Heterocyclic PAD4 inhibitor

Abstract

The present disclosure generally relates to compounds of formula I which are inhibitors of PAD4: 3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one, methods for producing these compounds, pharmaceutical compositions containing these compounds, and their use in the treatment of diseases or disorders associated with PAD4 enzyme activity.

Description

Technical Field

[0001] (Cross-reference) This application claims the benefit of priority to U.S. Provisional Application No. 63 / 365,370, filed May 26, 2022, the entire disclosure of which is incorporated herein by reference.

[0002] (Incorporation by reference of sequence listing) The sequence listing portion includes a sequence listing submitted as an XML file via EFS-WEB, the entire disclosure of which is incorporated herein by reference. The name of a copy of the XML file created on May 26, 2023 is "055920-608001WO_SeqList_ST26.xml" and the size is 3 KB.

[0003] (Field) The present invention generally relates to substituted heterocyclic compounds, methods for producing such compounds, pharmaceutical compositions containing such compounds, and the use of such compounds in the treatment of diseases or disorders associated with PAD4 enzyme activity.

Background Art

[0004] PAD4 (SEQ ID NO: 1) is a member of the peptidylarginine deiminase (PAD) family and is an enzyme capable of catalyzing the citrullination of arginine within a peptide sequence. PAD4 deiminates or citrullinates various proteins in vitro and in vivo, resulting in diverse functional responses in various diseases (Jones J.E. et al, Curr. Opin. Drug Discov. Devel., 12(5), (2009), 616-627). Examples of diseases or disorders include, in addition to cancer symptoms, rheumatoid arthritis, neutrophil-mediated diseases (such as vasculitis, systemic lupus erythematosus, ulcerative colitis). PAD4 inhibitors may also be more widely applicable as means and therapeutic agents for human diseases and disorders via epigenetic mechanisms.

[0005] PAD4 inhibitors are effective against rheumatoid arthritis (RA). RA is an autoimmune disease that affects approximately 1% of the population (Wegner N. et al, Immunol. Rev., 233(1), (2010), 34-54). Its characteristic is joint inflammation that weakens and destroys bone and cartilage. Although there is no consistency between PAD4 polymorphism and RA susceptibility, many population studies have suggested a slight genetic association (Kochi Y. et al, Ann. Rheum. Dis., 70, (2011), 512-515). PAD4 (along with its family member PAD2) is found in synovial tissue and is responsible for the deimination of various joint proteins. This process is presumed to render citrullinated substrates (such as fibrinogen, vimentin, and collagen) in RA joints resistant or to initiate an immune response. These anti-citrullinated protein antibodies (ACPA) are also used in tests for diagnosing RA (such as tests using commercially available CCP2 or cyclic citrullinated protein 2) because they are associated with the onset of the disease. Furthermore, enhanced citrullination can directly act on the functions of multiple joints and inflammatory mediators (such as fibrinogen, antithrombin, and multiple chemokines), and thus may be directly involved in the pathogenesis of the disease. Anti-PAD4 antibodies are measured in some RA patients, and anti-PAD4 antibodies may further correlate with bullous diseases.

[0006] PAD4 inhibitors are also useful for reducing neutrophil activity caused by diseases in various diseases. The formation process of neutrophil extracellular traps (NETs), a biological defense mechanism in which neutrophils capture and kill pathogens, is associated with histone citrullination, and multiple studies have suggested that this process is defective in PAD4 knockout mice (Neeli I. et al, J. Immunol., 180, (2008), 1895-1902, and Li P. et al, J. Exp. Med., 207(9), (2010), 1853-1862). Therefore, PAD4 inhibitors may be applicable to diseases in which NET formation in tissues contributes to local injury and pathological conditions. Such diseases include, but are not limited to, small vessel vasculitis (Kessenbrock K. et al, Nat. Med., 15(6), (2009), 623-625), systemic lupus erythematosus (Hakkim A. et al, Proc. Natl. Acad. Sci. USA, 107(21), (2010), 9813-9818, and Villanueva E. et al, J. Immunol., 187(1), (2011), 538-52), ulcerative colitis (Savchenko A. et al, Pathol. Int., 61(5), (2011), 290-7), cystic fibrosis, asthma (Dworski R. et al, J. Allergy Clin. Immunol., 127(5), (2011), 1260-6), deep vein thrombosis (Fuchs T. et al, Proc. Natl. Acad. Sci. USA, 107(36), (2010), 15880-5), periodontitis (Vitkov L. et al, Ultrastructural Pathol., 34(1), (2010), 25-30), sepsis (Clark S.R. et al, Nat. Med., 13(4), (2007), 463-9), appendicitis (Brinkmann V. et al, Science, 303, (2004), 1532-5), and stroke.Furthermore, in skin diseases such as cutaneous erythematosus (Villanueva E. et al, J. Immunol., 187(1), (2011), 538-52) and psoriasis (Lin A.M. et al., J. Immunol., 187(1), (2011), 490-500), there is evidence indicating that NETs may be involved in the disease conditions. Therefore, systemic or transdermal administration of PAD4 inhibitors may be effective against NET skin diseases. PAD4 inhibitors may also act on other functions of neutrophils and may be widely applicable to neutrophil-related diseases.

[0007] The effectiveness of PAD inhibitors (e.g., chloramidine) has been suggested in multiple studies in many animal model diseases, including collagen-induced arthritis (Willis V.C. et al, J. Immunol., 186(7), (2011), 4396-4404), dextran sulfate sodium (DSS)-induced experimental colitis (Chumanevich A.A. et al, Am. J. Physiol. Gastrointest. Liver Physiol., 300(6), (2011), G929-G938), spinal cord repair (Lange S. et al, Dev. Biol., 355(2), (2011), 205-14), and experimental autoimmune encephalomyelitis (EAE). Reports on DSS colitis also show that chloramidine promotes apoptosis of inflammatory cells both in vitro and in vivo, suggesting that PAD4 inhibitors may be more generally effective against a wide range of inflammatory diseases.

[0008] PAD4 inhibitors are also useful for the treatment of cancer (Slack J.L. et al, Cell. Mol. Life Sci., 68(4), (2011), 709-720). Overexpression of PAD4 has been observed in many cancers (Chang X. et al, BMC Cancer, 9, (2009), 40). The antiproliferative role of PAD4 inhibitors is suggested by the observation that PAD4 citrullinates the arginine residues of histones at the promoters of p53 target genes such as p21, which is involved in cell cycle inhibition and apoptosis induction (Li P. et al, Mol. Cell Biol., 28(15), (2008), 4745-4758).

[0009] The above-described role of PAD4 in deiminating arginine residues of histones may indicate the role of PAD4 in the epigenetic regulation of gene expression. PAD4 is a major PAD family member that has been observed to be contained in both the nucleus and the cytoplasm. The proposed explanation that PAD4 acts as a histone demethylase as well as a deiminase is inconsistent and has not yet been proven. However, PAD4 may reduce arginine residues by conversion to citrulline and indirectly reduce the methylation of histone arginine (and thus the associated epigenetic regulation). PAD4 inhibitors are useful as epigenetic means and therapeutic agents that affect the expression of various target genes in diseases of other conditions as well. Through such mechanisms, PAD4 inhibitors are considered to be effective in controlling citrullination levels in stem cells, and thus may therapeutically affect the pluripotency and differentiation ability of various stem cells, including but not limited to embryonic stem cells, neural stem cells, hematopoietic stem cells, and cancer stem cells. Therefore, there is a need to identify and develop PAD4 inhibitors for treating diseases or disorders mediated by PAD4. Summary of the Invention

[0010] Formula I:

Chemical formula

[0011] In another aspect, formula I': [Chemical formula] (wherein X, X', R 1 , R 2 , R 3 , R 4 , R 5 , m, and n are each defined as follows and as described herein) and pharmaceutically acceptable salts, isomers, enantiomers, or tautomers thereof.

[0012] In another aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or vehicles. In some aspects, the disclosed pharmaceutical compositions are suitable for oral administration, parenteral administration, mucosal administration, transdermal administration, or topical administration.

[0013] In another aspect, the present disclosure provides a method of inhibiting PAD4 enzyme, or a variant thereof, comprising contacting a biological sample with a compound of formula I or a pharmaceutically acceptable salt thereof.

[0014] In another aspect, the present disclosure provides a method of treating a disease or disorder associated with PAD4 enzyme activity, comprising administering to a subject in need of treatment a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt thereof. Such disorders or conditions include, in particular, rheumatoid arthritis, vasculitis, systemic lupus erythematosus, and ulcerative colitis, among others.

Mode for Carrying Out the Invention

[0015] General Description of the Compounds of the Present Disclosure: In some embodiments, the present disclosure provides a compound of Formula I:

Chemical Formula

[0016] 1. Definitions: The compounds of the present disclosure generally include the above-described compounds and are further exemplified by the classes, subclasses, and species of the present disclosure. Unless otherwise specified, the following definitions apply as used herein. For the purposes of the present disclosure, chemical elements are those of the CAS version of the Periodic Table of the Elements, Handbook of Chemistry and Physics, 75 thIt is identified according to Ed. Further, the general principles of organic chemistry as well as specific functional groups and reactivity are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0017] As used herein, the term "aliphatic" means a straight-chain (i.e., unbranched chain) or branched-chain, substituted or unsubstituted hydrocarbon chain containing one or more fully saturated or unsaturated moieties, or a monocyclic or bicyclic hydrocarbon having one other point of attachment to the molecule that contains one or more fully saturated or unsaturated moieties but is not aromatic (also referred to as "carbocyclic", "alicyclic" or "cycloalkyl"). Unless otherwise specified, aliphatic groups contain from 1 to 6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain from 1 to 5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain from 1 to 4 aliphatic carbon atoms. In yet another embodiment, aliphatic groups contain from 1 to 3 aliphatic carbon atoms, and in still another embodiment, aliphatic groups contain from 1 to 2 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.

[0018] In some embodiments, a "carbocyclic ring" (or "alicyclic" or "cycloalkyl") is a monocyclic or polycyclic C3-C8 hydrocarbon that contains one or more fully saturated or unsaturated moieties and is not aromatic, and may have one other point of attachment to the molecule. The polycyclic carbocyclic ring may be attached to one or two aromatic cycloalkyls or heterocycles via fusion, bridging, and / or one or more spiro bonds. Examples of typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, and the like.

[0019] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any form in which any basic nitrogen is quaternized; or, for example, nitrogen in a substitutable heterocycle such as N(3,4-dihydro-2H-pyrrolyl), NH (seen in pyrrolidinyl), or NR + (seen in N-substituted pyrrolidinyl, etc.). In some embodiments, oxidized forms of sulfur include S=O and S(=O)2.

[0020] As used herein, the term "unsaturated" means a moiety having one or more unsaturated units.

[0021] The term "halogen" means F, Cl, Br, or I.

