, 1 H) 7.11-7.16 (m , 1 H) 8.00 (d, J =2.8 Hz, 1 H) 8.52 (d, J =9.2 Hz, 1 H) 9.09 (d, J =12.8 Hz, 1 H); ESI-MS m/z [M+ H] ⁺ = 446.5. Preparation 78: Acetic acid 2-(6-bromo-1-ethyl-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2- Methyl propyl-1,1- d ₂ ester

To acetic acid 2-(6-bromo-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1, A solution of 1- d ₂ ester (1 g, 3.03 mmol) and 1-iodopropane (772.28 mg, 4.54 mmol) in DMF (10 mL) was added with K ₂ CO ₃ (837.20 mg, 6.06 mmol). The reaction mixture was stirred under nitrogen at 15°C for 12 hours, and then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 10%-30% EtOAc in petroleum ether to obtain the title compound (1 g, 92%) as a brown oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.17 (t, J = 7.2 Hz, 3 H) 1.75 (s, 6 H) 1.89 (s, 3 H) 3.83 (q, J = 7.2 Hz, 2 H) 7.85 (d, J= 2.0 Hz, 1 H) 8.04 (d, J= 2.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 358.0 . Preparation 79: Acetic acid 2-(1-ethyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester

步驟1：5-溴-2-(第三丁基胺基)菸鹼酸

To acetic acid 2-(6-bromo-1-ethyl-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methyl A solution of propyl-1,1- d ₂ ester (300 mg, 837.46 µmol) in dioxane (3 mL) is added 4,4,4',4',5,5,5',5'-A Methyl-2,2'-bis(1,3,2-dioxaborolane) (233.93 mg, 921.20 µmol), potassium acetate (246.57 mg, 2.51 mmol) and Pd(dppf)Cl ₂ ( 61.28 mg, 83.75 µmol). The reaction mixture was stirred at 90 °C under N ₂ for 6 hours, then poured into water and extracted with EtOAc. Dried organic layer was washed with brine Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ ) using a 5%-10% EtOAc gradient in petroleum to purify the crude product to obtain the title compound (270 mg, 80%) as a yellow solid. ESI-MS m/z [M+H] ⁺ = 406.1. Preparation 80: 6-Bromo-3-(tert-butyl)-1-methyl-1,3-dihydro- 2H -imidazo[4,5- b ]pyridin-2-one

Step 1: 5-Bromo-2-(tertiary butylamino)nicotinic acid

To a solution of 5-bromo-2-fluoronicotinic acid (1 g, 4.55 mmol) in DMSO (2 mL) at room temperature was added 2-methylpropan-2-amine (0.665 g, 9.09 mmol). The reaction mixture was stirred at 140°C for 2 hours in a microwave reactor, and then poured into water. The resulting solid was collected by filtration and dried in vacuum to obtain the title compound (672 mg, 54.1%). ESI-MS m/z [M+H] ⁺ = 273.2. Step 2: 6-Bromo-3-(tert-butyl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridin-2-one

Add 5-bromo-2-(tertiary butylamino)nicotinic acid (627 mg, 2.296 mmol) and Et ₃ N (0.352 mL, 2.53 mmol) in dioxane (10 mL) at room temperature To the solution was added diphenyl azide phosphate (0.543 mL, 2.53 mmol). The reaction mixture was heated at 100°C for 2 hours, then concentrated in vacuo and purified by chromatography (ISCO Gold® 40 g column) using a gradient of 0%-100% EtOAc in hexane for eluent. The fractions containing the product were collected, concentrated and dried in vacuo to give the title compound (562 mg, 91%) as an off-white solid. Step 3: 6-Bromo-3-(tert-butyl)-1-methyl-1,3-dihydro- 2H -imidazo[4,5- b ]pyridin-2-one

To 6-bromo-3-(tert-butyl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridin-2-one (250 mg, 0.925 mmol) and methyl iodide (0.174 mL, 2.78 mmol) in DMF (2 mL) was added with cesium carbonate (1206 mg, 3.70 mmol). The reaction mixture was stirred at room temperature, and then diluted with water. The resulting solid was collected by filtration, rinsed with water, and dried in vacuum to obtain the title compound (243 mg, 92%). ESI-MS m/z [M+H] ⁺ = 286.2. Preparation 81: 3-(3-(tert-butyl)-1-methyl-2-oxo-2,3-dihydro- 1H -imidazo[4,5- b ]pyridin-6-yl )-4-methylbenzoic acid

Add 6-bromo-3-(tert-butyl)-1-methyl-1,3-dihydro- 2H -imidazo[4,5- b ]pyridin-2-one to the microwave vial for assembly and stirring (243 mg, 0.855 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid ( 336 mg, 1.283 mmol) and dioxane (8 mL). The solution was stirred at room temperature for 5 minutes, then sodium bicarbonate (431 mg, 5.13 mmol) and Pd(dppf)Cl ₂ (188 mg, 0.257 mmol) were added. The solution was heated to 110°C in a microwave reactor for 15 minutes, and then concentrated in vacuo. Next, 1 N NaOH was added and the mixture was filtered. The filtrate was acidified to pH 3-4 with 1 N HCl, and the resulting solid was collected by vacuum filtration to obtain the title compound (310 mg). ESI-MS m/z [M+H] ⁺ = 340.4. Preparation 82: 6-Bromo-3-(1-hydroxy-2-methylpropan-2-yl)-1-methyl-1,3-dihydro- 2H -imidazo[4,5- b ]pyridine -2-one

To 6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridine-2- A solution of ketone (188 mg, 0.657 mmol) in DMF (1 mL) was added with NaH (28.9 mg, 0.723 mmol), and the mixture was stirred for 15 minutes. Iodomethane (0.041 mL, 0.657 mmol) was added, and the reaction mixture was stirred at 25°C for 20 minutes, then poured into water and extracted with EtOAc. The organic layers were combined, washed with saturated aqueous NaCl, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated, dried in vacuo and purified by column (ISCO Gold® 24 g column), using a gradient of 0%-100% EtOAc in hexane to elute. The fractions containing the product were collected, and then concentrated and dried in vacuo to give the title compound (126 mg, 63.9%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.66-1.67 (m, 6 H) 3.27-3.29 (m, 3 H) 3.85 (d, J = 6.33 Hz, 2 H) 4.81-4.86 (m, 1 H) 7.76 (s, 1 H) 8.01-8.07 (m, 1 H). ESI-MS m/z [M+H] ⁺ = 300.2. Preparation 83: 6-Bromo-3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxyethyl)-1,3-dihydro- 2H -imidazo[4, 5- b ]pyridin-2-one

To 6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridin-2-one (1.8 g , 6.29 mmol) and 2-bromoethane-1-ol (1.179 g, 9.44 mmol) in DMF (25 mL) was added K ₂ CO ₃ (1.739 g, 12.58 mmol). The reaction mixture was stirred at 90°C for 3 hours, then cooled to room temperature, diluted with EtOAc and washed with brine. The organic phase was dried over Na ₂ SO _4, filtered and concentrated to give the title compound (1.92 g, 92%), which was used without further purification. ESI-MS m/z [M+H] ⁺ = 332.2. Preparation 84: 6-Bromo-1-ethyl-3-(1-hydroxy-2-methylprop-2-yl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridine -2-one

步驟1：乙酸2-(6-(5-(環丙基胺甲醯基)-4-氟-2-甲基苯基)-1-(2-氟乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

To 6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridine-2- Add NaH (38.0 mg, 0.950 mmol) to a solution of ketone (247 mg, 0.863 mmol) in DMF (2 ml). The mixture was stirred at 25°C for 15 minutes. Add iodoethane (0.069 mL, 0.863 mmol). The reaction mixture was stirred at 25°C overnight, and then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated and dried in vacuum. The crude product was purified by silica column to obtain the title compound (100 mg, 37%). ESI-MS m/z [M+H] ⁺ = 316.3. Example 1: N -Cyclopropyl-2-fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-(5-(cyclopropylaminocarboxyl)-4-fluoro-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo- 1,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

Make 5-bromo- N -cyclopropyl-2-fluoro-4-methylbenzamide (100 mg, 367 µmol), 2-(1-(2-fluoroethyl)-2-oxoacetate -6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-3 H -imidazo[4 ,5- b )pyridin-3-yl)-2-methylpropyl ester (155 mg, 0.367 mmol), K ₂ CO ₃ (152 mg, 1.10 mmol) and XPhos Pd G3 (15.6 mg, 0.018 mmol) in The mixture in water (0.5 mL) and dioxane (10 mL) was degassed and _{purged with N 2} (3×), and then stirred at 100° C. for 6 hours under an _{N 2 atmosphere.} The reaction mixture was filtered on silica. The organic layer was concentrated in vacuo to give the title compound (150 mg, crude) as a yellow gum. ESI-MS m/z [M+H] ⁺ = 487.1. Step 2: N -Cyclopropyl-2-fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

步驟1：乙酸2-(6-(5-(環丙基胺甲醯基)-4-氟-2-甲基苯基)-2-甲基-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

To acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-4-fluoro-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo-1, A solution of 2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (150 mg, 0.308 mmol) in MeOH (10 mL) is added K ₂ CO ₃ (128 mg, 0.925 mmol). The mixture was stirred at 80°C for 14 hours, and then concentrated in vacuo. The resulting residue was purified by preparative HPLC to obtain the title compound (40 mg) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.52 -0.57 (m, 2 H) 0.66 -0.72 (m, 2 H) 1.72 (s, 6 H) 2.30 (s, 3 H) 2.80-2.85 ( m, 1 H) 3.92 (d, J =6.4 Hz, 2 H) 4.16-4.24 (m, 2 H) 4.62 (t, J =4.8 Hz, 1 H) 4.74 (t, J =4.8 Hz, 1 H) 4.99 (t, J =6.4 Hz, 1 H) 7.27 (d, J =11.2 Hz, 1 H) 7.42 (d, J =7.6 Hz, 1 H) 7.57 (d, J =0.8 Hz, 1 H) 7.96 ( d, J = 0.8 Hz, 1 H) 8.30 (d, J = 4.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 445.2. Example 2: N -Cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-2-methyl- 3H -imidazo[4,5- b ]Pyridin-6-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-(5-(cyclopropylaminocarboxyl)-4-fluoro-2-methylphenyl)-2-methyl-3 H -imidazo[4,5- b ]Pyridin-3-yl)-2-methylpropyl ester

To 2-(6-bromo-2-methyl- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl acetate (61 mg, 187.01 µmol) at 20°C ) And N -cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Benzamide (71.63 mg, 224.41 µmol) in dioxane (2 mL) and water (0.2 mL) with Na ₂ CO ₃ (59.46 mg, 561.03 µmol) and Pd(dppf)Cl ₂ (6.84 mg, 9.35 µmol). The suspension was degassed under vacuum and purged with nitrogen (3×). The reaction mixture was stirred at 90 °C under nitrogen for 12 hours, and then quenched by the addition of water and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated under reduced pressure and _{purified by preparative TLC (SiO 2} ) and eluted with EtOAc to obtain the title compound (30 mg, 37%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.60-0.67 (m, 2 H) 0.87-0.90 (m, 2 H) 1.98 (d, J = 2.80 Hz, 9 H) 2.30 (s, 3 H) 2.85 (s, 3 H) 2.92-2.99 (m, 1 H) 4.85 (s, 2 H) 6.83 (d, J = 13.60 Hz, 1 H) 7.05 (d, J = 12.80 Hz, 1 H) 7.79 (d, J= 2.00 Hz, 1 H) 8.01 (d, J= 8.00 Hz, 1 H) 8.19 (d, J= 2.00 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 439.2. Step 2: N -Cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-2-methyl- 3H -imidazo[4,5- b ]Pyridin-6-yl)-4-methylbenzamide

步驟1：5-(3-(1-((第三丁基二甲基矽基)氧基)-2-甲基丙-2-基)-2-甲氧基-3H -咪唑并[4,5-b ]吡啶-6-基)-N -環丙基-2-氟-4-甲基苯甲醯胺

To acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-4-fluoro-2-methylphenyl)-2-methyl-3 H -imidazo[4,5 -b ]Pyridin-3-yl)-2-methylpropyl ester (80 mg, 182 µmol) in MeOH (2 mL) with K ₂ CO ₃ (25.21 mg, 182 µmol). The reaction mixture was stirred at 50°C for 0.5 hours under nitrogen and then filtered. The filtrate was purified by preparative HPLC to obtain the title compound (28.5 mg, 71.6 µmol) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.50-0.57 (m, 2 H) 0.64-0.72 (m, 2 H) 1.83 (s, 6 H) 2.28 (s, 3 H) 2.77 (s, 3 H) 2.79-2.86 (m, 1 H) 4.01 (s, 2 H) 5.09 (s, 1 H) 7.27 (d, J = 11.20 Hz, 1 H) 7.42 (d, J = 7.60 Hz, 1 H) 7.88 (d, J= 2.00 Hz, 1 H) 8.21 (d, J= 2.00 Hz, 1 H) 8.32 (d, J= 4.00 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 397.2. Example 3: N -Cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-2-methoxy- 3H -imidazo[4,5- b )Pyridin-6-yl)-4-methylbenzamide

Step 1: 5-(3-(1-((tertiary butyldimethylsilyl)oxy)-2-methylprop-2-yl)-2-methoxy- 3H -imidazo[ 4,5- b ]pyridin-6-yl) -N -cyclopropyl-2-fluoro-4-methylbenzamide

Make 6-bromo-3-(1-((tertiary butyldimethylsilyl)oxy)-2-methylprop-2-yl)-2-methoxy- 3H -imidazo[4 ,5- b ]pyridine (160 mg, 386.09 µmol), N -cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)benzamide (123.23 mg, 386.09 µmol), Pd(dppf)Cl ₂ (28.25 mg, 38.61 µmol), Na ₂ CO ₃ (102.30 mg, 965.22 µmol) The mixture in dioxane (5 mL) and water (0.5 mL) was degassed and _{purged with N 2} (3×), and then stirred at 95° C. for 4 hours under an _{N 2 atmosphere.} The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO ₂ ) with a gradient of 0%-25% EtOAc in petroleum ether to obtain the title compound (160 mg, 78.7). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.21 (s, 6 H) 0.61-0.66 (m, 2 H) 0.72 (s, 9 H) 0.86-0.91 (m, 2 H) 1.86 (s, 6 H) ) 2.28 (s, 3 H) 2.92-2.99 (m, 1 H) 4.08 (s, 2 H) 4.17 (s, 3 H) 6.83 (d, J =11.2 Hz, 1 H) 7.05 (d, J =12.4 Hz, 1 H) 7.60 (d, J =2.0 Hz, 1 H) 7.98 (d, J =8.0 Hz, 1 H) 8.01 (d, J =2.4 Hz, 1 H); ESI-MS m/z [M +H] ⁺ = 527.3. Step 2: N -Cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-2-methoxy- 3H -imidazo[4,5- b )Pyridin-6-yl)-4-methylbenzamide

步驟1：乙酸2-(6-溴-1-(2-羥基乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

To 5-(3-(1-((tertiary butyldimethylsilyl)oxy)-2-methylprop-2-yl)-2-methoxy- 3H -imidazo[4, 5- b ]pyridin-6-yl) -N -cyclopropyl-2-fluoro-4-methylbenzamide (160 mg, 304 µmol) solution with tetrabutylammonium fluoride (1 M, 2.43 mL). The mixture was stirred at 15°C for 3 hours, and then NH ₄ Cl was added and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to obtain the title compound (61.4 mg, 47%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.29-0.24 (m, 2 H) 0.15-0.10 (m, 2 H) 0.92 (s, 6 H) 1.47 (s, 3 H) 1.98-2.05 ( m, 1 H) 3.13 (d, J =5.6 Hz, 2 H) 3.31 (s, 3 H) 4.33 (t, J =6.0 Hz, 1 H) 6.45 (d, J =11.2 Hz, 1 H) 6.60 ( d, J =7.6 Hz, 1 H) 6.95 (d, J =2.0 Hz, 1 H) 7.24 (d, J =2.0 Hz, 1 H) 7.48 (d, J =4.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 413.3. Example 4: N -Cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxyethyl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-bromo-1-(2-hydroxyethyl)-2-oxo-1,2-dihydro-3 H -imidazo[4,5- b ]pyridine-3- Yl)-2-methyl propyl ester

Acetic acid 2-(6-bromo-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (0.2 g, 0.6 mmol), 2-iodoethanol (0.095 mL, 1.2 mmol) and K ₂ CO ₃ (0.168 mg, 1.22 mmol) in DMF (5 mL) The reaction mixture was stirred at 25° C. for 10 hours. The mixture was then diluted with water and extracted with EtOAc. The organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to give the title compound (0.22 g, crude) of a gray oil. ESI-MS m/z [M+H] ⁺ = 374.0. Step 2: Acetic acid 2-(6-(5-(cyclopropylaminomethyl)-4-fluoro-2-methylphenyl)-1-(2-hydroxyethyl)-2-oxo- 1,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

Make acetic acid 2-(6-bromo-1-(2-hydroxyethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl) -2-methylpropyl ester (0.22 g, 0.59 mmol), N -cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)benzamide (208 mg, 0.650 mmol), Na ₂ CO ₃ (125 mg, 1.18 mmol), Pd(dppf)Cl ₂ (43.3 mg, 0.059 A mixture of mmol) in dioxane (10 mL) and water (2 mL) was degassed and _{purged with N 2} (3×), and then stirred at 90° C. for 6 hours under a _{N 2 atmosphere.} The mixture was concentrated under reduced pressure and purified by column chromatography (SiO ₂ ) using a gradient of 20%-50% EtOAc in petroleum ether to elute to obtain the title compound (0.25 g, 87 %). ESI-MS m/z [M+H] ⁺ = 485.2. Step 3: N -Cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxyethyl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

步驟1：乙酸2-(6-(5-(環丙基胺甲醯基)-4-氟-2-甲基苯基)-1-(2-氟乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基-1,1-d ₂ 酯

Acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-4-fluoro-2-methylphenyl)-1-(2-hydroxyethyl)-2-oxo-1, 2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (0.25 g, 0.52 mmol) and K ₂ CO ₃ (143 mg, 1.03 mmol) The mixture in MeOH (3 mL) was stirred at 50°C for 1 hour. The reaction mixture was purified by preparative HPLC to obtain the title compound (136 mg, 59.1%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.60-0.66 (m, 2 H) 0.85-0.92 (m, 2 H) 1.73 (s, 6 H) 2.31 (s, 3 H) 2.56-2.62 (m, 1 H) 2.90-2.97 (m, 1 H) 3.95-4.00 (m, 2 H) 4.02-4.06 (m, 4 H) 5.62 (t, J =8.0 Hz, 1 H) 6.85 (d, J =12.8 Hz , 1 H) 7.05 (d, J =12.8 Hz, 1 H) 7.28 (d, J =2.0 Hz, 1 H) 7.92 (d, J =2.0 Hz, 1 H) 7.96 (d, J =8.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 443.3. Example 5: N -Cyclopropyl-2-fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ ) -2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-(5-(cyclopropylaminocarboxyl)-4-fluoro-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo- 1,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester

To acetic acid 2-(6-bromo-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl) -2-methylpropyl-1,1- d ₂ ester (320 mg, 850.57 µmol), N -cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)benzamide (298.63 mg, 935.63 µmol) and K ₂ CO ₃ (235.12 mg, 1.70 mmol) in dioxane ( _{Add Pd(dppf)Cl 2} (62.24 mg, 85.06 µmol) to the mixture in 6 mL) and water (1 mL). The mixture was stirred at 90°C under nitrogen for 3 hours, then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to give the title compound (400 mg, crude) as a brown oil. ESI-MS m/z [M+H] ⁺ = 489.3. Step 2: N -Cyclopropyl-2-fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ ) -2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-4-fluoro-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo-1, 2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester (400 mg, 818.80 µmol) and LiOH.H ₂ A mixture of O (171.80 mg, 4.09 mmol) in THF (5 mL), DMF (1 mL) and water (1 mL) was stirred under nitrogen at 50°C for 2 hours. The mixture was then diluted with aqueous saturated NH ₄ Cl and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain the title compound (54.55 mg) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.48-0.59 (m, 2 H) 0.62-0.75 (m, 2 H) 1.71 (s, 6 H) 2.29 (s, 3 H) 2.80-2.86 ( m, 1H) 4.08-4.28 (m, 2 H) 4.62 (t, J= 4.8 Hz, 1 H) 4.74 (t, J= 4.8 Hz, 1 H) 4.94 (s, 1 H) 7.27 (d, J= 11.6 Hz, 1 H) 7.42 (d, J = 7.6 Hz, 1 H) 7.57 (d, J = 1.6 Hz, 1 H) 7.95 (d, J = 1.6 Hz, 1 H) 8.22-8.35 (m, 1 H ); ESI-MS m/z [M+H] ⁺ = 447.2. Example 6: 2-Fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo -2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide

步驟1：乙酸2-(1-(2-氟乙基)-6-(5-(異噁唑-3-基胺甲醯基)-2-甲基苯基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基-1,1-d ₂ 酯

The title compound was prepared as in Example 5 with 2-fluoro- N- (isoxazol-3-yl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)benzamide instead of N -cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)benzamide starts from the intermediate acetic acid 2-(6-(4-fluoro-5-(isoxazole-3- (Aminocarboxyl)-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo-1,2-dihydro-3 H -imidazo[4,5- b ] (Pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester continued. The title compound (6.52 mg) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.74 (s, 6 H) 2.37 (s, 3 H) 4.13-4.26 (m, 2 H) 4.65-4.83 (m, 2 H) 5.49 (s, 1 H ) 7.14-7.22 (m, 2 H) 7.96 (d, J =2.0 Hz, 1 H) 8.03 (d, J =8.0 Hz, 1 H) 8.36 (d, J =1.2 Hz, 1 H) 9.11 (d, J =14.8 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 474.2. Example 7: 3-(1-(2-Fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo-2,3 -Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(1-(2-fluoroethyl)-6-(5-(isoxazol-3-ylaminomethanyl)-2-methylphenyl)-2-oxo- 1,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester

To acetic acid 2-(6-bromo-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl) -2-Methylpropyl-1,1- d ₂ ester (412.71 mg, 1.10 mmol) and N -(isoxazol-3-yl)-4-methyl-3-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (300 mg, 914.16 µmol) in dioxane (3 mL) and water (0.3 mL) To the solution, add Na ₂ CO ₃ (290.67 mg, 2.74 mmol) and Pd(dppf)Cl ₂ (66.89 mg, 91.42 µmol). The reaction mixture _{was stirred at 90°C under N 2} for 5 hours, and then diluted with water. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated in vacuo and _{purified by column chromatography (SiO 2} ) using a gradient of 20%-50% EtOAc in petroleum ether to obtain the title compound (350 mg, 77 %). ESI-MS m/z [M+H] ⁺ = 498.2. Step 2: 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo-2,3 -Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide

To acetic acid 2-(1-(2-fluoroethyl)-6-(5-(isoxazol-3-ylaminomethanyl)-2-methylphenyl)-2-oxo-1, 2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester (350 mg, 703.50 µmol) in MeOH (5 mL _{Add K 2} CO ₃ (97.23 mg, 703.50 µmol) to the solution in ). The reaction mixture was stirred at 50°C for 15 minutes, and then adjusted to pH 3 with aqueous HCl (1 M). Water was added and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated in vacuo and purified by preparative HPLC, then successively recrystallized from EtOH (10 mL) and THF/MeOH (2:1, 2 mL). The solid was collected by filtration to obtain the first batch of the title compound (22.9 mg) as a white solid, and the filtrate was concentrated and purified by preparative HPLC to obtain the second batch of the title compound (100 mg, 74.5% purity) as a white solid ). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.73 (s, 6 H) 2.37 (s, 3 H) 4.14-4.26 (m, 2 H) 4.60-4.77 (m, 2 H) 4.97 (s, 1 H) 7.06 (d, J =1.6 Hz, 1 H) 7.50 (d, J =8.0 Hz, 1 H) 7.65 (s, 1 H) 7.92-8.00 (m, 2 H) 8.06 (d, J =1.6 Hz, 1 H) 8.84 (d, J =1.6 Hz, 1 H) 11.43 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 456.2. Example 8: 2-Fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo -2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(1H-pyrazol-3-yl)benzamide

步驟1：乙酸2-(1-(2-氟乙基)-6-(5-(異噻唑-3-基胺甲醯基)-2-甲基苯基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基-1,1-d ₂ 酯

The title compound was prepared as in Example 7, with 3-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alkyl-2-yl)benzamide)-1 H -pyrazole-1-carboxylic acid tertiary butyl ester instead of N- (isoxazol-3-yl)-4-methyl-3-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide starts from the intermediate acetic acid 2-(6-(5-( (1 H -pyrazol-3-yl)aminomethanyl)-4-fluoro-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo-1,2-di hydrogen -3 H - imidazo [4,5- b] pyridin-3-yl) -2-methylpropyl ester -1,1- d ₂ continues. The title compound (10 mg) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.72 (s, 6 H) 2.33 (s, 3 H) 4.12-4.25 (m, 2 H) 4.60-4.77 (m, 2 H) 4.96 (s, 1 H) 6.62 (s, 1 H) 7.32 (d, J =11.2 Hz, 1 H) 7.55 (d, J =7.6 Hz, 1 H) 7.61 (s, 1 H) 7.66 (s, 1 H) 8.02 ( s, 1 H) 10.73 (s, 1 H) 12.43 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 473.2. Example 9: 3-(1-(2-Fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo-2,3 -Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N -(isothiazol-3-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(1-(2-fluoroethyl)-6-(5-(isothiazol-3-ylaminomethyl)-2-methylphenyl)-2-oxo-1 ,2-Dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester

Make 3-bromo- N -(isothiazol-3-yl)-4-methylbenzamide (60 mg, 201.90 µmol), 2-(1-(2-fluoroethyl)-2-oxoacetate Base-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-3 H -imidazo [ 4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester (102.55 mg, 242.28 µmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (16.49 mg, A mixture of 20.19 µmol) and Na ₂ CO ₃ (42.80 mg, 403.81 µmol) in dioxane (1.5 mL) and water (0.3 mL) was degassed and _{purged with N 2} (3 ×). The reaction mixture was stirred at 90°C for 6 hours under an _{N 2 atmosphere, and then diluted with EtOAc and water.} The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-40% EtOAc in petroleum ether to obtain the title compound (50 mg, 48%) as a white oil. ESI-MS m/z [M+H] ⁺ = 514.2. Step 2: 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo-2,3 -Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N -(isothiazol-3-yl)-4-methylbenzamide

Make acetic acid 2-(1-(2-fluoroethyl)-6-(5-(isothiazol-3-ylaminomethanyl)-2-methylphenyl)-2-oxo-1,2 -Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester (50 mg, 97.36 µmol) and K ₂ CO ₃ ( A mixture of 13.46 mg, 97.36 µmol) in MeOH (1.5 mL) was degassed and _{purged with N 2} (3 ×). The reaction mixture was stirred at 50°C for 15 minutes under an _{N 2 atmosphere, and then diluted with EtOAc and water.} The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain the title compound (21.73 mg, 47%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.73 (s, 6 H) 2.37 (s, 3 H) 4.16-4.18 (m, 1 H) 4.23-4.25 (m, 1 H) 4.62-4.64 ( m, 1 H) 4.74-4.76 (m, 1 H) 4.98 (s, 1 H) 7.48 (d, J =7.6 Hz, 1 H) 7.65 (s, 1 H) 7.89 (d, J =4.8 Hz, 1 H) 7.96 (d, J =8.0 Hz, 1 H) 7.98 (s, 1 H) 8.07 (s, 1 H) 9.04 (d, J =4.8 Hz, 1 H) 11.48 (s, 1 H); ESI- MS m/z [M+H] ⁺ = 472.2. Example 10: 2-Fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo -2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N -(isothiazol-3-yl)-4-methylbenzamide

步驟1：N -環丙基-2-氟-5-(1-(1-羥基-2-甲基丙-2-基)-1H -吡咯并[2,3-b ]吡啶-5-基)-4-甲基苯甲醯胺

The title compound was prepared as in Example 9, substituting 5-bromo-2-fluoro- N- (isothiazol-3-yl)-4-methylbenzamide instead of 3-bromo- N- (isothiazole-3- Yl)-4-methylbenzamide and via the intermediate acetic acid 2-(6-(4-fluoro-5-(isothiazol-3-ylaminomethyl)-2-methylphenyl )-1-(2-Fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl The -1,1- d ₂ ester continues. The title compound (5.42 mg) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.72 (s, 6 H) 2.34 (s, 3 H) 4.16-4.24 (m, 2 H) 4.61-4.76 (m, 2 H) 4.96 (s, 1 H) 7.34 (d, J =11.6 Hz, 1 H) 7.58 (s, 1 H) 7.60 (d, J =5.2 Hz, 1 H) 7.85 (d, J =4.8 Hz, 1 H) 8.02 (d, J =1.6 Hz, 1 H) 9.05 (d, J =4.8 Hz, 1 H) 11.47 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 490.2. Example 11: N -Cyclopropyl-5-(3-ethyl-1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridine-5 -Yl)-2-fluoro-4-methylbenzamide

Step 1: N -Cyclopropyl-2-fluoro-5-(1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridine-5- Yl)-4-methylbenzamide

Add 2-(5-bromo-1 H -pyrrolo[2,3- b ]pyridin-1-yl)-2-methylpropan-1-ol (345 mg, 1.28 mmol) and N -at 25°C Cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid A solution of amine (470.52 mg, 1.47 mmol) in dioxane (3.6 mL) and water (0.6 mL) add K ₂ CO ₃ (354.33 mg, 2.56 mmol) and Pd(dppf)Cl ₂ (93.80 mg, 128.19 µmol) ). The suspension was degassed under vacuum and purged with nitrogen (3×). The reaction mixture was heated to 90°C under nitrogen for 12 hours, then diluted with brine and EtOAc and filtered. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated under reduced pressure and _{purified by column chromatography (SiO 2} ) with a gradient of 6%-33% EtOAc in petroleum ether to obtain the title compound (340 mg , 69.6%). ESI-MS m/z [M+H] ⁺ = 382.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.62-0.66 (m, 2 H) 0.86-0.90 (m, 2 H) 1.26-1.29 (m, 1 H) 1.70 (s, 6 H) 2.32 ( s, 3 H) 2.90-3.00 (m, 1 H) 3.95-4.20 (m, 2 H) 6.51 (d, J = 3.20 Hz, 1 H) 6.79-6.87 (m, 1 H) 7.05 (d, J= 12.80 Hz, 1 H) 7.45 (d, J= 3.60 Hz, 1 H) 7.86 (s, 1 H) 8.00 (d, J= 8.00 Hz, 1 H) 8.16 (s, 1 H). Step 2: 5-(3-Bromo-1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl) -N -ring Propyl-2-fluoro-4-methylbenzamide

To N -cyclopropyl-2-fluoro-5-(1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridine- A solution of 5-yl)-4-methylbenzamide (340 mg, 891.35 µmol) in DCM (10 mL) was added with NBS (166.58 mg, 935.92 µmol). The mixture was stirred at 0°C for 45 minutes, and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 6%-14% EtOAc in petroleum ether to obtain the title compound (360 mg, 87.7%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.63-0.66 (m, 2 H) 0.87-0.91 (m, 2 H) 1.69 (s, 6 H) 2.77 (s, 3 H) 2.92-2.99 (m, 1 H) 4.06 (s, 2 H) 6.85 (d, J = 12.80 Hz, 1 H) 7.04-7.09 (m, 1 H) 7.47 (s, 1 H) 7.82 (d, J = 1.60 Hz, 1 H) 8.00-8.04 (m, 1 H) 8.21 (d, J= 1.60 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 461.1. Step 3: N -Cyclopropyl-2-fluoro-5-(1-(1-hydroxy-2-methylprop-2-yl)-3-vinyl-1 H -pyrrolo[2,3- b )Pyridin-5-yl)-4-methylbenzamide