[0022] The term "aryl", used alone or as part of a larger moiety including "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 members. Here, at least one ring is aromatic, and each ring has 3 to 7 members. The term "aryl" may be used synonymously with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring and includes groups such as phenyl, biphenyl, naphthyl, anthracyl, etc., which may have one or more substituents. The scope of the term "aryl" as used herein also includes groups in which the aromatic ring is fused with one or more non-aromatic (e.g., indanyl, phthalimidyl, naphthalimidyl, phenanthridinyl, or tetrahydronaphthyl, etc.) rings.

[0023] The terms "heteroaryl" and "hetero..." used alone or as part of a larger moiety including "heteroalkyl" or "heteroalkoxy" refer to groups having 5 to 10 ring atoms, or 5, 6, or 9 ring atoms; groups sharing 6, 10, or 14 π electrons in a cyclic array; and groups having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur and includes optionally oxidized nitrogen or sulfur and optionally quaternized basic nitrogen. Examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "hetero..." also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl groups and the group or attachment site is on the heteroaromatic ring. Examples of such groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" may be used synonymously with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", and any of those terms includes rings that may be optionally substituted. The term "heteroalkyl" refers to an alkyl group substituted with a heteroaryl group, and the alkyl moiety and the heteroaryl moiety may be independently optionally substituted.

[0024] As used herein, the terms "heterocycle", "heterocyclyl", and "heterocyclic group" are used synonymously and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, or 1 to 4, of the heteroatoms defined above. When referring to the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen can be N (such as 3,4-dihydro-2H-pyrrolyl), NH (such as pyrrolidinyl), or + NR (such as N-substituted pyrrolidinyl).

[0025] The heterocycle can be attached by any heteroatom or carbon atom forming a stable structure to its pendant group, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl group", "heterocyclic ring", "heterocyclic moiety", and "heterocyclic group" are used synonymously herein, and also include a group in which a heterocyclyl is fused with one or more aryl, heteroaryl, or cycloaliphatic (such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl) and the group or the bonding site is on the heterocyclyl. The heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, and the alkyl moiety and the heterocyclyl moiety can be independently optionally substituted.

[0026] As used herein, the term "partially unsaturated" refers to a moiety of a ring that contains at least one double or triple bond. The term "partially unsaturated" is intended to include rings having multiple unsaturated moieties, but is not intended to include aryl or heteroaryl moieties as defined herein. As described herein, the compounds of the present disclosure may include moieties that are "optionally substituted." In general, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens on a particular moiety are replaced with an appropriate substituent. "Substituted" applies to one or more hydrogens that are shown directly or indirectly in the structure. For example,

Chem.

Chem.

Chem.

Chem.

[0027] Unless otherwise specified, an "optionally substituted" group may have an appropriate substituent at each substitutable position of the group, and in any structure, if two or more positions are substituted with two or more substituents selected from a particular group, the substituents may be the same or different at each bonding position. Combinations of substituents contemplated by the present disclosure form stable compounds or compounds that are chemically feasible. As used herein, the term "stable" refers to a compound that does not substantially change during its manufacture, detection, and in certain embodiments, during its recovery, purification, and under conditions for use for one or more purposes of the present disclosure.

[0028] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH2) 0-4R ○ ; -(CH2) 0-4 OR ○ ; -O(CH2) 0-4 R ○ 、-O-(CH2) 0-4 C(O)OR ○ ; -(CH2) 0-4 CH(OR ○ )2; -(CH2) 0-4 SR ○ ; R ○ which may be substituted by -(CH2) 0-4 Ph; R ○ which may be substituted by -(CH2) 0-4 O(CH2) 0-1 Ph; R ○ which may be substituted by -CH=CHPh; R ○ which may be substituted by -(CH2) 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; -(CH2) 0-4 N(R ○ )2; -(CH2) 0-4 N(R ○ )C(O)R ○ ; -N(R ○ )C(S)R ○ ; -(CH2) 0-4 N(R ○ )C(O)NR ○ 2; -N(R ○ )C(S)NR ○ 2; -(CH2) 0-4 N(R ○ )C(O)OR ○ ; -N(R ○ )N(R ○ )C(O)R ○ ; -N(R ○ )N(R ○ )C(O)NR ○ 2; -N(R ○ )N(R ○ )C(O)OR ○ ; -(CH2) 0-4 C(O)R ○ ; -C(S)R ○ ; -(CH2) 0-4 C(O)OR ○ ; -(CH2)0-4 C(O)SR ○ ; -(CH2) 0-4 C(O)OSiR ○ 3; -(CH2) 0-4 OC(O)R ○ ; -OC(O)(CH2) 0-4 SR ○ ; -(CH2) 0-4 SC(O)R ○ ; -(CH2) 0-4 C(O)NR ○ 2; -C(S)NR ○ 2; -C(S)SR ○ ; -SC(S)SR ○ 、-(CH2) 0-4 OC(O)NR ○ 2; -C(O)N(OR ○ )R ○ ; -C(O)C(O)R ○ ; -C(O)CH2C(O)R ○ ; -C(NOR ○ )R ○ ; -(CH2) 0-4 SSR ○ ; -(CH2) 0-4 S(O)2R ○ ; -(CH2) 0-4 S(O)2OR ○ ; -(CH2) 0-4 OS(O)2R ○ ; -S(O)2NR ○ 2; -(CH2) 0-4 S(O)R ○ ; -N(R ○ )S(O)2NR ○ 2; -N(R ○ )S(O)2R ○ ; -N(OR ○ )R ○ ; -C(NH)NR ○ 2; -P(O)2R ○ ; -P(O)R ○ 2; -OP(O)R ○ 2; -OP(O)(OR ○ )2; SiR ○ 3; -(C 1-4 linear or branched alkylene)O-N(R ○)2; or -(C 1-4 linear or branched alkylene)C(O)O-N(R ○ )2, where each R ○ may be substituted as defined below and is independently hydrogen, C 1-6 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5- to 6-membered heteroaryl ring); or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent R ○ may combine with the atoms therebetween to form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0029] R ○ (or a ring formed by the combination of two independent R ○ with the atoms therebetween) The appropriate monovalent substituents on are independently halogen, -(CH2) 0-2 R ● , -(haloR ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2, -O(haloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR● ,-(C 1-4 linear or branched alkylene)C(O)OR ● or -SSR ● where each R ● is unsubstituted or, if "halo" is present as a prefix, substituted by only one or more halogens, and C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph; or independently selected from a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atoms of R ○ include =O and =S.

[0030] Suitable divalent substituents on the saturated carbon atoms of a "optionally substituted" group include the following: =O (oxo), =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S-, where R * are each independently hydrogen, C 1-6 aliphatic optionally substituted as defined below, or selected from an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to a substitutable carbon adjacent to a "optionally substituted" group include -O(CR * 2) 2-3 O-, where R * are each independently hydrogen, C 1-6 aliphatic optionally substituted as defined below, or selected from an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0031] R * Suitable substituents on the aliphatic of are halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if "halo" is pre-modifying, substituted by only one or more halogens and, independently, is C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0032] Suitable substituents on the substitutable nitrogen of a "optionally substituted" group include -R + , -NR + 2, -C(O)R + , -C(O)OR + , -C(O)C(O)R + , -C(O)CH2C(O)R + , -S(O)2R + , -S(O)2NR + 2, -C(S)NR + 2, -C(NH)NR + 2, or -N(R + )S(O)2R + is included, where each R + is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent R +It combines with the intervening atoms to form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0033] R + Suitable substituents on the aliphatic of are independently halogen, -R ● ,-(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, when "halo" is pre-modified, is substituted with only one or more halogens and is independently C 1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 Ph; or a 5- to 6-membered saturated ring, partially unsaturated ring, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] As used herein, the term "subject" refers to any human or non-human organism in which an effect can be obtained by treatment with a PAD4 inhibitor. Examples of subjects include humans and animals.

[0035] As used herein, the term "treatment" refers to, for example, treating the medical condition of a human or animal subject and includes (a) suppressing the medical condition, i.e., blocking its progression; (b) alleviating the medical condition, i.e., reducing the medical condition; and / or (c) preventing the occurrence of the medical condition in the subject.

[0036] As used herein, the term "prevention" refers to prophylactic treatment (i.e., prevention and / or risk reduction) of asymptomatic conditions in a subject such as a human or an animal, which is aimed at reducing the probability of the occurrence of a clinical disease state. The subject may be selected for prophylactic treatment based on factors known to increase the risk of developing a clinical disease state as compared to the general population. "Prevention" therapy can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in a subject who has not yet presented with a clinical disease state, whereas secondary prevention is defined as prevention of secondary occurrence of the same or a similar clinical disease state.

[0037] The term "therapeutically effective amount" refers to the amount of a compound or composition described herein that is effective when administered alone or in combination to prevent or treat a disease or disorder associated with PAD4 enzyme activity. When used in combination, the term refers to the total amount of the active ingredient that provides a prophylactic or therapeutic effect, regardless of whether it is administered in combination, sequentially, or simultaneously.

[0038] "Pharmaceutically acceptable carrier" refers to a medium generally acceptable in the field of transporting biologically active agents to humans and / or animals. Pharmaceutically acceptable carriers are formulated according to many factors well within the expertise of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated, the patient to whom the composition containing the active agent is administered, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media. Such carriers can include, in addition to the active agent, many different components and additives, and such added components are included in the formulation for various reasons (e.g., stabilization of the active agent, binder, etc. known to those skilled in the art). Typical examples of the above carriers include, but are not limited to, diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, coating agents, etc. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in selecting them are described in various readily available literature, such as Allen, L. V., Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0039] This disclosure is intended to cover all isotopes of atoms contained in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. General examples include, but are not limited to, isotopes of hydrogen such as deuterium (symbol D or 2 H) and tritium (symbol T or 3 H). For example, a methyl group may be represented by CH3 or CD3. Isotopes of carbon include 13 C and 14 C. The disclosed compounds labeled with isotopes can be produced by using appropriate isotope-labeled reagents in place of the unlabeled reagents used otherwise, by conventional techniques generally known to those skilled in the art or by methods similar to those described herein.

[0040] The compounds of formula I form salts, and such salts are also within the scope of the present disclosure. Unless otherwise specified, references to the compounds of formula I herein are understood to include references to their salts. As used herein, the term "salt" refers to acid salts and / or base salts formed with inorganic and / or organic acids and bases. Further, when a compound of formula I has both a basic moiety and an acidic moiety, a zwitterion ("inner salt") can be formed and can be included within the term "salt" as used herein. Pharmaceutically acceptable salts include salts generally acceptable in the pharmaceutical art when administered to subjects such as humans and animals. Generally, a pharmaceutically acceptable salt is a non-toxic and physiologically acceptable salt. The salts of the compounds described in the present disclosure may be formed, for example, by reacting the compound with a certain amount of an acid or base (e.g., 1 equivalent), and then, for example, precipitating the salt in a solvent or freeze-drying the aqueous solution.

[0041] Compounds of formula I containing a basic moiety can form salts with various organic and inorganic acids. Examples of acid addition salts include acetates (e.g., salts formed with acetic acid or trihaloacetic acids (e.g., trifluoroacetic acid)), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrobromic acid), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., formed with sulfuric acid), sulfonates (e.g., those described herein), tartrates, thiocyanates, toluenesulfonates (e.g., tosylates), undecanoates, and the like.

[0042] Compounds of Formula I containing an acidic moiety can form salts with various organic and inorganic bases. Examples of base addition salts include ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), organic bases (e.g., salts with organic amines (e.g., benzathine, dicyclohexylamine, hydrabamine (formed with N,N-bis(dehydroabietyl)-ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine), and salts with amino acids (e.g., arginine, lysine, etc.)). The basic nitrogen-containing group may be quaternized with reagents (e.g., lower alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, lauryl, myristyl, and stearyl), aralkyl halides (e.g., bromides of benzyl and phenethyl), and others).

[0043] The present disclosure encompasses compounds of Formula I, or pharmaceutically acceptable salts thereof, methods for producing these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds in the treatment of diseases or disorders associated with PAD4 enzyme activity.

[0044] 2. Description of Embodiments: In some embodiments, the present disclosure provides Formula I: [Chemical formula] [Wherein, X is selected from C—R 6 and N; X' is selected from C—R 6' and N, where X and X' are not simultaneously N; R 1 is C 1-4 and is aliphatic; R2 is 0 to 4 R 7 C replaced with 1-6 It is aliphatic; R 3 is 0 to 3 R 8 C replaced with 1-6 It is aliphatic; R 4 is a halogen; R 5 is a halogen; Each R 6 and R 6' are independently hydrogen, halogen, -OR, -N(R)2, -OC(O)R, -N(R)C(O)R, -OL-(R 9 ) p , -Cy, and optionally substituted C 1-6 Selected from aliphatic; Each R 7 is independently selected from halogen, -OR, -N(R)2, and -Cy; Each R 8 is independently selected from halogen, -OR, -N(R)2, and -Cy; Each R 9 is independently selected from halogen, -OR, -N(R)2, and -Cy; L is a covalent bond or C 1-4 It is aliphatic; Each Cy is independently selected from a 3- to 7-membered saturated or partially unsaturated carbocycle; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where Cy is selected from 0-3 R 10 Replaced with; Each R 10 are independently selected from halogen, -OR, -N(R), -CN, -C(O)R, -C(O)OR, -C(O)N(R), oxo, and optionally substituted groups, wherein the optionally substituted groups are 1-6Selected from aliphatics; and 3- to 7-membered saturated or partially unsaturated heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or an optionally substituted group, and the optionally substituted group is C 1-6 Selected from aliphatics; 3- to 7-membered saturated or partially unsaturated carbocycles; phenyl; 3- to 7-membered saturated or partially unsaturated heterocycles having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5- to 6-membered heteroaryls having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each m and n is independently 0 or 1; and Each p is independently 1 to 4] To provide a compound of or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

[0045] In some embodiments, the present disclosure provides Formula I:

Chemical formula

[0046] In some embodiments, the present disclosure provides compounds of formulae I-a, I-b, I-c, I-d, I-e, I-f, I-g, and I-h:

Chemical formula

[0047] In some embodiments, the present disclosure provides compounds of formulae I-a-i, I-b-i, I-c-i, I-d-i, I-e-i, I-f-i, I-g-i, and I-h-i:

Chemical formula

[0048] As generally defined above, X is selected from C-R 6 and N. In some embodiments of formula I, X is C-R 6 is. In some embodiments of any formula I, X is N.

[0049] As generally defined above, X' is selected from C-R 6' and N, where X and X' are not simultaneously N. In some embodiments of formula I, X' is C-R 6'It is so. In some embodiments of Formula I, X' is N.

[0050] In some embodiments of Formula I, X is C—R 6 and X' is C—R 6' It is so. In some embodiments of Formula I, X is N and X' is C—R 6' It is so. In some embodiments of Formula I, X is C—R 6 and X' is N.

[0051] As generally defined above, R 1 is C 1-4 aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 1 is methyl.

[0052] As generally defined above, R 2 is C 7 aliphatic substituted with 0 to 4 R 1-6 groups. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 2 is C 7 aliphatic substituted with 0 to 4 R 1-4 groups. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 2 is C 7 aliphatic substituted with 0 to 4 R 1-2 groups.

[0053] In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 2 is C 7 substituted with one or two R 1-6 and is aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 2 is C 7 substituted with one or two R 1-4 and is aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 2 is C 7 substituted with one or two R 1-2 and is aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 2 is C 7 substituted with three or four R 1-6 and is aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 2 is C 7 substituted with three or four R 1-4 and is aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 2 is C 7 substituted with three or four R 1-2 and is aliphatic.

[0054] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 2 is

Chemical formula

[0055] As generally defined above, R 3 is C 8 substituted with 0 to 3 R 1-6 and is aliphatic. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 3 is C 8 substituted with 0 to 3 R 1-4 and is aliphatic. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 3 is C 8 substituted with 0 to 3 R 1-2 and is aliphatic.

[0056] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 3 is C 8 substituted with 1 to 3 R 1-6 and is aliphatic. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 3 is C 8C replaced by 1-4 is aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 3 is C substituted with 1 to 3 R 8 and is aliphatic. 1-2

[0057] In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 3 is

Chemical formula

[0058] As generally defined above, R 4 is halogen. In various embodiments, at any substitutable position of the fused bicyclic moiety of any of Formulas I, I', I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, is substituted with R 4 In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 4 is fluoro or chloro.

[0059] As generally defined above, R 5 is halogen. In some embodiments of any of Formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, and I-h, R 5 is fluoro.

[0060] As generally defined above, each R 6 and R6' is selected from hydrogen, halogen, -OR, -N(R)2, -OC(O)R, -N(R)C(O)R, -O-L-(R 9 ) p , -Cy, and optionally substituted C 1-6 selected from aliphatics. In some embodiments of Formula I, R 6 is hydrogen.

[0061] In some embodiments of any of Formula I, I-a, I-a-i, I-c, I-c-i, I-g, and I-g-i, R 6 is halogen. In some of the above embodiments of any of Formula I, I-a, I-a-i, I-c, I-c-i, I-g, and I-g-i, R 6 is fluoro.

[0062] In some embodiments of any of Formula I, I-a, I-a-i, I-c, I-c-i, I-g, and I-g-i, R 6 is -OR.

[0063] In some embodiments of any of Formula I, I-a, I-a-i, I-c, I-c-i, I-g, and I-g-i, R 6 is -N(R)2.

[0064] In some embodiments of any of Formula I, I-a, I-a-i, I-c, I-c-i, I-g, and I-g-i, R 6 is -OC(O)R.

[0065] In some embodiments of any of Formula I, I-a, I-a-i, I-c, I-c-i, I-g, and I-g-i, R 6 is -N(R)C(O)R. In some embodiments of any of Formula I, I-a, I-a-i, I-c, I-c-i, I-g, and I-g-i, R 6 is -NHC(O)R. In some of the above embodiments of any of Formula I, I-a, I-a-i, I-c, I-c-i, I-g, and I-g-i, R is R ○ optionally substituted with C 1-6is aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-c, I-c-i, I-g, and I-g-i, R 6 is -NHC(O)R, where R is C ○ optionally substituted with R 1-6 and is aliphatic, where R ○ is a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0066] In some embodiments of any of Formulas I, I-a, I-a-i, I-c, I-c-i, I-g, and I-g-i, R 6 is -Cy.

[0067] In some embodiments of any of Formulas I, I-a, I-a-i, I-c, I-c-i, I-g, and I-g-i, R 6 is -O-L-(R 9 ) p wherein.

[0068] In some embodiments of any of Formulas I, I-a, I-a-i, I-c, I-c-i, I-g, and I-g-i, R 6 is optionally substituted C 1-6 aliphatic. In some of the above embodiments of any of Formulas I, I-a, I-a-i, I-c, I-c-i, I-g, and I-g-i, R 6 is -CH3.

[0069] In some embodiments of any of Formulas I, I-a, I-a-i, I-c, I-c-i, I-g, and I-g-i, R 6 is -CH3, -OCH3,

Chemical formula

Chemical formula

Chemical formula

[0070] In some embodiments of any part of Formula I, R 6' is hydrogen.

[0071] In some embodiments of any of Formula I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6' is halogen. In some of the above embodiments, R 6' is fluoro.

[0072] In some embodiments of any of Formula I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6' is optionally substituted C 1-6 aliphatic. In some embodiments of any of Formula I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6' is optionally substituted C 1-4 aliphatic. In some embodiments of any of Formula I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6' is optionally substituted C 1-2 aliphatic. In some embodiments of any of Formula I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6' is optionally substituted C 2-3 aliphatic. In some of the above embodiments of any of Formula I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6' is -C(CH3)2OH.

[0073] In some embodiments of any of Formula I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6' is -OR.

[0074] In some embodiments of any of Formula I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6' is -N(R)2.

[0075] In some embodiments of any of Formulas I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6' is -OC(O)R.

[0076] In some embodiments of any of Formulas I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6' is -N(R)C(O)R.

[0077] In some embodiments of any of Formulas I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6' is -Cy.

[0078] In some embodiments of any of Formulas I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6' is -O-L-(R 9 ) p is.

[0079] In some embodiments of any of Formulas I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6' is selected from fluoro, -OCH3, and -C(CH3)2OH.

[0080] As generally defined above, R 7 is selected from halogen, -OR, -N(R)2, and -Cy. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 7 is halogen. In some of the above embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 7is fluoro. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 7 is -OR. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 7 is -N(R)2. In some of the above embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R is hydrogen. Thus, in some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 7 is -NH2. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 7 is -Cy. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 7 is selected from fluoro, -NH2, and -Cy.

[0081] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 2 is

Chemical formula

[0082] As generally defined above, R 8 is selected from halogen, -OR, -N(R)2, and -Cy. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 8 is -Cy. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 8 is -OR. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 8 is halogen. In some of the above embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 8 is fluoro.

[0083] In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 3 is

Chemical formula

[0084] As generally defined above, R 9 is selected from halogen, -OR, -N(R)2, and -Cy. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, R9 is a halogen. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, R 9 is fluoro. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, R 9 is -OR. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, R 9 is -N(R)2. In some of the above embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, R is hydrogen. Thus, in some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, R 9 is -NH2. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, R 9 is -Cy.

[0085] As generally defined above, L is a covalent bond or C 1-4 is aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, L is a covalent bond. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, L is C 1-4 is aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, L is C 1-3It is aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, L is C 1-2 It is aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, L is C 2-3 It is aliphatic.

[0086] In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, -L-(R 9 ) p is

Chemical formula

[0087] In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, R 9 is fluoro,

Chemical formula

[0088] As generally defined above, Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where Cy is substituted with 0 to 3 R 10 In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is 1 to 2 R 10is replaced. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is 1 to 3 Rs 10 is replaced.