To 5-(3-bromo-1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl) -N at 20℃ -Cyclopropyl-2-fluoro-4-methylbenzamide (320 mg, 695.14 µmol), potassium trifluoro(vinyl) borate (121.05 mg, 903.68 µmol) and K ₂ CO ₃ (192.15 mg, 1.39 _{Add PdCl 2} (dtbpf) (22.65 mg, 34.76 µmol) to a solution of dioxane (4 mL) and water (0.4 mL). The mixture was heated and stirred at 100°C for 3 hours under nitrogen. Brine and EtOAc were added. The mixture was stirred for 10 minutes and filtered. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 9%-25% EtOAc in petroleum ether to obtain the title compound (110 mg, 38.8%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.64-0.66 (m, 2 H) 0.88-0.90 (m, 2 H) 1.70 (s, 6 H) 2.33 (s, 3 H) 2.93-2.97 (m, 1 H) 4.05 (s, 2 H) 5.21 (d, J = 12.00 Hz, 1 H) 5.64 (d, J = 18.00 Hz, 1 H) 6.79-6.87 (m, 2 H) 7.07 (d, J = 12.80 Hz, 1 H) 7.48 (s, 1 H) 8.03 (d, J= 8.40 Hz, 1 H) 8.10 (d, J= 2.00 Hz, 1 H) 8.18 (d, J= 2.00 Hz, 1 H); ESI -MS m/z [M+H] ⁺ = 408.1. Step 4: N -Cyclopropyl-5-(3-ethyl-1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridine-5 -Yl)-2-fluoro-4-methylbenzamide

步驟1：2-(5-溴-3-碘-1H -吡咯并[2,3-b ]吡啶-1-基)-2-甲基丙-1-醇

To N -cyclopropyl-2-fluoro-5-(1-(1-hydroxy-2-methylprop-2-yl)-3-vinyl-1 H -pyrrolo[2,3 -b ]Pyridin-5-yl)-4-methylbenzamide (20 mg, 49 µmol) in MeOH (1 mL) with Pd/C (70 mg, 10% purity). The suspension was degassed under vacuum and _{purged with H 2} (3×), and _{stirred under H 2} (15 psi) at 25 °C for 20 minutes. The mixture was filtered, concentrated under reduced pressure, and purified by preparative HPLC to give the title compound (5.17 mg) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.61-0.68 (m, 2 H) 0.85-0.94 (m, 2 H) 1.24-1.36 (m, 4 H) 1.66 (s, 6 H) 2.32 (s, 3 H) 2.70-2.80 (m, 2 H) 2.92-3.00 (m, 1 H) 4.04 (s, 2 H) 6.84 (d, J = 12.40 Hz, 1 H) 7.05 (d, J = 12.80 Hz, 1 H) 7.20 (s, 1 H) 7.82 (d, J= 2.00 Hz, 1 H) 8.02 (d, J= 8.00 Hz, 1 H) 8.13 (d, J= 2.00 Hz, 1 H); ESI-MS m /z [M+H] ⁺ = 410.2. Example 12: N -Cyclopropyl-2-fluoro-5-(1-(1-hydroxy-2-methylprop-2-yl)-3-(2-hydroxyethyl)-1 H -pyrrolo[ 2,3- b pyridin-5-yl)-4-methylbenzamide

Step 1: 2-(5-Bromo-3-iodo- 1H -pyrrolo[2,3- b ]pyridin-1-yl)-2-methylpropan-1-ol

To 2-(5-bromo- 1H -pyrrolo[2,3- b ]pyridin-1-yl)-2-methylpropan-1-ol (842 mg, 3.13 mmol) in DCM ( Add NIS (703.87 mg, 3.13 mmol) to the solution in 10 mL). The reaction mixture was stirred at 25°C for 1 hour, and then quenched by the addition of water and extracted with EtOAc. , Dried combined organic layers were washed with brine, Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC and eluted with 30% EtOAc in petroleum ether to obtain the title compound (900 mg, 72.8%) as a yellow solid. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.67 (s, 6 H) 4.03 (d, J= 3.6 Hz, 2 H) 5.60 (s, 1 H) 7.49 (s, 1 H) 7.90 (d, J= 2.4 Hz, 1 H) 8.30 (d, J= 2.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 394.8. Step 2: 2-(5-Bromo-3-vinyl-1 H -pyrrolo[2,3- b ]pyridin-1-yl)-2-methylpropan-1-ol

To 2-(5-bromo-3-iodo-1 H -pyrrolo[2,3- b ]pyridin-1-yl)-2-methylpropan-1-ol (400 mg, 1.01 mmol) and trifluoro (Vinyl) potassium borate (149.20 mg, 1.11 mmol) in dioxane (5 mL) and water (0.5 mL) was added K ₂ CO ₃ (279.90 mg, 2.03 mmol) and Pd(dppf)Cl ₂ ( 74.09 mg, 101.26 µmol). The mixture was stirred at 80°C for 3 hours, and then filtered and concentrated under reduced pressure. The residue was purified by preparative TLC and eluted with 25% EtOAc in petroleum ether to obtain the title compound (200 mg, 66.9%) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ ppm 1.66 (s, 6 H) 4.03 (s, 2 H) 5.24 (dd, J = 1.2, 11.6 Hz, 1 H) 5.64 (dd, J = 0.8, 18.0 Hz, 1 H) 6.76 (dd, J= 11.6, 18.0 Hz, 1 H) 8.30 (s, 2 H) 7.43 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 295.0. Step 3: 2-(5-Bromo-3-(2-hydroxyethyl)-1 H -pyrrolo[2,3- b ]pyridin-1-yl)-2-methylpropan-1-ol

Add 2-(5-bromo-3-vinyl-1 H -pyrrolo[2,3- b ]pyridin-1-yl)-2-methylpropan-1-ol (200 mg, 678 A solution of µmol) in THF (1 mL) was mixed with BH ₃ -Me ₂ S (10 M, 203.27 µL) and stirred for 1 hour. Next, add NaOH (1 M, 2.03 mL) and H ₂ O ₂ (209.52 mg, 2.03 mmol, 177.56 µL, 33% purity) at 0°C. The reaction mixture was stirred at 25°C for 2 hours, then quenched by the addition of MeOH, washed with aqueous sodium sulfite solution, and concentrated under reduced pressure. The residue was purified by preparative TLC and eluted with 50% EtOAc in petroleum ether to obtain the title compound (40 mg, 19%) as a yellow oil. ESI-MS m/z [M+H] ⁺ = 313.0. Step 4: N -Cyclopropyl-2-fluoro-5-(1-(1-hydroxy-2-methylprop-2-yl)-3-(2-hydroxyethyl)-1 H -pyrrolo[ 2,3- b pyridin-5-yl)-4-methylbenzamide

To 2-(5-bromo-3-(2-hydroxyethyl)-1 H -pyrrolo[2,3- b ]pyridin-1-yl)-2-methylpropan-1-ol (40 mg, 128 µmol) and N -cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Based) benzamide (48.92 mg, 153.3 µmol) in dioxane (1.8 mL) and water (0.3 mL) with K ₂ CO ₃ (35.30 mg, 255.4 µmol) and Pd(dppf)Cl ₂ (9.35 mg, 12.8 µmol). The mixture was stirred at 90°C for 12 hours, then filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain the title compound (22.06 mg, 38.97%) as a white solid. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 0.57-0.51 (m, 2 H) 0.72-0.66 (m, 2 H) 2.30 (s, 3 H) 1.68 (s, 6 H) 2.84 (t, J = 6.8 Hz, 3 H) 3.73-3.57 (m, 2 H) 3.97 (d, J = 5.2 Hz, 2 H) 4.65 (br t, J = 5.6 Hz, 1 H) 4.65 (br t, J = 5.6 Hz , 1 H) 5.09 (t, J = 5.6 Hz, 1 H) 7.27 (d, J = 11.6 Hz, 1 H) 7.46-7.39 (m, 2 H) 7.91 (d, J = 2.0 Hz, 1 H) 8.17 (d, J= 2.0 Hz, 1 H) 8.33 (d, J= 3.2 Hz, 1 H); ESI-MS [M+H] ⁺ = 426.1. Example 13: N -Cyclopropyl-2-fluoro-5-(1-(1-hydroxy-2-methylprop-2-yl)-2-methyl-1 H -pyrrolo[2,3- b ]Pyridin-5-yl)-4-methylbenzamide

步驟1：5-(3-(1-((第三丁基二甲基矽基)氧基)-2-甲基丙-2-基)-2-乙氧基-3H -咪唑并[4,5-b ]吡啶-6-基)-N -環丙基-2-氟-4-甲基苯甲醯胺

Under N ₂ a solution of 2- (5-chloro-2-methyl -1 H - pyrrolo [2,3- b] pyridin-1-yl) -2-methyl-propan-1-ol (549 mg, 2.30 mmol) and N -cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- _{Add K 2} CO ₃ (635.70 mg, 4.60 mmol) and XPhos Pd G3 (97.33) to a mixture of benzamide (807.46 mg, 2.53 mmol) in dioxane (5 mL) and water (1 mL) at once. mg, 114.99 µmol). The reaction mixture was stirred at 90°C for 12 hours, then diluted with water, and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a 20%-50% EtOAc gradient in petroleum ether, followed by preparative HPLC to obtain the title compound (400 mg, 46.0%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.60-0.67 (m, 2 H) 0.85-0.93 (m, 2 H) 1.69 (s, 6 H) 2.31 (s, 3 H) 2.72 (s, 3 H) ) 2.95 (m, 1 H) 4.21 (s, 2 H) 6.32 (s, 1 H) 6.83 (d, J = 13.4 Hz, 1 H) 7.01-7.09 (m, 2 H) 7.70 (d, J = 2.2 Hz, 1 H) 8.00 (d, J= 8.4 Hz, 1 H) 8.07 (d, J= 2.2 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 396.1. Example 14: N -Cyclopropyl-5-(2-ethoxy-3-(1-hydroxy-2-methylpropan-2-yl)-3 H -imidazo[4,5- b ]pyridine- 6-yl)-2-fluoro-4-methylbenzamide

Step 1: 5-(3-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-2-ethoxy- 3H -imidazo[ 4,5- b ]pyridin-6-yl) -N -cyclopropyl-2-fluoro-4-methylbenzamide

Bring 6-bromo-3-(1-((tertiary butyldimethylsilyl)oxy)-2-methylprop-2-yl)-2-ethoxy- 3H -imidazo[4 ,5- b )pyridine (1.2 g, 2.80 mmol), N -cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)benzamide (1.07 g, 3.36 mmol), K ₂ CO ₃ (774.19 mg, 5.60 mmol) and Pd(dppf)Cl ₂ (102.47 mg, 140.04 µmol) A mixture in dioxane (10 mL) and water (2 mL) was stirred under nitrogen at 90 °C for 4 hours, then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography using a 0%-20% petroleum ether gradient in EtOAc to obtain the title compound (400 mg, 26.4%) as a purple oil. ESI-MS m/z [M+H] ⁺ = 541.3. Step 2: N -Cyclopropyl-5-(2-ethoxy-3-(1-hydroxy-2-methylprop-2-yl)-3 H -imidazo[4,5- b ]pyridine- 6-yl)-2-fluoro-4-methylbenzamide

步驟1：5-(3-(1-((第三丁基二甲基矽基)氧基)丙-2-基)-2-甲氧基-3H -咪唑并[4,5-b ]吡啶-6-基)-N -環丙基-2-氟-4-甲基苯甲醯胺

The 5-(3-(1-((tertiary butyldimethylsilyl)oxy)-2-methylprop-2-yl)-2-ethoxy- 3H -imidazo[4, 5- b ]pyridin-6-yl) -N -cyclopropyl-2-fluoro-4-methylbenzamide (400 mg, 740 µmol) and tetrabutylammonium fluoride (1 M, 3.70 mL, The mixture of 5 equivalents) was stirred under nitrogen at 15°C for 12 hours, then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography using a 0%-30% petroleum ether gradient in EtOAc. The resulting precipitate was triturated in petroleum ether and EtOAc (5:1), collected by filtration and purified by preparative HPLC. The product was recrystallized from EtOH and then from EtOH and THF (10:1) to give the title compound (50 mg, 16%) as a white solid. ¹ H NMR (400 Hz, DMSO- d ₆ ) δ ppm 0.50-0.56 (m, 2% H) 0.63-0.75 (m, 2 H) 1.43 (t, J = 7.2 Hz, 3 H) 1.73 (s, 6 H) 2.28 (s, 3 H) 2.74-2.89 (m, 1 H) 3.95 (d, J = 6.4 Hz, 2 H) 4.56 (q, J = 6.8 Hz, 2 H) 5.17 (t, J = 6.4 Hz , 1 H) 7.26 (d, J = 11.6 Hz, 1 H) 7.40 (d, J = 7.2 Hz, 1 H) 7.75 (s, 1 H) 8.04 (s, 1 H) 8.31 (d, J = 3.2 Hz , 1 H); ESI-MS m/z [M+H] ⁺ = 427.1. Example 15: N -Cyclopropyl-2-fluoro-5-(3-(1-hydroxyprop-2-yl)-2-methoxy- 3H -imidazo[4,5- b ]pyridine-6 -Yl)-4-methylbenzamide

Step 1: 5-(3-(1-((Third-butyldimethylsilyl)oxy)prop-2-yl)-2-methoxy- 3H -imidazo[4,5- b ]Pyridin-6-yl) -N -cyclopropyl-2-fluoro-4-methylbenzamide

Make 6-bromo-3-(1-((tertiary butyldimethylsilyl)oxy)prop-2-yl)-2-methoxy- 3H -imidazo[4,5- b ] Pyridine (300 mg, 749 µmol), N -cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborole Cyclopentane-2-yl)benzamide (263.07 mg, 824.21 µmol), Na ₂ CO ₃ (158.83 mg, 1.50 mmol), Pd(dppf)Cl ₂ (54.83 mg, 74.93 µmol) in dioxane ( The mixture in 3 mL) and water (0.6 mL) was degassed and _{purged with N 2} (3×). The reaction mixture was stirred at 90°C for 6 hours under an _{N 2 atmosphere, and then EtOAc and water were added.} The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-50% EtOAc in petroleum ether to obtain the title compound (360 mg, 93.7%) as a yellow solid. ESI-MS m/z [M+H] ⁺ = 513.3. Step 2: N -Cyclopropyl-2-fluoro-5-(3-(1-hydroxyprop-2-yl)-2-methoxy- 3H -imidazo[4,5- b ]pyridine-6 -Yl)-4-methylbenzamide

步驟1：5-(3-(2-((第三丁基二甲基矽基)氧基)乙基)-2-甲氧基-3H -咪唑并[4,5-b ]吡啶-6-基)-N -環丙基-2-氟-4-甲基苯甲醯胺

To 5-(3-(1-((tertiary butyldimethylsilyl)oxy)prop-2-yl)-2-methoxy- 3H -imidazo[4,5- b ]pyridine -6-yl) -N -cyclopropyl-2-fluoro-4-methylbenzamide (360 mg, 702 µmol) in tetrabutylammonium fluoride (1 M, 3.51 mL). The mixture was stirred at 20°C for 2 hours, then concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain the title compound (125.61 mg, 44.9%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.52-0.56 (m, 1 H) 0.66-0.71 (m, 1 H) 1.49 (d, J = 6.8 Hz, 3 H) 2.27 (s, 3 H ) 2.81-2.85 (m, 1 H) 3.70-3.74 (m, 1 H) 4.01 (t, J =10.0 Hz, 1 H) 4.14 (s, 3 H) 4.62-4.67 (m, 1 H) 4.99 (s , 1 H) 7.28 (d, J =11.2 Hz, 1 H) 7.42 (d, J =7.6 Hz, 1 H) 7.78 (d, J =2.0 Hz, 1 H) 8.06 (d, J =2.0 Hz, 1 H) 8.32 (d, J = 4.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 399.2. Example 16: N -Cyclopropyl-2-fluoro-5-(3-(2-hydroxyethyl)-2-methoxy- 3H -imidazo[4,5- b ]pyridin-6-yl) -4-methylbenzamide

Step 1: 5-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-methoxy- 3H -imidazo[4,5- b ]pyridine- 6-yl) -N -cyclopropyl-2-fluoro-4-methylbenzamide

To 6-bromo-3-(2-((tertiary butyldimethylsilyl)oxy)ethyl)-2-methoxy- 3H -imidazo[4,5- b ]pyridine(200 mg, 518 µmol) in dioxane (2 mL) and water (0.7 mL), add N -cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)benzamide (181.75 mg, 569.42 µmol), Na ₂ CO ₃ (164.60 mg, 1.55 mmol) and Pd(dppf) Cl ₂ (37.88 mg, 51.77 µmol). The reaction mixture was stirred at 90°C for 6 hours, then poured into water and extracted with EtOAc. Dried organic layer was washed with brine Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ ) with a gradient of 15%-50% EtOAc in petroleum ether to obtain the title compound (150 mg, 58.1%) as a yellow oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.21 (s, 6 H) 0.51-0.58 (m, 3 H) 0.67 (br s, 2 H) 1.07 (s, 9 H) 1.05-1.10 (m , 1 H) 2.25 (s, 3 H) 2.72-2.83 (m, 1 H) 3.92-3.99 (m, 3 H) 4.15 (s, 3 H) 4.20 (t, J = 4.8 Hz, 2 H) 7.19- 7.31 (m, 1 H) 7.40 (d, J = 7.6 Hz, 1 H) 7.78 (d, J = 2.0 Hz, 1 H) 8.06 (d, J = 2.0 Hz, 1 H) 8.28-8.39 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 499.2. Step 2: N -Cyclopropyl-2-fluoro-5-(3-(2-hydroxyethyl)-2-methoxy- 3H -imidazo[4,5- b ]pyridin-6-yl) -4-methylbenzamide

The 5-(3-(2-((tertiary butyldimethylsilyl)oxy)ethyl)-2-methoxy- 3H -imidazo[4,5- b ]pyridine-6- A solution of N -cyclopropyl-2-fluoro-4-methylbenzamide (150 mg, 301 µmol) and tetrabutylammonium fluoride (1 M, 1.50 mL) was stirred at 30°C for 2 Hours, then poured into water and extracted with EtOAc. Dried organic layer was washed with brine Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain the title compound (45 mg, 39%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.51-0.59 (m, 2 H) 0.64-0.73 (m, 2 H) 2.27 (s, 3 H) 2.78-2.83 (m, 1 H) 3.68- 3.77 (m, 2 H) 4.13 (t, J = 5.6 Hz, 2 H) 4.16 (s, 3 H) 4.96 (br t, J = 5.6 Hz, 1 H) 7.28 (d, J = 12 Hz, 1 H ) 7.41 (d, J = 7.6 Hz, 1 H) 7.79 (d, J = 2.0 Hz, 1 H) 8.07 (d, J = 2.0 Hz, 1 H) 8.34 (br d, J = 4.0 Hz, 1 H) ; ESI-MS m/z [M+H] ⁺ = 385.2. Example 17: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-3 H -imidazo[4,5- b ]pyridin-6-yl)-4 -Methylbenzamide

Make 2-(6-bromo- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl acetate (400 mg, 1.28 mmol), N -cyclopropyl-4 -Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (463.12 mg, 1.54 mmol), A _{mixture of Na 2} CO ₃ (407.44 mg, 3.84 mmol), PdCl ₂ (dtbpf) (83.51 mg, 128.14 µmol) and water (1 mL) in 1,4-dioxane (10 mL) was degassed and degassed with N ₂ Purge (3 ×). The reaction mixture was stirred at 90°C for 15 hours under an _{N 2 atmosphere, then diluted with water and extracted with EtOAc.} The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-100% EtOAc in petroleum ether to purify the resulting residue, and then further purified by preparative HPLC to obtain the title compound as a white solid (73.2 mg, 15.7%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.62-0.65 (m, 2 H) 0.78-0.82 (m, 2 H) 1.84 (s, 6 H) 2.32 (s, 3 H) 2.82-2.87 (m , 1 H), 4.16 (s, 2 H) 7.42 (d, J = 8.0 Hz, 1 H) 7.72 (d, J = 2.0 Hz, 1 H) 7.75 (d, J = 8.0 Hz, 1 H) 7.99 ( s, 1 H) 8.37 (s, 1 H) 8.47 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 365.1. Example 18: N -Cyclopropyl-3-(1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)-4 -Methylbenzamide

Make 2-(5-bromo-1 H -pyrrolo[2,3- b ]pyridin-1-yl)-2-methylpropan-1-ol (50 mg, 185.78 µmol), N -cyclopropyl- 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (67.15 mg, 222.93 µmol) , Na ₂ CO ₃ (39.38 mg, 371.56 µmol), Pd(dppf)Cl ₂ (13.59 mg, 18.58 µmol) and a mixture of water (0.4 mL) in 1,4-dioxane (2 mL) are degassed and Purge with N ₂ (3×). The reaction mixture _{was stirred at 90 °C under N 2} atmosphere for 10 hours, then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain the title compound (23.08 mg, 34.2%) as a gray solid. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.63-0.64 (m, 2 H) 0.77-0.81 (m, 2 H) 1.75 (s, 6 H) 2.33 (s, 3 H) 2.82-2.87 (m , 1 H) 4.15 (s, 2 H), 6.50 (d, J = 3.6 Hz, 1 H) 7.40 (d, J = 7.6 Hz, 1 H) 7.59 (d, J = 4.0 Hz, 1 H) 7.71- 7.73 (m, 2 H) 7.91 (d, J= 2.0 Hz, 1 H) 8.19 (d, J= 2.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 364.1. Example 19: N -Cyclopropyl-3-(1-(2-hydroxyethyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)-4-methylbenzamide

To 2-(5-bromo-1 H -pyrrolo[2,3- b ]pyridin-1-yl)ethan-1-ol (50 mg, 207.40 µmol) in dioxane (5 mL) and water (1 mL), add N -cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Benzamide (68.71 mg, 228.14 µmol), K ₂ CO ₃ (229.31 mg, 1.66 mmol) and Pd(dppf)Cl ₂ (15.18 mg, 20.74 µmol). The reaction mixture was stirred at 90°C for 12 hours, then poured into water and extracted with EtOAc. Dried organic layer was washed with brine Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain the title compound (17.74 mg, 25.5%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.62-0.68 (m, 2 H) 0.78-0.85 (m, 2 H) 2.34 (s, 3 H) 2.83-2.90 (m, 1 H) 3.97 (t , J = 5.6 Hz, 2 H) 4.46 (t, J = 5.6 Hz, 2 H) 4.51-4.68 (m, 1 H) 4.56-4.64 (m, 1 H) 4.61 (s, 1 H) 6.56 (d, J = 3.6 Hz, 1 H) 7.43 (d, J = 8 Hz, 1 H) 7.53 (d, J = 3.6 Hz, 1 H) 7.71-7.79 (m, 2 H) 7.98 (d, J = 2.0 Hz, 1 H) 8.21 (d, J= 2.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 336.1. Example 20: N - cyclopropyl-3- (3- (2-hydroxyethyl) -3 H - imidazo [4,5- b] pyridin-6-yl) -4-methyl-benzoyl amine

步驟1：乙酸2-(6-(5-(環丙基胺甲醯基)-2-甲基苯基)-2-甲氧基-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

Towards 2-(6-bromo-3 H -imidazo[4,5- b ]pyridin-3-yl)ethyl acetate (175 mg, 615.96 µmol) and N -cyclopropyl-4-methyl-3 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (222.62 mg, 739.15 µmol) in dioxane (3 _{Add K 2} CO ₃ (297.95 mg, 2.16 mmol) and Pd(dppf)Cl ₂ (45.07 mg, 61.60 µmol) to the solution in mL) and water (0.3 mL). The reaction mixture was stirred at 90°C for 5 hours, and then diluted with water. The aqueous phase was extracted with EtOAc and the organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound (65 mg, 31%) as a white solid. ¹ HNMR (400MHz, CDCl ₃ ) δ ppm 0.58-0.67 (m, 2 H) 0.79-0.91 (m, 2 H) 1.25 (s, 1 H) 2.24 (s, 3 H) 2.91 (td, J ₁ = 3.2 Hz, J ₂ =6.8 Hz, 1 H) 3.31 (s, 1 H) 4.04-4.15 (m, 2 H) 4.42-4.50 (m, 2 H) 6.73 (s, 1 H) 7.33 (d, J =8.0 Hz, 1 H) 7.59 (s, 1 H) 7.74-7.67 (m, 1 H) 7.86 (s, 1 H) 8.13 (s, 1 H) 8.21 (s, 1 H); ESI-MS m/z [ M+H] ⁺ = 337.1. Example 21: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-2-methoxy- 3H -imidazo[4,5- b ]pyridine- 6-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-(5-(cyclopropylaminocarboxyl)-2-methylphenyl)-2-methoxy- 3H -imidazo[4,5- b ]pyridine- 3-yl)-2-methylpropyl ester

Make 2-(6-bromo-2-methoxy- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl acetate (180 mg, 526.03 µmol), N -Cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (158.43 mg, 526.03 µmol), K ₂ CO ₃ (363.50 mg, 2.63 mmol), Pd(dppf)Cl ₂ (38.49 mg, 52.60 µmol) in dioxane (5 mL) and water (1 mL), degassed And purged with N ₂ (3×). The reaction mixture was stirred at 90°C for 16 hours under an _{N 2 atmosphere, and then diluted with water.} The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with EtOAc to obtain the title compound (180 mg, 78.4%) as a yellow oil. ESI-MS m/z [M+H] ⁺ = 437.3. Step 2: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-2-methoxy- 3H -imidazo[4,5- b ]pyridine- 6-yl)-4-methylbenzamide

步驟1：乙酸2-(6-(5-(環丙基胺甲醯基)-2-甲基苯基)-2-甲基-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

Acetic acid 2-(6-(5-(cyclopropylaminocarboxyl)-2-methylphenyl)-2-methoxy- 3H -imidazo[4,5- b ]pyridine-3- A mixture of methyl)-2-methylpropyl ester (150 mg, 343.64 µmol) and K ₂ CO ₃ (237.47 mg, 1.72 mmol) in MeOH (3 mL) was stirred at 70° C. for 1 hour, and then filtered. The filtrate was purified by preparative HPLC. The fractions containing the product were combined, concentrated and lyophilized to give the title compound (15.67 mg, 11.6%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.56-0.68 (m, 2 H), 0.78-0.96 (m, 2 H), 1.64 (s, 6 H), 1.87 (s, 1 H), 2.32 (s, 3 H), 2.91 (dt, J ₁ = 3.2 Hz, J ₂ =7.2 Hz, 1 H), 4.15 (s, 2 H), 4.27 (s, 3 H), 6.25-6.37 (m, 2 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.60 (d, J = 2.0 Hz, 1 H), 7.64-7.79 (m, 1 H), 8.03 (d, J = 2.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 395.2. Example 22: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-2-methyl- 3H -imidazo[4,5- b ]pyridine-6 -Yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-(5-(cyclopropylaminocarboxyl)-2-methylphenyl)-2-methyl-3 H -imidazo[4,5- b ]pyridine-3 -Yl)-2-methylpropyl ester

To acetic acid 2-(6-bromo-2-methyl-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (70 mg, 214.60 µmol) at 20°C ) Add N -cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl) to a solution of dioxane (4 mL), MeOH (0.1 mL) and water (1 mL) -1,3,2-Dioxaborolan-2-yl)benzamide (77.56 mg, 257.52 µmol), K ₂ CO ₃ (88.98 mg, 643.80 µmol) and Pd(dppf)Cl ₂ (7.85 mg, 10.73 µmol). The suspension was degassed under vacuum and purged with nitrogen (3×), then heated to 90° C. under nitrogen for 7 hours with stirring. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to give the title compound (55 mg, crude) as a pale yellow oil. ESI-MS m/z [M+H] ⁺ = 421.3. Step 2: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-2-methyl-3 H -imidazo[4,5- b ]pyridine-6 -Yl)-4-methylbenzamide

To acetic acid 2-(6-(5-(cyclopropylaminomethyl)-2-methylphenyl)-2-methyl- 3H -imidazo[4,5- b ]pyridine at 20℃ _{Add K 2} CO ₃ (36.15 mg, 261.59 µmol) to a solution of -3-yl)-2-methylpropyl ester (55 mg, 130.80 µmol) in MeOH (2 mL). The mixture was heated under nitrogen at 50°C for 2 hours and stirred, and then purified by preparative HPLC to obtain the title compound (12 mg, 24%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.59-0.65 (m, 2 H) 0.84-0.91 (m, 2 H) 1.73 (s, 6 H) 2.32 (s, 3 H) 2.88-2.95 (m, 4 H) 4.25 (s, 2 H) 6.26 (s, 1 H) 7.37 (d, J = 8.00 Hz, 1 H) 7.62 (d, J = 2.00 Hz, 1 H) 7.69 (dd, J ₁ =1.60 Hz , J ₂ =7.60 Hz, 1 H) 7.90 (d, J= 2.00 Hz, 1 H) 8.20 (d, J= 1.60 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 379.2. Example 23: 3-(3-Chloro-1-(1-hydroxy-2-methylpropan-2-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl) -N -ring Propyl-4-methylbenzamide

步驟1：乙酸2-(6-溴-1-(2-氟乙基)-7-甲基-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

To N -cyclopropyl-3-(1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl) at 20℃ Add NCS (30.2 mg, 0.226 mmol) to a solution of -4-methylbenzamide (70 mg, 0.174 mmol) in DMF (6 mL). The reaction mixture was stirred at 60°C for 10 hours, then poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried _{over Na 2} SO _4. The crude product was dried under reduced pressure and purified by preparative HPLC to obtain the formate (23 mg, 33.2%) of the title compound as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.55-0.56 (m, 2 H) 0.65-0.68 (m, 2 H) 1.70 (s, 6 H) 2.31 (s, 3 H) 2.83-2.86 ( m, 1 H) 3.97 (s, 2 H) 5.05 (s, 1 H) 7.41 (d, J =8.0 Hz, 1 H) 7.75-7.78 (m, 3H) 7.87 (d, J =1.6 Hz, 1 H ) 8.33 (d, J =1.6 Hz, 1 H) 8.42 (d, J =3.6 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 398.3. Example 24: N -Cyclopropyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-7-methyl-2-oxo -2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-bromo-1-(2-fluoroethyl)-7-methyl-2-oxo-1,2-dihydro-3 H -imidazo[4,5- b ]Pyridin-3-yl)-2-methylpropyl ester

To acetic acid 2-(6-bromo-7-methyl-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methyl A solution of propyl ester (0.15 g, 0.438 µmol) and 1-bromo-2-fluoroethane (167 mg, 1.32 mmol) in acetonitrile (10 mL) was added K ₂ CO ₃ (121 mg, 0.877 mmol). The reaction mixture was stirred at 80°C for 16 hours, and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) and eluted with 10% EtOAc in petroleum ether to obtain the title compound (140 mg, 80.6%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.84 (s, 6 H) 1.97 (s, 3 H) 2.62 (s, 3 H) 4.32 (t, J =4.8 Hz, 1 H) 4.39 (t, J =5.2 Hz, 1 H) 4.63 (t, J =5.2 Hz, 1 H) 4.69 (s, 2 H) 4.75 (t, J =4.8 Hz, 1 H) 8.01 (s, 1 H); ESI-MS m /z [M+H] ⁺ = 390.3. Step 2: Acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-2-methylphenyl)-1-(2-fluoroethyl)-7-methyl-2-oxo -1 H -imidazo[4,5- b ]pyridine-3(2 H )-yl)-2-methylpropyl ester

Acetic acid 2-(6-bromo-1-(2-fluoroethyl)-7-methyl-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridine -3-yl)-2-methylpropyl ester (140 mg, 0.361 µmol), N -cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3 ,2-Dioxaborolan-2-yl)benzamide (130 mg, 0.433 µmol), K ₂ CO ₃ aqueous solution (2 M, 0.541 mL) and PdCl ₂ (dtbpf) (23.5 mg, A solution of 0.036 mmol) in dioxane (4 mL) was degassed and _{purged with N 2} (3×). The reaction mixture was stirred at 100°C for 3 hours, then diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ ) using a 10%-50% EtOAc gradient in petroleum ether to obtain the title compound (110 mg, 58.1%) as a yellow solid. ESI-MS m/z [M+H] ⁺ = 483.4. Step 3: N -Cyclopropyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-7-methyl-2-oxo -2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

To acetic acid 2-(6-(5-(cyclopropylaminomethyl)-2-methylphenyl)-1-(2-fluoroethyl)-7-methyl-2-oxo-1 A solution of H -imidazo[4,5- b ]pyridine-3( 2H )-yl)-2-methylpropyl ester (110 mg, 0.228 mmol) in MeOH (10 mL) is added K ₂ CO ₃ (158 mg, 1.14 mmol). The reaction mixture was stirred at 60°C for 2 hours, then diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a 10%-50% EtOAc gradient in petroleum ether to purify the resulting residue, and further purified by preparative HPLC to obtain the title compound (76.5) as a white solid mg, ). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.61-0.63 (m, 2 H) 0.85-0.90 (m, 2 H) 1.73 (s, 6 H) 2.21 (s, 3 H) 2.24 (s, 3 H) 2.88-2.92 (m, 1 H) 4.03 (s, 2 H) 4.38 (t, J =4.8 Hz, 1 H) 4.44 (t, J =4.8 Hz, 1 H) 4.67 (t, J =4.8 Hz, 1 H) 4.78 (d, J =4.8 Hz, 1 H) 5.73 (s, 1 H) 6.19 (s, 1 H) 7.36 (d, J =8.0 Hz, 1 H) 7.48 (d, J =1.6 Hz, 1 H) 7.72 (dd, J ₁ =1.6 Hz, J ₂ =2.0 Hz, 1 H) 7.77 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 441.3. Example 25: N -Cyclopropyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-5-methyl-2-oxo -2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