[0089] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 3-membered saturated carbocyclic ring. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 4-membered saturated carbocyclic ring. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 5-membered saturated or partially unsaturated carbocyclic ring. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 5-membered saturated carbocyclic ring. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 6-membered saturated or partially unsaturated carbocyclic ring. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 6-membered partially unsaturated carbocyclic ring. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 7-membered saturated or partially unsaturated carbocyclic ring.In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 7-membered saturated carbocyclic ring.

[0090] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 3-membered saturated heterocycle having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 4-membered saturated heterocycle having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 5-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 5-membered saturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 6-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.In some embodiments of any of formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 6-membered saturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 7-membered saturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0091] In some embodiments of any of formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is phenyl.

[0092] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 5-membered heteroaryl having 2 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 5-membered heteroaryl having 2 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0093] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is a 6-membered heteroaryl having 1 to 2 nitrogen atoms.

[0094] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, Cy is

Chemical formula

[0095] As generally defined above, R 10 is selected from halogen, -OR, -N(R)2, -CN, -C(O)R, -C(O)OR, -C(O)N(R)2, oxo, and an optionally substituted group, and the optionally substituted group is C 1-6 selected from aliphatic and a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is halogen. In some of the above embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is fluoro or chloro.

[0096] In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is -OR.

[0097] In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is -N(R)2.

[0098] In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is -CN.

[0099] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is -C(O)R. In some of the above embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R is C 1-6 is aliphatic. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is -C(O)R, where R is C 1-6 is aliphatic. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is -C(O)R, where R is C 1-4 is aliphatic. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is -C(O)R, where R is C 1-2 is aliphatic.

[0100] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is -C(O)R, where R is optionally substituted C 1-6It is aliphatic. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is -C(O)R, where R is C optionally substituted with -OR ○ which is aliphatic. In some of the above embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 1-6 is hydrogen or C ○ which is aliphatic. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 1-6 is -C(O)R, where R is C optionally substituted with -OR 10 which is aliphatic. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R ○ is -C(O)R, where R is C optionally substituted with -OR 1-4 which is aliphatic. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is -C(O)R, where R is C optionally substituted with -OR ○ which is aliphatic. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 1-2 is aliphatic.

[0101] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is -C(O)OR.

[0102] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is -C(O)N(R)2.

[0103] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is oxo.

[0104] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is optionally substituted C 1-6 aliphatic. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is optionally substituted C 1-4 aliphatic. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is optionally substituted C 1-2 aliphatic. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is -CH3.

[0105] In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is an optionally substituted 3-membered saturated or partially unsaturated heterocycle having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is an optionally substituted 4-membered saturated or partially unsaturated heterocycle having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is an optionally substituted 5-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10is an optionally substituted 5-membered saturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is an optionally substituted 6-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is an optionally substituted 6-membered saturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is an optionally substituted 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is an optionally substituted 7-membered saturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0106] In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 10 is oxo, fluoro, chloro, -CN, -CH3, [Chemical formula] selected from.

[0107] As generally defined above, R is hydrogen or a group which may be optionally substituted, and the group which may be optionally substituted is C 1-6 aliphatic; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R is hydrogen. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R is a group which may be optionally substituted, and the group which may be optionally substituted is C 1-6 aliphatic; a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R is an optionally substituted C 1-6 aliphatic. In some of the above embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R is halogen or -OR ○ optionally substituted with 1-6It is aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R ○ is hydrogen or C 1-6 is aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R is halogen or -OR ○ optionally substituted with C 1-6 is aliphatic, where R ○ is hydrogen or C 1-6 is aliphatic.

[0108] As generally defined above, each m and n is 0 or 1. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, m is 0. In some embodiments of any of Formulas I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, m is 1. In some embodiments of any of Formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, and I-h, n is 0. In some embodiments of any of Formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, and I-h, n is 1. In some embodiments of Formula I, m is 1 and n is 0. In some embodiments of Formula I, m and n are each 0.

[0109] As generally defined above, p is from 1 to 4. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, p is 1. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, p is from 1 to 2. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, p is 2. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-e, I-e-i, I-g, and I-g-i, p is 3.

[0110] In some embodiments, the compound of Formula I is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0111] 4. Pharmaceutical Composition In some embodiments, the disclosure provides a composition comprising a compound provided by the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the disclosure is an amount effective to significantly inhibit PAD4 in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the disclosure is an amount effective to significantly inhibit PAD4 in a biological sample or in a patient. In certain embodiments, the composition provided by the disclosure is formulated for administration to a patient in need thereof. In some embodiments, the composition provided by the disclosure is formulated for oral administration to a patient.

[0112] As used herein, the term "subject" is used synonymously with the term "patient" and means an animal or a mammal. In some embodiments, the subject or patient is a human. In other embodiments, the subject (or patient) is an animal subject (or patient). In some embodiments, the animal subject (or patient) is a dog, a cat, or a horse.

[0113] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a carrier, adjuvant, or vehicle that is non-toxic and does not impair the pharmacological activity of the compound when formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions provided by the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0114] The compositions provided by the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, intravaginally or by implantation reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion. The compositions may be administered orally, intraperitoneally or intravenously. The sterile injectable preparation of the compositions provided by the present disclosure may be an aqueous solution or an oily suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation is a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent (such as a solution of 1,3-butanediol). Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending agent.

[0115] For this purpose, any sterile, non-volatile oil containing synthetic monoglycerides or diglycerides may be used. Fatty acids (such as oleic acid and its glyceride derivatives) are useful in the manufacture of injectables, and pharmaceutically acceptable natural oils (such as olive oil or castor oil), especially those that have been polyoxyethylated, are also useful. These oils or suspensions may also contain diluents or dispersants of long-chain alcohols (such as carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions). Other commonly used surfactants (such as Tweens, Spans, and other emulsifiers or bioavailability enhancing substances commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms) may be used for formulation.

[0116] The pharmaceutically acceptable compositions provided by the present disclosure may be orally administered in any acceptable oral formulation including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of oral tablets, commonly used carriers include lactose and corn starch. Lubricants (such as magnesium stearate) are also commonly added. In the case of capsules for oral administration, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifier and a suspending agent. Optionally, certain sweetening, flavoring or coloring agents may be added.

[0117] Alternatively, the pharmaceutically acceptable compositions provided by the present disclosure may be administered as suppositories for rectal administration. These can be manufactured by mixing with suitable non-irritating excipients such that they are solid at room temperature but liquid at rectal temperature and melt in the rectum to release the drug. Such substances include cocoa butter, beeswax and polyethylene glycol.

[0118] The pharmaceutically acceptable compositions provided by the present disclosure may be particularly administered topically in the case of treatment targeting a site or organ that is easily locally accessible, such as a disease of the eye, skin, or lower digestive tract. Suitable topical formulations are readily manufactured for these sites or organs, respectively. For topical administration to the lower digestive tract, rectal administration (see above) or a suitable enema formulation may be effective. A topical transdermal patch may be used. In topical administration, the pharmaceutically acceptable compositions of the present application may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for use in topical administration of the compounds provided by the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.

[0119] Alternatively, the pharmaceutically acceptable compositions of the present application may be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0120] When administered to the eye, the pharmaceutically acceptable compositions of the present application may be formulated as a micronized suspension of sterile pH-adjusted isotonic saline or a solution of sterile pH-adjusted isotonic saline, with a preservative (e.g., benzalkonium chloride) appropriately added. Alternatively, when administered to the eye, the pharmaceutically acceptable composition may be formulated as an ointment (e.g., petrolatum).

[0121] The pharmaceutically acceptable compositions provided by the present disclosure may be administered by nasal aerosol or nasal inhalation. The composition is manufactured according to techniques well known in the field of pharmaceutical formulations and may be manufactured as a solution of physiological saline with benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants added.

[0122] Furthermore, the pharmaceutically acceptable compositions provided by the present disclosure may be formulated for oral administration. Such formulations may be administered with food or without food. In some embodiments, the pharmaceutically acceptable compositions provided by the present disclosure are administered without food. In other embodiments, the pharmaceutically acceptable compositions provided by the present disclosure are administered with food.

[0123] The pharmaceutically acceptable compositions provided by the present disclosure can be administered to humans and other animals, as needed, by oral administration, rectal administration, parenteral administration, intravesical administration, intravaginal administration, intraperitoneal administration, topical administration (such as powders, ointments, or eye drops), buccal administration (such as oral or nasal sprays), etc. In certain embodiments, the compounds described in the present disclosure are administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg or about 1 mg / kg to about 25 mg / kg, once or more than once a day, depending on the weight of the subject, and the desired therapeutic effect may be obtained.

[0124] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art (such as water or other solvents, solubilizing agents, and emulsifying agents (such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof)). In addition to the inert diluent, the oral composition may contain adjuvants (such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and fragrances).

[0125] Injectable preparations (for example, sterile injectable aqueous or oily suspensions) may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent (for example, a solution of 1,3 - butanediol). Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, U.S.P. isotonic sodium chloride solution. Further, sterile fixed oils are conventionally used as solvents or suspending agents. For this purpose, any sterile, non-volatile oil including synthetic monoglycerides or diglycerides may be used. Further, fatty acids (for example, oleic acid) may also be used in the manufacture of injectable preparations.

[0126] Injectable preparations may be sterilized, for example, by filtration through a sterilizing filter, or by adding a sterilizing agent to a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable solvent prior to use.

[0127] To prolong the effect of the compounds provided by the present disclosure, it is often desirable to retard the absorption of the compounds in subcutaneous or intramuscular injections, which can be achieved by using a suspension of crystalline or amorphous substances with low solubility in water. The absorption rate of the compound then depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, retarding the absorption of a parenterally administered compound is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot preparations are manufactured by forming a microencapsulated matrix of the compound in a biodegradable polymer such as a lactic / glycolic acid polymer. The release rate of the compound can be controlled according to the ratio of the compound to the polymer and the nature of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot preparations may also be prepared by incorporating the compound into liposomes or microemulsions that are compatible with living tissues.

[0128] Compositions for rectal or vaginal administration may be suppositories produced by mixing the compounds described in the present disclosure with a suitable non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol or suppository wax which is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity to release the active compound).

[0129] Solid preparations for oral administration include capsules, tablets, pills, powders, and granules. In such solid preparations, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate) and / or (a) fillers or extenders (such as starch, lactose, sucrose, glucose, mannitol, and silicic acid), (b) binders (such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), (c) wetting agents (such as glycerol), (d) disintegrants (such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate), (e) dissolution retardants (such as paraffin), (f) absorption promoters (such as quaternary ammonium compounds), (g) wetting agents (such as cetyl alcohol and glycerol monostearate), (h) absorbents (such as kaolin and bentonite clay), and (i) lubricants (such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof). In the case of capsules, tablets and pills, the preparation may also contain buffering agents.