步驟1：乙酸2-(6-(5-(環丙基胺甲醯基)-2-甲基苯基)-1-(2-氟乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基-1,1-d ₂ 酯

The title compound was prepared as in Example 24 with 2-(6-bromo-5-methyl-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridine- 3-yl)-2-methylpropyl ester (0.4 g, 1.17 mmol, 1 equivalent) instead of acetic acid 2-(6-bromo-7-methyl-2-oxo-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester starts and passes through the intermediate acetic acid 2-(6-bromo-1-(2-fluoroethyl)- 5-methyl-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester and acetic acid 2-(6 -(5-(Cyclopropylaminomethanyl)-2-methylphenyl)-1-(2-fluoroethyl)-5-methyl-2-oxo-1,2-dihydro- 3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester proceeded. The title compound (8 mg, 5.5% step 3) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.60-0.64 (m, 2 H) 0.86-0.90 (m, 2 H) 1.73 (t, J = 3.2 Hz, 6 H) 2.14 (s, 3 H ) 2.23 (s, 3 H) 2.89-2.93 (m, 1 H) 4.03-4.06 (m, 1 H) 4.08-4.11 (m, 1 H) 4.13-4.18 (m, 1 H) 4.65 (t, J = 4.4 Hz, 1 H) 4.76 (t, J =4.8 Hz, 1 H) 5.99 (t, J =6.8 Hz, 1 H) 6.19 (s, 1 H) 7.05 (d, J =0.8 Hz, 1 H) 7.34 (d, J =7.6 Hz, 1 H) 7.51 (d, J =1.6 Hz, 1 H) 7.65 (dd, J ₁ =2.0 Hz, J ₂ =8.0 Hz, 1 H); ESI-MS m/z [ M+H] ⁺ = 441.3. Example 26: N -cyclopropyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-side Oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-(5-(cyclopropylaminomethyl)-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo-1,2- Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester

To acetic acid 2-(6-bromo-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl) -2-methylpropyl-1,1- d ₂ ester (100 mg, 265.80 µmol), N -cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaborolan-2-yl)benzamide (88.06 mg, 292.38 µmol) and K ₂ CO ₃ (73.47 mg, 531.61 µmol) in dioxane (2 mL) and _{Add Pd(dppf)Cl 2} (19.45 mg, 26.58 µmol) to the mixture in water (0.5 mL). The reaction mixture was stirred at 90°C under nitrogen for 3 hours, then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to give the title compound (150 mg, crude) as a brown oil. ESI-MS m/z [M+H] ⁺ = 471.4 . Step 2: N -cyclopropyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-side Oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

步驟1：乙酸2-(6-溴-1-乙基-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-(甲基-d ₃ )丙基-3,3,3-d ₃ 酯

Acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo-1,2-dihydro -3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester (500 mg, 1.06 mmol), LiOH (127.24 mg, 5.31 mmol) A mixture of H ₂ O (250 mg, 13.88 mmol) in THF (5 mL) and DMF (0.5 mL) was stirred at 50° C. for 12 hours, then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ ) using a 0%-100% EtOAc gradient in petroleum ether to purify the resulting residue, and then purified by preparative HPLC to obtain the title compound as a white solid (81.5 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.51-0.59 (m, 2 H) 0.63-0.73 (m, 2 H) 1.72 (s, 6 H) 2.26-2.34 (m, 3 H) 2.81- 2.87 (m, 1 H) 4.12-4.26 (m, 2 H) 4.57-4.78 (m, 2 H) 4.90-4.99 (m, 1 H) 4.90-4.99 (m, 1 H) 4.95 (s, 1 H) 7.40 (d, J = 8.0 Hz, 1 H) 7.59 (d, J = 1.6 Hz, 1 H) 7.70-7.78 (m, 2 H) 7.97 (d, J = 2.0 Hz, 1 H) 8.37 (d, J = 4.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 429.3 . Example 27: N -Cyclopropyl-3-(1-ethyl-3-(2-(hydroxymethyl)prop-2-yl-1,1,1,3,3,3- d ₆ )-2 -Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-bromo-1-ethyl-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2- (Methyl- d ₃ )propyl-3,3,3- d ₃ ester

Acetic acid 2-(6-bromo-2-oxo-1,2-dihydro- 3H -imidazo[4,5-b]pyridin-3-yl)-2-(methyl- d ₃ ) Propyl-3,3,3- d ₃ ester (200 mg, 598.45 µmol), iodoethane (140.01 mg, 897.67 µmol) and K ₂ CO ₃ (165.42 mg, 1.20 mmol) in DMF (2 mL) the solution was stirred for 3 hours at 15 deg.] C under N _2. Add ethyl acetate and water. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) with a gradient of 0%-30% EtOAc in petroleum ether to obtain the title compound (210 mg, 96.9%) as a brown oil. ESI-MS m/z [M+H] ⁺ = 364.2. Step 2: Acetic acid 2-(6-(5-(cyclopropylaminocarboxyl)-2-methylphenyl)-1-ethyl-2-oxo-1,2-dihydro-3 H -Imidazo[4,5- b ]pyridin-3-yl)-2-(methyl- d ₃ )propyl-3,3,3- d ₃ ester

To acetic acid 2-(6-bromo-1-ethyl-2-side oxy-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-(methyl yl - d ₃₎ -3,3,3- d _3-propyl ester (210 mg, 579.71 μmol), N - cyclopropyl-4-methyl-3- (4,4,5,5 -1,3,2-dioxaborolan-2-yl)benzamide (192.06 mg, 637.68 µmol) and K ₂ CO ₃ (160.24 mg, 1.16 mmol) in dioxane (4 mL _{Add Pd(dppf)Cl 2} (42.42 mg, 57.97 µmol) to the mixture of) and water (1 mL). The reaction mixture was stirred for 2 hours at 90 deg.] C under N _2. Add ethyl acetate and water. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-50% EtOAc in petroleum ether to purify the residue to obtain the title compound (210 mg, 79.3%) as a yellow solid. ESI-MS m/z [M+H] ⁺ = 457.4. Step 3: N -Cyclopropyl-3-(1-ethyl-3-(2-(hydroxymethyl)prop-2-yl-1,1,1,3,3,3- d ₆ )-2 -Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

步驟1：乙酸2-(6-溴-1-(2-氟乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-(甲基-d ₃ )丙基-3,3,3-d ₃ 酯

Acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-2-methylphenyl)-1-ethyl-2-oxo-1,2-dihydro- 3H -imidazole And [4,5- b ]pyridin-3-yl)-2-(methyl- d ₃ )propyl-3,3,3- d ₃ ester (210 mg, 459.96 µmol) and K ₂ CO ₃ (127.14 The mixture of mg, 919.91 µmol) in MeOH (5 mL) is degassed and _{purged with N 2} (3 ×). The reaction mixture was stirred at 50°C for 2 hours under a _{N 2 atmosphere.} Add ethyl acetate and water. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (93.05 mg, 48.8%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.54-0.58 (m, 2 H) 0.67-0.71 (m, 2 H) 1.06 (t, J =7.0 Hz, 1 H) 1.21 (t, J = 7.0 Hz, 3 H) 2.33 (s, 3 H) 2.82-2.88 (m, 1 H) 3.87-3.93 (m, 4 H) 5.00 (t, J =6.4 Hz, 1 H) 7.42 (d, J =8.0 Hz, 1 H) 7.61 (s, 3 H) 7.76 (t, J =8.8 Hz, 2 H) 7.96 (s, 1 H) 8.39 (d, J =4.4 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 415.2. Example 28: N -Cyclopropyl-3-(1-(2-fluoroethyl)-3-(2-(hydroxymethyl)prop-2-yl-1,1,1,3,3,3- d ₆ )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-bromo-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridine-3- Yl)-2-(methyl- d ₃ )propyl-3,3,3- d ₃ ester

Acetic acid 2-(6-bromo-2-oxo-1,2-dihydro- 3H -imidazo[4,5-b]pyridin-3-yl)-2-(methyl- d ₃ ) Propyl-3,3,3- d ₃ ester (300 mg, 897.67 µmol), K ₂ CO ₃ (248.13 mg, 1.80 mmol) and 1-bromo-2-fluoroethane (170.95 mg, 1.35 mmol) in DMF The solution in (2 mL) was stirred at 15°C for 3 hours under _{N 2.} Add ethyl acetate and water. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 3%-20% EtOAc in petroleum ether to obtain the title compound (320 mg, 93.8%) as a brown oil. ESI-MS m/z [M+H] ⁺ = 380.2. Step 2: Acetic acid 2-(6-(5-(cyclopropylaminomethyl)-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo-1,2- Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-(methyl- d ₃ )propyl-3,3,3- d ₃ ester

To acetic acid 2-(6-bromo-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl) -2-(methyl- d ₃ )propyl-3,3,3- d ₃ ester (320 mg, 841.57 µmol), N -cyclopropyl-4-methyl-3-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (278.82 mg, 925.73 µmol) and K ₂ CO ₃ (232.62 mg, 1.68 mmol) in two _{Add Pd(dppf)Cl 2} (61.58 mg, 84.16 µmol) to the mixture of oxane (4 mL) and water (0.8 mL). The reaction mixture was stirred for 2 hours at 90 deg.] C under N _2. Add ethyl acetate and water. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a 5%-30% EtOAc gradient in petroleum ether to obtain the title compound (300 mg, 75.1%) as a yellow solid. ESI-MS m/z [M+H] ⁺ = 475.4. Step 3: N -Cyclopropyl-3-(1-(2-fluoroethyl)-3-(2-(hydroxymethyl)propan-2-yl-1,1,1,3,3,3- d ₆ )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

步驟1：3-(3-溴-1-(1-羥基-2-甲基丙-2-基)-1H -吡咯并[2,3-b ]吡啶-5-基)-N -環丙基-4-甲基苯甲醯胺

Acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo-1,2-dihydro -3 H -imidazo[4,5- b ]pyridin-3-yl)-2-(methyl- d ₃ )propyl-3,3,3- d ₃ ester (300 mg, 632.17 µmol) and LiOH A solution of (75.70 mg, 3.16 mmol) in THF (5 mL), DMF (0.5 mL) and water (0.25 mL) was stirred at 50°C for 12 hours. Then the mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2) using a gradient of 0%-100% EtOAc in petroleum ether to purify the resulting residue, and then purified by preparative HPLC to obtain the title compound as a white solid ( 67.2 mg, 24.6%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.52-0.58 (m, 2 H) 0.65-0.71 (m, 2 H) 2.31 (s, 3 H) 2.82-2.87 (m, 1 H) 3.92 ( d, J = 6.4 Hz, 2 H) 4.17 (d, J = 4.8 Hz, 1 H) 4.23 (t, J = 4.8 Hz, 1 H) 4.62 (t, J = 4.8 Hz, 1 H) 4.74 (t, J = 4.8 Hz, 1 H) 4.98 (t, J = 6.4 Hz, 1 H) 7.40 (d, J = 8.0 Hz, 1 H) 7.59 (s, 1 H) 7.72 (s, 1 H) 7.76 (d, J= 8.0 Hz, 1 H) 7.97 (d, J= 2.0 Hz, 1 H) 8.38 (d, J= 4.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 433.3. Example 29: N -Cyclopropyl-3-(3-ethyl-1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridine-5 -Yl)-4-methylbenzamide

Step 1: 3-(3-Bromo-1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl) -N -ring Propyl-4-methylbenzamide

To N -cyclopropyl-3-(1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl) at 0℃ A solution of -4-methylbenzamide (500 mg, 1.24 mmol) in DCM (15 mL) was added with NBS (232 mg, 1.31 mmol). The reaction mixture was stirred at 0°C for 0.5 hour and then concentrated. The crude product was purified by column chromatography (SiO ₂ ) with a gradient of 10%-50% EtOAc in petroleum ether to obtain the title compound (0.48 g, 85%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.62-0.65 (m, 2 H) 0.85-0.89 (m, 2 H) 1.69 (s, 6 H) 2.33 (s, 3 H) 2.89-2.93 (m, 1 H) 4.05 (s, 2 H) 6.29 (s, 1 H) 6.57 (s, 1 H) 7.37 (d, J =8.0 Hz, 1 H) 7.47 (s, 1 H) 7.63 (d, J =2.0 Hz, 1 H) 7.70 (dd, J ₁ =1.6 Hz, J ₂ =8.0 Hz,1 H) 7.83 (d, J =2.0 Hz, 1 H) 8.23 (d, J =2.4 Hz, 1 H); ESI -MS m/z [M+H] ⁺ = 444.0. Step 2: N -Cyclopropyl-3-(1-(1-hydroxy-2-methylprop-2-yl)-3-vinyl-1 H -pyrrolo[2,3- b ]pyridine-5 -Yl)-4-methylbenzamide

To 3-(3-bromo-1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl) -N at 15℃ -Cyclopropyl-4-methylbenzamide (300 mg, 0.657 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborole A solution of pentane (131 mg, 0.855 mmol) and K ₂ CO ₃ (181 mg, 1.32 mmol) in dioxane (5 mL) and water (0.5 mL) add PdCl ₂ (dtbpf) (21.4 mg, 0.033 mmol) ). The reaction mixture was stirred at 100°C for 5 hours, then poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, and dried _{over Na 2} SO _4. The crude product was dried under reduced pressure and purified by column chromatography (SiO ₂ ) with a gradient of 10%-50% EtOAc in petroleum ether to obtain the title compound (160 mg, 62.6%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.61-0.63 (m, 2 H) 0.84-0.90 (m, 2 H) 1.69 (s, 6 H) 2.34 (s, 3 H) 2.90-2.93 (m, 1 H) 4.04 (s, 2 H) 5.20 (d, J =11.6 Hz, 1 H) 5.64 (d, J =18.0 Hz, 1 H) 6.28 (s, 1 H) 6.77-6.82 (m, 1 H) 6.85 (s,1 H) 7.37 (d, J =8.0 Hz, 1 H) 7.48 (s, 1 H) 7.63 (d, J =1.6 Hz, 1 H) 7.70 (dd, J =1.6 Hz, J =5.6 Hz,1 H) 8.12 (d, J =2.0 Hz, 1 H) 8.20 (d, J =2.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 390.4. Step 3: N -Cyclopropyl-3-(3-ethyl-1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridine-5 -Yl)-4-methylbenzamide

Under N ₂ atmosphere, to N -cyclopropyl-3-(1-(1-hydroxy-2-methylprop-2-yl)-3-vinyl-1 H -pyrrolo[2,3- b ] A solution of pyridin-5-yl)-4-methylbenzamide (30 mg, 0.734 mmol) in MeOH (2 mL) was added with Pd/C (5 mg, 10% purity). The mixture was stirred at 20°C for 2 hours under an _{H 2 atmosphere (15 psi) and then filtered.} The filtrate was concentrated and purified by preparative HPLC to obtain the title compound (10 mg, 3.4%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.54-0.57 (m, 2 H) 0.66-0.68 (m, 2 H) 1.26 (t, J =7.6 Hz, 3 H) 1.68 (s, 6 H ) 2.31 (s, 3 H) 2.66-2.75 (m, 2 H) 2.84-2.86 (m, 1 H) 3.97 (s, 2 H) 5.08 (s, 1 H) 7.39 (d, J =9.2 Hz, 2 H) 7.75 (d, J =7.2 Hz, 2 H) 7.90 (d, J =2.0 Hz, 1 H) 8.19 (d, J =2.0 Hz, 1 H) 8.38 (d, J =4.0 Hz, 1 H) ; ESI-MS m/z [M+H] ⁺ = 392.1. Example 30: N -Cyclopropyl-3-(1-(1-hydroxy-2-methylprop-2-yl)-3-methyl-1 H -pyrrolo[2,3- b ]pyridine-5 -Yl)-4-methylbenzamide

步驟1：乙酸2-(5-(5-(環丙基胺甲醯基)-2-甲基苯基)-3-乙烯基-1H -吡咯并[2,3-b ]吡啶-1-基)-2-甲基丙基酯

To 3-(3-bromo-1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl) -N at 15℃ -Cyclopropyl-4-methylbenzamide (80 mg, 175 µmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane _{Add K 3} PO ₄ (74.4 mg, 0.350 mmol) to a solution of hexane (52.8 mg, 0.210 mmol) and XPhos Pd G3 (7.42 mg, 9 µmol) in THF (1 mL) and water (0.1 mL). The mixture was stirred at 70°C for 15 hours, then diluted with water, and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by preparative TLC (SiO ₂ ) and eluted with 50% EtOAc in petroleum ether to obtain the title compound (17.0 mg, 26%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.61-0.64 (m, 2 H) 0.83-0.86 (m, 2 H) 1.65 (s, 6 H) 2.31 (s, 3 H) 2.33 (s, 3 H) ) 2.89-2.93 (m, 1 H) 4.03 (s, 2 H) 6.37 (s, 1 H) 7.20 (s, 1 H) 7.34 (d, J =8.0 Hz, 1 H) 7.64 (d, J =2.0 Hz, 1H) 7.67 (dd, J ₁ =2.0 Hz, J ₂ =8.0 Hz, 1 H) 7.81 (d, J =2.0 Hz, 1 H) 8.14 (d, J =2.0 Hz, 1 H); ESI- MS m/z [M+H] ⁺ = 378.0. Example 31: N -cyclopropyl-3-(1-(1-hydroxy-2-methylprop-2-yl)-3-(2-hydroxyethyl)-1 H -pyrrolo[2,3- b )Pyridin-5-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(5-(5-(cyclopropylaminocarboxyl)-2-methylphenyl)-3-vinyl-1 H -pyrrolo[2,3- b ]pyridine-1 -Yl)-2-methylpropyl ester

N -cyclopropyl-3-(1-(1-hydroxy-2-methylprop-2-yl)-3-vinyl- 1H -pyrrolo[2,3- b ]pyridin-5-yl ) A mixture of 4-methylbenzamide (100 mg, 0.244 mmol) and acetic anhydride (0.046 mL, 0.489 mmol) in pyridine (1 mL) was stirred at 70°C for 2 hours. The mixture was then concentrated, diluted with water, and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure to give the title compound (110 mg, 96%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.61-0.63 (m, 2 H) 0.86-0.89 (m, 2 H) 1.85 (s, 6 H) 1.99 (s, 3 H) 2.35 (s, 3 H) ) 2.90-2.93 (m, 1 H) 4.82 (s, 2 H) 5.17 (d, J =11.6 Hz, 1 H) 5.64 (d, J =17.6 Hz, 1 H) 6.25 (s, 1 H) 6.78- 6.83 (m, 1 H) 7.36-7.37 (m,1 H) 7.38 (d, J =8.0 Hz, 1 H) 7.41 (s, 1 H) 7.61 (d, J =2.0 Hz, 1 H) 7.72 (dd , J ₁ =2.0 Hz, J ₂ =8.0 Hz, 1 H) 8.06 (d, J =2.0 Hz, 1 H) 8.23 (d, J =2.0 Hz, 1 H); ESI-MS m/z [M+ H] ⁺ = 432.1. Step 2: N -Cyclopropyl-3-(1-(1-hydroxy-2-methylprop-2-yl)-3-(2-hydroxyethyl)-1 H -pyrrolo[2,3- b )Pyridin-5-yl)-4-methylbenzamide

步驟1：N -環丙基-3-(1-(1-羥基-2-甲基丙-2-基)-3-(丙-1-烯-2-基)-1H -吡咯并[2,3-b ]吡啶-5-基)-4-甲基苯甲醯胺

To acetic acid 2-(5-(5-(cyclopropylaminomethanyl)-2-methylphenyl)-3-vinyl-1 H -pyrrolo[2,3- b ]pyridine at 0℃ A solution of -1-yl)-2-methylpropyl ester (90 mg, 0.196 mmol) in THF (2 mL) was added 9-borabicyclo[3.3.1]nonane (0.5 M, 1.18 mL). The mixture was stirred at 20°C for 20 hours, then an aqueous NaOH solution (3 M, 0.45 mL) was added at 0°C, followed by H ₂ O ₂ (0.36 mL, 6.24 mmol, 50% purity) at 0°C. The mixture was stirred at 20°C for 12 hours, then diluted with water, and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, and concentrated under reduced pressure. The residue obtained was purified by preparative TLC (SiO ₂ ) using 5% MeOH in EtOAc for elution. The crude product was dissolved in MeOH (5 mL). The mixture was adjusted to pH 2 with 1 N HCl, then stirred at 30°C for 3 hours, and concentrated. The resulting residue was diluted with water, _{adjusted to pH 9 with K 2} CO ₃ (solid), and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by preparative TLC (SiO ₂ ) and eluted with 10% MeOH in DCM to obtain the title compound (15.74 mg, 19.7%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.61-0.63 (m, 2 H) 0.83-0.86 (m, 2 H) 1.68 (s, 6 H) 2.32 (s, 3 H) 2.90-2.91 (m, 1 H) 2.99 (t, J =6.0 Hz, 2 H) 3.90 (s, 2 H) 4.03 (s, 2 H) 6.38 (s, 1 H) 7.06 (s, 1 H) 7.30 (d, J =1.6 Hz, 1 H) 7.31-7.35 (m, 2 H) 7.65 (dd, J ₁ =2.0 Hz, J ₂ =6.0 Hz, 1 H) 7.87 (d, J =2.0 Hz, 1 H) 8.16 (d, J =2.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 408.3. Example 32: N -Cyclopropyl-3-(1-(1-hydroxy-2-methylprop-2-yl)-3-isopropyl-1 H -pyrrolo[2,3- b ]pyridine- 5-yl)-4-methylbenzamide

Step 1: N -Cyclopropyl-3-(1-(1-hydroxy-2-methylprop-2-yl)-3-(prop-1-en-2-yl)-1 H -pyrrolo[ 2,3- b pyridin-5-yl)-4-methylbenzamide

Make 3-(3-bromo-1-(1-hydroxy-2-methylpropan-2-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl) -N at 15℃ -Cyclopropyl-4-methylbenzamide (50 mg, 0.104 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3 ,2-Dioxaborolane (22.7 mg, 0.135 mmol), PdCl ₂ (dtbpf) (3.39 mg, 0.005 mmol), K ₂ CO ₃ (2 M, 0.104 mL) in dioxane (3 mL The mixture in) is degassed and _{purged with N 2} (3×). The reaction mixture _{was stirred at 100 °C under N 2} atmosphere for 3 hours, and then partitioned between water and EtOAc. The organic layer was separated, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography (SiO ₂ ) using a gradient of 10%-50% EtOAc in petroleum ether to obtain the title compound (30 mg, crude) as a colorless solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.62-0.63 (m, 2 H) 0.88 (d, J =5.6 Hz, 2 H) 1.25 (s, 6 H) 2.21 (s, 3 H) 2.34 (s , 3 H) 2.90-2.94 (m, 1 H) 4.06 (s, 2 H) 5.09 (d, J =1.6 Hz, 1 H) 5.40 (s, 1 H) 6.22 (s, 1 H) 7.38 (d, J =8.0 Hz, 1 H) 7.45 (s, 1 H) 7.63 (d, J =2.0 Hz, 1 H) 7.70 (dd, J ₁ =1.6 Hz, J ₂ =7.6 Hz, 1 H) 8.17 (d, J =2.0 Hz, 1 H) 8.20 (d, J =2.4 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 404.4. Step 2: N -Cyclopropyl-3-(1-(1-hydroxy-2-methylprop-2-yl)-3-isopropyl-1 H -pyrrolo[2,3- b ]pyridine- 5-yl)-4-methylbenzamide

步驟1：3-(3-(1-((第三丁基二甲基矽基)氧基)-2-甲基丙-2-基)-2-乙氧基-3H -咪唑并[4,5-b ]吡啶-6-基)-N -環丙基-4-甲基苯甲醯胺

Under N ₂ to N - cyclopropyl-3- (1- (1-hydroxy-2-methylpropan-2-yl) -3- (prop-1 -en-2-yl) -1 H - pyrrole And [2,3- b ]pyridin-5-yl)-4-methylbenzamide (25 mg, 0.047 mmol) in MeOH (5 mL) was added Pd/C (50 mg, 10% purity ). The suspension was degassed under vacuum and _{purged with H 2} several times. The reaction mixture was stirred for 1 hour at 15 deg.] C under H ₂ (15 psi) and filtered. The filtrate was concentrated and purified by preparative HPLC to obtain the title compound (8.59 mg, 45.1%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.62-0.63 (m, 2 H) 0.85-0.89 (m, 2 H) 1.36 (d, J = 6.8 Hz, 6 H) 1.67 (s, 6 H) 2.34 (s, 3 H) 2.90-2.95 (m, 1 H) 3.13-3.20 (m, 1 H) 4.04 (s, 2 H) 6.24 (s, 1 H) 7.17 (s, 1 H) 7.37 (d, J =8.0 Hz, 1 H) 7.63 (d, J =2.0 Hz, 1 H) 7.68 (dd, J ₁ =1.6 Hz, J ₂ =2.0 Hz, 1 H) 7.89 (d, J =2.0 Hz, 1 H) 8.16 (d, J =2.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 406.2. Example 33: N -Cyclopropyl-3-(2-ethoxy-3-(1-hydroxy-2-methylprop-2-yl)-3 H -imidazo[4,5- b ]pyridine- 6-yl)-4-methylbenzamide

Step 1: 3-(3-(1-((Third-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-2-ethoxy- 3H -imidazo[ 4,5- b ]pyridin-6-yl) -N -cyclopropyl-4-methylbenzamide

Make 6-bromo-3-(1-((tertiary butyldimethylsilyl)oxy)-2-methylprop-2-yl)-2-ethoxy- 3H -imidazo[4 ,5- b ]pyridine (190 mg, 443.47 µmol), N -cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Cyclopentane-2-yl)benzamide (140.25 mg, 465.64 µmol), Pd(dppf)Cl ₂ (32.45 mg, 44.35 µmol) and K ₂ CO ₃ (153.23 mg, 1.11 mmol) in dioxane The mixture in (6 mL) and water (2 mL) was degassed and _{purged with N 2} (3×). The reaction mixture _{was stirred at 90 °C under N 2} atmosphere for 4 hours, then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-20% EtOAc in petroleum ether to obtain the title compound (196 mg, 84.5%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.19 (s, 6 H) 0.59-0.64 (m, 2 H) 0.73 (s, 9 H) 0.84-0.90 (m, 2 H) 1.58 (s, 3 H) ) 1.88 (s, 6 H) 2.25-2.35 (m, 1 H) 2.31 (s, 2 H) 2.86-2.97 (m, 1 H) 4.08-4.13 (m, 2 H) 4.55-4.65 (dd, J ₁ =2.0 Hz, J ₂ =7.2 Hz, 2 H) 4.57-4.53 (m, 1 H) 6.21 (s, 1 H) 7.35 (d, J = 8.0 Hz, 1 H) 7.59 (d, J = 2.0 Hz, 1 H) 7.62 (d, J= 2.0 Hz, 1 H) 7.66-7.69 (dd, J ₁ =2.0 Hz, J ₂ =8.0 Hz, 1 H) 8.04 (d, J= 2.0 Hz, 1 H); ESI -MS m/z [M+H] ⁺ = 523.3. Step 2: N -Cyclopropyl-3-(2-ethoxy-3-(1-hydroxy-2-methylprop-2-yl)-3 H -imidazo[4,5- b ]pyridine- 6-yl)-4-methylbenzamide

步驟1：乙酸2-((5-溴-3-丙醯胺基吡啶-2-基)胺基)-2-甲基丙基酯

The intermediate 3-(3-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-2-ethoxy- 3H -imidazo[ 4,5- b ]pyridin-6-yl) -N -cyclopropyl-4-methylbenzamide (50 mg, 95.65 µmol) was added to TBAF (1 M in THF, 1.91 mL). The reaction mixture was stirred at 15°C for 2 hours, and then at room temperature for 30 minutes. The reaction mixture was quenched with saturated bicarbonate solution, diluted with saturated aqueous NH ₄ Cl and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain the title compound (24 mg, 61%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) 0.52-0.59 (m, 2 H) 0.67-0.70 (m, 2 H) 1.43 (m, 3 H) 1.74 (s, 6 H) 2.31 (s, 3 H) ) 3.96 (s, 2 H) 4.57 (d, J = 8.0 Hz, 2 H) 5.19 (s, 1 H) 7.40 (d, J = 8.0 Hz, 1 H) 7.79-7.72 (m, 3 H) 8.08 ( d, J= 1.6 Hz, 1 H) 8.40 (d, J= 3.6 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 409.2. Example 34: N -Cyclopropyl-3-(2-ethyl-3-(1-hydroxy-2-methylprop-2-yl)-3 H -imidazo[4,5- b ]pyridine-6 -Yl)-4-methylbenzamide

Step 1: Acetic acid 2-((5-bromo-3-propanamidopyridin-2-yl)amino)-2-methylpropyl ester

To acetic acid 2-((3-amino-5-bromopyridin-2-yl)amino)-2-methylpropyl ester (0.5 g, 1.65 mmol) and DIPEA (0.576 mL, 3.31 mmol) at 0℃ ) In THF (1 mL), add propyl chloride (0.168 mg, 1.82 mmol). The reaction mixture was warmed to 15°C and stirred for 3 hours. The mixture was then diluted with water and extracted with EtOAc. The organic layers were combined, concentrated under reduced pressure, and _{purified by column chromatography (SiO 2} ) with a gradient of 2%-30% EtOAc in petroleum ether to obtain the title compound as a green solid ( 300 mg, 50.6%). ESI-MS m/z [M+H] ⁺ = 358.2. Step 2: 2-(6-Bromo-2-ethyl- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropan-1-ol

To a solution of 2-((5-bromo-3-propanamidopyridin-2-yl)amino)-2-methylpropyl acetate (200 mg, 0.558 mmol) in propionic acid (2 mL) Add tetramethoxymethane (3.80 mg, 0.028 mmol). The reaction mixture was heated to 120°C and stirred for 12 hours. The mixture was then diluted with water and extracted with EtOAc. The aqueous layer was acidified to pH=7.0 with aqueous NaHCO ₃ (10 mL) and extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure to obtain the title compound (138 mg, 82.9%) as a yellow solid. Step 3: N -Cyclopropyl-3-(2-ethyl-3-(1-hydroxy-2-methylprop-2-yl)-3 H -imidazo[4,5- b ]pyridine-6 -Yl)-4-methylbenzamide

步驟1：乙酸2-((5-溴-3-丁醯胺基吡啶-2-基)胺基)-2-甲基丙基酯

Make 2-(6-bromo-2-ethyl- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropan-1-ol (138 mg, 0.463 mmol), N -Cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (153 mg, 0.509 mmol), Pd(dppf)Cl ₂ (16.9 mg, 0.023 mmol) and K ₂ CO ₃ (192 mg, 1.39 mmol) in a mixture of dioxane (2 mL) and water (0.5 mL) to degas And purged with N ₂ (3×). The reaction mixture _{was stirred at 90°C for 12 hours under a N 2} atmosphere, then concentrated under reduced pressure and eluted by column chromatography (SiO ₂ ) using a gradient of 2%-100% EtOAc in petroleum ether Come to purify. The crude product was further purified by preparative HPLC to obtain the formate salt of the title compound (49.62 mg, 24.4%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.62-0.65 (m, 2 H) 0.84-0.89 (m, 2 H) 1.18 (t, J =7.6 Hz 3 H) 1.63 (s, 6 H) 2.35 ( s, 3 H) 2.59 (q, J =7.6 Hz 2 H) 2.87-2.91 (m, 1 H) 4.32 (s, 2 H) 6.59 (s, 1 H) 7.26 (d, J =1.2 Hz 1 H) 7.31 (d, J =8.8 Hz 1 H) 7.62-7.63 (m, 2 H) 8.59 (d, J =1.6 Hz, 1 H) 8.67 (s, 1 H) 11.62 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 393.2. Example 35: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-2-propyl- 3H -imidazo[4,5- b ]pyridine-6 -Yl)-4-methylbenzamide

Step 1: Acetic acid 2-((5-bromo-3-butyramidopyridin-2-yl)amino)-2-methylpropyl ester