[0130] Solid compositions of a similar type may use lactose or milk sugar and high molecular weight polyethylene glycol, etc. as excipients and may be used as fillers in soft and hard gelatin capsules. Solid preparations such as tablets, dragees, capsules, pills, and granule tablets can be manufactured by coating with coatings and shells (such as enteric coatings and other coatings well-known in the pharmaceutical field). These may optionally contain opacifying agents and may be compositions that contain only the active ingredient or preferentially release the active ingredient and are slowly released as appropriate in a specific part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may use lactose or milk sugar and high molecular weight polyethylene glycol, etc. as excipients and may be used as fillers in soft and hard gelatin capsules.

[0131] The active compound can be microencapsulated with one or more of the above-mentioned excipients. Solid preparations such as tablets, dragees, capsules, pills, and granules can be manufactured by coating with coatings and shells (such as enteric coatings, sustained-release coatings, and other coatings well-known in the pharmaceutical field). In such solid preparations, the active compound may be mixed with at least one inert diluent (such as sucrose, lactose, or starch). Such preparations may conventionally contain additive substances other than inert diluents (such as lubricants for tableting and other tableting aids such as magnesium stearate and microcrystalline cellulose). In the case of capsules, tablets, and pills, the preparation may contain a buffering agent.

[0132] Formulations for topical or transdermal administration of the compounds provided by the present disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under aseptic conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffering agents. Ophthalmic formulations, ear drops, and eye drops are also considered to be within the scope of the present disclosure. Furthermore, the present disclosure contemplates the use of transdermal patches, which have the advantage of being able to provide controlled delivery of the compound into the body. Such formulations can be manufactured by dissolving or dispersing the compound in a suitable solvent. Absorption enhancers can also be used to increase the amount of compound passing through the skin. The rate can be controlled by providing a release control membrane or by dispersing the compound in a polymer matrix or gel.

[0133] The amount of the compounds of the present disclosure that can be combined with a carrier substance in producing a composition of a single dosage form varies depending on the subject to be treated and the specific method of administration. The compositions of the present application should be formulated such that the patients to whom these compositions are administered can be administered at a dosage of the inhibitor of 0.01 to 100 mg / kg (body weight) / day.

[0134] The compounds of the present disclosure can be administered alone or in combination with one or more other therapeutic compounds. In combination therapy, they can be administered in the form of an integrated combination, or the compounds of the present disclosure and one or more other therapeutic compounds can be administered alternately, or each independently, or there is a possibility of administering an integrated combination and one or more other therapeutic compounds in combination. Examples of such other therapeutic agents include corticosteroids, loxapram, calphostin, cytokine-suppressive anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressive agents; nuclear import and export inhibitors (e.g., deoxyspergualin (DSG)); non-steroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen, celecoxib, and rofecoxib); steroids (e.g., prednisone or dexamethasone); antiviral drugs (e.g., abacavir); anti-proliferative agents (e.g., methotrexate, leflunomide, FK506 (tacrolimus, Prograf)); cytotoxic drugs (e.g., azathioprine and cyclophosphamide); TNF-α inhibitors (e.g., tenidap, anti-TNF antibodies or soluble TNF receptors, and rapamycin (sirolimus or Rapamune), or derivatives thereof. The compounds of the present disclosure can be further administered in addition to chemotherapy, radiotherapy, immunotherapy, phototherapy, surgery, or combinations thereof, particularly for treating tumors. Similar to adjuvant therapy in the treatment strategies described above, long-term treatment is also possible. Other treatments include treatments for maintaining the condition of patients after tumor regression, or prophylactic chemotherapy in, for example, at-risk patients.

[0135] The above additional agents may be administered separately from the composition containing the compound of the present invention as part of a plurality of dosing regimens. Alternatively, the above agents may be part of a single dosage form and may be mixed with the compound of the present disclosure in a single composition. When administered as part of a plurality of dosing regimens, the two active agents may be administered simultaneously, sequentially, or alternately at intervals usually within 5 hours.

[0136] As used herein, the term "combination" and related terms refer to the co - administration or sequential administration of therapeutic agents in accordance with the present disclosure. For example, the compounds of the present disclosure may be co - administered or sequentially administered with another therapeutic agent in separate formulations or in an integrated single dosage form. Accordingly, the present disclosure provides a single dosage form comprising a compound of the present disclosure, another therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0137] (In the composition containing the other therapeutic agent as described above), the amounts of the compound of the present application and the other therapeutic agent that can be combined with the carrier substance to form a single dosage form vary depending on the subject to be treated and the specific administration method. The compositions of the present disclosure should be formulated such that the dosage of the compound of the present application is administered at 0.01 - 100 mg / kg (body weight) / day.

[0138] In the above - mentioned composition containing another therapeutic agent, the other therapeutic agent and the compound of the present disclosure may act synergistically. Accordingly, the amount of the other therapeutic agent in such a composition is less than the amount required in a monotherapy using only that therapeutic agent.

[0139] The amount of the other therapeutic agent in the compositions of the present disclosure is less than or equal to the amount normally contained in a composition containing that other therapeutic agent as the sole active ingredient. The amount of the other therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount normally contained in a composition containing that other drug as the sole therapeutic active ingredient.

[0140] It should also be understood that the specific dosage and treatment regimen in any particular patient will vary depending on a variety of factors, including the activity of the specific compound being used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the specific disease or disorder being treated. The amount of the compound of the present disclosure in the composition also varies depending on the specific compound in the composition.

[0141] 5. Use of the Compound The compounds and compositions described herein are generally useful for the inhibition of PAD4.

[0142] In the present disclosure, the activity of a compound used as an inhibitor of PAD4 may be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays for determining the inhibition of PAD4. The detailed conditions of the assay of a compound used as an inhibitor of PAD4 in the present disclosure are shown in the following examples. In some embodiments, the compounds of the present application selectively inhibit PAD4 over PAD2.

[0143] As used herein, the term "treatment" refers to the amelioration, reduction, delay in onset, or inhibition of progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be performed after one or more symptoms have progressed. In other embodiments, treatment may be performed before symptoms have developed. For example, treatment may be performed on a subject predisposed to a disease (e.g., from the perspective of the history of symptoms and / or genetic factors or other factors that predispose to onset) before the symptoms develop. Treatment may be continued after the symptoms have resolved, for example, to prevent or delay recurrence.

[0144] Since the compounds of the present application are inhibitors of PAD4, they are useful for treating one or more diseases or disorders associated with PAD4 enzyme activity. Thus, in one embodiment, the present disclosure provides a method for treating a disease or disorder associated with PAD4 enzyme activity, the method comprising administering to a patient in need thereof a compound of the present disclosure, or a pharmaceutically acceptable composition thereof.

[0145] In certain embodiments, a disease or disorder associated with PAD4 enzyme activity is a disease, condition, or disorder in which inappropriate PAD4 activity is involved. In some embodiments, the disease or disorder associated with PAD4 enzyme activity is selected from the group consisting of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis. In further embodiments, the disease or disorder associated with PAD4 enzyme activity is rheumatoid arthritis. In further embodiments, the disease or disorder associated with PAD4 enzyme activity is systemic lupus. In further embodiments, the disease or disorder associated with PAD4 enzyme activity is vasculitis. In further embodiments, the disease or disorder associated with PAD4 enzyme activity is cutaneous lupus erythematosus. In further embodiments, the disease or disorder associated with PAD4 enzyme activity is psoriasis.

[0146] In certain embodiments, the present application provides a method for treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, the method comprising administering to a human subject in need thereof a therapeutically effective amount of a compound of the present application or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.

[0147] In one embodiment, the present application provides a method for treating rheumatoid arthritis, which comprises administering a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof of the present application to a human subject in need thereof. In one embodiment, the present application provides a method for treating systemic lupus erythematosus, which comprises administering a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof of the present application to a human subject in need thereof. In one embodiment, the present application provides a method for treating vasculitis, which comprises administering a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof of the present application to a human subject in need thereof. In one embodiment, the present application provides a method for treating cutaneous erythematosus, which comprises administering a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof of the present application to a human subject in need thereof. In one embodiment, the present application provides a method for treating psoriasis, which comprises administering a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof of the present application to a human subject in need thereof.

[0148] In some embodiments, diseases or disorders associated with PAD4 enzyme activity include acid-induced lung injury, pustulosis acneiformis (PAPA), acute lymphoblastic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergic asthma, allergic bronchopulmonary aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, weight loss, angina, angioedema, anhidrotic ectodermal dysplasia, ankylosing spondylitis, anterior uveitis, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, Behçet's disease, Bell's palsy, beryllium lung, Braun syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolism disorder, cataract, cerebral aneurysm, chemical irritation-induced inflammation, choroiditis, chronic heart failure, chronic lung disease of prematurity, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, Crohn's disease, cryopyrin-associated periodic syndrome, cryptococcus, cystic fibrosis, deficiency of interleukin-1 receptor antagonist molecule (DIRA), dermatitis, dermal endotoxemia, dermatomyositis, diffuse panbronchiolitis, endometriosis, endotoxemia, epistaxis, erythroleukemia, familial amyloid polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, gastrointestinal diseases, head trauma, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Schönlein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster, herpes simplex, HIV-1, Hodgkin's disease, Huntington's disease, pulmonary fibrosis, hyperammonemia, hypercalcemia, hypercholesterolemia, hyper IgD syndrome with periodic fever (HIDS), aplastic anemia, other anemia, idiopathic thrombocytopenic purpura, dyschromatosis, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect sting-induced inflammation, iritis, irritation-induced inflammation, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney damage due to parasitic infection, kidney transplant rejection, leptospirosis, leukemia, Reiter's syndrome, lung injury, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease,Selected from the group consisting of Maculopapular-Wells syndrome (urticaria, deafness, amyloidosis), multiple sclerosis, muscle weakness, muscular dystrophy, myasthenia gravis, myocarditis, juvenile polyposis, myelodysplastic syndrome, myositis, rhinitis, necrotizing enterocolitis, neonatal-onset multi-organ inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, non-allergic asthma, obesity, ophthalmic allergy, optic neuritis, organ transplantation, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), inflammation due to plant irritation, pneumonia, lung infection, inflammation due to Toxicodendron / urushiol, polyarteritis nodosa, polychondritis, polycystic kidney, polymyositis, psoriasis, psychosomatic disorders, lung diseases, pulmonary hypertension, pulmonary fibrosis, pyoderma gangrenosum, septic arthritis, kidney diseases, retinal diseases, rheumatic heart disease, rheumatic diseases, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell disease, sickle cell anemia, silica-induced diseases, Sjögren's syndrome, skin diseases, sleep apnea syndrome, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplantation, TNF receptor-associated periodic syndrome (TRAPS), toxoplasmosis, transplantation, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, granulomatosis with polyangiitis, interstitial pneumonia, psoriatic arthritis, juvenile idiopathic arthritis, Sjögren's syndrome, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, antiphospholipid syndrome, sepsis, deep vein thrombosis, fibrosis, Alzheimer's, scleroderma and CREST syndrome.,

[0149] In one embodiment, the present disclosure provides a compound for use in therapy or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a compound for use in the treatment of a disease or disorder in which inappropriate PAD4 activity is involved, or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a compound for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a compound for use in the treatment of rheumatoid arthritis, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a compound for use in the treatment of systemic lupus, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a compound for use in the treatment of vasculitis, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a compound for use in the treatment of cutaneous lupus erythematosus, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a compound for use in the treatment of psoriasis, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides the use of a compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disorder in which inappropriate PAD4 activity is involved. In another embodiment, the present disclosure provides the use of a compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis.In another embodiment, the present disclosure provides the use of a compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis. In another embodiment, the present disclosure provides the use of a compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of systemic lupus. In another embodiment, the present disclosure provides the use of a compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of vasculitis. In another embodiment, the present invention provides the use of a compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cutaneous erythematosus. In another embodiment, the present disclosure provides the use of a compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of psoriasis. In a further embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing a disease or disorder in which inappropriate PAD4 activity is involved, the pharmaceutical composition comprising a compound of the present application, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In a further embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, vasculitis, systemic erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous erythematosus, or psoriasis, the pharmaceutical composition comprising a compound of the present application, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In a further embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, the pharmaceutical composition comprising a compound of the present application, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.In a further embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing systemic lupus, the pharmaceutical composition comprising the compound of the present application, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In a further embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing vasculitis, the pharmaceutical composition comprising the compound of the present application, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In a further embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing cutaneous erythematosus, the pharmaceutical composition comprising the compound of the present application, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In a further embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing psoriasis, the pharmaceutical composition comprising the compound of the present application, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.