To acetic acid 2-((3-amino-5-bromopyridin-2-yl)amino)-2-methylpropyl ester (0.5 g, 1.65 mmol) and DIPEA (0.576 mL, 3.31 mmol) at 0℃ ) A solution in THF (10 mL) was added with butyryl chloride (0.176 mL, 1.69 mmol). The reaction mixture was stirred at 10°C for 2 hours, and then at 50°C for another 4 hours. The mixture was concentrated in vacuo and purified by column chromatography (SiO ₂ ) with a gradient of 3%-50% EtOAc in petroleum ether to obtain the title compound (550 mg, 89.3 %). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.04 (t, J =7.2 Hz 2 H) 1.45 (s, 6 H) 1.75-1.81 (m, 2 H) 2.40 (d, J =7.2 Hz 2 H) 3.10 (s, 3 H) 4.29 (s, 1 H) 4.73 (s, 1 H) 6.84 (s, 1 H) 7.69 (s, 1 H) 8.02 (s, 1 H). Step 2: 2-(6-Bromo-2-propyl- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropan-1-ol

To a mixture of 2-((5-bromo-3-butyramidopyridin-2-yl)amino)-2-methylpropyl acetate (150 mg, 0.403 mmol) in butyric acid (3 mL) Add tetramethoxymethane (2.74 mg, 0.02 mmol). The reaction mixture was stirred at 110°C for 16 hours, then warmed to 120°C and stirred for 4 hours. The mixture was acidified to pH 3 via the addition of 1 M HCl (30 mL), and then extracted with EtOAc. The aqueous phase was adjusted to pH 11 by adding saturated _{aqueous Na 2} CO _{3 and extracted with EtOAc.} The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated in vacuo to give the title compound (110 mg, 87.4%) as a yellow solid. Step 3: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-2-propyl-3 H -imidazo[4,5- b ]pyridine-6 -Yl)-4-methylbenzamide

步驟1：乙酸2-(1-乙基-6-(2-甲基-5-(甲基胺甲醯基)苯基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

Make 2-(6-bromo-2-propyl- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropan-1-ol (81.5 mg, 0.271 mmol), N -Cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (110 mg, 0.352 mmol), Pd(dppf)Cl ₂ (9.90 mg, 0.014 mmol) and K ₂ CO ₃ (112 mg, 0.812 mmol) in a mixture of dioxane (5 mL) and water (0.5 mL) to degas And purged with N ₂ (3×). The reaction mixture was stirred at 100°C for 4 hours under _{N 2 atmosphere.} Additional Pd(dppf)Cl ₂ (9.90 mg, 0.014 mmol) was added, and the reaction mixture was stirred at 100° C. for another 4 hours, then concentrated under vacuum and by column chromatography (SiO ₂ ), using DCM Among them, 2%-10% MeOH gradient elution was carried out for purification, and the title compound (17.09 mg, 15.5%) was obtained as a dark brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.64-0.69 (m, 2 H) 0.79-0.83 (m, 2 H) 0.98 (t, J =4.0 Hz 3 H) 1.57 (s, 6 H) 1.66- 1.74 (m, 2 H) 2.34 (s, 3 H) 2.58 (t, J = 7.2 Hz 2 H) 2.84-2.87 (m, 1 H) 3.72 (s, 1 H) 4.33 (s, 2 H) 7.05 ( s, 1 H) 7.25-7.28 (m, 1 H) 7.50 (s, 1 H) 7.65-7.70 (m, 2 H) 8.58 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 407.3. Example 36: 3-(1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo[4, 5- b pyridin-6-yl) -N ,4-dimethylbenzamide

Step 1: Acetic acid 2-(1-ethyl-6-(2-methyl-5-(methylaminomethanyl)phenyl)-2-oxo-1,2-dihydro-3 H- Imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

Make acetic acid 2-(6-bromo-1-ethyl-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methyl Propyl ester (45.35 mg, 127.32 µmol), N ,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Based) benzamide (38.53 mg, 140.05 µmol), K ₂ CO ₃ (87.98 mg, 636.58 µmol) and Pd(dppf)Cl ₂ (9.32 mg, 12.73 µmol) in water (1 mL) and dioxane The mixture in (5 mL) was degassed and _{purged with N 2} (3×). The reaction mixture was stirred at 90°C for 5 hours under an _{N 2 atmosphere, and then diluted with water.} The aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo to give the title compound (40 mg, crude) of a yellow solid. Step 2: 3-(1-Ethyl-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4, 5- b pyridin-6-yl) -N ,4-dimethylbenzamide

步驟1：乙酸2-(1-(2-氟乙基)-6-(2-甲基-5-(甲基胺甲醯基)苯基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

To acetic acid 2-(1-ethyl-6-(2-methyl-5-(methylaminocarboxyl)phenyl)-2-oxo-1,2-dihydro- 3H -imidazo A solution of [4,5- b ]pyridin-3-yl)-2-methylpropyl ester (40 mg, 94.23 µmol) in MeOH (5 mL) was added with K ₂ CO ₃ (39.07 mg, 282.69 µmol). The reaction mixture was stirred at 70°C for 3 hours and then filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC. The fractions containing the product were concentrated, and the product was lyophilized to obtain the title compound (12.3 mg, 34%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.36 (t, J = 7.2 Hz, 3 H) 1.63 (s, 1 H) 1.71-1.77 (m, 6 H) 2.03 (s, 1 H) 2.36 (s, 3 H) 3.05 (d, J = 4.8 Hz, 3 H) 3.95 (q, J = 7.2 Hz, 2 H) 4.06 (s, 2 H) 5.65-5.80 (m, 1 H) 6.19 (s, 1 H) 7.18 (d, J = 2.0 Hz, 1 H) 7.39 (d, J = 8.0 Hz, 1 H) 7.68 (d, J = 8.0 Hz, 2 H) 7.69 (s, 1 H) 7.96 (d, J= 2.0 Hz, 1 H). Example 37: 3-(1-(2-Fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl) -N ,4-dimethylbenzamide

Step 1: Acetic acid 2-(1-(2-fluoroethyl)-6-(2-methyl-5-(methylaminomethanyl)phenyl)-2-oxo-1,2-di Hydrogen-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

Make acetic acid 2-(6-bromo-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl) -2-methylpropyl ester (100 mg, 267.23 µmol), N ,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborole Cyclopentane-2-yl)benzamide (80.88 mg, 293.96 µmol), K ₂ CO ₃ (369.34 mg, 2.67 mmol) and Pd(dppf)Cl ₂ (19.55 mg, 26.72 µmol) in dioxane ( The mixture in 5 mL) and water (1 mL) was degassed and _{purged with N 2} (3×). The reaction mixture was stirred at 90°C for 5 hours under an _{N 2 atmosphere, and then diluted with water.} The aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude product was purified by preparative TLC and eluted with 50% EtOAc in petroleum ether to obtain the title compound (85 mg, 72%) as a yellow oil. ESI-MS m/z [M+H] ⁺ = 443.3. Step 2: 3-(1-(2-Fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl) -N ,4-dimethylbenzamide

步驟1：乙酸2-(1-(2,2-二氟乙基)-6-(2-甲基-5-(甲基胺甲醯基)苯基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

To acetic acid 2-(1-(2-fluoroethyl)-6-(2-methyl-5-(methylaminomethanyl)phenyl)-2-oxo-1,2-dihydro- 3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (80.00 mg, 180.80 µmol) in THF (2 mL), DMF (0.2 mL) and water (0.1 mL _{Add LiOH.H 2} O (37.93 mg, 903.99 µmol) to the solution in ). The reaction mixture was stirred at 50°C for 2 hours, and then diluted with water. The aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to obtain the title compound (12 mg, 17%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.73 (s, 6 H) 2.32 (s, 3 H) 2.77 (d, J =4.4 Hz, 3 H) 3.93 (s, 2 H) 4.11-4.28 (m, 2 H) 4.57-4.77 (m, 2 H) 5.02 (s, 1 H) 7.41 (d, J =8.0 Hz, 1 H) 7.61 (d, J =1.6 Hz, 1 H) 7.73-7.79 ( m, 2 H) 7.99 (d, J =2.0 Hz, 1 H) 8.44 (d, J =4.8 Hz, 1H); ESI-MS m/z [M+H] ⁺ = 401.2. Example 38: 3-(1-(2,2-Difluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro- 1 H -imidazo[4,5- b ]pyridin-6-yl) -N ,4-dimethylbenzamide

Step 1: Acetic acid 2-(1-(2,2-difluoroethyl)-6-(2-methyl-5-(methylaminomethanyl)phenyl)-2-oxo-1, 2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

Make acetic acid 2-(6-bromo-1-(2,2-difluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridine-3 -Yl)-2-methylpropyl ester (75 mg, 191.23 µmol), N ,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxide Heteroborolan-2-yl)benzamide (57.88 mg, 210.35 µmol), K ₂ CO ₃ (264.30 mg, 1.91 mmol) and Pd(dppf)Cl ₂ (13.99 mg, 19.12 µmol) in two The mixture of oxane (5 mL) and water (1 mL) was degassed and _{purged with N 2} (3×). The reaction mixture was stirred at 90°C for 5 hours under an _{N 2 atmosphere, and then diluted with water.} The aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude product was purified by preparative TLC using 50% EtOAc in petroleum ether to obtain the title compound (60 mg, 68%) as a yellow solid. Step 2: 3-(1-(2,2-Difluoroethyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro- 1 H -imidazo[4,5- b ]pyridin-6-yl) -N ,4-dimethylbenzamide

To acetic acid 2-(1-(2,2-difluoroethyl)-6-(2-methyl-5-(methylaminomethanyl)phenyl)-2-oxo-1,2- Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (50 mg, 108.58 µmol) in THF (2 mL), DMF (0.2 mL) and water _{Add LiOH.H 2} O (22.78 mg, 542.92 µmol) to the solution in (0.1 mL). The reaction mixture was stirred at 50°C for 2 hours, and then diluted with water. The aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to obtain the title compound (6 mg, 7%) as a white solid. ¹ HNMR (400 MHz, DMSO- d ₆ ) δ ppm 1.73 (s, 6 H) 2.32 (s, 3 H) 2.77 (d, J =4.4 Hz, 3 H) 3.93 (s, 2 H) 4.27-4.42 ( m, 2 H) 5.00 (s, 1 H) 6.12-6.55 (m, 1 H) 7.42 (d, J =8.0 Hz, 1 H) 7.65 (s, 1 H) 7.72-7.80 (m, 2 H) 8.01 (d, J = 1.6 Hz, 1 H) 8.44 (d, J = 4.8 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 419.2. Example 39: 5-(1-(2,2-Difluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro- 1 H -imidazo[4,5- b ]pyridin-6-yl)-2-fluoro- N ,4-dimethylbenzamide

步驟1：乙酸2-(6-(5-(環丙基胺甲醯基)-2-甲基苯基)-1-(2-羥基乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

The title compound was prepared as in Example 38 with 2-fluoro- N ,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl) benzamide instead of N ,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -Yl)benzamide and via the intermediate acetic acid 2-(1-(2,2-difluoroethyl)-6-(4-fluoro-2-methyl-5-(methylaminomethyl) (Acidyl)phenyl)-2-Pendant oxy-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester proceed. The title compound (7.72 mg) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.74 (s, 6 H), 2.32 (s, 3 H), 3.02-3.09 (m, 3 H), 4.06 (d, J = 7.20 Hz, 2 H) , 4.19-4.27 (m, 2 H), 5.44 (t, J = 7.64 Hz, 1 H), 5.89-6.22 (m, 1 H), 6.75 (s, 1 H) , 7.09 (d, J = 12.72 Hz , 1 H) , 7.25 (s, 1 H) , 7.89-8.00 (m, 2 H); ESI-MS m/z [M+H] ⁺ = 437.3. Example 40: N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxyethyl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-(5-(cyclopropylaminomethyl)-2-methylphenyl)-1-(2-hydroxyethyl)-2-oxo-1,2- Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

To acetic acid 2-(6-bromo-1-(2-hydroxyethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridine- 3-yl)-2-methylpropyl ester (60 mg, 161.20 µmol) and N -cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)benzamide (53.41 mg, 177.32 µmol) in a mixture of dioxane (2 mL) and water (0.2 mL) add K ₂ CO ₃ (111.39) mg, 805.99 µmol) and Pd(dppf)Cl ₂ (11.79 mg, 16.12 µmol). The suspension was degassed under vacuum and purged with nitrogen (3×), then heated to 90° C. and stirred under nitrogen for 2.5 hours. The mixture was purified by column chromatography (SiO ₂ ) using a gradient of 30%-80% EtOAc in petroleum ether to purify the mixture to obtain the title compound (44 mg, 59%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.58-0.65 (m, 2 H) 0.80-0.90 (m, 2 H) 1.92 (s, 6 H) 2.05 (s, 3 H) 2.31 (s, 3 H) ) 2.85-2.91 (m, 1 H) 3.74 (s, 1 H) 3.96 (d, J = 3.60 Hz, 2 H) 4.00 (d, J = 2.00 Hz, 2 H) 4.73 (s, 2 H) 6.37 ( s, 1 H) 7.22 (d, J = 2.00 Hz, 1 H) 7.32 (d, J = 7.60 Hz, 1 H) 7.58-7.67 (m, 2 H) 7.92 (d, J = 1.60 Hz, 1 H) ; ESI-MS m/z [M+H] ⁺ = 467.3. Step 2: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxyethyl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

To acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-2-methylphenyl)-1-(2-hydroxyethyl)-2-oxo-1 at 20°C, A solution of 2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (106 mg, 227.21 µmol) in MeOH (3 mL) is added K ₂ CO ₃ (94.21 mg, 681.63 µmol). The reaction mixture was heated to 75°C and stirred at 75°C under nitrogen for 2 hours. The mixture was then concentrated under reduced pressure and purified by preparative HPLC to give the title compound (32 mg, 33%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.48-0.60 (m, 2 H) 0.61-0.74 (m, 2 H) 1.72 (s, 6 H) 2.30-2.34 (m, 3 H) 2.80- 2.90 (m, 1 H) 3.64 (d, J = 4.00 Hz, 2 H) 3.82-3.98 (m, 4 H) 4.84 (s, 1 H) 5.03 (t, J = 6.40 Hz, 1 H) 7.40 (d , J = 8.40 Hz, 1 H) 7.56 (d, J = 2.00 Hz, 1 H) 7.68-7.80 (m, 2 H) 7.95 (d, J = 2.00 Hz, 1 H) 8.40 (d, J = 4.00 Hz , 1 H); ESI-MS m/z [M+H] ⁺ = 425.1. Example 41: 4-Chloro- N -cyclopropyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)benzamide

步驟1：乙酸2-(6-(5-(環丙基胺甲醯基)-2-氟苯基)-1-(2-氟乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

Under N ₂ to acetic acid 2-(1-(2-fluoroethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Cyclopentane-2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (321 mg, 0.761 mmol) , 3-bromo-4-chloro- N -cyclopropylbenzamide (200 mg, 0.692 mmol) and K ₂ CO ₃ (287 mg, 2.08 mmol) in dioxane (5 mL) and water (1 mL Add Pd(dppf)Cl ₂ (15.2 mg, 0.021 mmol) to the solution in ). The reaction mixture _{was heated to 120°C under N 2} for 16 hours, then concentrated in vacuo and purified by column chromatography using a gradient of 0%-2% EtOAc in petroleum ether for elution. The crude product was triturated with EtOAc (10 mL) at 15°C for 30 minutes to give the title compound (115 mg, 36.4%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.55-0.59 (m, 2 H) 0.68-0.76 (m, 2 H) 1.73 (s, 6 H) 2.82-2.88 (m, 1 H) 3.92 ( d, J =6.4 Hz, 2 H) 4.15-4.23 (m, 2 H) 4.63 (t, J =4.4 Hz, 1 H) 4.74 (t, J =4.4 Hz, 1 H) 4.97 (t, J =2.4 Hz, 1 H) 7.70 (t, J =8.0 Hz, 2 H) 7.85 (d, J =2.4 Hz, 1 H) 7.91 (t, J =3.2 Hz, 1 H) 8.06 (t, J =2.0 Hz, 1 H) 8.54 (t, J =4.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 446.9. Example 42: N -Cyclopropyl-4-fluoro-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)benzamide

Step 1: Acetic acid 2-(6-(5-(cyclopropylaminomethyl)-2-fluorophenyl)-1-(2-fluoroethyl)-2-oxo-1,2-di Hydrogen-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

Make 3-bromo- N -cyclopropyl-4-fluorobenzamide (300 mg, 1.16 mmol), 2-(1-(2-fluoroethyl)-2-oxo-6-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ] Pyridin-3-yl)-2-methylpropyl ester (0.466 mg, 1.11 mmol), PdCl ₂ (dtbpf) (14.4 mg, 0.022 mmol) and Na ₂ CO ₃ (0.352 mg, 3.32 mmol) in dioxane The mixture in (10 mL) and water (0.5 mL) was degassed and _{purged with N 2} (3×). The reaction mixture was stirred under N ₂ atmosphere at 100 ℃ 14 hours and then concentrated in vacuo to give the title compound (1.42 g, crude), which was used without further purification. ESI-MS m/z [M+H] ⁺ = 473.4. Step 2: N -Cyclopropyl-4-fluoro-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)benzamide

Acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-2-fluorophenyl)-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (590 mg, 1.25 mmol) and K ₂ CO ₃ (518 mg, 3.75 mmol) in MeOH (10 mL The mixture in) was stirred at 65°C for 4 hours and then filtered. The filtrate was concentrated in vacuo and _{purified by column chromatography (SiO 2} ) using a gradient of 2%-50% EtOAc in petroleum ether to obtain the title compound (65 mg, 12%) as a white solid ). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.56-0.60 (m, 2 H) 0.70-0.74 (m, 2 H) 1.73 (s, 6 H) 2.83-2.88 (m, 1 H) 3.92 ( d, J =6.4 Hz, 2 H) 4.14-4.25 (m, 2 H) 4.64 (t, J =4.8 Hz, 1 H) 4.76 (t, J =4.8 Hz,1 H) 4.95 (t, J =4.0 Hz,1 H) 7.43 (dd, J ₁ =8.8 Hz, J ₂ =10.4 Hz, 1 H) 7.75 (s, 1 H) 7.87-7.90 (m, 1 H) 8.02 (d, J =2.0 Hz, 1 H) 8.19 (s, 1 H) 8.50 (d, J = 4.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 431.2. Example 43: N -Cyclopropyl-4-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-5-methylpyridine amide

步驟1：乙酸2-(6-(5-(環丁基胺甲醯基)-2-甲基苯基)-1-(2-氟乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

At 10 deg.] C to 2- (1- (2-fluoroethyl) -2-oxo under N ₂ -6- (4,4,5,5- tetramethyl-1,3,2 Dioxaborolan-2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (70 mg , 0.166 mmol) in dioxane (5 mL) and water (0.5 mL), add K ₂ CO ₃ (46 mg, 0.333 mmol), 4-bromo- N -cyclopropyl-5-methylpyridine Amine (47.1 mg, 0.172 mmol) and Pd(dppf)Cl ₂ (12.2 mg, 0.017 mmol). The reaction mixture was stirred at 110°C for 4 hours and then concentrated to a residue, which was dissolved in MeOH (5 mL) and mixed with K ₂ CO ₃ (200 mg, 1.45 mmol) at 15°C. The mixture was heated to 80°C, stirred for 3 hours and filtered. The filtrate was concentrated and _{purified by column chromatography (SiO 2} ), using a gradient of 0%-1% MeOH in DCM for elution. The product was further purified by preparative HPLC to obtain the title compound (6.84 mg, 10%) as a white solid. ESI-MS m/z [M+H] ⁺ = 428.2. Example 44: N -Cyclobutyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-(5-(cyclobutylaminomethyl)-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo-1,2- Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

To a solution of 3-bromo- N -cyclobutyl-4-methylbenzamide (100 mg, 372.93 µmol) in dioxane (3 mL) and water (1 mL) was added acetic acid 2-(1- (2-fluoroethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 ,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (172.81 mg, 410.22 µmol), K ₂ CO ₃ (154.62 mg, 1.12 mmol) ) And Pd(dppf)Cl ₂ (27.29 mg, 37.29 µmol). The reaction mixture was stirred at 90°C for 12 hours, then poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, and dried under reduced pressure to give the title compound as a brown solid (300 mg, crude). ESI-MS m/z [M+H] ⁺ =483.2. Step 2: N -Cyclobutyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

步驟1：乙酸2-(6-(5-(環丙基胺甲醯基)-3-氟-2-甲基苯基)-1-(2-氟乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

To acetic acid 2-(6-(5-(cyclobutylaminomethyl)-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo-1,2-dihydro -3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (300 mg, 621.70 µmol) in THF (5 mL), DMF (0.5 mL) and water (0.25 mL) was added LiOH.H ₂ O (130.44 mg, 3.11 mmol). The reaction mixture was stirred at 50°C for 4 hours, then poured into water and extracted with EtOAc. Dried organic layer was washed with brine Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain the formate (33.67 mg, 12.3%) of the title compound as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.58-1.69 (m, 2 H) 1.74 (s, 6 H) 1.98-2.12 (m, 2 H) 2.16-2.25 (m, 2 H) 2.32 ( s, 3 H) 3.94 (s, 2 H) 4.11-4.19 (m, 1 H) 4.21-4.30 (m, 1 H) 4.32-4.48 (m, 1 H) 4.63 (t, J = 4.8 Hz, 1 H ) 4.75 (t, J = 4.4 Hz, 1 H) 5.01 (s, 1 H) 7.42 (d, J = 8.0 Hz, 1 H) 7.61 (s, 1 H) 7.73-7.83 (m, 2 H) 8.00 ( d, J= 1.6 Hz, 1 H) 8.47 (br s, 1 H) 8.57 (d, J= 7.6 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 4411. Example 45: N -Cyclopropyl-3-fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-3-fluoro-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo- 1,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

Under N ₂ of 3-bromo - N - cyclopropyl-5-fluoro-4-methyl-benzoyl amine (100 mg, 0.367 mmol), 2- (1- (2-fluoroethyl) -2 -Pendant oxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-3 H- Imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (147.44 mg, 0.35 mmol) and Na ₂ CO ₃ (111 mg, 1.05 mmol) in dioxane (3 mL) _{Add PdCl 2} (dtbpf) (22.8 mg, 0.035 mmol) to the mixture in water (0.2 mL). The reaction mixture _{was stirred at 100°C under N 2} atmosphere for 6 hours, and then concentrated under reduced pressure to give the title compound (170 mg, crude) as a black solid. ESI-MS m/z [M+H] ⁺ = 487.2. Step 2: N -Cyclopropyl-3-fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

步驟1：乙酸2-(6-(3-氯-5-(環丙基胺甲醯基)-2-甲基苯基)-1-(2-氟乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

Add 2-(6-(5-(cyclopropylaminomethyl)-3-fluoro-2-methylphenyl)-1-(2-fluoroethyl)-2-oxoacetate to 2-(6-(5-(cyclopropylaminomethanyl)-3-fluoro-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo at 15℃ Benzyl-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (170 mg, 0.133 mmol) in MeOH (2 mL) _{K 2} CO ₃ (55.2 mg, 0.399 mmol) was added to the solution. The reaction mixture was heated to 70°C, stirred at 70°C for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain the title compound (11.22 mg, 19%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.55-0.57 (m, 2 H) 0.68-0.70 (m, 2 H) 1.73 (s, 6 H) 2.21 (d, J = 1.6 Hz, 3 H ) 2.83-2.87 (m, 1 H) 3.93 (d, J =6.4 Hz, 1 H) 4.16 (t, J =4.4 Hz, 1 H) 4.23 (t, J =4.0 Hz, 1 H) 4.62 (t, J =4.8 Hz, 1 H) 4.74 (t, J =4.8 Hz, 1 H) 4.98 (t, J =6.4 Hz, 1 H) 7.62-7.64 (m, 3 H) 8.00 (d, J =2.0 Hz, 1 H) 8.49 (d, J = 4.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 445.2. Example 46: 3-Chloro- N -cyclopropyl-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-(3-chloro-5-(cyclopropylaminomethyl)-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo- 1,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

In the 3-chloro-N ₂ - N - cyclopropyl-5-iodo-4-methyl-benzoyl amine (86 mg, 0.246 μmol) and 2- (1- (2-fluoroethyl) -2 -Pendant oxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-3 H- A mixture of imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (109 mg, 0.259 mmol) in dioxane (2 mL) and water (0.5 mL) add K ₂ CO ₃ (102 mg, 0.739 mmol) and PdCl ₂ (dtbpf) (16.1 mg, 0.025 mmol). The reaction mixture was _{purged with N 2} (3×), heated to 100° C., stirred for 12 hours and then concentrated under reduced pressure to give the title compound (124 mg, crude) as a black solid. ESI-MS m/z [M+H] ⁺ = 503.1. Step 2: 3-Chloro- N -cyclopropyl-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Add 2-(6-(3-chloro-5-(cyclopropylaminomethyl)-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo to acetic acid at 15℃ Benzyl-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (124 mg, 0.246 mmol) in MeOH (2 mL) _{K 2} CO ₃ (102 mg, 0.739 mmol) was added to the solution. The reaction mixture was heated to 70°C, stirred for 2 hours and then concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain the title compound (21.4 mg, 18.9%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.55-0.58 (m, 3 H) 0.68-0.70 (m, 2 H) 1.73 (s, 6 H) 2.32 (s, 3 H) 2.83-2.87 ( m, 1 H) 3.92 (d, J =6.4 Hz, 2 H) 4.15-4.16 (m, 1 H) 4.22 (t, J =4.4 Hz, 1 H) 4.62 (t, J =4.4 Hz, 1 H) 4.74 (t, J =4.8 Hz, 1 H) 4.98 (t, J =6.8 Hz, 1 H) 7.61 (d, J =1.6 Hz, 1 H) 7.71 (d, J =1.6 Hz, 1 H) 7.92 ( d, J =1.6 Hz, 1 H) 7.98 (d, J =1.4 Hz, 1 H) 8.53 (d, J =4.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 461.2. Example 47: N -Cyclopropyl-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-6-methylnicotinamide

步驟1：乙酸2-(1-(2-氟乙基)-6-(2-甲基-5-((1-甲基環丙基)胺甲醯基)苯基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

Under N ₂ to acetic acid 2-(1-(2-fluoroethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Cyclopentane-2-yl)-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (376 mg, 0.894 mmol) , 5-bromo- N -cyclopropyl-6-methylnicotinamide (200 mg, 0.745 mmol) and K ₂ CO ₃ (309 mg, 2.23 mmol) in dioxane (3 mL) and water (1 Add Pd(dppf)Cl ₂ (54.5 mg, 0.075 mmol) to the solution in mL). The reaction mixture was heated under N ₂ at 120 ℃ 15 hours and then concentrated under reduced pressure, diluted with water and extracted with EtOAc. The organic layers were combined, washed with water, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain the title compound (35.7 mg, 11%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.55-0.59 (m, 2 H) 0.68-0.72 (m, 2 H) 1.72 (s, 6 H) 2.52 (s, 3 H) 2.82-2.89 ( m, 1 H) 3.92 (s, 2 H) 4.15-4.24 (m, 2 H) 4.60-4.64 (m, 1 H) 4.72-4.76 (m, 1 H) 7.68 (d, J =2.0 Hz, 1 H ) 8.03 (t, J =1.6 Hz, 2 H) 8.58 (d, J =4.0 Hz, 1 H) 8.88 (d, J =2.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 428.0. Example 48: 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(1-methylcyclopropyl)benzamide

Step 1: Acetic acid 2-(1-(2-fluoroethyl)-6-(2-methyl-5-((1-methylcyclopropyl)aminomethanyl)phenyl)-2-oxo -1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

To acetic acid 2-(1-(2-fluoroethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (100 mg, 237.38 µmol) and 3-bromo A solution of -4-methyl- N -(1-methylcyclopropyl)benzamide (76.38 mg, 284.85 µmol) in dioxane (3 mL) and water (0.3 mL) add Na ₂ CO ₃ (75.48 mg, 712.13 µmol) and Pd(dppf)Cl ₂ (17.37 mg, 23.74 µmol). The reaction mixture _{was stirred at 90°C under N 2} for 3 hours, and then diluted with water. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude product was purified by preparative TLC and eluted with 50% EtOAc in petroleum ether to obtain the title compound (124 mg, 99.5%) as a pale yellow oil. ESI-MS m/z [M+H] ⁺ = 483.2. Step 2: 3-(1-(2-Fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(1-methylcyclopropyl)benzamide

步驟1：乙酸2-(1-(2-氟乙基)-6-(2-甲基-5-((1-((2-(三甲基矽基)乙氧基)甲基)-1H -吡唑-3-基)胺甲醯基)苯基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

To acetic acid 2-(1-(2-fluoroethyl)-6-(2-methyl-5-((1-methylcyclopropyl)aminomethanyl)phenyl)-2-oxo- 1,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (120 mg, 248.68 µmol) in THF (2 mL), DMF (0.2 _{Add LiOH.H 2} O (52.17 mg, 1.24 mmol) to the solution in mL) and water (0.05 mL). The reaction mixture was stirred at 50°C for 5 hours, and then diluted with saturated _{aqueous NH 4} Cl. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to obtain the title compound (36 mg, 33%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.53-0.65 (m, 2 H) 0.68-0.77 (m, 2 H) 1.36 (s, 3 H) 1.73 (s, 6 H) 2.30 (s, 3 H) 3.93 (d, J = 6.0 Hz, 2 H) 4.13-4.27 (m, 2 H) 4.59-4.77 (m, 2 H) 5.00 (t, J = 6.4 Hz, 1 H) 7.38 (d, J =8.0 Hz, 1 H) 7.59 (d, J =1.6 Hz, 1 H) 7.70-7.78 (m, 2 H) 7.97 (d, J =1.6 Hz, 1 H) 8.60 (s, 1 H); ESI- MS m/z [M+H] ⁺ = 441.2. Example 49: 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(1 H -pyrazol-3-yl)benzamide

Step 1: Acetic acid 2-(1-(2-fluoroethyl)-6-(2-methyl-5-((1-((2-(trimethylsilyl)ethoxy)methyl)- 1 H -pyrazol-3-yl)aminomethanyl)phenyl)-2-side oxy-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl) -2-methyl propyl ester

To 3-bromo-4-methyl- N -(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazol-3-yl)benzamide (150 mg, 365.51 µmol) and 2-(1-(2-fluoroethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxa) acetate Boran-2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (184.78 mg, 438.62 µmol _{) Add Na 2} CO ₃ (116.22 mg, 1.10 mmol) and Pd(dppf)Cl ₂ (26.74 mg, 36.55 µmol) to a solution in dioxane (3 mL) and water (0.3 mL). The reaction mixture _{was stirred at 90°C under N 2} for 3 hours, and then diluted with water. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by preparative TLC and eluted with 50% EtOAc in petroleum ether to obtain the title compound (188 mg, 78.5%) as a brown oil. ESI-MS m/z [M+H] ⁺ = 625.3. Step 2: Acetic acid 2-(6-(5-((1 H -pyrazol-3-yl)aminomethanyl)-2-methylphenyl)-1-(2-fluoroethyl)-2- Pendant oxy-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

To acetic acid 2-(1-(2-fluoroethyl)-6-(2-methyl-5-((1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -Pyrazol-3-yl)aminocarboxyl)phenyl)-2-Pendant oxy-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2 -A solution of methyl propyl ester (185 mg, 296.11 µmol) in DCM (2 mL) was added with TFA (3.08 g, 27.01 mmol). The reaction mixture was stirred at 15°C for 2 hours, then concentrated under reduced pressure and poured into a saturated aqueous NaHCO ₃ solution. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude product was purified by preparative TLC and eluted with MeOH:DCM (1:10) to obtain the title compound (120 mg, 81.9%) as a yellow oil. ESI-MS m/z [M+H] ⁺ = 495.3. Step 3: 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(1 H -pyrazol-3-yl)benzamide

步驟1：乙酸2-(6-(4-氟-2-甲基-5-((1-(四氫-2H -吡喃-2-基)-1H -吡唑-3-基)胺甲醯基)苯基)-1-(2-氟乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

To acetic acid 2-(6-(5-((1 H -pyrazol-3-yl)aminomethanyl)-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo -1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (120 mg, 242.66 µmol) in THF (3 mL), DMF _{Add LiOH.H 2} O (50.91 mg, 1.21 mmol) to a solution in (0.3 mL) and water (0.05 mL). The reaction mixture was stirred at 50°C for 5 hours, and then diluted with saturated _{aqueous NH 4} Cl. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to obtain the title compound (7 mg, 6%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.74 (s, 6 H) 2.36 (s, 3 H) 3.94 (s, 2 H) 4.15-4.27 (m, 2 H) 4.62-4.78 (m, 2 H) 5.02 (s, 1 H) 6.62 (s, 1 H) 7.46 (d, J =8.0 Hz, 1 H) 7.59-7.67 (m, 2 H) 7.91-7.96 (m, 2 H) 8.07 (d , J =2.0 Hz, 1 H) 10.84 (s, 1 H) 12.44 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 453.2. Example 50: 2-Fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro -1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(1 H -pyrazol-3-yl)benzamide