[0150] All features of each aspect of the present invention are applicable to all other aspects with necessary modifications. To better understand the invention described herein, the following examples are provided. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0151] 6. Examples The following examples were prepared, isolated, and identified using the methods of the present disclosure. The following examples illustrate a part of the scope of the present disclosure and do not limit the scope of the present disclosure. [Table 1] [Table 2]

[0152] Description of preparative HPLC method and analytical LCMS method Method A: Preparative HPLC: Column: XBridge C18 OBD Prep, 100Å, 10μm, 19mm x 250mm; Mobile phase A: Water + 0.05% TFA, Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: Elute at 35% B - 60% B for 4.8 minutes; Detection: UV (210 / 254 nm) Method B: Analytical LCMS: Column: Shim-pack XR-ODS, 3x50mm, 2.2μm; Mobile phase A: Water + 0.05% TFA, Mobile phase B: ACN + 0.05% TFA; Flow rate: 1.2 mL / min; Gradient: Elute at 5% B - 95% B for 2 minutes, then at 95% for 0.7 minutes, and then at 95% B - 5% B for 0.05 minutes; Detection: MS and UV (254 nm) Method C: Analytical LCMS: Column: L-column3 C18, 3.0mm x 30mm, Particle size: 2.0μm; Mobile phase A: Water + 5 mM ammonium bicarbonate, Mobile phase B: ACN; Flow rate: 1.5 mL / min; Gradient: Elute from 10% B - 95% B over 1.2 minutes, then at 95% B for 0.60 minutes; Detection: UV (254 / 220 nm) Method D: Analytical LCMS: Column: HALO C18, 3x30mm, 2.7μm; Mobile phase A: Water + 0.05% TFA, Mobile phase B: Acetonitrile + 0.05% TFA; Flow rate: 1.5 mL / min; Gradient: Elute at 5% B - 95% B for 2.5 minutes, then at 95% for 1 minute, and then at 95% B - 5% B for 0.05 minutes; Detection: MS and UV (254 nm) Method E: Preparative HPLC: Column: XSelect CSH Prep C18 OBD, 19x250mm, 5μm; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: Elute at 22% B - 50% B for 5.5 minutes; Detection: UV (254 nm) Method F: Preparative HPLC: Column: SunFire C18 OBD Prep 19x250mm, 5μm; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: Elute at 30% B - 55% B for 5.5 minutes; Detection: UV (254 nm) Method G: Fractionation HPLC: Column: Atlantis Prep T3 OBD Column, 19x250mm, 10μm; Mobile phase A: water + 0.05% TFA, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: Elute with 20% B - 50% B for 6 minutes, then 50% B; Detection: UV (210 / 254nm) Method H: Analytical LCMS: Column: YMC Meteoric Core C18 BIO column, 3x50mm, 2.6μm; Mobile phase A: water + 5 mM NH4HCO3, Mobile phase B: ACN; Flow rate: 1.2 mL / min; Gradient: Elute with 10% B - 95% B for 1.20 minutes, then elute with 95% B for 0.68 minutes, then elute with 95% B - 10% B for 0.05 minutes; Detection: UV (254nm) Method I: Analytical LCMS; Column: HALO C18, 3x30mm, 2.7mm; Mobile phase A: water + 0.05% TFA, Mobile phase B: acetonitrile + 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: Elute with 5% B - 100% B for 1.3 minutes, then elute with 100% for 0.5 minutes, then elute with 100% B - 5% B for 0.03 minutes; Detection: UV (254nm) Method J: Column: Waters BEH C18, 2.1x50mm, 1.7μm; Mobile phase A: 95% / 5% water / ACN + 10 mmol ammonium acetate, Mobile phase B: 5% / 95% acetonitrile:water + 10 mM ammonium acetate; Flow rate: 0.8 mL / min; Gradient: Elute with 5% B - 95% B over 1.5 minutes, then elute with 95% B for 0.5 minutes, then elute with 95% B - 5% B for 0.1 minutes; Detection: PDA (210 - 400nm) / MS (Full ion detection: positive / negative mode) Method K: Column: Waters BEH C18 Column, 2.1x50mm, 1.7μm; Mobile phase A: water + 0.1% formic acid (v / v), Mobile phase B: acetonitrile + 0.1% formic acid (v / v); Flow rate: 0.8 mL / min; Gradient: Elute with 5% B - 95% B over 1.5 minutes, then elute with 95% B for 0.5 minutes, then elute with 95% B - 5% B for 0.1 minutes; Detection: PDA (210 - 400nm) / MS (Full ion detection: positive / negative mode)

[0153] (Synthesis Example) General Procedure 1: Alkylation of Lactam Using Cyclic Sulfamidate To a stirred solution of lactam (1.0 equiv) / DMF (0.05 M), NaH (60%, 2.0 equiv) and cyclic sulfamidate (1.4 equiv) were added at 0 °C, and the reaction was allowed to return to room temperature over 2 h. When TLC indicated completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate (x3). The organic layer was washed with brine (x2), concentrated, and purified by column chromatography to afford the desired product.

[0154] General Procedure 2: Deprotection of N-Boc Using TFA A solution of N-Boc amine (1.0 equiv) / DCM:TFA (3:1, 0.02 M) was stirred at room temperature for 30 min. When TLC indicated completion of the reaction, the mixture was concentrated and the product was purified by preparative HPLC or column chromatography.

[0155] General Procedure 3: Reduction of Ester or Acid Using Lithium Aluminum Hydride To a stirred solution of acid or ester (1.0 equiv) / THF (0.3 M), LiAlH4 (2.0 equiv) was added at 0 °C and the mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction was then quenched with water (0.5 mL) / NaOH (15%, ratio 1:4) and stirred at room temperature for 20 min. The solid was filtered off and the solution was concentrated under reduced pressure. The resulting crude product was purified by column chromatography.

[0156] General Procedure 4: Oxidation of Alcohol Using Manganese Dioxide To a stirred solution of alcohol (1.0 equiv) / DCM (0.1 M), MnO2 (10 equiv) was added at room temperature under a nitrogen atmosphere and the mixture was stirred at room temperature for 12 h. When LCMS indicated completion of the reaction, the solid was filtered off and the resulting mixture was concentrated to afford the crude product. This was used without further isolation or purified by column chromatography.

[0157] General Procedure 5: Alkylation of Heterocyclic NH or Phenolic OH Using Cesium Carbonate Base To a stirred solution of the substituted indole (1.0 equiv, 250 mg, 1.47 mmol) / DMF (0.2 M), Cs2CO3 (3.0 equiv), TBAI (0.1 equiv), and the alkyl electrophile (1.5 equiv) were added at room temperature and heated at 50 °C for 1.5 h. When the completion of the reaction was indicated by TLC, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (x3). The organic layer was washed with brine (x2), dried over sodium sulfate, concentrated, and purified by column chromatography.

[0158] General Procedure 6: Cyclization to Form Tricyclic Benzimidazole from Nitroaniline To a stirred solution of the aldehyde (1.0 equiv) / ethanol:water (2:1, 0.08 M), aniline (1.0 equiv) and Na2S2O4 (3.0 equiv) were added at room temperature and heated at 90 °C for 2 h. When the completion of the reaction was indicated by TLC, the reaction mixture was concentrated under reduced pressure to remove ethanol, diluted with water (20 mL), and then extracted with DCM / MeOH (10:1) (x3). The organic layer was dried over sodium sulfate, concentrated, and purified by preparative TLC or column chromatography.

[0159] General Procedure 7: Alkylation of Indole NH Using Sodium Hydride Base To a stirred solution of the substituted indole (1.0 equiv) / DMF (0.15 M), NaH (1.5 equiv) was added portionwise at 0 °C under a nitrogen atmosphere and the mixture was allowed to return to room temperature. The mixture was stirred at room temperature for 0.5 h and then the alkyl electrophile (1.5 equiv) was added portionwise at 0 °C under a nitrogen atmosphere and the mixture was allowed to return to room temperature. The resulting mixture was stirred at room temperature for 2 h and the reaction was monitored by TLC or LCMS. Then water was added to quench the reaction and the mixture was extracted with ethyl acetate (x2). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography.

[0160] General Procedure 8: Deprotection of N-Sulfonic Acid Using HCl To a stirred solution of N-sulfonic acid (60 mg, 0.09 mmol) / THF (2 mL), 2M HCl (1 mL) was added and the mixture was stirred at 50 °C for 30 minutes. When LCMS indicated the completion of the reaction, the final compound was purified as described in the examples.

[0161] General Procedure 9: Deprotection of Benzyloxy Ethers by Hydrogenation To a stirred solution of benzyloxy ether (1.0 equiv) / solvent mixture (0.02 - 0.1M), 10% Pd / C (1.0 equiv) was added portionwise at room temperature under a nitrogen atmosphere. The solution was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was monitored by TLC and LCMS. The solid was filtered off and the resulting mixture was concentrated. The crude product obtained was used without further purification or purified by column chromatography.

[0162] General Procedure 10: Mitsunobu Reaction To a solution of phenol (2.1 g, 6.33 mmol, 1.0 equiv) and alcohol (3.0 equiv) / toluene (0.15M), PPh3 (2.0 equiv) and DTBAD (2.0 equiv) were added at room temperature under a nitrogen atmosphere and the mixture was stirred at 80 °C for 6 hours. The reaction was monitored by TLC and LCMS. Water was added to quench the reaction and the mixture was extracted with ethyl acetate (x2). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified as described in each procedure.

[0163] General Procedure 11: Cyclization to Form Tricyclic Benzimidazoles from Dianilines To a solution of aldehyde (1 equiv) and dianiline (1 equiv) / DMF:water (30:1, 0.25M), oxone (4.6 g, 7.5 mmol) was added and the mixture was stirred at room temperature for 16 hours. Then water was added to quench the reaction and the mixture was extracted with ethyl acetate (x2). The combined organic extracts were washed with water (x2) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified as described in each procedure.

[0164] General Procedure 12: Alkylation of Phenol by Epoxide Ring Opening To a solution of phenol (1 equiv) / ethanol (0.05 - 0.3 M), epoxide (3 - 10 equiv) and TEA (5 equiv) were added, and the mixture was irradiated with microwave at 100 °C for 2 h. The reaction was monitored by LCMS, and the mixture was concentrated under reduced pressure. The obtained crude product was purified as described in each procedure.

[0165] General Procedure 13: Activation of Alcohol by Sulfonyl Chloride To a solution of alcohol (x equiv) / DCM (0.01 - 0.2 M), TEA (2 - 4 equiv) and sulfonyl chloride (1.2 - 2.0 equiv) were added at 0 °C, and the mixture was stirred at room temperature for 1 - 2 h. The reaction was monitored by LCMS. Then saturated aqueous NH4Cl solution was added at 0 °C to quench the reaction, and the mixture was extracted with DCM (x3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 0 °C to give the title compound.

[0166] General Procedure 14: Alkylation of Imidazole NH Using Cesium Carbonate Base To a solution of substituted indole (1 equiv) / DMF (0.1 M), imidazole reagent (1 - 9 equiv) and cesium carbonate (3 equiv) were added, and the mixture was stirred at 50 °C for 1 - 16 h. The reaction was monitored by LCMS. The mixture was quenched with water and extracted with ethyl acetate (x2). The organic layer was washed with water (x2) and brine (x2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified as described in each procedure.

[0167] Intermediate 1: tert-Butyl (S)-4-(fluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

Chemical Structure

[0168] Step 1: Synthesis of Methyl (S)-2-((tert-Butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)propanoate (2S)-2-(tert-Butoxycarbonylamino)-3-hydroxy-propanoic acid methyl ester (90 g, 410 mmol) and imidazole (30.7 g, 452 mmol) / DCM (900 mL) solution, TBSCl (80.4 g, 534 mmol) was added at 0 °C. After the addition, the mixture was stirred at 20 °C for 2 hours, and TLC indicated that the starting material was completely consumed. The reaction was quenched with water (1 L) at 0 °C and extracted with DCM (800 mL x 3). The combined organic layers were washed with brine (1 L x 2), dried over anhydrous Na2SO4, filtered, concentrated, and the title compound (140 g, crude) was obtained as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ: 5.34 (d, J = 8.4 Hz, 1H), 4.36 (d, J = 8.8 Hz, 1H), 4.06 (d, J = 2.4 Hz, 1H), 4.03 (d, J = 2.4 Hz, 1H), 3.75 (s, 3H), 1.46 (s, 9H), 0.87 (s, 9H), 0.03 (d, J = 5.2 Hz, 6H)

[0169] Step 2: Synthesis of tert-Butyl N-[(1R)-1-[[tert-Butyl(dimethyl)silyl]oxymethyl]-2-hydroxy-ethyl]carbamate To a suspension of LiAlH4 (27.9 g, 734 mmol) / THF (1.2 L), a solution of (S)-2-((tert-Butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)propanoic acid methyl ester (144 g, 432 mmol) / THF (300 mL) was added at 0 °C. After the addition, the reaction mixture was then stirred at 0 °C for 1 hour, and TLC indicated that the starting material was completely consumed. The reaction was quenched with saturated aqueous NH4Cl solution (800 mL) and filtered. Ethyl acetate (800 mL x 2) was added to the filtrate, washed with brine (800 mL), and dried over anhydrous Na2SO4. The mixture was filtered and concentrated, and the title compound (110 g, crude) was obtained as a pale yellow oil. 11H NMR (400 MHz, CDCl3) δ: 5.06 (s, 1H), 3.75 - 3.58 (m, 4H), 2.70 - 2.61 (m, 1H), 1.38 (s, 9H), 0.82 (s, 9H), 0.00 (s, 6H)

[0170] Step 3: Synthesis of tert-butyl (3R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-oxo-oxathiazolidine-3-carboxylate A solution of SOCl2 (77.1 g, 648 mmol) / DCM (400 mL) was added to a solution of imidazole (147 g, 2.16 mol) / DCM (700 mL) at 0 °C. After the addition, the mixture was stirred at 18 °C for 1 h. Then, a solution of tert-butyl N-[(1R)-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-hydroxy-ethyl]carbamate (110 g, 360 mmol) / DCM (600 mL) was added to the above mixture at -10 °C, and after the addition, the mixture was stirred at 18 °C for 1 h. TLC showed that the starting material was completely consumed. The reaction was quenched with aqueous citric acid solution (10%, 800 mL) and extracted with DCM (1 L x 2). The combined organic layers were washed with water (1 L x 2), dried over anhydrous Na2SO4, filtered, concentrated, and the title compound (104 g, crude) was obtained as a pale yellow oil. 1 1H NMR (400 MHz, CDCl3) δ: 5.00 - 4.98 (m, 1H), 4.83 - 4.72 (m, 2H), 4.07 - 4.03 (m, 1H), 3.79 - 3.72 (m, 1H), 1.53 (s, 9H), 0.89 (s, 9H), 0.07 (s, 6H)

[0171] Step 4: Synthesis of tert-butyl (3R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-oxathiazolidine-3-carboxylate To a solution of tert-butyl (3R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-oxo-oxathiazolidine-3-carboxylate (52 g, 148 mmol) in MeCN (1000 mL) was added a solution of RuCl3 (30.7 mg, 148 μmol) and NaIO4 (31.6 g, 148 mmol) in H2O (500 mL) at 18 °C. After the addition, the mixture was stirred at 18 °C for 1 h, and TLC indicated complete consumption of the starting material. Two identical reaction mixtures were combined and diluted with water (1 L), and the aqueous layer was extracted with DCM (1 L x 2). The combined organic layers were washed with water (500 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated, and the title compound (80 g, crude) was obtained as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ: 4.64 - 4.58 (m, 2H), 4.28 - 4.27 (m, 1H), 3.89 - 3.76 (m, 2H), 1.56 (s, 9H), 0.90 (s, 9H), 0.09 (s, 6H)

[0172] Step 5: Synthesis of tert-butyl N-[(1S)-1-(fluoromethyl)-2-hydroxy-ethyl]carbamate To a solution of tert-butyl (4S)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-oxathiazolidine-3-carboxylate (85 g, 231 mmol) in THF (850 mL) was added TBAF (1 M, 277 mL), and the mixture was stirred at 20 °C for 1 h. TLC indicated complete consumption of the starting material. The reaction was quenched with saturated aqueous NH4Cl solution (100 mL) and extracted with ethyl acetate (800 mL x 2). The combined organic layers were washed with water (500 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated. The residue obtained was purified by MPLC (petroleum ether / ethyl acetate = 2 / 1), and the title compound (20 g, 45% yield) was obtained as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ: 5.05 (d, J = 7.6 Hz, 2H), 4.57 - 4.44 (m, 2H), 3.81 - 3.73 (m, 3H), 1.45 (s, 9H)

[0173] Step 6: Synthesis of tert-butyl (4S)-4-(fluoromethyl)-2-oxo-oxathiazolidine-3-carboxylate A solution of SOCl2 (22.2 g, 186 mmol) / DCM (200 mL) was added dropwise to a solution of imidazole (42.3 g, 621 mmol) / DCM (200 mL) at 0 °C, and then the mixture was stirred at 20 °C for 1 h. Then tert-butyl N-[(1S)-1-(fluoromethyl)-2-hydroxy-ethyl]carbamate (20 g, 103 mmol) dissolved in DCM (200 mL) was added dropwise at -10 °C, and finally this mixture was stirred at 20 °C for 1 h. TLC indicated that the starting material was completely consumed. The reaction was quenched by adjusting the pH to 5 with aqueous citric acid solution (10%) and extracted with DCM (300 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated, and the title compound (22 g, crude) was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ: 5.29 - 4.97 (m, 2H), 4.86 - 4.57 (m, 2H), 4.42 - 4.10 (m, 3H), 1.52 (s, 9H)

[0174] Step 7: Synthesis of tert-butyl (S)-4-(fluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide A solution of tert-butyl (4S)-4-(fluoromethyl)-2-oxo-oxathiazolidine-3-carboxylate (22 g, 91.9 mmol) in MeCN (440 mL) was added with RuCl3 (191 mg, 919 μmol), and then a solution of NaIO4 (19.7 g, 91.9 mmol) in water (220 mL) was added dropwise under a N2 atmosphere. Finally, the mixture was stirred at 20 °C for 1 h. TLC indicated that the starting material was completely consumed and new spots appeared. The reaction mixture was filtered, the filter cake was washed with DCM (300 mL), water (300 mL) and DCM (800 mL) were added, then separated, the organic layers were combined, washed with water (300 mL x 2) and brine (200 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated, and the title compound (17.5 g, crude) was obtained as a yellow solid. 1 1H NMR (400 MHz, CDCl3) δ: 4.73 - 4.53 (m, 5H), 1.57 (s, 9H)

[0175] Intermediate 2. tert-butyl (S)-(1-fluoro-3-(2-(methylamino)-3-nitro-5-oxo-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)propan-2-yl)carbamate

Chemical formula

[0176] Step 1: Synthesis of tert-butyl 2-chloro-5-oxo-7,8-dihydro-1,6-naphthyridine-6-carboxylate Two identical reactions were carried out simultaneously. To a solution of tert-butyl 2-chloro-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (25 g, 93.0 mmol) / CCl4 (250 mL) and MeCN (25 mL) was added a solution of NaIO4 (59.7 g, 279 mmol) / water (175 mL), then RuCl3 (193 mg, 930 μmol) was added under a N2 atmosphere, and finally the mixture was stirred at 15 °C for 16 h. The two identical reaction mixtures were combined, the mixture was filtered, concentrated, and the solvent was removed. Water (800 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with aqueous Na2SO solution (500 mL) and brine (300 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated, and the title compound (40 g, crude) was obtained as a gray solid. 1 H NMR (400 MHz, DMSO-d6) δ: 8.28 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 3.98 (t, J = 6.0 Hz, 2H), 3.13 (t, J = 6.4 Hz, 2H), 1.46 (s, 9H)