Step 1: 2- (6- (4-fluoro-2-methyl-5 - ((1- (tetrahydro -2 H - pyran-2-yl) -1 H - pyrazol-3-yl) Aminocarboxyl)phenyl)-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl) -2-methyl propyl ester

At 20 ℃ of 5-bromo-2-fluoro-4-methyl - N - (1- (tetrahydro -2 H - pyran-2-yl) -1 H - pyrazol-3-yl) benzoate Amide (117 mg, 261.41 µmol) and acetic acid 2-(1-(2-fluoroethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (132.15 mg, 313.69 µmol) in a mixture of dioxane (3 mL) and water (0.3 mL) add K ₂ CO ₃ (108.39 mg, 784.23 µmol) and Pd(dppf)Cl ₂ (9.56 mg, 13.07 µmol). The suspension was degassed under vacuum and purged with nitrogen (3×). The reaction mixture was heated to 90°C and stirred under nitrogen for 7 hours, then diluted with water and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated under reduced pressure and _{purified by preparative TLC (SiO 2} ) with 67% EtOAc in petroleum to obtain the title compound (115 mg, 61.9%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.60-1.76 (m, 4 H) 1.91 (s, 6 H) 2.01 (s, 3 H) 2.08-2.27 (m, 2 H) 2.35 (s, 3 H) ) 4.08-4.21 (m, 4 H) 4.73-4.83 (m, 4 H) 5.28 (dd, J ₁ =2.40 Hz, J ₂ =10.00 Hz, 1 H) 6.91 (d, J = 2.40 Hz, 1 H) 7.12 (d, J = 12.80 Hz, 1 H) 7.20 (s, 1 H) 7.55 (d, J = 2.40 Hz, 1 H) 7.94 (d, J = 1.60 Hz, 1 H) 8.00-8.08 (m, 1 H) 8.99 (d, J= 14.40 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 597.4. Step 2: 2-Fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro -1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(1 H -pyrazol-3-yl)benzamide

步驟1：乙酸2-(6-(4-氟-2-甲基-5-(甲基胺甲醯基)苯基)-1-(2-氟乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

To acetic acid 2-(6-(4-fluoro-2-methyl-5-((1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazole-3- Yl)aminocarboxyl)phenyl)-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridine-3- Base)-2-methylpropyl ester (115 mg, 161.91 µmol) was added to HCl (4 M, 5 mL) in dioxane. The reaction mixture was stirred under nitrogen at 20°C for 12 hours, then diluted with water and adjusted to pH 7-8 _{by adding saturated aqueous NaHCO 3 solution.} The mixture was extracted with EtOAc, and the organic layers were combined, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to obtain the title compound (15.5 mg, 20.3%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.72 (s, 6 H) 2.33 (s, 3 H) 3.93 (d, J = 6.00 Hz, 2 H) 4.16 (t, J = 5.20 Hz, 1 H) 4.23 (t, J = 4.40 Hz, 1 H) 4.63 (t, J = 4.80 Hz, 1 H) 4.74 (t, J = 4.80 Hz, 1 H) 4.99 (t, J = 6.40 Hz, 1 H) 6.62 (s, 1 H) 7.32 (d, J = 11.20 Hz, 1 H) 7.55 (d, J = 7.60 Hz, 1 H) 7.61 (d, J = 1.20 Hz, 1 H) 7.65 (s, 1 H) 8.02 (d, J= 1.60 Hz, 1 H) 10.71 (s, 1 H) 12.43 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 471.2. Example 51: 2-Fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro -1 H -imidazo[4,5- b ]pyridin-6-yl) -N ,4-dimethylbenzamide

Step 1: Acetic acid 2-(6-(4-fluoro-2-methyl-5-(methylaminomethyl)phenyl)-1-(2-fluoroethyl)-2-oxo-1 ,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

Combine 5-bromo-2-fluoro- N ,4-dimethylbenzamide (60 mg, 217.01 µmol), 2-(1-(2-fluoroethyl)-2-oxo-6- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]Pyridin-3-yl)-2-methylpropyl ester (100.56 mg, 238.71 µmol), Pd(dppf)Cl ₂ (15.88 mg, 21.70 µmol) and K ₂ CO ₃ (89.98 mg, 651.02 µmol) in A mixture of dioxane (10 mL) and water (1 mL) was heated to 100°C and _{stirred under N 2} for 15 hours. The mixture was then concentrated in vacuo and purified by preparative TLC using 10% MeOH in DCM to elute the title compound (70 mg, 64%) as a yellow oil. ESI-MS m/z [M+H] ⁺ = 461.3. Step 2: 2-Fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro -1 H -imidazo[4,5- b ]pyridin-6-yl) -N ,4-dimethylbenzamide

Acetic acid 2-(6-(4-fluoro-2-methyl-5-(methylaminocarboxyl)phenyl)-1-(2-fluoroethyl)-2-oxo-1,2 -Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (70 mg, 139.86 µmol), water (1.00 g, 55.51 mmol) and LiOH.H _{A mixture of 2} O (16.75 mg, 399.16 µmol) in THF (10 mL) and DMF (1 mL) was heated to 50°C and _{stirred at 50°C under N 2} for 4 hours. Ethyl acetate and water were added, and the aqueous layer and the organic layer were separated. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The resulting residue was purified by preparative HPLC to obtain the title compound (18.21 mg, 31%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.73 (s, 6 H), 2.32 (s, 3 H), 3.05 (d, J =4.52 Hz, 3 H), 4.07 (s, 2 H), 4.15 (br t, J =4.58 Hz, 2 H), 4.22 (br t, J =4.58 Hz, 1 H), 4.66 (t, J =4.58 Hz, 1 H), 4.78 (t, J =4.52 Hz, 1 H), 6.82 (br d, J =8.08 Hz, 1 H), 7.08 (d, J =12.84 Hz, 1 H), 7.27 (br s, 1 H), 7.93 (d, J =1.80 Hz, 1 H ), 7.97 (d, J =8.08 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 419.3. Example 52: 2-Fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro -1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(1-methyl-1 H -pyrazol-3-yl)benzamide

步驟1：乙酸2-(6-(4-氯-5-(環丙基胺甲醯基)-2-甲基苯基)-1-(2-氟乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

The title compound was prepared as in Example 51, substituting 5-bromo-2-fluoro-4-methyl- N- (1-methyl- 1H -pyrazol-3-yl)benzamide instead of 5-bromo- 2-Fluoro- N ,4-dimethylbenzamide starts and passes through the intermediate acetic acid 2-(6-(4-fluoro-2-methyl-5-((1-methyl-1 H- (Pyrazol-3-yl)aminocarboxyl)phenyl)-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]Pyridin-3-yl)-2-methylpropyl ester proceed. The title compound (117.07 mg) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.72 (s, 6 H) 2.33 (s, 3 H) 3.77 (s, 3 H) 3.92-3.93 (d, J = 6.4 Hz, 2 H) 4.15 -4.24 (m, 2 H) 4.63 (t, J =4.4 Hz, 1 H) 4.74 (t, J =4.8 Hz, 1 H) 4.97-5.00 (m, 1 H) 6.56 (s, 1 H) 7.30- 7.33 (d, J = 11.6 Hz, 1 H) 7.53-7.55 (d, J = 7.6 Hz, 1 H) 7.60 (s, 2 H) 8.00-8.01 (d, J = 2.0 Hz, 1 H) 10.70 (s , 1 H); ESI-MS m/z [M+H] ⁺ = 485.2. Example 53: 2-Chloro- N -cyclopropyl-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-(4-chloro-5-(cyclopropylaminomethyl)-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo- 1,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

To acetic acid 2-(1-(2-fluoroethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (200 mg, 0.476 mmol) and 2-chloro -A mixture of N -cyclopropyl-5-iodo-4-methylbenzamide (176 mg, 0.523 mmol) in THF (5 mL) and water (3 mL) was added Na ₂ CO ₃ (75.7 mg, 0.714 mmol) and Pd(dppf)Cl ₂ (34.8 mg, 0.048 mmol). The suspension was stirred at 70°C for 4 hours, then filtered and concentrated in vacuo. The residue was purified by preparative TLC and eluted with 50% EtOAc in petroleum ether to obtain the title compound (160 mg, 50.1%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.64-0.67 (m, 2 H) 0.87-0.92 (m, 2 H) 1.90 (s, 6 H) 2.01 (s, 3 H) 2.29 (s, 3 H) ) 2.92-2.95 (m, 1 H) 4.10-4.19 (m, 2 H) 4.65-4.70 (m, 1 H) 4.76-4.79 (m, 3 H) 6.43 (s, 1 H) 7.17 (s, 1 H) ) 7.33 (s, 1 H) 7.60 (s, 1 H) 7.91 (d, J = 1.6 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 503.2. Step 2: 2-Chloro- N -cyclopropyl-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

To acetic acid 2-(6-(4-chloro-5-(cyclopropylaminomethyl)-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo-1, A solution of 2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (55 mg, 0.082 mmol) in MeOH (1 mL) is added K ₂ CO ₃ (34.00 mg, 0.246 mmol). The reaction mixture was heated to 50°C, stirred for 30 minutes, and then diluted with water and extracted with DCM. The organic layers were combined, dried over Na ₂ SO _4, and concentrated under reduced pressure. The resulting residue was lyophilized to obtain the title compound (77.8 mg, 98.4%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.46-0.53 (m, 2 H) 0.65-0.70 (m, 2 H) 1.17 (s, 6 H) 2.29 (s, 3 H) 2.77-2.84 ( m, 1 H) 3.92 (s, 2 H) 4.16 (t, J =4.4 Hz, 1 H) 4.23 (t, J =4.8 Hz, 1 H) 4.62 (m, J =4.8 Hz, 1 H) 4.74 ( t, J =4.8 Hz, 1 H) 4.95-5.04 (m, 1 H) 7.27 (s, 1 H) 7.48 (s, 1 H) 7.56 (d, J =1.6 Hz, 1 H) 7.96 (d, J =2.0 Hz, 1 H) 8.44 (d, J =4.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 461.2. Example 54: 3-(1-(2-Fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -((1 S ,2 S )-2-methylcyclopropyl)benzamide

步驟1：乙酸2-(6-(5-(環丙基胺甲醯基)-2,4-二氟苯基)-1-(2-氟乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

The title compound was prepared as in Example 48, substituting 3-bromo-4-methyl- N -((1 S ,2 S )-2-methylcyclopropyl)benzamide instead of 3-bromo-4-methyl Benzyl- N- (1-methylcyclopropyl)benzamide starts from the intermediate 2-(1-(2-fluoroethyl)-6-(2-methyl-5-(( (1 S ,2 S )-2-Methylcyclopropyl)aminomethanyl)phenyl)-2-Pendant oxy-1,2-dihydro- 3H -imidazo[4,5- b ] (Pyridin-3-yl)-2-methylpropyl ester continued. The title compound (25.94 mg) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.59-0.80 (m, 2 H), 0.98 (d, J = 5.98 Hz, 1 H), 1.16 (d, J = 6.12 Hz, 3 H), 1.74 ( s, 6 H), 2.32 (s, 3 H), 2.60 (dd, J = 7.08 Hz, 1 H), 4.06 (d, J = 4.52 Hz, 2 H), 4.12-4.25 (m, 2 H), 4.62-4.87 (m, 2 H), 5.64 (s, 1 H), 6.19 (s, 1 H), 7.28-7.29 (m, 1 H), 7.35 (d, J = 8.07 Hz, 1 H), 7.58 -7.68 (m, 2 H), 7.96 (d, J= 1.58 Hz, 1 H). ESI-MS m/z [M+H] ⁺ = 441.3. Example 55: N -Cyclopropyl-2,4-difluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-side Oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)benzamide

Step 1: Acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-2,4-difluorophenyl)-1-(2-fluoroethyl)-2-oxo-1, 2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

To a solution of 5-bromo- N -cyclopropyl-2,4-difluorobenzamide (350 mg, 1.27 mmol) in dioxane (5 mL) and water (1 mL) was added acetic acid 2-( 1-(2-fluoroethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (534.07 mg, 1.27 mmol), K ₂ CO ₃ (525.64 mg, 3.80 mmol) and Pd(dppf)Cl ₂ (92.76 mg, 126.78 µmol). The reaction mixture was stirred at 90°C for 16 hours, then poured into water and extracted with EtOAc. Dried organic layer was washed with brine Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ ) with a gradient of 10%-100% EtOAc in petroleum ether to obtain the title compound (300 mg, 48.3%) as a yellow solid. ESI-MS m/z [M+H] ⁺ = 491.2. Step 2: N -Cyclopropyl-2,4-difluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-side Oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)benzamide

步驟1：乙酸2-(6-(5-(環丙基胺甲醯基)-2-(三氟甲基)苯基)-1-(2-氟乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

To acetic acid 2-(6-(5-(cyclopropylaminomethyl)-2,4-difluorophenyl)-1-(2-fluoroethyl)-2-oxo-1,2- Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (300 mg, 611.65 µmol) in MeOH (3 mL) with K ₂ CO ₃ (84.53 mg, 611.65 µmol). The reaction mixture was stirred at 50°C for 15 minutes, then adjusted to pH 3 with HCl (1 M), poured into water, and extracted with EtOAc. Dried organic layer was washed with brine Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by recrystallization from EtOH (5 mL) to obtain the title compound (108.1 mg, 39.4%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.50-0.60 (m, 2 H) 0.67-0.80 (m, 2 H) 1.73 (s, 6 H) 2.82-2.86 (m, 1 H) 3.92 ( d, J = 6.4 Hz, 2 H) 4.12-4.32 (m, 2 H) 4.57-4.83 (m, 2 H) 4.90-4.95 (m, 1 H) 7.51 (t, J = 10.4 Hz, 1 H) 7.67 -7.83 (m, 2 H) 8.16 (s, 1 H) 8.45 (d, J= 4.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 449.3. Example 56: N -Cyclopropyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-(trifluoromethyl)benzamide

Step 1: Acetic acid 2-(6-(5-(cyclopropylaminomethyl)-2-(trifluoromethyl)phenyl)-1-(2-fluoroethyl)-2-oxo- 1,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

To a solution of 3-bromo- N -cyclopropyl-4-(trifluoromethyl)benzamide (80 mg, 259.66 µmol) in dioxane (2 mL) and water (0.4 mL) was added acetic acid 2 -(1-(2-Fluoroethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- Yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (109.39 mg, 259.66 µmol), K ₂ CO ₃ (107.66 mg, 778.98 µmol) and Pd(dppf)Cl ₂ (19.00 mg, 25.97 µmol). The reaction mixture was stirred at 90 °C under N ₂ for 12 hours, then poured into water and extracted with EtOAc. The organic layer was washed with brine, _{dried over Na 2} SO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ ) with a gradient of 8%-50% EtOAc in petroleum ether to obtain the title compound (100 mg, 74%) as a yellow solid. ESI-MS m/z [M+H] ⁺ = 523.2. Step 2: N -Cyclopropyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-(trifluoromethyl)benzamide

To acetic acid 2-(6-(5-(cyclopropylaminomethyl)-2-(trifluoromethyl)phenyl)-1-(2-fluoroethyl)-2-oxo-1, A solution of 2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (100 mg, 191.39 µmol) in MeOH (1.5 mL) is added K ₂ CO ₃ (26.45 mg, 191.39 µmol). The reaction mixture was stirred at 50°C for 30 minutes, then adjusted to pH 3 with HCl (1 M), poured into water and extracted with EtOAc. Dried organic layer was washed with brine Na ₂ SO _4, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain the title compound (27.8 mg, 30.2%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.53-0.62 (m, 2 H) 0.65-0.78 (m, 2 H) 1.74 (s, 6 H) 2.80 -2.90 (m, 1 H) 3.93 ( d, J = 5.6 Hz, 2 H) 4.10-4.27 (m, 2 H) 4.56-4.77 (m, 2 H) 4.80-4.97 (m, 1 H) 7.56 (s, 1 H) 7.89 (s, 1 H) ) 7.93-8.00 (m, 2 H) 8.04-8.09 (m, 1 H) 8.67 (d, J= 4.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 481.3. Example 57: N -Cyclopropyl-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-2-methoxy-4-methylbenzamide

The title compound was prepared as in Example 56, using 5-bromo- N -cyclopropyl-2-methoxy-4-methylbenzamide instead of 3-bromo- N -cyclopropyl-4-(trifluoro (Methyl)benzamide starts and passes through the intermediate acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-4-methoxy-2-methylphenyl)-1-( 2-fluoroethyl)-2-pendant oxy-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester proceeded. The title compound (25 mg) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.51-0.58 (m, 2 H) 0.61-0.80 (m, 2 H) 1.73 (s, 6 H) 2.26-2.36 (m, 3 H) 2.70- 2.84 (m, 1 H) 3.86-3.96 (m, 5 H) 4.11-4.27 (m, 2 H) 4.55-4.78 (m, 2 H) 5.01 (br t, J = 6.0 Hz, 1 H) 7.10 (s , 1 H) 7.52 (d, J= 1.2 Hz, 1 H) 7.57 (s, 1 H) 7.92 (d, J= 2.0 Hz, 1 H) 8.05 (d, J= 4.0 Hz, 1 H); ESI- MS m/z [M+H] ⁺ = 457.3. Example 58: N -(Bicyclo[1.1.1]pentane-2-yl)-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl) )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

The title compound was prepared as in Example 56, substituting N- (bicyclo[1.1.1]pentan-2-yl)-3-bromo-4-methylbenzamide instead of 3-bromo- N -cyclopropyl -4-(trifluoromethyl)benzamide starts and passes through the intermediate acetic acid 2-(6-(5-(bicyclo[1.1.1]pentan-2-ylaminomethanyl)-2 -Methylphenyl)-1-(2-fluoroethyl)-2-oxo-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2 -Methyl propyl ester continues. The title compound (101.32 mg) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.73 (s, 6 H) 2.07 (s, 6 H) 2.31 (s, 3 H) 2.45 (s, 1 H) 3.93 (d, J =6.4 Hz , 2 H) 4.16 (t, J ₁ =4.4 Hz, J ₂ =4.0 Hz, 1 H) 4.20-4.26 (m, 1 H) 4.62 (t, J =4.8 Hz, 1 H) 4.74 (t, J = 4.8 Hz, 1 H) 5.01 (t, J =6.4 Hz, 1 H) 7.40 (d, J =8.0 Hz, 1 H) 7.61 (s, 1 H) 7.73-7.79 (m, 2 H) 7.99 (d, J = 1.6 Hz, 1 H) 8.93 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 453.1. Example 59: N -Cyclopropyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-(fluoromethyl)benzamide

步驟1：乙酸2-(1-(2-氟乙基)-6-(2-甲基-5-(((1S ,2R )-2-甲基環丙基)胺甲醯基)苯基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

The title compound was prepared as in Example 56, using 3-bromo- N -cyclopropyl-4-(fluoromethyl)benzamide instead of 3-bromo- N -cyclopropyl-4-(trifluoromethyl) Benzamide starts and passes through the intermediate acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-2-(fluoromethyl)phenyl)-1-(2-fluoroethyl) -2-Pendant oxy-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester proceeded. The title compound (16 mg) was obtained as a white solid. ESI-MS m/z [M+H] ⁺ = 445.2. Example 60: 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5-b]pyridin-6-yl)-4-methyl- N -((1 S ,2 R )-2-methylcyclopropyl)benzamide

Step 1: Acetic acid 2-(1-(2-fluoroethyl)-6-(2-methyl-5-(((1 S ,2 R )-2-methylcyclopropyl)aminomethanyl) (Phenyl)-2-Pendant oxy-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

Under N ₂ to 3-bromo-4-methyl- N -((1 S ,2 R )-2-methylcyclopropyl)benzamide (80 mg, 298.34 µmol) and acetic acid 2-(1 -(2-Fluoroethyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (138.25 mg, 328.18 µmol) in dioxane (5 mL) and water _{Add Na 2} CO ₃ (79.05 mg, 745.85 µmol) and Pd(dppf)Cl ₂ (21.83 mg, 29.83 µmol) to the solution in (0.5 mL). The reaction mixture _{was stirred at 90 °C under N 2} for 12 hours, and then diluted with EtOAc. The organic phase was washed with water and brine, _{dried over Na 2} SO ₄ , filtered, concentrated under reduced pressure and _{purified by preparative TLC (SiO 2} ) using 50% EtOAc in petroleum ether for elution to obtain The title compound (90 mg, 63%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.23 (d, J = 4.4 Hz, 1 H) 1.02-1.10 (m, 1 H) 1.13 (s, 4 H) 1.92 (s, 6 H) 2.02 (s , 3 H) 2.33 (s, 3 H) 2.94 (s, 1 H) 4.13 (t, J = 4.4 Hz, 1 H) 4.20 (t, J = 4.4 Hz, 1 H) 4.67 (t, J = 4.8 Hz , 1 H) 4.77 (s, 2 H) 4.79-4.81 (m, 1 H) 7.21 (s, 1 H) 7.35-7.39 (m, 1 H) 7.63 (d, J =2.0 Hz, 1 H) 7.67 ( dd, J = 2.0, 8.0 Hz, 1 H) 7.96 (d, J =2.0 Hz, 1 H) 8.18 (d, J =2.0 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 483.3. Step 2: N -Cyclopropyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-(fluoromethyl)benzamide

步驟1：乙酸2-(6-(5-(環丙基胺甲醯基)-2-(二氟甲基)苯基)-1-(2-氟乙基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

To acetic acid 2-(1-(2-fluoroethyl)-6-(2-methyl-5-(((1 S ,2 R )-2-methylcyclopropyl)aminomethanyl)phenyl )-2-Pendant oxy-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (90 mg, 186.51 µmol) in THF (5 mL), DMF (0.5 mL), MeOH (2 mL) and water (1 mL), add LiOH.H ₂ O (39.13 mg, 932.55 µmol) and K ₂ CO ₃ (51.55 mg, 373.02 µmol) . The reaction mixture was stirred for 15 minutes at 50 deg.] C under N _2, and then diluted with EtOAc. The organic phase was washed with water and brine, dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure and purified by preparative HPLC, to give of the title compound as a white solid (39 mg, 46%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.39 (d, J =5.2 Hz, 1 H) 0.85 (d, J =5.6 Hz, 1 H) 0.94 (s, 4 H) 1.73 (s, 6 H) 2.31 (s, 3 H) 2.81 (s, 1 H) 3.93 (d, J = 6.0 Hz, 2 H) 4.16 (t, J = 4.8 Hz, 1 H) 4.22 (t, J = 4.4 Hz, 1 H) 4.61 (t, J = 4.4 Hz, 1 H) 4.73 (t, J = 4.8 Hz, 1 H) 5.00 (t, J = 6.4 Hz, 1 H) 7.41 (d, J = 8.0 Hz, 1 H) 7.60 (s, 1 H) 7.75-7.80 (m, 2 H) 7.99 (s, 1 H) 8.22 (d, J = 3.2 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 441.2 . Example 61: N -Cyclopropyl-4-(difluoromethyl)-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2 -Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)benzamide

Step 1: Acetic acid 2-(6-(5-(cyclopropylaminomethyl)-2-(difluoromethyl)phenyl)-1-(2-fluoroethyl)-2-oxo- 1,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

To 3-bromo- N -cyclopropyl-4-(difluoromethyl)benzamide (60 mg, 206.82 µmol) and 2-(1-(2-fluoroethyl)-2-oxoacetate -6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-3 H -imidazo[4 ,5- b ]pyridin-3-yl)-2-methylpropyl ester (104.55 mg, 248.18 µmol) in dioxane (2 mL) and water (0.5 mL), add Na ₂ CO ₃ (65.76) mg, 620.46 µmol) and Pd(dppf)Cl ₂ (7.57 mg, 10.34 µmol). The reaction mixture was degassed and _{purged with N 2} (3×), _{stirred at 90° C. for 6 hours under an N 2} atmosphere, and then poured into water and extracted with EtOAc. The organic phase was dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ ) and eluted with EtOAc to obtain the title compound (60 mg, 58%) as a yellow oil. ESI-MS m/z [M+H] ⁺ = 505.2. Step 2: N -Cyclopropyl-4-(difluoromethyl)-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2 -Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)benzamide

Make acetic acid 2-(6-(5-(cyclopropylaminomethanyl)-2-(difluoromethyl)phenyl)-1-(2-fluoroethyl)-2-oxo-1, 2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (60 mg, 118.93 µmol) and K ₂ CO ₃ (16.44 mg, 118.93 µmol) The solution in MeOH (2 mL) was degassed and _{purged with N 2} (3×), and stirred at 50° C. for 10 minutes under a _{N 2 atmosphere.} Then the mixture was poured into water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain the title compound (11.11 mg, 20%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.58-0.60 (m, 2 H) 0.71-0.76 (m, 2 H) 1.73 (s, 6 H) 2.87 (dd, J ₁ =7.2 ₂ =6.8 , 1 H) 3.93 (s, 2 H) 4.25-4.14 (m, 2 H) 4.67-4.52 (m, 1 H) 4.75 (s, 1 H) 4.98 (s, 1 H) 7.14-6.83 (m, 1 H) 7.59 (s, 1 H) 7.88-7.82 (m, 2 H) 8.05-7.94 (m, 2 H) 8.62 (d, J= 3.6 Hz, 1 H); ESI-MS m/z [M+H ] ⁺ = 463.1. Example 62: 3-(1-(2-Fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(pyridin-2-yl)benzamide

The title compound was prepared as in Example 56, using 3-bromo-4-methyl- N- (pyridin-2-yl)benzamide instead of 3-bromo- N -cyclopropyl-4-(trifluoromethyl ) Benzamide starting from the intermediate acetic acid 2-(1-(2-fluoroethyl)-6-(2-methyl-5-(pyridin-2-ylaminomethanyl)phenyl) -2-Pendant oxy-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester proceeded. The title compound (12.9 mg, 21.7%) was obtained as a brown solid. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.78 (s, 6 H), 2.38 (s, 3 H), 4.1 (s, 2 H), 4.20-4.29 (m, 2 H), 4.64 -4.79 (m, 2 H), 7.15-7.18 (m, 1 H), 7.50 (d, J =8.0 Hz, 1 H), 7.55 (s, 1 H), 7.82-7.93 (m, 3 H), 8.06 ( s, 1 H), 8.22 (d, J =8.8 Hz, 1 H), 8.35 (d, J =4.8 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 464.20. Example 63: 3-(1-(2-Fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl)-N-methanyl-4-methylbenzamide

步驟1：3-(3-(1-乙醯氧基-2-甲基丙-2-基)-1-(2-氟乙基)-2-側氧基-2,3-二氫-1H -咪唑并[4,5-b ]吡啶-6-基)-4-甲基苯甲酸甲基酯

Acetic acid 2-(6-(5-aminomethyl-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazole And [4,5- b ]pyridin-3-yl)-2-methylpropyl ester (100 mg, 233.40 µmol) and a mixture of DMF-DMA (897.00 mg, 7.53 mmol, 1 mL) under N ₂ Stir at 100°C for 2 hours. Then the mixture was concentrated in vacuo and purified by preparative HPLC to give the title compound (15.47 mg, 16%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.75 (s, 6 H) 2.38 (s, 3 H) 4.06 (s, 2 H) 4.06-4.24 (m, 2 H) 4.68-4.81 (m, 2 H ) 5.51 (m, 1 H) 7.29 (m, 1 H) 7.48 (d, J = 7.6 Hz, 1 H) 7.74-7.79 (m, 2 H) 7.97 (d, J = 2.0 Hz, 1 H) 8.85 ( s, 1 H) 9.36 (d, J= 9.6 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 415.2. Example 64: 3-(1-(2-Fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(oxazol-2-yl)benzamide

Step 1: 3-(3-(1-Acetyloxy-2-methylprop-2-yl)-1-(2-fluoroethyl)-2-oxo-2,3-dihydro- 1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzoic acid methyl ester

To a solution of 3-bromo-4-methylbenzoic acid methyl ester (100 mg, 436.55 µmol) in dioxane (2 mL) and water (0.4 mL) was added 2-(1-(2-fluoroethyl) acetic acid Yl)-2-side oxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro -3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (183.90 mg, 436.55 µmol), K ₂ CO ₃ (181.00 mg, 1.31 mmol) and Pd(dppf )Cl ₂ (31.94 mg, 43.65 µmol). The reaction mixture was stirred for 5 hours at 90 deg.] C under N _2, and then concentrated. The resulting residue was diluted with water and extracted with EtOAc. The organic layers were combined, concentrated and purified by column chromatography using a gradient of 0%-20% EtOAc in petroleum ether to obtain the title compound (120 mg, 62%) as a pale yellow oil . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.90(s, 3 H) 4.17-4.19(m, 1 H) 4.24-4.26 (m, 1 H) 4.56(s, 2 H) 4.62-4.64 (m , 1 H) 4.74 (s, 1 H) 7.43-7.45 (m, 2 H) 7.88 (s, 1 H) 7.93-7.96 (m, 2 H); ESI-MS m/z [M+H] ⁺ = 444.19. Step 2: 3-(1-(2-Fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzoic acid

To 3-(3-(1-acetoxy-2-methylpropan-2-yl)-1-(2-fluoroethyl)-2-oxo-2,3-dihydro-1 H -Imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzoic acid methyl ester (60 mg, 135.30 µmol) in THF (0.5 mL) and water (0.5 mL) with LiOH (6.48 mg, 270.60 µmol). The reaction mixture was stirred at 25°C for 1 hour, then diluted with water, adjusted to pH 3 with aqueous HCl (1 M) and extracted with EtOAc. The organic layers were combined and concentrated to give the title compound (50 mg, 95%) as a pale yellow oil. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.78 (s, 6 H) 2.35 (s, 3 H) 4.19-4.28 (m, 2 H) 4.63-4.66 (m, 1 H) 4.75-4.77 (m , 2 H) 7.44 (d, J =8.0 Hz, 1 H) 7.49 (s, 1 H) 7.89-7.99 (m, 3 H); ESI-MS m/z [M+H] ⁺ = 388.16. Step 3: 3-(1-(2-Fluoroethyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(oxazol-2-yl)benzamide

步驟1：3-(1-(2-氟乙基)-3-(1-羥基-2-甲基丙-2-基)-2-側氧基-2,3-二氫-1H -咪唑并[4,5-b ]吡啶-6-基)-4-甲基苯甲醯胺

To 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo [4,5- b ]Pyridin-6-yl)-4-methylbenzoic acid (50 mg, 129.06 µmol) in DMF (1 mL) with oxazole-2-amine (10.85 mg, 129.06 µmol) , HOBt (19.18 mg, 141.97 µmol), Et ₃ N (516.26 µmol, 71.86 µL), EDCI (27.22 mg, 141.97 µmol) and DMAP (31.54 mg, 258.13 µmol). The reaction mixture _{was stirred at 90 °C under N 2} for 12 hours, diluted with water and extracted with EtOAc. The organic layers were combined and concentrated. The resulting residue was purified by preparative HPLC to obtain the title compound (3 mg, 5%) as a brown solid. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.78 (s, 6H) 2.37 (s, 3H) 4.1 (s, 2 H) 4.21-4.29 (m, 2 H) 4.64-4.77 (m, 2 H) 7.18 (s, 1 H) 7.53 (s, 2 H) 7.74 (s, 1H) 7.82-7.92 (m, 2 H) 8.03 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 454.18. Example 65: N -Acetyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: 3-(1-(2-Fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

To acetic acid 2-(6-(5-aminomethyl-2-methylphenyl)-1-(2-fluoroethyl)-2-oxo-1,2-dihydro-3 H -imidazole And [4,5- b ]pyridin-3-yl)-2-methylpropyl ester (100 mg, 233.40 µmol) in MeOH (1 mL) add K ₂ CO ₃ (32.26 mg, 233.40 µmol) . The reaction mixture was stirred at 60°C for 20 minutes and then concentrated in vacuo to give the title compound (90 mg, crude). ESI-MS m/z [M+H] ⁺ = 387.1. Step 2: 3-(3-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-1-(2-fluoroethyl)-2- Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

To 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo [4,5- b ]Pyridin-6-yl)-4-methylbenzamide (90 mg, 232.91 µmol) and imidazole (23.78 mg, 349.36 µmol) in DCM (1 mL) are mixed with TBSCl ( 42.12 mg, 279.49 µmol). The reaction mixture was stirred at 25°C for 2 hours, then poured into water and extracted with DCM. The organic layer was concentrated in vacuo and purified by preparative TLC to give the title compound (90 mg, 77%) as a white solid. ESI-MS m/z [M+H] ⁺ = 501.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm -0.12(s, 6 H) 0.74 (s, 9 H) 1.89 (s, 6 H) 2.32 (s, 3 H) 4.06-4.18 (m, 4 H) 4.63-4.77 (m, 2 H) 5.53-6.04 (m, 2 H) 7.18 (m, 1 H) 7.38 (d, J = 8.0 Hz, 1 H) 7.69-7.73 (m, 2 H) 7.95 (s, 1 H). Step 3: N -Acetyl-3-(3-(1-((tertiary butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-1-(2-fluoro Ethyl)-2-side oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Add 3-(3-(1-((tertiary butyldimethylsilyl)oxy)-2-methylprop-2-yl)-1-(2-fluoroethyl)-2-oxo Yl-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide (90 mg, 179.76 µmol) and acetic anhydride (1.09 g, The 10.68 mmol) mixture was stirred at 80°C for 12 hours, then concentrated in vacuo and purified by preparative TLC to give the title compound (30 mg, 31%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm -0.12 (s, 6 H) 0.75 (s, 9 H) 1.89 (s, 6 H) 2.35 (s, 3 H) 2.63 (s, 3 H) 4.10- 4.19 (m, 4 H) 4.63-4.77 (m, 2 H) 7.17 (t, J = 1.6 Hz, 1 H) 7.43 (d, J = 7.6 Hz, 1 H) 7.70-7.75 (m, 2 H) 7.94 (d, J = 2.0 Hz, 1 H) 8.50 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 543.3. Step 4: N -Acetyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

步驟1：乙酸2-(1-(2-氟乙基)-6-(5-(異噁唑-3-基胺甲醯基)-2-甲基苯基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

The N -acetyl-3-(3-(1-((tertiary butyldimethylsilyl)oxy)-2-methylprop-2-yl)-1-(2-fluoroethyl )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide (10 mg, 18.43 µmol) and A mixture of HCl (1 M, 0.5 mL) in THF (1 mL) was stirred at 25°C for 10 minutes, then concentrated in vacuo at 25°C and purified by preparative HPLC to give the title compound as a brown solid ( 7.59 mg, 96%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.72 (s, 6 H) 2.35 (m, 6 H) 3.92 (d, J = 4.8 Hz, 2 H) 4.14-4.24 (m, 2 H) 4.61-4.75 (m, 2 H) 5.01 (s, 1 H) 7.47 (d, J = 8.0 Hz, 1 H) 7.61 (d, J = 1.2 Hz, 1 H) 7.25-7.17 (m, 2 H) 7.83-7.86 ( m, 4 H) 8.02 (d, J =2.0 Hz, 1 H) 10.98 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 429.2. Example 66: 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(1-(2-fluoroethyl)-6-(5-(isoxazol-3-ylaminomethanyl)-2-methylphenyl)-2-oxo- 1,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

To N -(isoxazol-3-yl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Yl)benzamide (80 mg, 213.79 µmol) and 2-(6-bromo-1-(2-fluoroethyl)-2-oxo-1,2-dihydro-3 H -imidazo [4,5- b ]Pyridin-3-yl)-2-methylpropyl ester (77.17 mg, 235.17 µmol) in dioxane (3 mL) and water (0.3 mL), add Na ₂ CO ₃ (67.98 mg, 641.36 µmol) and Pd(dppf)Cl ₂ (15.64 mg, 21.38 µmol). The reaction mixture was stirred for 2 hours at 90 deg.] C under N _2, and then diluted with water. The aqueous phase was extracted with EtOAc and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC and eluted with EtOAc to obtain the title compound (67 mg, 63%) as a brown oil. ESI-MS m/z [M+H] ⁺ = 496.3. Step 2: 3-(1-(2-Fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide

To acetic acid 2-(1-(2-fluoroethyl)-6-(5-(isoxazol-3-ylaminomethanyl)-2-methylphenyl)-2-oxo-1, 2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (65 mg, 131.18 µmol) in THF (3 mL), DMF (0.3 mL) _{Add LiOH.H 2} O (27.52 mg, 655.90 µmol) to the solution in water (0.02 mL). The reaction mixture was stirred at 50 ℃ 5 hours and then diluted with ₄ Cl aqueous saturated NH. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to obtain the title compound (15 mg, 25%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.75 (d, J =1.6 Hz, 6 H) 2.38 (s, 3 H) 4.07 (s, 2 H) 4.14-4.26 (m, 2 H) 4.66-4.83 (m, 2 H) 5.55 (s, 1 H) 7.22 (s, 1 H) 7.30 (d, J =1.2 Hz, 1 H) 7.46 (d, J =7.6 Hz, 1 H) 7.80-7.89 (m, 2 H) 7.96-8.04 (m, 1 H) 8.32 (s, 1 H) 9.02 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 454.2. Example 67: N -Cyclopropyl-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-2,4-dimethylbenzamide

步驟1：乙酸2-(1-乙基-6-(4-氟-2-甲基-5-(甲基胺甲醯基)苯基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

Under N ₂ to acetic acid 2-(6-bromo-1-(2-fluoroethyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridine- 3-yl)-2-methylpropyl ester (157 mg, 0.373 mmol), 5-bromo- N -cyclopropyl-2,4-dimethylbenzamide (100 mg, 0.373 mmol) and K ₂ Add XPhos Pd G3 (6.31 mg, 0.007 mmol) to a solution of CO ₃ (155 mg, 1.12 mmol) in dioxane (3 mL) and water (1 mL). Under N ₂ and the reaction mixture was heated to 120 deg.] C for 15 hours and then concentrated under reduced pressure. The resulting residue was diluted with water and extracted with EtOAc. The organic layers were combined, washed with water, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain the title compound (68.2 mg, 41.5%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.48-0.52 (m, 2 H) 0.64-0.69 (m, 2 H) 1.71 (s, 6 H) 2.26 (s, 3 H) 2.35 (s, 3 H) ) 2.84-2.79 (m, 1 H) 3.92 (s, 2 H) 4.15-4.24 (m, 2 H) 4.61 (t, J =4.8 Hz, 1 H) 4.73 (t, J =4.8 Hz, 1 H) 4.99 (s, 1 H) 7.18 (d, J =3.2 Hz, 2 H) 7.54 (d, J =1.2 Hz, 1 H) 7.95 (s, 1 H) 8.22 (d, J =4.4 Hz, 1 H) ; ESI-MS m/z [M+H] ⁺ = 441.0. Example 68: 5-(1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo[4, 5- b )pyridin-6-yl)-2-fluoro- N ,4-dimethylbenzamide

Step 1: Acetic acid 2-(1-ethyl-6-(4-fluoro-2-methyl-5-(methylaminomethyl)phenyl)-2-oxo-1,2-dihydro -3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

Combine 5-bromo-2-fluoro- N ,4-dimethylbenzamide (60 mg, 217.01 µmol), acetic acid 2-(1-ethyl-2-oxo-6-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridine-3 -Yl)-2-methylpropyl ester (96.27 mg, 238.71 µmol), K ₂ CO ₃ (74.98 mg, 542.52 µmol) and Pd(dppf)Cl ₂ (15.88 mg, 21.70 µmol) in dioxane (5 The mixture in mL) and water (0.5 mL) was heated to 100°C and _{stirred under N 2} for 12 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was purified by preparative TLC using 10% DCM in MeOH for elution to obtain the title compound (25 mg, 24%) as a yellow oil. ESI-MS m/z [M+H] ⁺ = 443.1. Step 2: 5-(1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4, 5- b )pyridin-6-yl)-2-fluoro- N ,4-dimethylbenzamide

Acetic acid 2-(1-ethyl-6-(4-fluoro-2-methyl-5-(methylaminomethyl)phenyl)-2-oxo-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (25 mg, 51.41 µmol), water (500.00 mg, 27.75 mmol) and LiOH.H ₂ O (6.16 mg , 146.79 µmol) in THF (5 mL) and DMF (0.5 mL) was heated to 50°C and _{stirred under N 2} for 5 hours. Ethyl acetate and water were added to the mixture, and the layers were separated. Dried aqueous layer was extracted with EtOAc and the organic layers were combined, washed with brine over Na ₂ SO _4, filtered and concentrated in vacuo. The resulting residue was purified by preparative HPLC to obtain the title compound (8.93 mg, 43.4%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.35 (t, J= 7.20 Hz, 3 H), 1.74 (s, 6 H), 2.34 (s, 3 H), 3.06 (d, J= 4.64 Hz, 3 H), 3.94 (q, J = 7.06 Hz, 2 H), 4.05 (d, J = 6.10 Hz, 2 H), 5.64 (s, 1 H), 6.75 (s, 1 H), 7.08 (d, J= 12.72 Hz, 1 H) , 7.13 (d, J= 1.58 Hz, 1 H) , 7.92 (d, J= 1.58 Hz, 1 H) , 8.01 (d, J= 8.30 Hz, 1 H); ESI- MS m/z [M+H] ⁺ = 401.3. Example 69: 3-(1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo[4, 5- b )pyridin-6-yl)-4-methyl- N -(1 H -pyrazol-3-yl)benzamide

Step 1: Acetic acid 2-(1-ethyl-6-(2-methyl-5-((1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazol-3-yl )Aminomethanyl)phenyl)-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

At 20 ℃ 3-bromo-4-methyl - N - (1- (tetrahydro -2 H - pyran-2-yl) -1 H - pyrazol-3-yl) benzoyl-amine (119 mg, 289.79 µmol) and acetic acid 2-(1-ethyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) -2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (175.30 mg, 434.69 µmol) in dioxane _{Add K 2} CO ₃ (120.16 mg, 869.38 µmol) and Pd(dppf)Cl ₂ (10.60 mg, 14.49 µmol) to the mixture in (3 mL) and water (0.3 mL). The suspension was degassed under vacuum and purged with nitrogen (3×). The reaction mixture was heated to 90°C and stirred under nitrogen for 7 hours, then diluted with water and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated under reduced pressure and the _{resulting residue was purified by preparative TLC (SiO 2} ) using 67% EtOAc in petroleum ether to obtain the title compound (101 mg, 41.2%) as a pale yellow solid ). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.32-1.36 (m, 3 H) 1.91 (s, 6 H) 1.99-2.02 (m, 4 H) 2.04 (s, 2 H) 2.08 (s, 3 H) ) 2.37 (s, 3 H) 3.90-3.95 (m, 2 H) 4.03-4.17 (m, 2 H) 4.76-4.77 (m, 2 H) 5.24 (dd, J ₁ =2.00 Hz, J ₂ =8.40 Hz , 1 H) 6.91 (d, J = 2.40 Hz, 1 H) 7.10-7.12 (m, 1 H) 7.41 (d, J = 8.40 Hz, 1 H) 7.54 (d, J = 2.40 Hz, 1 H) 7.77 -7.81 (m, 2 H) 7.95 (d, J= 2.00 Hz, 1 H) 8.64 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 561.4. Step 2: 3-(1-Ethyl-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4, 5- b )pyridin-6-yl)-4-methyl- N -(1 H -pyrazol-3-yl)benzamide

To acetic acid 2-(1-ethyl-6-(2-methyl-5-((1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazole-3 -Yl)aminomethanyl)phenyl)-2-pendant oxy-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl The ester (101 mg, 180.15 µmol) was added to HCl (4 M, 5 mL) in dioxane. The reaction mixture was stirred under nitrogen at 20°C for 15 hours, then diluted with water, _{adjusted to pH 7-8 by adding saturated aqueous NaHCO 3} solution and extracted with EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC to obtain the title compound (10 mg, 13%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.36 (t, J= 8.00 Hz, 3 H) 1.75 (s, 6 H) 2.38 (s, 3 H) 3.91-3.98 (m, 2 H) 4.06 (s , 2 H) 6.86 (s, 1 H) 7.18 (d, J = 1.60 Hz, 1 H) 7.43 (d, J = 8.00 Hz, 1 H) 7.54 (s, 1 H) 7.79-7.85 (m, 2 H ) 7.97 (d, J= 1.60 Hz, 1 H) 8.74 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 435.3. Example 70: 5-(1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo[4, 5- b )pyridin-6-yl)-2-fluoro-4-methyl- N -(1 H -pyrazol-3-yl)benzamide

步驟1：乙酸2-(1-乙基-6-(2-甲基-5-((1-甲基-1H -吡唑-3-基)胺甲醯基)苯基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

The title compound is prepared as described in Example 69, using 5-bromo-2-fluoro-4-methyl - N - (1- (tetrahydro -2 H - pyran-2-yl) -1 H - pyrazol-3 - yl) benzoyl ylamine instead of 3-bromo-4-methyl - N - (1- (tetrahydro -2 H - pyran-2-yl) -1 H - pyrazol-3-yl) benzoyl The amine starts and passes through the intermediate acetic acid 2-(1-ethyl-6-(4-fluoro-2-methyl-5-((1-(tetrahydro- 2H -pyran-2-yl)- 1 H -pyrazol-3-yl)aminomethanyl)phenyl)-2-side oxy-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl) The -2-methyl propyl ester continued. The title compound (12.20 mg) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.36 (t, J = 7.20 Hz, 3 H) 1.74 (s, 6 H) 2.37 (s, 3 H) 3.90-3.98 (m, 2 H) 4.05 (s , 2 H) 5.61 (s, 1 H) 6.81 (d, J = 2.00 Hz, 1 H) 7.13-7.19 (m, 2 H) 7.55 (d, J = 2.40 Hz, 1 H) 7.94 (d, J= 2.00 Hz, 1 H) 8.07 (d, J= 8.00 Hz, 1 H) 9.02 (d, J= 15.20 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 453.2. Example 71: 3-(1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo[4, 5- b )pyridin-6-yl)-4-methyl- N -(1-methyl-1 H -pyrazol-3-yl)benzamide

Step 1: Acetic acid 2-(1-ethyl-6-(2-methyl-5-((1-methyl-1 H -pyrazol-3-yl)aminocarboxyl)phenyl)-2- Pendant oxy-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

Combine 3-bromo-4-methyl- N -(1-methyl-1 H -pyrazol-3-yl)benzamide (100 mg, 339.97 µmol), acetic acid 2-(1-ethyl-2 -Pendant oxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-3 H- Imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (150.81 mg, 373.96 µmol), K ₂ CO ₃ (140.96 mg, 1.02 mmol) and Pd(dppf)Cl ₂ ( A solution of 12.44 mg, 17.00 µmol) in dioxane (5 mL) and water (0.5 mL) was stirred at 95° C. for 16 hours under _{N 2 and then concentrated under reduced pressure.} The resulting residue was purified by column chromatography (SiO ₂ ) using a gradient of 0%-20% EtOAc in petroleum ether to obtain the title compound (168 mg, crude) as a black solid. ESI-MS m/z [M+H] ⁺ = 491.4. Step 2: 3-(1-Ethyl-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4, 5- b )pyridin-6-yl)-4-methyl- N -(1-methyl-1 H -pyrazol-3-yl)benzamide

To acetic acid 2-(1-ethyl-6-(2-methyl-5-((1-methyl- 1H -pyrazol-3-yl)aminomethanyl)phenyl)-2-oxo 1-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (168 mg, 342.47 µmol) in MeOH (2 mL) Add K ₂ CO ₃ (94.66 mg, 684.94 µmol) to the solution. The reaction mixture was stirred at 50°C for 6 hours and then filtered. The filtrate was concentrated under reduced pressure and purified by preparative HPLC to obtain the title compound (62.38 mg, 40.6%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.37 (t, J = 7.2 Hz, 3 H) 1.75 (s, 6 H) 2.38 (s, 3 H) 3.83 (s, 3 H) 3.93-3.98 (m , 2 H) 4.06 (s, 2 H) 5.65 (s, 1 H) 6.84 (d, J = 2.4 Hz, 1 H) 7.18 (d, J = 2.0 Hz, 1 H) 7.31 (d, J = 2.4 Hz , 1 H) 7.44 (d, J= 8.4 Hz, 1 H) 7.79-7.80 (m, 2 H) 7.97 (d, J= 1.6 Hz, 1 H) 8.47 (s, 1 H); ESI-MS m/ z [M+H] ⁺ = 449.3. Example 72: 3-(1-Ethyl-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo[4, 5- b )pyridin-6-yl)-4-methyl- N -(1-methyl-1 H -pyrazol-5-yl)benzamide

The title compound was prepared as in Example 71, substituting 3-bromo-4-methyl- N- (1-methyl-1 H -pyrazol-5-yl)benzamide instead of 3-bromo-4-methyl -N -(1-methyl-1 H -pyrazol-3-yl)benzamide starting from the intermediate acetic acid 2-(1-ethyl-6-(2-methyl-5-( (1-Methyl- 1H -pyrazol-5-yl)carboxamide)phenyl)-2-Pendant oxy-1,2-dihydro- 3H -imidazo[4,5- b ] (Pyridin-3-yl)-2-methylpropyl ester continued. The title compound (26.08 mg) was obtained as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.22 (t, J =7.2 Hz, 3 H) 1.72 (s, 6 H) 2.38 (s, 3 H) 3.68 (s, 3 H) 3.84-3.96 (m, 4 H) 5.01 (s, 1 H) 6.21 (s, 1 H) 7.39 (d, J =1.6 Hz, 1 H) 7.51 (d, J =8.4 Hz, 1 H) 7.64 (d, J = 1.6 Hz, 1 H) 7.87-7.94 (m, 2 H) 8.01 (d, J = 1.6 Hz, 1 H) 10.28 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 449.3. Example 73: 5-(1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo[4, 5- b )pyridin-6-yl)-2-fluoro-4-methyl- N -(1-methyl-1 H -pyrazol-3-yl)benzamide

The title compound was prepared as in Example 71, substituting 5-bromo-2-fluoro-4-methyl- N- (1-methyl- 1H -pyrazol-3-yl)benzamide instead of 3-bromo- 4-Methyl- N- (1-methyl- 1H -pyrazol-3-yl)benzamide starts from the intermediate acetic acid 2-(1-ethyl-6-(4-fluoro- 2-Methyl-5-((1-methyl-1 H -pyrazol-3-yl)aminocarboxyl)phenyl)-2-oxo-1,2-dihydro-3 H -imidazole And [4,5- b ]pyridin-3-yl)-2-methylpropyl ester continue. The title compound (61.97 mg) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.21 (t, J = 7.2 Hz, 3 H) 1.71 (s, 6 H) 2.34 (s, 3 H) 3.77 (s, 3 H) 3.88-3.92 (m, 4 H), 5.00 (t, J = 6.4 Hz, 1 H) 6.56 (s, 1 H) 7.32 (d, J = 11.2 Hz, 1 H) 7.56 (d, J = 7.2 Hz, 1 H) 7.60 (s, 2 H) 7.98 (s, 1 H) 10.70 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 467.2. Example 74: 5-(1-Ethyl-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4, 5- b )pyridin-6-yl)-2-fluoro- N -(isoxazol-3-yl)-4-methylbenzamide

步驟1：乙酸2-(6-(4-氟-5-(異噁唑-3-基胺甲醯基)-2-甲基苯基)-1-甲基-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基酯

The title compound was prepared as in Example 71, substituting 5-bromo-2-fluoro- N- (isoxazol-3-yl)-4-methylbenzamide instead of 3-bromo-4-methyl- N- (1-Methyl- 1H -pyrazol-3-yl)benzamide starts and passes through the intermediate acetic acid 2-(1-ethyl-6-(4-fluoro-5-(isoxazole- 3-ylaminomethanyl)-2-methylphenyl)-2-pendant oxy-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2 -Methyl propyl ester continues. The title compound (9.84 mg) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.36 (t, J = 7.2 Hz, 3 H) 1.74 (s, 6 H) 2.39 (s, 3 H) 3.92-3.97 (m, 2 H) 4.06 (d , J = 8.0 Hz, 2 H) 5.57 (t, J = 8.0 Hz, 1 H) 7.14 (d, J = 2.0 Hz, 1 H) 7.18-7.21 (m, 2 H) 7.94 (d, J = 2.0 Hz , 1 H) 8.05 (d, J= 8.4 Hz, 1 H) 8.36 (d, J= 1.6 Hz, 1 H) 9.12 (d, J= 15.2 Hz, 1 H); ESI-MS m/z [M+ H] ⁺ = 454.2. Example 75: 2-Fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-methyl-2-oxo-2,3-dihydro-1 H -imidazole And [4,5- b ]pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(6-(4-fluoro-5-(isoxazol-3-ylaminomethyl)-2-methylphenyl)-1-methyl-2-oxo-1 ,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester

To acetic acid 2-methyl-2-(1-methyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)propyl ester (150 mg, 308.28 µmol) and 5-bromo-2-fluoro- A solution of N -(isoxazol-3-yl)-4-methylbenzamide (92.21 mg, 308.28 µmol) in dioxane (10 mL) and water (1 mL) is added K ₂ CO ₃ ( 127.82 mg, 924.85 µmol) and Pd(dppf)Cl ₂ (22.56 mg, 30.83 µmol). The reaction mixture was stirred for 16 hours at 95 deg.] C under N _2, and then partitioned between water and EtOAc. The organic phase was separated, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ ) using a 5%-50% EtOAc gradient in petroleum ether to obtain the title compound (70 mg, 37%) as a yellow solid. ESI-MS m/z [M+H] ⁺ = 482.1. Step 2: 2-Fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-methyl-2-oxo-2,3-dihydro-1 H -imidazole And [4,5- b ]pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide

步驟1：乙酸2-(1-乙基-6-(4-氟-5-(異噻唑-3-基胺甲醯基)-2-甲基苯基)-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基-1,1-d ₂ 酯

To acetic acid 2-(6-(4-fluoro-5-(isoxazol-3-ylaminomethyl)-2-methylphenyl)-1-methyl-2-oxo-1,2 -Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl ester (70 mg, 114.56 µmol) in MeOH (1 mL) with K ₂ CO ₃ (31.67 mg, 229.13 µmol). The reaction mixture was stirred at 50°C for 4 hours, then filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain the title compound (13.16 mg, 29.9%) as a yellow gum. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.74 (s, 6 H) 2.38 (s, 3 H) 3.43 (s, 3 H) 4.07 (d, J =8.0 Hz, 2 H) 5.55 (t, J =8.0 Hz, 1 H) 7.13 (d, J =2.0 Hz, 1 H) 7.17-7.21 (m, 2 H) 7.95 (d, J =1.6 Hz, 1 H) 8.05 (d, J =8.0 Hz, 1 H) 8.36 (d, J = 1.6 Hz, 1 H) 9.12 (d, J = 5.2 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 440.2. Example 76: 5-(1-Ethyl-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-2-fluoro- N -(isothiazol-3-yl)-4-methylbenzamide

Step 1: Acetic acid 2-(1-ethyl-6-(4-fluoro-5-(isothiazol-3-ylaminomethyl)-2-methylphenyl)-2-oxo-1, 2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester

To 5-bromo-2-fluoro- N -isothiazol-3-yl-4-methyl-benzamide (50 mg, 158.65 µmol) in dioxane (2 mL) and water (0.4 mL) Add acetic acid 2-(1-ethyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl to the solution) )-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester (70.73 mg, 174.51 µmol), K ₂ CO ₃ (65.78 mg, 475.95 µmol) and Pd(dppf)Cl ₂ (11.61 mg, 15.86 µmol). The reaction mixture was stirred at 90 °C under N ₂ for 7 hours, then poured into water and extracted with EtOAc. Dried organic layer was washed with brine Na ₂ SO _4, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO ₂ ) and eluted with 50% EtOAc in petroleum ether to obtain the title compound (30 mg, 37%) as a yellow solid. ESI-MS m/z [M+H] ⁺ = 514.1. Step 2: 5-(1-Ethyl-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-2-fluoro- N -(isothiazol-3-yl)-4-methylbenzamide

To acetic acid 2-(1-ethyl-6-(4-fluoro-5-(isothiazol-3-ylaminomethanyl)-2-methylphenyl)-2-oxo-1,2- Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester (30 mg, 58.41 µmol) in MeOH (1.5 mL) Add K ₂ CO ₃ (24.22 mg, 175.24 µmol) to the solution. The reaction mixture was stirred at 50°C for 1 hour and then filtered. The filtrate was purified by preparative HPLC to obtain the title compound (11.37 mg, 41.3%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.21 (t, J = 7.2 Hz, 3 H) 1.70 (s, 6 H) 2.35 (s, 3 H) 3.82-3.94 (m, 2 H) 4.97 (s, 1 H) 7.34 (d, J = 11.6 Hz, 1 H) 7.54-7.65 (m, 2 H) 7.85 (d, J = 4.8 Hz, 1 H) 8.00 (d, J = 2.0 Hz, 1 H ) 9.06 (d, J= 4.8 Hz, 1 H) 11.47 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 472.2. Example 77: 3-(1-Ethyl-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N -(isothiazol-3-yl)-4-methylbenzamide

步驟1：乙酸2-(6-(5-((1H -吡唑-3-基)胺甲醯基)-4-氟-2-甲基苯基)-1-乙基-2-側氧基-1,2-二氫-3H -咪唑并[4,5-b ]吡啶-3-基)-2-甲基丙基-1,1-d ₂ 酯

The title compound was prepared as in Example 76, substituting 3-bromo- N- (isothiazol-3-yl)-4-methylbenzamide instead of 5-bromo-2-fluoro- N -isothiazol-3-yl -4-Methyl-benzamide starts and passes through the intermediate acetic acid 2-(1-ethyl-6-(5-(isothiazol-3-ylaminomethyl)-2-methylphenyl )-2-Pendant oxy-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester continue . The title compound (30 mg) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.23 (t, J = 6.8 Hz, 3 H) 1.72 (s, 6 H) 2.39 (s, 3H) 3.85-3.97 (m, 2 H) 5.00 ( s, 1 H) 7.49 (d, J = 8.0 Hz, 1 H) 7.66 (d, J = 2.0 Hz, 1 H) 7.90 (d, J = 4.8 Hz, 1 H) 7.96 (dd, J ₁ = 2.0, J ₂ = 8.0 Hz, 1 H) 8.00 (d, J = 1.6 Hz, 1 H) 8.05 (d, J = 2.0 Hz, 1 H) 9.05 (d, J = 4.8 Hz, 1 H) 11.48 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 454.1. Example 78: 5-(1-Ethyl-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-2-fluoro-4-methyl- N -(1 H -pyrazol-3-yl)benzamide

Step 1: Acetic acid 2-(6-(5-((1 H -pyrazol-3-yl)aminomethanyl)-4-fluoro-2-methylphenyl)-1-ethyl-2-side Oxy-1,2-dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester

To acetic acid 2-(6-bromo-1-ethyl-2-oxo-1,2-dihydro- 3H -imidazo[4,5- b ]pyridin-3-yl)-2-methyl Propyl-1,1- d ₂ ester (600 mg, 1.67 mmol) and 3-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)benzamide)-1 H -pyrazole-1-carboxylic acid tert-butyl ester (745.82 mg, 1.67 mmol) in dioxane (6 mL) _{Add Na 2} CO ₃ (532.57 mg, 5.02 mmol) and Pd(dppf)Cl _{2 .CH 2} Cl ₂ (136.78 mg, 167.49 µmol) to the solution in water (0.6 mL). The reaction mixture was stirred at 90°C for 5 hours, and then diluted with water. The aqueous phase was extracted with EtOAc, and the organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ ) using a gradient of 10%-50% EtOAc in petroleum ether to purify the resulting residue to obtain the title compound (400 mg, 48%) as a pale yellow solid. ESI-MS m/z [M+H] ⁺ = 497.1. This reaction also produces the by-product 3-(5-(3-(1-acetoxy-2-methylprop-2-yl-1,1- d ₂ )-1-ethyl- as a light yellow solid 2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-2-fluoro-4-methylbenzamide)-1 H- Tert-butyl pyrazole-1-carboxylate (260 mg, 26%); ESI-MS m/z [M+H] ⁺ = 597.1. Step 2: 5-(1-Ethyl-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-2-fluoro-4-methyl- N -(1 H -pyrazol-3-yl)benzamide

To acetic acid 2-(6-(5-((1 H -pyrazol-3-yl)aminomethanyl)-4-fluoro-2-methylphenyl)-1-ethyl-2-oxo -1,2-Dihydro-3 H -imidazo[4,5- b ]pyridin-3-yl)-2-methylpropyl-1,1- d ₂ ester (400 mg, 805.59 µmol) in MeOH _{Add K 2} CO ₃ (111.34 mg, 805.59 µmol) to the solution in (8 mL). The reaction mixture was stirred at 50°C for 20 minutes, then adjusted to pH 3 with aqueous HCl (1 M) and concentrated in vacuo. The crude product was purified by preparative HPLC to obtain the title compound (235 mg,) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.20 (t, J =7.2 Hz, 3 H) 1.70 (s, 6 H) 2.34 (s, 3 H) 3.88 (q, J =6.8 Hz, 2 H) 4.98 (s, 1 H) 6.62 (s, 1 H) 7.31 (d, J =11.2 Hz, 1 H) 7.55 (d, J =7.6 Hz, 1 H) 7.62 (d, J =1.6 Hz, 1 H) 7.65 (s, 1 H) 7.99 (d, J =1.6 Hz, 1 H) 10.74 (s, 1 H) 12.44 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 455.2 . Example 79: 3-(3-(tert-butyl)-1-methyl-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl ) -N -(isoxazol-3-yl)-4-methylbenzamide

To 3-(3-(tertiary butyl)-1-methyl-2-oxo-2,3-dihydro- 1H -imidazo[4,5- b ]pyridine-6 at room temperature -Yl)-4-methylbenzoic acid (50 mg, 0.147 mmol) in DCM (1 mL) was added oxalyl chloride (0.019 mL, 0.221 mmol), followed by DMF (4.56 µL, 0.059 mmol). The mixture was stirred for 1 hour. Next, K ₂ CO ₃ (81 mg, 0.589 mmol) and isoxazol-3-amine (18.58 mg, 0.221 mmol) were added, and the reaction mixture was stirred at room temperature for 30 minutes, at which time HATU (70 mg , 0.184 mmol) and N -methylmorpholine (0.1 mL, 0.91 mmol). The reaction mixture was stirred overnight, then diluted with water and extracted with EtOAc. The organic layers were combined, dried over Na ₂ SO _4, concentrated, and dried in vacuo. The residue was purified by chromatography (ISCO Gold® 12 g column) using a gradient of 0%-100% EtOAc in hexane to purify the residue. The fractions containing the product were collected, concentrated and dried in vacuum, and then purified by SFC to obtain the title compound (0.8 mg, 1.3%) as a white film. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.87 (s, 9 H) 2.37-2.41 (m, 3 H) 3.39-3.41 (m, 3 H) 7.01-7.08 (m, 1 H) 7.38-7.45 (m, 1 H) 7.45-7.53 (m, 1 H) 7.82-7.94 (m, 2 H) 7.98-8.05 (m, 1 H) 8.49-8.60 (m, 1 H); ESI-MS m/z [ M+H] ⁺ = 406.4. Example 80: 3-(3-(tert-butyl)-1-methyl-2-oxo-2,3-dihydro- 1H -imidazo[4,5- b ]pyridin-6-yl ) -N -Cyclopropyl-4-methylbenzamide

步驟1：3-(3-(1-羥基-2-甲基丙-2-基)-1-甲基-2-側氧基-2,3-二氫-1H -咪唑并[4,5-b ]吡啶-6-基)-4-甲基苯甲酸甲基酯

To 3-(3-(tertiary butyl)-1-methyl-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridine-6 at 25℃ -Yl)-4-methylbenzoic acid (40 mg, 0.118 mmol) and N -methylmorpholine (0.065 mL, 0.589 mmol) in DMF (1 mL) add cyclopropylamine (26.9 mg, 0.471 mmol) , Then HATU (58.3 mg, 0.153 mmol) was added. The reaction mixture was stirred at 25°C for 3 hours, and then diluted with water. The resulting solid was collected by filtration and purified to obtain the title compound (9.2 mg, 21%) as a colorless film. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.52-0.59 (m, 2 H) 0.69-0.77 (m, 2 H) 1.79 (s, 9 H) 2.24-2.28 (m, 3 H) 2.74-2.82 (m, 1 H) 3.22-3.25 (m, 2 H) 4.60-4.82 (m, 3 H) 7.27-7.34 (m, 2 H) 7.61-7.68 (m, 2 H) 7.88-7.92 (m, 1 H ); ESI-MS m/z [M+H] ⁺ = 379.4. Example 81: 3-(3-(1-hydroxy-2-methylprop-2-yl)-1-methyl-2-oxo-2,3-dihydro- 1H -imidazo[4, 5- b )pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide

Step 1: 3-(3-(1-hydroxy-2-methylprop-2-yl)-1-methyl-2-oxo-2,3-dihydro-1 H -imidazo[4, 5- b pyridin-6-yl)-4-methylbenzoic acid methyl ester

Add 6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1-methyl-1,3-dihydro- 2H -imidazo[4, 5- b )pyridin-2-one (126 mg, 0.420 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl)benzoic acid methyl ester (151 mg, 0.546 mmol). Dioxane (2 mL) was added, and the solution was stirred at 25°C for 5 minutes. Next, NaHCO ₃ (212 mg, 2.52 mmol) and Pd(dppf)Cl ₂ (61.4 mg, 0.084 mmol) were added, and the solution was heated to 110° C. for 15 minutes in a microwave reactor. LCMS indicated incomplete conversion, so the reaction mixture was heated at 120°C for 1 hour. The reaction is still incomplete, so add fresh methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid Base ester (151 mg, 0.546 mmol) and Pd(dppf)Cl ₂ (61.4 mg, 0.084 mmol), and the reaction mixture was heated at 120°C for 20 minutes. LCMS indicated that the reaction was approximately 50% complete. The reaction mixture was dried over Na ₂ SO _4, diluted with EtOAc and filtered. The filtrate was concentrated in vacuo to give the title compound (25 mg, 16%), which was used without further purification. ESI-MS m/z [M+H] ⁺ = 370.4. Step 2: 3-(3-(1-hydroxy-2-methylprop-2-yl)-1-methyl-2-oxo-2,3-dihydro-1 H -imidazo[4, 5- b pyridin-6-yl)-4-methylbenzoic acid

Fill the scintillation vial with 3-(3-(1-hydroxy-2-methylprop-2-yl)-1-methyl-2-oxo-2,3-dihydro- 1H -imidazo[ 4,5- b ]pyridin-6-yl)-4-methylbenzoic acid methyl ester (0.025 g, 0.068 mmol), dioxane (1 mL) and 2 N LiOH aqueous solution (0.169 mL, 0.338 mmol). The reaction mixture was stirred at room temperature for 3 days, then poured onto ice, and neutralized with 5 N aqueous HCl. The solid product was separated by vacuum filtration and washed with slightly acidic water to obtain the title compound (23 mg, 96%) as an off-white solid. ESI-MS m/z [M+H] ⁺ = 356.4. Step 3: 3-(3-(1-hydroxy-2-methylprop-2-yl)-1-methyl-2-oxo-2,3-dihydro- 1H -imidazo[4, 5- b )pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide

Fill the scintillation vial with 3-(3-(1-hydroxy-2-methylprop-2-yl)-1-methyl-2-oxo-2,3-dihydro- 1H -imidazo[ 4,5- b )pyridin-6-yl)-4-methylbenzoic acid (0.023 g, 0.065 mmol), HATU (0.037 g, 0.097 mmol), DMA (1 mL) and DIPEA (0.034 mL, 0.194 mmol) . After 10 minutes, isoxazol-3-amine (9.56 µL, 0.129 mmol) is added. The reaction mixture was stirred at room temperature overnight, and then slowly poured onto ice. The resulting precipitate was separated by vacuum filtration and washed with water. The crude solid was dissolved in DCM and purified by chromatography (ISCO® 12 g silica gel column) using a gradient of 0%-100% EtOAc in heptane to purify. The fractions containing the product were combined and dried in a nitrogen stream to obtain the title compound (0.5 mg, 1.8%) as a white film. ESI-MS m/z [M+H] ⁺ = 422.4. Example 82: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-methyl-2-oxo-2,3-dihydro-1 H -Imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

步驟1：(R )-6-溴-3-(1-羥基-2-甲基丙-2-基)-1-(2-羥基丙基)-1,3-二氫-2H -咪唑并[4,5-b ]吡啶-2-酮

Fill the microwave vial with 6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1-methyl-1,3-dihydro- 2H -imidazo[4,5- b ]Pyridin-2-one (0.064 g, 0.213 mmol), N -cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Cyclopentane-2-yl)benzamide (0.077 g, 0.256 mmol), tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.021 mmol), 2 N Na ₂ CO ₃ aqueous solution (0.320 mL , 0.640 mmol) and DME (2 mL). The reaction mixture was degassed with nitrogen, and the vial was capped and heated in a microwave reactor at 130°C for 1 hour. After the reaction, the solvent was removed via a stream of nitrogen, and the residue was taken in EtOAc (10 mL) and water (5 mL). The organic layer was washed with water (5 mL) and the solvent was removed via a stream of nitrogen. The residue was dispersed in DCM and purified by chromatography (ISCO® 12 g silica gel column) using a gradient of 0%-100% EtOAc in heptane to purify. The fractions containing the product were combined and dried by nitrogen flow to obtain the title compound (19 mg, 23%) as a white film. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.54-0.60 (m, 2 H) 0.65-0.75 (m, 2 H) 1.72 (s, 6 H) 2.27-2.37 (m, 4 H) 2.85 ( tq, J =7.41, 3.92 Hz, 2 H) 3.34 (s, 3 H) 3.92 (d, J =6.42 Hz, 2 H) 5.00 (t, J =6.51 Hz, 1 H) 7.41 (d, J =7.98 Hz, 1 H) 7.54 (d, J =1.93 Hz, 1 H) 7.73 (s, 1 H) 7.77 (d, J =8.06 Hz, 1 H) 7.95 (d, J =2.02 Hz, 1 H) 8.38 ( d, J = 4.22 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 395.5. Example 83: ( R ) -N -cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxypropyl)-2- Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: ( R )-6-bromo-3-(1-hydroxy-2-methylpropan-2-yl)-1-(2-hydroxypropyl)-1,3-dihydro-2 H -imidazole And [4,5- b ]pyridin-2-one

To 6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridin-2-one (100 mg , 0.349 mmol) and ( R )-1-chloropropan-2-ol (49.6 mg, 0.524 mmol) in DMF (3 mL) was added K ₂ CO ₃ (97 mg, 0.699 mmol). The reaction mixture was stirred at 90°C for 18 hours, then cooled to room temperature, diluted with EtOAc and washed with brine. The organic layer was dried over Na ₂ SO _4, filtered and concentrated to give the title compound (120 mg, 100%), which was used without further purification. ESI-MS m/z [M+H] ⁺ = 346.3. Step 2: ( R ) -N -Cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxypropyl)-2- Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

步驟1：(S )-6-溴-3-(1-羥基-2-甲基丙-2-基)-1-(2-羥基丙基)-1,3-二氫-2H -咪唑并[4,5-b ]吡啶-2-酮

To ( R )-6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxypropyl)-1,3-dihydro-2 H -Imidazo[4,5- b ]pyridin-2-one (60 mg, 0.174 mmol) and N -cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)benzamide (61.2 mg, 0.192 mmol) in 1,4-dioxane (3 mL) and water (0.300 mL) _{Add K 2} CO ₃ (120 mg, 0.872 mmol) and Pd(dppf)Cl ₂ (12.75 mg, 0.017 mmol) to the mixture in ). The suspension was purged with N _2. The reaction mixture was heated to 100°C in a microwave reactor for 2 hours, then diluted with EtOAc and washed with water and brine. The organic phase was dried over Na ₂ SO _4, filtered, concentrated and purified by SFC. The fractions containing the product were combined and concentrated to obtain the title compound (12 mg, 15%) as a transparent film. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.63-0.69 (m, 2 H) 0.84 (q, J = 6.42 Hz, 2 H) 1.25 (d, J = 6.33 Hz, 3 H) 1.78 (s, 7 H) 2.32-2.37 (m, 3 H) 2.85-2.93 (m, 1 H) 3.35-3.40 (m, 1 H) 3.77-3.95 (m, 2 H) 4.06-4.20 (m, 3 H) 7.19 ( d, J= 11.65 Hz, 1 H) 7.48-7.62 (m, 2 H) 7.95-8.00 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 457.5. Example 84: ( S ) -N -cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxypropyl)-2- Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: ( S )-6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxypropyl)-1,3-dihydro-2 H -imidazole And [4,5- b ]pyridin-2-one

To 6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridin-2-one (100 mg , 0.349 mmol) and ( S )-1-chloropropan-2-ol (49.6 mg, 0.524 mmol) in DMF (3 mL) was added K ₂ CO ₃ (97 mg, 0.699 mmol). The reaction mixture was stirred at 90°C for 18 hours, then cooled to room temperature, diluted with EtOAc and washed with brine. The organic phase was dried over Na ₂ SO _4, filtered and concentrated to give the title compound (120 mg, 100%), which was used without further purification. ESI-MS m/z [M+H] ⁺ = 344.3. Step 2: ( S ) -N -cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxypropyl)-2- Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

步驟1：6-溴-3-(1-羥基-2-甲基丙-2-基)-1-(3-羥基丙基)-1,3-二氫-2H -咪唑并[4,5-b ]吡啶-2-酮

To ( S )-6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxypropyl)-1,3-dihydro-2 H -Imidazo[4,5- b ]pyridin-2-one (120 mg, 0.349 mmol) and N -cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)benzamide (122 mg, 0.383 mmol) in 1,4-dioxane (3 mL) and water (0.300 mL) _{Add K 2} CO ₃ (241 mg, 1.743 mmol) and Pd(dppf)Cl ₂ (25.5 mg, 0.035 mmol) to the mixture in ). The suspension was purged with N _2. The reaction mixture was heated to 100°C in a microwave reactor for 2 hours, then diluted with EtOAc and washed with water and brine. The organic phase was dried over Na ₂ SO _4, filtered, concentrated and purified by SFC. The fractions containing the product were combined and concentrated to obtain the title compound (93 mg, 58%) as a yellow film. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.61-0.69 (m, 2 H) 0.83 (q, J = 6.51 Hz, 2 H) 1.25 (d, J = 6.24 Hz, 3 H) 1.78 (s, 7 H) 2.34 (s, 3 H) 2.85-2.92 (m, 1 H) 3.80-3.97 (m, 2 H) 4.08-4.19 (m, 3 H) 7.19 (d, J = 11.55 Hz, 1 H) 7.53 (s, 1 H) 7.58 (d, J= 7.43 Hz, 1 H) 7.95-8.00 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 457.5. Example 85: N -Cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(3-hydroxypropyl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: 6-Bromo-3-(1-hydroxy-2-methylprop-2-yl)-1-(3-hydroxypropyl)-1,3-dihydro- 2H -imidazo[4, 5- b ]pyridin-2-one

To 6-bromo-3-(1-hydroxy-2-methylpropan-2-yl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridin-2-one (50 mg , 0.175 mmol) and 3-bromoprop-1-ol (36.4 mg, 0.262 mmol) in DMF (3 mL) was added K ₂ CO ₃ (48.3 mg, 0.349 mmol). The reaction mixture was stirred at 90°C for 18 hours, then cooled to room temperature, diluted with EtOAc and washed with brine. The organic phase was dried over Na ₂ SO _4, filtered and concentrated to give the title compound (60 mg, 100%), which was used without further purification. ESI-MS m/z [M+H] ⁺ = 346.3. Step 2: N -Cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(3-hydroxypropyl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

To 6-bromo-3-(1-hydroxy-2-methylpropan-2-yl)-1-(3-hydroxypropyl)-1,3-dihydro-2 H -imidazo[ 4,5- b )pyridin-2-one (60 mg, 0.174 mmol) and N -cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaborolan-2-yl)benzamide (61.2 mg, 0.192 mmol) in 1,4-dioxane (3 mL) and water (0.300 mL) Add K ₂ CO ₃ (120 mg, 0.872 mmol) and Pd(dppf)Cl ₂ (12.75 mg, 0.017 mmol). The suspension was purged with N _2. The reaction mixture was heated to 100°C in a microwave reactor for 2 hours, then diluted with EtOAc and washed with water and brine. The organic phase was dried over Na ₂ SO _4, filtered, concentrated and purified by SFC. The fractions containing the product were combined and concentrated to obtain the title compound (31 mg, 39%) as a transparent film. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.61-0.67 (m, 2 H) 0.84 (q, J = 6.63 Hz, 2 H) 1.78 (s, 6 H) 1.95 (quin, J = 6.44 Hz, 2 H) 2.35 (s, 3 H) 2.84-2.92 (m, 1 H) 3.62 (t, J = 6.01 Hz, 2 H) 4.03 (t, J = 6.88 Hz, 2 H) 4.09 (s, 2 H) 7.15-7.23 (m, 1 H) 7.51-7.55 (m, 1 H) 7.59 (d, J= 7.43 Hz, 1 H) 7.98 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 457.5. Example 86: 2-Fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxyethyl)-2-oxo-2,3-dihydro -1 H -imidazo[4,5- b ]pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide

步驟1：3-(2-氟-5-(3-(1-羥基-2-甲基丙-2-基)-1-(2-羥基乙基)-2-側氧基-2,3-二氫-1H -咪唑并[4,5-b ]吡啶-6-基)-4-甲基苯甲醯胺基)-1H -吡唑-1-甲酸第三丁基酯

To 6-bromo-3-(1-hydroxy-2-methylpropan-2-yl)-1-(2-hydroxyethyl)-1,3-dihydro-2 H -imidazo[ 4,5- b )pyridin-2-one (45.8 mg, 0.139 mmol) and 2-fluoro- N -(isoxazol-3-yl)-4-methyl-5-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (48 mg, 0.139 mmol) in 1,4-dioxane (3 mL) and water ( 0.300 mL) was added K ₂ CO ₃ (96 mg, 0.693 mmol) and Pd(dppf)Cl ₂ (10.15 mg, 0.014 mmol). The suspension was purged with N _2. The reaction mixture was heated to 100°C in a microwave reactor for 2 hours, then diluted with EtOAc and washed with water and brine. The organic phase was dried over Na ₂ SO _4, filtered, concentrated and purified by SFC. The fractions containing the product were combined and concentrated to obtain the title compound (22 mg, 34%) as a yellow film. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.79 (s, 6 H) 2.38 (s, 3 H) 3.82-3.89 (m, 2 H) 4.04 (t, J = 5.09 Hz, 2 H) 4.10 ( s, 2 H) 7.06 (s, 1 H) 7.28 (d, J = 11.55 Hz, 1 H) 7.55 (s, 1 H) 7.69 (d, J = 7.34 Hz, 1 H) 8.00 (s, 1 H) 8.59-8.64 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 470.4. Example 87: 2-Fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxyethyl)-2-oxo-2,3-dihydro -1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(1 H -pyrazol-3-yl)benzamide

Step 1: 3-(2-Fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxyethyl)-2-oxo-2,3 -Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide)-1 H -pyrazole-1-carboxylic acid tert-butyl ester

To 6-bromo-3-(1-hydroxy-2-methylpropan-2-yl)-1-(2-hydroxyethyl)-1,3-dihydro-2 H -imidazo[ 4,5- b )pyridin-2-one (89 mg, 0.269 mmol) and 3-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)benzamide)-1 H -pyrazole-1-carboxylic acid tert-butyl ester (120 mg, 0.269 mmol) in 1,4-diox _{Add K 2} CO ₃ (186 mg, 1.347 mmol) and Pd(dppf)Cl ₂ (19.72 mg, 0.027 mmol) to a mixture of alkane (3 mL) and water (0.300 mL). The suspension was purged with N _2. The reaction mixture was heated to 100°C in a microwave reactor for 2 hours, then diluted with EtOAc and washed with water and brine. The organic phase was dried over Na ₂ SO _4, filtered and concentrated to give the title compound (150 mg, 98%), which was used without further purification. ESI-MS m/z [M+H] ⁺ = 569.6. Step 2: 2-Fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxyethyl)-2-oxo-2,3-dihydro -1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(1 H -pyrazol-3-yl)benzamide

步驟1：6-溴-3-(1-羥基-2-甲基丙-2-基)-1-(2-羥基-2-甲基丙基)-1,3-二氫-2H -咪唑并[4,5-b ]吡啶-2-酮

Add 3-(2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxyethyl)-2-oxo-2,3-di Hydrogen-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide)-1 H -pyrazole-1-carboxylic acid tertiary butyl ester (150 mg, A mixture of 0.264 mmol) in TFA (1 mL) and DCM (1 mL) was stirred at room temperature for 45 minutes, and then concentrated and purified by SFC. The fractions containing the product were combined and concentrated to obtain the title compound (43 mg, 35%) as a colorless film. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.79 (s, 6 H) 2.38 (s, 3 H) 3.81-3.89 (m, 2 H) 4.04 (t, J = 5.00 Hz, 2 H) 4.10 ( s, 2 H) 6.69 (s, 1 H) 7.27 (d, J = 11.83 Hz, 1 H) 7.55 (s, 1 H) 7.62 (s, 1 H) 7.73 (d, J = 7.52 Hz, 1 H) 7.98-8.02 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 470.4. Example 88: N -Cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxy-2-methylpropyl)-2 -Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: 6-Bromo-3-(1-hydroxy-2-methylpropan-2-yl)-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2 H- Imidazo[4,5- b ]pyridin-2-one

To 6-bromo-3-(1-hydroxy-2-methylpropan-2-yl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridin-2-one (120 mg , 0.419 mmol) and 1-bromo-2-methylpropan-2-ol (96 mg, 0.629 mmol) in DMF (3 mL) was added K ₂ CO ₃ (116 mg, 0.839 mmol). The reaction mixture was stirred at 80°C for 18 hours, then cooled to room temperature, diluted with EtOAc and washed with brine. The organic phase was dried over Na ₂ SO _4, filtered and concentrated to give the title compound (150 mg, crude), which was used without further purification. ESI-MS m/z [M+H] ⁺ = 360.3. Step 2: N -Cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxy-2-methylpropyl)-2 -Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

To 6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2 at 20℃ H -imidazo[4,5- b ]pyridin-2-one (150 mg, 0.419 mmol) and N -cyclopropyl-2-fluoro-4-methyl-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (147 mg, 0.461 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added K ₂ CO ₃ (289 mg, 2.094 mmol) and PdCl ₂ (dppf) (30.6 mg, 0.042 mmol). The suspension was purged with N _2. The reaction mixture was heated to 100°C in a microwave reactor for 2 hours, then diluted with EtOAc and washed with water and brine. The organic phase was dried over Na ₂ SO _4, filtered, concentrated and purified by SFC. The fractions containing the product were combined and concentrated to obtain the title compound (113 mg, 57.4%) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.60-0.69 (m, 2 H) 0.80-0.88 (m, 2 H) 1.28 (s, 6 H) 1.78 (s, 6 H) 2.34 (s, 3 H) 2.84-2.96 (m, 1 H) 3.88 (s, 2 H) 4.10 (s, 2 H) 7.14-7.25 (m, 1 H) 7.54-7.63 (m, 2 H) 7.97 (s, 1 H) ; ESI-MS m/z [M+H] ⁺ = 471.5. Example 89: 3-(1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo[4, 5- b )pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide

步驟1：6-溴-3-(1-羥基-2-甲基丙-2-基)-1-異丙基-1,3-二氫-2H -咪唑并[4,5-b ]吡啶-2-酮

To 6-bromo-1-ethyl-3-(1-hydroxy-2-methylprop-2-yl)-1,3-dihydro-2 H -imidazo[4,5- b ]pyridine-2 -Ketone (100mg, 0.318 mmol), N -(isoxazol-3-yl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa A mixture of boron-2-yl)benzamide (104 mg, 0.318 mmol) in 1,4-dioxane (2 mL) was added 2 N Na ₂ CO ₃ aqueous solution (0.318 mL, 0.637 mmol) ). The mixture was degassed with nitrogen. Next, PdCl ₂ (dtbpf) (20.74 mg, 0.032 mmol) was added. The reaction mixture was heated at 130°C for 1 hour, then diluted with water and extracted by EtOAc. The organic layers were combined, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated, dried in vacuo and purified by SFC to give the title compound (7 mg, 5%) as a reddish brown solid. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.28-1.44 (m, 9 H) 1.74-1.85 (m, 7 H) 2.37-2.45 (m, 3 H) 3.91-4.07 (m, 2 H) 4.07 -4.17 (m, 2 H) 6.92-7.15 (m, 1 H) 7.45-7.60 (m, 2 H) 7.79-7.97 (m, 2 H) 7.99-8.09 (m, 1 H) 8.49-8.63 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 436.4. Example 90: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-isopropyl-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: 6-Bromo-3-(1-hydroxy-2-methylprop-2-yl)-1-isopropyl-1,3-dihydro-2 H -imidazo[4,5- b ] Pyridin-2-one

To 6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridine-2- Add NaH (30.8 mg, 0.769 mmol) to a solution of ketone (200 mg, 0.699 mmol) in DMF (2 mL). The solution was stirred for 15 minutes, and then 2-iodopropane (69.9 µL, 0.699 mmol) was added. The reaction mixture was stirred at 25°C overnight, then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO _4, filtered and concentrated. The crude product was purified by silica column chromatography to obtain the title compound (60 mg, 26%). ESI-MS m/z [M+H] ⁺ = 328.2. Step 2: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-isopropyl-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

To the 6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1-isopropyl-1,3-dioxane filled in 1,4-dioxane (2 mL) Hydrogen-2 H -imidazo[4,5- b ]pyridin-2-one (60 mg, 0.183 mmol) and N -cyclopropyl-4-methyl-3-(4,4,5,5-tetra _{Add 2 N Na 2} CO ₃ aqueous solution (183 µL, 0.366 mmol) to a vial of methyl-1,3,2-dioxaborolan-2-yl)benzamide (55.1 mg, 0.183 mmol) ). The mixture was degassed with nitrogen. Next, PdCl ₂ (dtbpf) (11.91 mg, 0.018 mmol) was added, and the vial was capped and heated in a microwave reactor at 130° C. for 1 hour. The crude product was purified by SFC to obtain the title compound (28 mg, 36%) as a brown film. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.58-0.72 (m, 2 H) 0.75-0.88 (m, 2 H) 1.26-1.41 (m, 1 H) 1.48-1.59 (m, 6 H) 1.77 (s, 6 H) 2.18 -2.40 (m, 3 H) 2.79-2.94 (m, 1 H) 4.01-4.18 (m, 2 H) 7.35-7.49 (m, 1 H) 7.51-7.66 (m, 1 H) ) 7.67-7.81 (m, 2 H) 7.88-8.07 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 423.5.

方案G 實例91：N -環丙基-3-(1-乙基-3-(1-羥基-2-甲基丙-2-基)-2-側氧基-2,3-二氫-1H -咪唑并[4,5-b ]吡啶-6-基)-4-甲基苯甲醯胺

As in Example 90, each of the following Examples 91 to 107 is prepared according to Scheme G, where: (Step 1) will change the 6-bromo-3-(1-hydroxy-2-methylpropan-2) in DMF -Yl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridin-2-one (G-1) was treated with NaH, and then it was combined with halogenated alkane (XR ^1N ) at room temperature The next reaction is to obtain N -alkylated aryl halide (G-2); and (Step 2) the N -alkylated aryl halide in 1,4-dioxane is reacted with N -cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide is in The _{reaction was carried out at 130°C in the presence of an aqueous Na 2} CO ₃ solution and PdCl ₂ (dtbpf) to provide the title compound (G-3).

Scheme G Example 91: N -cyclopropyl-3-(1-ethyl-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro- 1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.60-0.71 (m, 2 H) 0.76-0.87 (m, 2 H) 1.33 (t, J = 7.20 Hz, 3 H) 1.77 (s, 6 H) 2.36 (s, 3 H) 2.87 (br t, J =3.71 Hz, 1 H) 3.98 (q, J =7.15 Hz, 2 H) 4.09 (s, 2 H) 7.41 (d, J =7.89 Hz, 1 H ) 7.50 (d, J =1.83 Hz, 1 H) 7.73 (s, 1 H) 7.75 (d, J =7.83 Hz, 1 H) 8.00 (d, J =1.83 Hz, 1 H); ESI-MS m/ z [M+H] ⁺ = 409.4. Example 92: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-1-(2,2,2-trifluoroethyl) -2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.61-0.69 (m, 2 H) 0.79-0.85 (m, 2 H) 1.80 (s, 6 H) 2.35 (s, 3 H) 2.87 (s, 1 H) 4.12 (s, 2 H) 4.71 (q, J =8.99 Hz, 2 H) 7.43 (d, J =7.98 Hz, 1 H) 7.56 (s, 1 H) 7.72 (s, 1 H) 7.76 (d , J =7.74 Hz, 1 H) 8.07 (d, J =1.83 Hz, 1 H); ESI-MS m/z [M+H] ⁺ = 463.3. Example 93: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-1-propyl-2,3-dihydro-1 H -Imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.59-0.72 (m, 2 H) 0.77-0.87 (m, 2 H) 0.98 (t, J =7.38 Hz, 3 H) 1.72-1.84 (m, 8 H) 2.36 (s, 3 H) 2.82-2.91 (m, 1 H) 3.91 (t, J =7.11 Hz, 2 H) 4.10 (s, 2 H) 7.43 (d, J =7.98 Hz, 1 H) 7.49 (s, 1 H) 7.72 (s, 1 H) 7.75 (d, J =7.70 Hz, 1 H) 8.01 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 423.5. Example 94: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-isobutyl-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.59-0.72 (m, 2 H) 0.76-0.90 (m, 2 H) 0.98 (d, J = 6.69 Hz, 6 H) 1.78 (s, 6 H) 2.10-2.26 (m, 1 H) 2.35 (s, 3 H) 2.82-2.92 (m, 1 H) 3.74 (d, J =7.43 Hz, 2 H) 4.10 (s, 2 H) 7.40-7.44 (m, 1 H) 7.46-7.49 (m, 1 H) 7.70-7.78 (m, 2 H) 8.00 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 437.5. Example 95: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(oxetan-3-yl)-2-oxo-2 ,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.60-0.74 (m, 2 H) 0.75-0.90 (m, 2 H) 1.76-1.84 (m, 6 H) 2.27-2.44 (m, 3 H) 2.80 -2.95 (m, 1 H) 4.07-4.15 (m, 2 H) 5.07-5.23 (m, 4 H) 5.57-5.72 (m, 1 H) 7.38-7.52 (m, 1 H) 7.68-7.81 (m, 2 H) 7.81-7.91 (m, 1 H) 8.02-8.17 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 437.5. Example 96: N -Cyclopropyl-3-(1-(cyclopropylmethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.33-0.49 (m, 2 H) 0.51-0.62 (m, 2 H) 0.62-0.70 (m, 2 H) 0.75-0.91 (m, 2 H) 1.12 -1.37 (m, 1 H) 1.78 (s, 6 H) 2.27-2.48 (m, 3 H) 2.81-2.97 (m, 1 H) 3.71-3.90 (m, 2 H) 4.00-4.21 (m, 2 H) ) 7.25-7.48 (m, 1 H) 7.47-7.58 (m, 1 H) 7.68-7.81 (m, 2 H) 7.92-8.08 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 435.5. Example 97: N -Cyclopropyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.42-0.52 (m, 2 H) 0.59-0.72 (m, 2 H) 1.56-1.66 (m, 6 H) 2.16 (s, 3 H) 2.64-2.74 (m, 1 H) 3.90-3.95 (m, 2 H) 3.98-4.18 (m, 2 H) 4.41-4.52 (m, 1 H) 4.57-4.62 (m, 1 H) 7.19-7.27 (m, 1 H) ) 7.30-7.36 (m, 1 H) 7.51-7.61 (m, 2 H) 7.80-7.86 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 427.4. Example 98: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-1-((tetrahydrofuran-3-yl)methyl)- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.61-0.70 (m, 2 H) 0.82 (br d, J =6.05 Hz, 2 H) 1.78 (s, 7 H) 2.05 (br d, J =7.43 Hz, 1 H) 2.36 (s, 3 H) 2.76-2.93 (m, 2 H) 3.37 (s, 1 H) 3.65 (dd, J =8.71, 5.14 Hz, 1 H) 3.72-3.81 (m, 2 H ) 3.88-4.00 (m, 3 H) 4.10 (s, 2 H) 7.42 (d, J =7.89 Hz, 1 H) 7.54 (s, 1 H) 7.69-7.78 (m, 2 H) 8.02 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 465.5. Example 99: N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(3-methoxypropyl)-2-oxo-2, 3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.46-0.70 (m, 2 H) 0.72-0.89 (m, 2 H) 1.77 (s, 7 H) 1.92-2.07 (m, 2 H) 2.17-2.49 (m, 4 H) 2.81-2.91 (m, 1 H) 3.24-3.29 (m, 3 H) 3.36-3.39 (m, 3 H) 3.39-3.46 (m, 3 H) 3.93-4.06 (m, 2 H ) 4.06-4.12 (m, 2 H) 7.33-7.46 (m, 1 H) 7.64-7.81 (m, 2 H) 7.91-8.07 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 453.5. Example 100: N -Cyclopropyl-3-(1-(2,2-difluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2 ,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.59-0.71 (m, 2 H) 0.77-0.91 (m, 2 H) 1.79 (s, 6 H) 2.23-2.44 (m, 3 H) 2.79-2.94 (m, 1 H) 4.02-4.18 (m, 2 H) 4.25-4.45 (m, 2 H) 5.99-6.41 (m, 1 H) 7.34-7.49 (m, 1 H) 7.50-7.58 (m, 1 H) ) 7.67-7.80 (m, 2 H) 7.95-8.11 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 445.4. Example 101: 3-(1-(cyclobutylmethyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo [4,5- b ]pyridin-6-yl) -N -cyclopropyl-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.59-0.72 (m, 2 H) 0.77-0.87 (m, 2 H) 1.77 (s, 6 H) 1.84-1.97 (m, 4 H) 1.98-2.11 (m, 2 H) 2.35 (s, 3 H) 2.78-2.91 (m, 2 H) 3.96 (d, J =7.15 Hz, 2 H) 4.09 (s, 2 H) 7.43 (d, J =7.89 Hz, 1 H) 7.49 (s, 1 H) 7.71 (s, 1 H) 7.75 (d, J =7.72 Hz, 1 H) 8.00 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 449.5. Example 102: N -Cyclopropyl-3-(1-((2,2-difluorocyclopropyl)methyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2- Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.62-0.69 (m, 2 H) 0.82 (q, J = 6.24 Hz, 2 H) 1.30-1.49 (m, 1 H) 1.54-1.66 (m, 1 H) 1.79 (s, 6 H) 2.17 (br dd, J =12.56, 5.32 Hz, 1 H) 2.36 (s, 3 H) 2.87 (dt, J =7.22, 3.50 Hz, 1 H) 3.97 (dd, J =15.13, 7.61 Hz, 1 H) 4.08-4.21 (m, 3 H) 7.42 (d, J =7.89 Hz, 1 H) 7.52 (s, 1 H) 7.72 (s, 1 H) 7.75 (d, J = 7.80 Hz, 1 H) 8.02 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 471.5. Example 103: N -Cyclopropyl-3-(1-(2-(dimethylamino)ethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo Yl-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.58-0.74 (m, 2 H) 0.75-0.89 (m, 2 H) 1.73 (s, 1 H) 1.79 (s, 6 H) 2.31-2.38 (m , 8 H) 2.67-2.77 (m, 2 H) 2.88 (br d, J =3.58 Hz, 1 H) 4.02-4.13 (m, 4 H) 7.43 (d, J =7.89 Hz, 1 H) 7.52 (s , 1 H) 7.72 (s, 1 H) 7.75 (d, J =8.60 Hz, 1 H) 8.01 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 452.5. Example 104: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(isoxazol-5-ylmethyl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.58-0.72 (m, 2 H) 0.74-0.89 (m, 2 H) 1.80 (s, 6 H) 2.32 (s, 3 H) 2.87 (s, 1 H) 4.11 (s, 2 H) 5.33 (s, 2 H) 6.44 (s, 1 H) 7.41 (d, J =7.98 Hz, 1 H) 7.52 (s, 1 H) 7.69-7.78 (m, 2 H ) 8.04 (s, 1 H) 8.35 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 462.5. Example 105: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(isoxazol-4-ylmethyl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.56-0.71 (m, 2 H) 0.71-0.87 (m, 2 H) 1.80 (s, 6 H) 2.32 (s, 3 H) 2.78-2.98 (m , 1 H) 4.07-4.20 (m, 2 H) 4.99-5.11 (m, 2 H) 7.36-7.49 (m, 1 H) 7.49-7.60 (m, 1 H) 7.66-7.84 (m, 2 H) 7.93 -8.10 (m, 1 H) 8.33-8.56 (m, 1 H) 8.64-8.89 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 462.5. Example 106: N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(isoxazol-3-ylmethyl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.53-0.72 (m, 2 H) 0.77-0.90 (m, 2 H) 1.79 (s, 6 H) 2.28 (s, 3 H) 2.74-2.95 (m , 1 H) 4.10 (s, 2 H) 5.17-5.38 (m, 2 H) 6.38-6.67 (m, 1 H) 7.28-7.54 (m, 2 H) 7.62-7.86 (m, 2 H) 7.89-8.12 (m, 1 H) 8.51-8.76 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 462.5. Example 107: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylpropan-2-yl)-1-((1-methyl-1H-pyrazol-4-yl)methyl )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

及 實例109：N -環丙基-3-(3-(1-(2-甲氧基乙氧基)-2-甲基丙-2-基)-1-(2-甲氧基乙基)-2-側氧基-2,3-二氫-1H -咪唑并[4,5-b ]吡啶-6-基)-4-甲基苯甲醯胺

步驟1：6-溴-3-(1-羥基-2-甲基丙-2-基)-1-(2-甲氧基乙基)-1,3-二氫-2H -咪唑并[4,5-b ]吡啶-2-酮

及 6-溴-3-(1-(2-甲氧基乙氧基)-2-甲基丙-2-基)-1-(2-甲氧基乙基)-1,3-二氫-2H -咪唑并[4,5-b ]吡啶-2-酮

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.60-0.71 (m, 2 H) 0.76-0.89 (m, 2 H) 1.79 (s, 6 H) 2.26-2.34 (m, 3 H) 2.79-2.95 (m, 1 H) 3.78-3.90 (m, 3 H) 4.06-4.18 (m, 2 H) 4.94-5.05 (m, 2 H) 7.38-7.44 (m, 1 H) 7.47-7.53 (m, 2 H) ) 7.63-7.72 (m, 2 H) 7.72-7.78 (m, 1 H) 7.96-8.02 (m, 1 H); ESI-MS m/z [M+H] ⁺ = 475.5. Example 108: N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-methoxyethyl)-2-oxo-2, 3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

And Example 109: N -Cyclopropyl-3-(3-(1-(2-methoxyethoxy)-2-methylprop-2-yl)-1-(2-methoxyethyl )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide

Step 1: 6-Bromo-3-(1-hydroxy-2-methylprop-2-yl)-1-(2-methoxyethyl)-1,3-dihydro- 2H -imidazo[ 4,5- b ]pyridin-2-one

And 6-bromo-3-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)-1-(2-methoxyethyl)-1,3-dihydro -2 H -imidazo[4,5- b ]pyridin-2-one

To 6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridine-2- Add NaH (25.4 mg, 0.634 mmol) to a solution of ketone (165 mg, 0.577 mmol) in DMF (2 mL). The solution was stirred for 15 minutes, and then 1-iodo-2-methoxyethane (322 mg, 1.730 mmol) was added. The reaction mixture was stirred at 25°C overnight, then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, _{dried over Na 2} SO ₄ and filtered. The filtrate was concentrated and dried in vacuum to obtain a crude mixture containing 6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1-(2-methoxyethyl)-1 ,3-Dihydro- 2H -imidazo[4,5- b ]pyridin-2-one, ESI-MS m/z [M+H] ⁺ = 344.3, and 6-bromo-3-(1-( 2-methoxyethoxy)-2-methylprop-2-yl)-1-(2-methoxyethyl)-1,3-dihydro- 2H -imidazo[4,5- b ] Pyridin-2-one, ESI-MS m/z [M+H] ⁺ = 404.3. Step 2: N -Cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-methoxyethyl)-2-oxo-2, 3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide and N -cyclopropyl-3-(3-(1-(2- (Methoxyethoxy)-2-methylprop-2-yl)-1-(2-methoxyethyl)-2-oxo-2,3-dihydro- 1H -imidazo[ 4,5- b )pyridin-6-yl)-4-methylbenzamide

Will be loaded with 6-bromo-3-(1-hydroxy-2-methylprop-2-yl)-1-(2-methoxyethyl)-1,3-dihydro- 2H -imidazo[ 4,5- b )pyridin-2-one (0.199 g, 0.577 mmol) and 6-bromo-3-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)- 1-(2-Methoxyethyl)-1,3-dihydro- 2H -imidazo[4,5- b ]pyridin-2-one (0.232 g, 0.577 mmol) (presumed) equal molar Mixture and N -cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide A vial of amine (0.174 g, 0.577 mmol), 2 N Na ₂ CO ₃ aqueous solution (0.577 mL, 1.154 mmol) and 1,4-dioxane (5 mL) was degassed with nitrogen. Next, PdCl ₂ (dtbpf) (0.038 g, 0.058 mmol) was added, and the vial was capped and heated in a microwave reactor at 130°C for 1 hour. The reaction mixture was then diluted with water and extracted with EtOAc. The organic phase was dried over Na ₂ SO _4, concentrated and purified by SFC. Obtain the compound N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-methoxyethyl)-2-oxo group with brown film -2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide (60 mg, 24%); compound N is obtained as a brown film -Cyclopropyl-3-(3-(1-(2-methoxyethoxy)-2-methylprop-2-yl)-1-(2-methoxyethyl)-2-side Oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide (18 mg, 6%).

Example 108: ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.59-0.69 (m, 2 H) 0.75-0.85 (m, 2 H) 1.76 (s, 6 H) 2.34 (s, 3 H) 2.82- 2.89 (m, 1 H) 3.35 (s, 3 H) 3.68 (t, J =5.04 Hz, 2 H) 4.04-4.12 (m, 4 H) 7.40 (d, J =7.98 Hz, 1 H) 7.51 (s , 1 H) 7.70 (s, 1 H) 7.73 (d, J =7.80 Hz, 1 H) 7.98 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 439.5.

Example 109: ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.60-0.72 (m, 2 H) 0.75-0.90 (m, 2 H) 1.88 (s, 6 H) 2.87 (s, 1 H) 3.25 ( s, 3 H) 3.30-3.37 (m, 3 H) 3.42-3.50 (m, 2 H) 3.55-3.63 (m, 2 H) 3.68 (t, J = 5.14 Hz, 2 H) 4.07 (t, J = 5.09 Hz, 2 H) 4.14 (s, 2 H) 7.42 (d, J =7.66 Hz, 1 H) 7.46 (s, 1 H) 7.71 (s, 1 H) 7.74 (d, J =7.59 Hz, 1 H ) 7.98 (s, 1 H); ESI-MS m/z [M+H] ⁺ = 497.6.

Examples listed in Table 1 set forth RIPK2 compound of inhibition data, the larger the pIC ₅₀ values represent a higher effect. The compounds were tested according to the analysis described in the section titled biological activity above. Table 1: RIPK2 examples of the compound of inhibition (pIC ₅₀₎ Instance pIC ₅₀ Instance pIC ₅₀ Instance pIC ₅₀ Instance pIC ₅₀ Instance pIC ₅₀ 1 8.6 26 8.6 51 7.9 76 8.5 101 8.3 2 8.6 27 8.6 52 8.1 77 8.7 102 8.5 3 ＞8.6 28 8.6 53 8.0 78 8.5 103 6.8 4 8.5 29 8.3 54 7.9 79 6.9 104 7.5 5 8.5 30 7.5 55 8.2 80 6.9 105 7.8 6 8.4 31 8.2 56 6.0 81 7.8 106 7.7 7 8.5 32 8.5 57 6.1 82 7.7 107 7.7 8 8.6 33 ＞8.6 58 6.0 83 8.0 108 7.9 9 8.6 34 ＜5.0 59 8.2 84 8.5 109 6.4 10 8.5 35 5.5 60 6.0 85 8.4 11 ＞8.6 36 7.8 61 7.5 86 8.5 12 ＞8.6 37 7.8 62 7.4 87 8.3 13 ＞8.6 38 7.6 63 7.4 88 8.4 14 ＞8.6 39 7.9 64 8.1 89 8.5 15 7.6 40 8.5 65 7.0 90 8.3 16 7.6 41 8.4 66 8.8 91 8.4 17 6.9 42 7.7 67 7.4 92 8.2 18 7.4 43 7.4 68 7.9 93 8.4 19 6.4 44 7.7 69 8.4 94 8.6 20 6.4 45 8.2 70 8.4 95 7.6 twenty one ＞8.6 46 6.5 71 8.2 96 ＞8.6 twenty two 8.1 47 7.4 72 7.1 97 8.5 twenty three 7.4 48 7.1 73 8.1 98 8.0 twenty four 7.2 49 8.3 74 8.0 99 7.7 25 5.2 50 8.4 75 8.0 100 8.5

Unless the context clearly dictates otherwise, as used in the scope of this specification and the accompanying patent applications, singular articles such as "一 (a, an)" and "the (the)" can refer to a single object or a plurality of objects. Thus, for example, reference to a composition containing a "compound" may include a single compound or two or more compounds. The above description is intended to be illustrative and not restrictive. Those skilled in the art will understand many embodiments after reading the above description. Therefore, the scope of the present invention should be determined with reference to the scope of the attached patent application, and includes the full scope of equivalent content authorized by the scope of the patent application. The disclosures of all articles and references (including patents, patent applications and publications) cited in this disclosure are incorporated herein by reference in their entirety for all purposes.

Claims (28)

A compound of formula 1,

Or a pharmaceutically acceptable salt thereof, wherein: α is a single bond, β is a double bond, X ¹ is NR ^1N , and R ² is a pendant oxy group; or α is a double bond, β is a single bond, and X ^{1 is} selected From N and CR ^1C , and R ^{2 is} selected from hydrogen, C _1-4 alkyl and C _1-4 alkoxy; R ^{1C is} selected from hydrogen, halo and C _1-6 alkyl, the C _1-6 alkane The group is substituted with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, C _1-4 alkoxy and optionally substituted with one or two C _1-4 alkyl groups R ^{1N is} selected from C _1-4 alkyl, C _3-8 cycloalkyl-(CH ₂ ) _n , C _2-8 heterocyclyl-(CH ₂ ) _n and C _1-9 heteroaryl -(CH ₂ ) _n , wherein each of the C _1-4 alkyl group, the C _3-8 cycloalkyl group, the C _2-8 heterocyclic group, and the C _1-9 heteroaryl moiety is controlled by 0 Substitution by up to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, C _1-4 alkyl, C _1-4 alkoxy and optionally with one or two C _{1- 4} Alkyl-substituted amine groups, and the C _1-4 alkyl group and the C _1-4 alkoxy substituent which optionally exist are each independently selected from 0 to 3 halo groups as the case may be N is selected from 0, 1, 2 and 3; R ³ is a C _1-6 alkyl group, which is substituted with 0 to 3 substituents independently selected from the following optionally present: halo, hydroxy , Cyano, optionally C _1-4 alkoxy substituted by C _1-4 alkoxy and optionally amine substituted by one or two C _1-4 alkyl groups, wherein one or more of ^{R 3} Each hydrogen atom may be deuterium; R ⁴ and R ⁵ are each independently selected from hydrogen, halo and C _1-4 alkyl; X ^{6 is} selected from N and C(R ⁶ ); X ^{7 is} selected from N and C( R ⁷ ); R ⁶ and R ⁷ are each independently derived from hydrogen, halo, C _1-4 alkyl and C _1-4 alkoxy; R ^{8 is} selected from hydrogen, halo, C _1-4 alkyl and C _1-4 alkoxy, wherein the C _1-4 alkyl and the C _1-4 alkoxy substituent are substituted with 0 to 3 optionally present substituents independently selected from halo; and R ^{9 is} selected From C _1-6 alkyl, C _3-8 cycloalkyl, C _2-8 heterocyclyl and C _1-9 heteroaryl, each of which is optionally substituted with 0 to 3 independently selected from the following Substitution: halo, hydroxy, cyano, pendant oxy, C _1-4 alkyl, C _1-4 alkoxy and optionally amine substituted with one or two C _1-4 alkyl groups, where the The C _1-4 alkyl group and the C _1-4 alkoxy substituent that are present are each independently substituted with 0 to 3 optionally present substituents independently selected from halo; and wherein the heterocyclic group And each of the heteroaryl moieties independently has 1 to 4 ring members that are heteroatoms, and each of these heteroatoms is independently selected from N, O, and S. Such as the compound or pharmaceutically acceptable salt of claim 1, wherein α is a single bond, β is a double bond, X ¹ is NR ^1N , and R ² is a pendant oxy group. The compound or pharmaceutically acceptable salt of any one of claims 1 and 2, wherein R ^{1N is} selected from C _1-4 alkyl, C _3-6 cycloalkyl-(CH ₂ ) _n , C _{3- 5} Heterocyclic group-(CH ₂ ) _n and C _1-5 heteroaryl-(CH ₂ ) _n , wherein the C _1-4 alkyl group, the C _3-6 cycloalkyl group, the C _3-5 heterocyclic group Each of the group and the C _1-5 heteroaryl moiety is substituted with 0 to 3 optionally present substituents as defined in claim 1. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein each of the 0 to 3 optional substituents of ^{R 1N is independently selected from halo, hydroxyl,} C _1-4 alkyl, C _1-4 alkoxy and optionally amine substituted with one or two C _{1-4 alkyl.} The compound or pharmaceutically acceptable salt of any one of claims 1 and 2, wherein R ^1N is a C _1-4 alkyl group, which may exist through 0 to 3 as defined in claim 1 Substituents are substituted. The compound or pharmaceutically acceptable salt of claim 5, wherein the C _1-4 ^{alkyl substituent of R 1N} is substituted with 0 to 3 substituents independently selected from the following optionally present: halo, Hydroxy, C _1-4 alkyl, C _1-4 alkoxy and optionally amino substituted with one or two C _{1-4 alkyl.} The compound or pharmaceutically acceptable salt of any one of claims 1 to 6, wherein n is 1. The compound or pharmaceutically acceptable salt of claim 1, wherein α is a double bond, β is a single bond, X ¹ is N, and R ^{2 is} selected from hydrogen, C _1-4 alkyl and C _1-4 alkane Oxy. The compound or pharmaceutically acceptable salt of claim 1, wherein α is a double bond, β is a single bond, X ¹ is CR ^1C , and R ^{2 is} selected from hydrogen, C _1-4 alkyl and C _1-4 Alkoxy. The compound or pharmaceutically acceptable salt of claim 9, wherein R ^{1C is} selected from hydrogen, halo and C _1-4 alkyl substituted with hydroxy. The compound or pharmaceutically acceptable salt of claim 9, wherein R ^1C is hydrogen. The compound or pharmaceutically acceptable salt according to any one of claims 8 to 11, wherein R ^{2 is} selected from hydrogen, methyl, ethyl, propyl, methoxy and ethoxy. The substituent of the requested item 1 to 12 of a compound of acceptable or pharmaceutically acceptable salt thereof, wherein R ³ of hydroxy-substituted-based C _1-4 alkyl or optionally substituted with C _1-4 alkoxy-C _{1 -4} Alkoxy. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 13, wherein R ⁴ and R ⁵ are each hydrogen. The compound or pharmaceutically acceptable salt of any one of claims 1 to 14, wherein X ⁶ is C (R ⁶ ) and X ⁷ is C (R ⁷ ). The compound or pharmaceutically acceptable salt according to any one of claims 1 to 15, wherein R ⁶ and R ⁷ are each independently selected from hydrogen and fluorine. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 16, wherein R ⁸ is a methyl group. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 17, wherein R ^{9 is} selected from C _1-4 alkyl, C _3-6 cycloalkyl, C _3-5 heterocyclyl and C _1-5 heteroaryl groups, each of which is substituted with 0 to 3 optionally present substituents independently selected from the following: halo, hydroxyl, cyano, pendant oxy, C _1-4 alkyl, C _{1- 4} alkoxy and optionally substituted with one or two substituents of C _1-4 alkylamino, optionally wherein the presence of the C _1-4 alkyl and C _1-4 alkoxy are each independently substituted with a substituent 0 to 3 optional substituents independently selected from halo are substituted. A compound or a pharmaceutically acceptable salt according to claim 18, wherein R ⁹ is a C _3-6 cycloalkyl group, which is substituted with 0 to 3 optionally present substituents as defined in claim 1. The compound of claim 1, which is selected from the following compounds: N -cyclopropyl-2-fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylpropan-2) -Yl)-2-side oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl -2-Fluoro-5-(3-(1-hydroxy-2-methylpropan-2-yl)-2-methyl-3 H -imidazo[4,5- b ]pyridin-6-yl)- 4-methylbenzamide; N -cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-2-methoxy-3 H -imidazole And [4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylpropan- 2-yl)-1-(2-hydroxyethyl)-2-oxo-2,3-dihydro- 1H -imidazo[4,5- b ]pyridin-6-yl)-4-methyl Benzamide; N -cyclopropyl-2-fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; 2-fluoro-5 -(1-(2-Fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo-2,3-dihydro- 1 H -imidazo[4,5- b ]pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide; 3-(1-(2-fluoroethyl) Yl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo-2,3-dihydro-1 H -imidazo[4,5 -b ]pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide; 2-fluoro-5-(1-(2-fluoroethyl)-3- (1-Hydroxy-2-methylpropan-2-yl-1,1- d ₂ )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridine- 6-yl)-4-methyl- N -(1H-pyrazol-3-yl)benzamide; 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methyl Propan-2-yl-1,1- d ₂ )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N -( Isothiazol-3-yl)-4-methylbenzamide; 2-fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl) -1,1- d ₂ )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N -(isothiazol-3-yl )-4-methylbenzamide; N -cyclopropyl-5-(3-ethyl- 1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)-2-fluoro-4-methylbenzamide; N -Cyclopropyl-2-fluoro-5-(1-(1-hydroxy-2-methylpropan-2-yl)-3-(2-hydroxyethyl)-1 H -pyrrolo[2,3 -b ]pyridin-5-yl)-4-methylbenzamide; N -cyclopropyl-2-fluoro-5-(1-(1-hydroxy-2-methylprop-2-yl)- 2-Methyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl)-4-methylbenzamide; N -cyclopropyl-5-(2-ethoxy-3- (1-Hydroxy-2-methylpropan-2-yl)-3 H -imidazo[4,5- b ]pyridin-6-yl)-2-fluoro-4-methylbenzamide; N- Cyclopropyl-2-fluoro-5-(3-(1-hydroxyprop-2-yl)-2-methoxy-3 H -imidazo[4,5- b ]pyridin-6-yl)-4 -Methylbenzamide; N -Cyclopropyl-2-fluoro-5-(3-(2-hydroxyethyl)-2-methoxy- 3H -imidazo[4,5- b ]pyridine -6-yl)-4-methylbenzamide; N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-3 H -imidazo[4, 5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3-(1-(1-hydroxy-2-methylprop-2-yl)-1 H- Pyrrolo[2,3- b ]pyridin-5-yl)-4-methylbenzamide; N -cyclopropyl-3-(1-(2-hydroxyethyl)-1 H -pyrrolo[ 2,3- b ]pyridin-5-yl)-4-methylbenzamide; N -cyclopropyl-3-(3-(2-hydroxyethyl)-3 H -imidazo[4,5 -b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-2-methoxy Group- 3H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3-(3-(1-hydroxy-2-methyl Propan-2-yl)-2-methyl-3 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; 3-(3-chloro-1-( 1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl) -N -cyclopropyl-4-methylbenzamide; N -Cyclopropyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-7-methyl-2-oxo-2,3 -Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3-(1-(2-fluoroethyl) -3-(1-hydroxy-2-methylpropan-2-yl)-5- Methyl-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl- 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo-2,3-dihydro -1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3-(1-ethyl-3-(2-(hydroxyl Methyl)propan-2-yl-1,1,1,3,3,3- d ₆ )-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ] Pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3-(1-(2-fluoroethyl)-3-(2-(hydroxymethyl)prop-2-yl) -1,1,1,3,3,3- d ₆ )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4 -Methylbenzamide; N -cyclopropyl-3-(3-ethyl-1-(1-hydroxy-2-methylprop-2-yl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)-4-methylbenzamide; N -cyclopropyl-3-(1-(1-hydroxy-2-methylprop-2-yl)-3-methyl- 1 H -pyrrolo[2,3- b ]pyridin-5-yl)-4-methylbenzamide; N -cyclopropyl-3-(1-(1-hydroxy-2-methylpropan- 2-yl)-3-(2-hydroxyethyl)-1 H -pyrrolo[2,3- b ]pyridin-5-yl)-4-methylbenzamide; N -cyclopropyl-3 -(1-(1-Hydroxy-2-methylprop-2-yl)-3-isopropyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl)-4-methylbenzene Formamide; N -cyclopropyl-3-(2-ethoxy-3-(1-hydroxy-2-methylprop-2-yl)-3 H -imidazo[4,5- b ]pyridine -6-yl)-4-methylbenzamide; N -cyclopropyl-3-(2-ethyl-3-(1-hydroxy-2-methylprop-2-yl)-3 H- Imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl) )-2-propyl- 3H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; 3-(1-ethyl-3-(1-hydroxy- 2-methylpropan-2-yl)-2-side oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N ,4-dimethyl Benzamide; 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N ,4-dimethyl Benzamide; 3-(1-(2,2-difluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N ,4-dimethylbenzamide; 5-(1-(2,2-difluoroethyl)- 3-(1-Hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)- 2-Fluoro- N ,4-dimethylbenzamide; N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxyethyl) Yl)-2-side oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; 4-chloro- N- Cyclopropyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H -Imidazo[4,5- b ]pyridin-6-yl)benzamide; N -cyclopropyl-4-fluoro-3-(1-(2-fluoroethyl)-3-(1-hydroxy -2-Methylprop-2-yl)-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)benzamide; N- Cyclopropyl-4-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H -Imidazo[4,5- b ]pyridin-6-yl)-5-methylpyridinium; N -cyclobutyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy -2-Methylpropan-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzyl Amide; N -cyclopropyl-3-fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo- 2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; 3-chloro- N -cyclopropyl-5-(1- (2-Fluoroethyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo(4,5- b ]Pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylpropan-2 -Yl)-2-side oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-6-methylnicotinamide; 3-(1- (2-Fluoroethyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo(4,5- b ]Pyridin-6-yl)-4-methyl- N -(1-methylcyclopropyl)benzamide; 3-(1-(2-fluoroethyl)-3 -(1-Hydroxy-2-methylprop-2-yl)-2-side oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4 -Methyl- N -(1 H -pyrazol-3-yl)benzamide; 2-fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methyl) Propan-2-yl)-2-side oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(1 H- Pyrazol-3-yl)benzamide; 2-fluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-side Oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N ,4-dimethylbenzamide; 2-fluoro-5-(1- (2-Fluoroethyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo(4,5- b ]Pyridin-6-yl)-4-methyl- N -(1-methyl-1 H -pyrazol-3-yl)benzamide; 2-chloro- N -cyclopropyl-5-(1 -(2-Fluoroethyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2 -Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -((1 S ,2 S )-2-methan Cyclopropyl) benzamide; N -cyclopropyl-2,4-difluoro-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylpropan-2) -Yl)-2-side oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)benzamide; N -cyclopropyl-3-(1 -(2-Fluoroethyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-(trifluoromethyl)benzamide; N -cyclopropyl-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2- (Methylprop-2-yl)-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-2-methoxy-4-methyl Benzamide; N -(bicyclo[1.1.1]pentan-2-yl)-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop- 2-yl)-2-side oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2 ,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-(fluoromethyl)benzamide; 3-(1-(2-fluoroethyl)- 3-(1-Hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4,5-b]pyridin-6-yl)- 4-methyl- N -((1 S ,2 R )-2-methylcyclopropyl)benzamide; N -cyclopropyl-4-(difluoromethyl)-3-(1-( 2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ] Pyridin-6-yl) benzamide; 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2, 3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N- (pyridin-2-yl)benzamide; 3-(1-(2 -Fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo[4,5- b ]pyridine -6-yl)-N-methanyl-4-methylbenzamide; 3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl) )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(oxazol-2-yl)benzene Formamide; N -Acetyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3 -Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; 3-(1-(2-fluoroethyl)-3-(1- Hydroxy-2-methylpropan-2-yl)-2-side oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N -(isooxa Azol-3-yl)-4-methylbenzamide; N -cyclopropyl-5-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylpropan-2- Yl)-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-2,4-dimethylbenzamide; 5-( 1-Ethyl-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridine- 6-yl)-2-fluoro- N ,4-dimethylbenzamide; 3-(1-ethyl-3-(1-hydroxy-2-methylprop-2-yl)-2-side Oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(1 H -pyrazol-3-yl)benzoic acid Amine; 5-(1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-2-fluoro-4-methyl- N -(1 H -pyrazol-3-yl)benzamide; 3-(1- Ethyl-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridine-6- Yl)-4-methyl- N -(1-methyl-1 H -pyrazol-3-yl)benzamide; 3-(1-ethyl-3-(1-hydroxy-2-methyl) Propan-2-yl)-2-side oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methyl- N -(1-methyl -1 H -pyrazol-5-yl)benzamide; 5-(1-ethyl-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2 ,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-2-fluoro-4-methyl- N -(1-methyl-1 H -pyrazole-3- Yl)benzamide; 5-(1-ethyl-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H -imidazole And [4,5- b ]pyridin-6-yl)-2-fluoro- N -(isoxazol-3-yl)-4-methylbenzamide; 2-fluoro-5-(3-( 1-hydroxy-2-methylpropan-2-yl)-1-methyl-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl ) -N -(isoxazol-3-yl)-4-methylbenzamide; 5-(1-ethyl-3-(1-hydroxy-2-methylprop-2-yl-1, 1- d ₂ )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-2-fluoro- N -(isothiazole-3- Yl)-4-methylbenzamide; 3-(1-ethyl-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2- pendant oxy -2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N -(isothiazol-3-yl)-4-methylbenzamide; 5-( 1-Ethyl-3-(1-hydroxy-2-methylprop-2-yl-1,1- d ₂ )-2-oxo-2,3-dihydro-1 H -imidazo[4 ,5- b ]pyridin-6-yl)-2-fluoro-4-methyl- N -(1 H -pyrazol-3-yl)benzamide; 3-(3-(tertiary butyl) -1-Methyl-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N -(isoxazol-3-yl)- 4-methylbenzamide; 3-(3-(tertiary butyl)-1-methyl-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]Pyridin-6-yl) -N -cyclopropyl-4-methylbenzamide; 3-(3-(1-hydroxy-2-methylprop-2-yl)-1-methyl-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]Pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide; N -cyclopropyl-3-(3-(1-hydroxy-2-methylpropane -2-yl)-1-methyl-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide Amine; ( R ) -N -cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxypropyl)-2-side Oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; ( S ) -N -cyclopropyl-2- Fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxypropyl)-2-oxo-2,3-dihydro-1 H -imidazole And [4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-2-fluoro-5-(3-(1-hydroxy-2-methylpropan- 2-yl)-1-(3-hydroxypropyl)-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methyl Benzamide; 2-fluoro-5-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-hydroxyethyl)-2-oxo-2,3 -Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl) -N -(isoxazol-3-yl)-4-methylbenzamide; 2-fluoro-5- (3-(1-Hydroxy-2-methylpropan-2-yl)-1-(2-hydroxyethyl)-2-oxo-2,3-dihydro- 1H -imidazo[4, 5- b ]pyridin-6-yl)-4-methyl- N -(1 H -pyrazol-3-yl)benzamide; N -cyclopropyl-2-fluoro-5-(3-( 1-Hydroxy-2-methylpropan-2-yl)-1-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1 H -imidazo[4 ,5- b ]pyridin-6-yl)-4-methylbenzamide; 3-(1-ethyl-3-(1-hydroxy-2-methylprop-2-yl)-2-side -2,3-dihydro -1 H - imidazo [4,5- b] pyridin-6-yl) - N - (isoxazol-3-yl) -4-methyl-benzoyl amine; N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-isopropyl-2-oxo-2,3-dihydro-1 H -imidazole And [4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3-(1-ethyl-3-(1-hydroxy-2-methylpropane) -2-yl)-2-side oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridine- 6-yl)-4-methylbenzamide; N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-1-( 2,2,2-Trifluoroethyl)-2,3-dihydro- 1H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -ring Propyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-1-propyl-2,3-dihydro-1 H -imidazo[4, 5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-iso Butyl-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl- 3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(oxetan-3-yl)-2-oxetan-3-yl)-2-oxo-2,3-dihydro-1 H- Imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3-(1-(cyclopropylmethyl)-3-(1-hydroxyl -2-Methylpropan-2-yl)-2-oxo-2,3-dihydro- 1H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzyl Amide; N -cyclopropyl-3-(1-(2-fluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3- Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3-(3-(1-hydroxy-2-methyl Propyl-2-yl)-2-side oxy-1-((tetrahydrofuran-3-yl)methyl)-2,3-dihydro-1 H -imidazo[4,5- b ]pyridine-6 -Yl)-4-methylbenzamide; N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(3-methoxypropyl )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3 -(1-(2,2-Difluoroethyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo-2,3-dihydro-1 H -imidazole And [4,5- b ]pyridin-6-yl)-4-methylbenzamide; 3-(1-(cyclobutylmethyl)-3-(1-hydroxy-2-methylprop-2- Yl)-2-Pendant oxy-2,3-dihydro- 1H -imidazo[4,5- b ]pyridin-6-yl) -N -cyclopropyl-4-methylbenzamide; N -cyclopropyl-3-(1-((2,2-difluorocyclopropyl)methyl)-3-(1-hydroxy-2-methylprop-2-yl)-2-oxo -2,3-Dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3 -(1-(2-(Dimethylamino)ethyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-oxo-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3-(3-(1-hydroxy-2-methylpropan-2) -Yl)-1-(isoxazol-5-ylmethyl)-2-pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)- 4-methylbenzamide; N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(isoxazol-4-ylmethyl)- 2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3-( 3-(1-hydroxy-2-methylprop-2-yl)-1-(isoxazol-3-ylmethyl)-2-oxo-2,3-dihydro-1 H -imidazo [4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)- 1-((1-methyl-1H-pyrazol-4-yl)methyl)-2-oxo-2,3-dihydro- 1H -imidazo[4,5- b ]pyridine-6 -Yl)-4-methylbenzamide; N -cyclopropyl-3-(3-(1-hydroxy-2-methylprop-2-yl)-1-(2-methoxyethyl )-2-Pendant oxy-2,3-dihydro-1 H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; N -cyclopropyl-3 -(3-(1-(2-Methoxyethoxy)-2-methylprop-2-yl)-1-(2-methoxyethyl)-2-oxo-2,3 -Dihydro- 1H -imidazo[4,5- b ]pyridin-6-yl)-4-methylbenzamide; and a pharmaceutically acceptable salt of any of these compounds. A pharmaceutical composition comprising: Such as the compound or pharmaceutically acceptable salt of any one of claims 1 to 20; and Pharmaceutically acceptable excipients. Such as the compound or pharmaceutically acceptable salt of any one of claims 1 to 20, which is used as a medicament. The compound or pharmaceutically acceptable salt of any one of claims 1 to 20, which is used to treat a disease, disorder or condition selected from the group consisting of allergic rhinitis, asthma, atopic dermatitis, rheumatoid Arthritis, Multiple Sclerosis, Systemic Lupus Erythematosus, Lupus Nephritis, Psoriasis, Immune Thrombocytopenic Purpura, Inflammatory Bowel Disease, Chronic Obstructive Pulmonary Disease, Sjögren's Syndrome, Joint Adhesive Spine Inflammation, Behcet's disease, graft versus host disease, pemphigus vulgaris, idiopathic plasma cell lymphadenopathy, atherosclerosis, myocardial infarction and thrombosis. A method for inhibiting RIPK2 in an individual, the method comprising administering a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 20 to the individual. A method of treating a disease, disorder or condition in an individual, the method comprising administering to the individual a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 20, wherein the disease, disorder or condition Related to RIPK2. A method of treating a disease, disorder or condition in an individual, the method comprising administering to the individual a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 20, wherein the disease, disorder or condition It is selected from type I hypersensitivity, autoimmune diseases and inflammatory disorders, cancer and non-malignant proliferative disorders. A method of treating a disease, disorder or condition in an individual, the method comprising administering to the individual a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 20, wherein the disease, disorder or condition Selected from allergic rhinitis, asthma, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, psoriasis, immune thrombocytopenic purpura, inflammatory bowel disease, chronic obstruction Pulmonary disease, Schrögren’s syndrome, Adhesive spondylitis, Beside’s disease, graft-versus-host disease, pemphigus vulgaris, idiopathic plasma cell lymphadenopathy, atherosclerosis, myocardial infarction and thrombosis. A combination comprising the compound or pharmaceutically acceptable salt of any one of claims 1 to 20 and at least one additional pharmacologically active agent.