[0177] Step 2: Synthesis of tert-butyl 2-[benzyl(methyl)amino]-5-oxo-7,8-dihydro-1,6-naphthyridine-6-carboxylate Two identical reactions were carried out simultaneously. To a solution of tert-butyl 2-chloro-5-oxo-7,8-dihydro-1,6-naphthyridine-6-carboxylate (20 g, 70.7 mmol) / tert-butanol (400 mL) and glycol (400 mL) was added N-methyl-1-phenyl-methanamine (42.9 g, 354 mmol), and then the mixture was stirred at 50 °C for 16 h. TLC indicated that the starting material was completely consumed and a new spot appeared. The reaction mixture was concentrated to remove t-BuOH, and the obtained residue was purified by silica gel column (petroleum ether:ethyl acetate = 30:1 to 5:1), and the title compound (40 g, 77% yield) was obtained as a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ: 7.40 (d, J = 9.2 Hz, 1H), 7.35 - 7.21 (m, 5H), 6.67 (d, J = 9.2 Hz, 1H), 4.87 (s, 2H), 3.87 (t, J = 6.0 Hz, 2H), 3.11 (s, 3H), 2.91 (t, J = 6.0 Hz, 2H), 1.48 (s, 9H)

[0178] Step 3: Synthesis of 2-[benzyl(methyl)amino]-7,8-dihydro-6H-1,6-naphthyridin-5-one To a solution of tert-butyl 2-[benzyl(methyl)amino]-5-oxo-7,8-dihydro-1,6-naphthyridine-6-carboxylate (28 g, 76.2 mmol) in DCM (300 mL) was added dropwise TFA (158 g, 1.39 mol) at 0 °C, and then the mixture was stirred at 20 °C for 1 h. TLC indicated that the starting material was completely consumed and a new spot appeared. The reaction mixture was concentrated, and the resulting residue was diluted with DCM (200 mL), and the pH was adjusted to 8 with aqueous Na2CO3 solution. The solution was extracted with DCM (200 mL x 2) and washed with brine (400 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and the title compound (17.5 g, 86% yield) was obtained as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ: 7.83 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.33 - 7.20 (m, 5H), 6.58 (d, J = 8.8 Hz, 1H), 4.84 (s, 2H), 3.38 - 3.35 (m, 2H), 3.07 (s, 3H), 2.81 (t, J = 6.8 Hz, 2H)

[0179] Step 4: Synthesis of tert-butyl N-[(1S)-1-[[2-[benzyl(methyl)amino]-5-oxo-7,8-dihydro-1,6-naphthyridin-6-yl]methyl]-2-fluoro-ethyl]carbamate According to the general procedure 1, intermediate 1 (11 g, 43.1 mmol) was reacted with 2-[benzyl(methyl)amino]-7,8-dihydro-6H-1,6-naphthyridin-5-one (7.68 g, 28.7 mmol). The obtained residue was purified by silica gel column (DCM:MeOH = 50:1~20:1) to give the title compound (9.7 g, 76% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ: 7.87 (d, J = 8.8 Hz, 1H), 7.33 - 7.29 (m, 2H), 7.24 - 7.19 (m, 3H), 6.94 (d, J = 8.8 Hz, 1H), 6.25 (d, J = 8.8 Hz, 1H), 4.86 (s, 2H), 4.50 - 4.31 (m, 2H), 3.59 - 3.54 (m, 4H), 3.08 (s, 3H), 1.32 (s, 9H)

[0180] Step 5: Synthesis of tert-butyl (S)-(1-fluoro-3-(2-(methylamino)-3-nitro-5-oxo-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)propan-2-yl)carbamate Two identical reactions were carried out simultaneously. To a solution of tert-butyl N-[(1S)-1-[[2-[benzyl(methyl)amino]-5-oxo-7,8-dihydro-1,6-naphthyridin-6-yl]methyl]-2-fluoro-ethyl]carbamate (6 g, 13.6 mmol) / H2SO4 (110 g, 60 mL) at 0 °C, KNO3 (5.50 g, 54.4 mmol) was added dropwise, and the mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed. The two identical reaction mixtures were poured into ice water (1 L), extracted with ethyl acetate (300 mL × 2), and the aqueous layer was slowly basified to pH = 9 - 10 by adding Na2CO3. Subsequently, THF (1.2 L) and Boc2O (3.55 g, 16.27 mmol) were added to this mixture and stirred at 25 °C for 16 h. LCMS indicated that the reaction was complete. The mixture was extracted with ethyl acetate (2 L × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by silica gel column (petroleum ether:ethyl acetate = 10:1 - 1:1) to obtain the title compound (4.13 g, 38% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ: 8.86 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 6.98 (d, J = 8.8 Hz, 1H), 4.45 (d, J = 5.6 Hz, 1H), 4.35 (d, J = 5.2 Hz, 1H), 3.68 - 3.32 (m, 4H), 3.08 (s, 3H), 3.07 - 3.02 (m, 2H), 1.31 (s, 9H)

[0181] Intermediate 3. 2-(Methylamino)-3-nitro-7,8-dihydro-1,6-naphthyridin-5(6H)-one

Chemical formula

[0182] Step 1: Synthesis of tert-butyl 2-chloro-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate To a stirred solution of tert-butyl 2-chloro-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (500 mg, 1.86 mmol) in CCl4 (7.5 mL) and MeCN (0.75 mL) were added NaIO4 (1.2 g, 5.58 mmol) and water (2.5 mL). Subsequently, RuCl3·H2O (126 mg, 0.56 mmol) was added and the mixture was stirred vigorously at room temperature for 2 h. When completion of the reaction was indicated by LCMS, the mixture was filtered and extracted with DCM (3 x 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue obtained was purified by silica gel (petroleum ether:ethyl acetate = 2:1) to afford the title compound (447 mg, 85%) as a white solid. LCMS (ESI, m / z): 283 [M+H] +

[0183] Step 2: Synthesis of 2-chloro-7,8-dihydro-1,6-naphthyridin-5(6H)-one tert-Butyl 2-chloro-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (100 mg, 0.35 mmol) was reacted according to General Procedure 2. The product was used in the next step without further purification. LCMS (ESI, m / z): 183 [M+H] +

[0184] Step 3: Synthesis of 2-(methylamino)-7,8-dihydro-1,6-naphthyridin-5(6H)-one To a stirred solution of 2-chloro-7,8-dihydro-6H-1,6-naphthyridin-5-one (200 mg, 1.1 mmol) in ethylene glycol (7 mL) and tert-butanol (7 mL) was added methylamine (2 M, THF solution, 2.8 mL, 5.48 mmol), and the mixture was stirred at 220 °C for 2 h. When completion of the reaction was indicated by LCMS, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to give the title compound (170 mg, 88%) as a white solid. LCMS (ESI, m / z): 178 [M+H] +

[0185] Step 4: Synthesis of 2-(methylamino)-3-nitro-7,8-dihydro-1,6-naphthyridin-5(6H)-one To a stirred solution of 2-(methylamino)-7,8-dihydro-6H-1,6-naphthyridin-5-one (170 mg, 0.96 mmol) in H2SO4 (2 mL) was added KNO3 (194 mg, 1.92 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 h. When completion of the reaction was indicated by LCMS, the mixture was quenched with water (20 mL) at 0 °C, the solution was adjusted to pH 8 - 9 with sodium bicarbonate, and then extracted with ethyl acetate (3 x 30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to give the title compound (200 mg, 94%) as a yellow solid. LCMS (ESI, m / z): 223 [M+H] +

[0186] Intermediate 4. (R)-Tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide

Chemical Structure

[0187] Step 1: (3aR)-Tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1-oxide To a solution of imidazole (17.4 g, 256 mmol) in DCM (40 mL), a solution of SOCl2 (9.14 g, 76.82 mmol) in DCM (80 mL) was added dropwise under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature for 1 hour. To the above mixture, a solution of (S)-morpholin-3-ylmethanol (5 g, 42.68 mmol) in DCM (80 mL) was added dropwise under a nitrogen atmosphere. The mixture was stirred at room temperature overnight, and the reaction was monitored by LCMS. The resulting mixture was diluted with water (200 mL) and acidified to pH 6 with citric acid. The reaction mixture was then extracted with DCM (3 x 200 mL), the combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the title compound (6 g, 86%) was obtained as a yellow oil. LCMS (ESI, m / z): 164 [M+H]+

[0188] Step 2: (R)-Tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide To a solution of (3aR)-tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1-oxide (6 g, 36.77 mmol) and RuCl3 (938 mg, 3.68 mmol) in MeCN (200 mL), a solution of NaIO4 (8.65 g, 40.44 mmol) in water (200 mL) was added under a nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature under a nitrogen atmosphere for 0.5 hour. The reaction was monitored by LCMS. The mixed solution was concentrated under reduced pressure, and the resulting crude product was extracted with ethyl acetate (2 x 300 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound (3.2 g, 48%) as a white solid. LCMS (ESI, m / z): 180 [M+H]+

[0189] Intermediate 5. tert-Butyl (S)-(1-(2-(1-(Cyclopropylmethyl)-7-hydroxy-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate

Chemical formula

[0190] Step 1: Ethyl 7-benzyloxy-1H-indole-2-carboxylate To a solution of 2-benzyloxyaniline (15 g, 75.28 mmol) and ethyl 2-oxopropanoate (19.23 g, 165.6 mmol) in DMSO (600 mL), AcOH (4.52 g, 75.3 mmol) and Pd(OAc)2 (1.7 g, 7.5 mmol) were added under a nitrogen atmosphere, and the mixture was stirred at 70 °C for 16 h under an oxygen atmosphere. Then water (1 L) was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 x 1 L), washed with water (2 x 1 L) and brine (2 x 1 L), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title compound (8 g, 35.9%) as a pale yellow solid. LCMS (ESI, m / z): 296 [M+H]+

[0191] Step 2: (7-(Benzyloxy)-1H-indol-2-yl)methanol Ethyl 7-benzyloxy-1H-indole-2-carboxylate (8 g, 27.1 mmol) was reacted according to General Procedure 3. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (4.5 g, 62%) as a pale yellow solid. LCMS (ESI, m / z): 254 [M+H]+

[0192] Step 3: 7-(Benzyloxy)-1H-indole-2-carbaldehyde (7-Benzyloxy-1H-indol-2-yl)methanol (4.5 g, 17.7 mmol) was reacted according to General Procedure 4. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (4 g, 90%) as a pale yellow solid. LCMS (ESI, m / z): 252 [M+H]+

[0193] Step 4: 7-(Benzyloxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde 7-Benzyloxy-1H-indole-2-carbaldehyde (4 g, 15.9 mmol) was reacted with Cs2CO3 (15.6 g, 47.7 mmol) and bromomethylcyclopropane (3.2 g, 23.9 mmol) according to General Procedure 5. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (4.1 g, 84%) as a yellow solid. LCMS (ESI, m / z): 306 [M+H]+

[0194] Step 5: tert-Butyl (S)-(1-(2-(7-(benzyloxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate A solution of 7-benzyloxy-1-(cyclopropylmethyl)indole-2-carbaldehyde (2.3 g, 7.5 mmol) and Intermediate 7 (3 g, 7.5 mmol) was reacted according to General Procedure 11. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (2.4 g, 49%) as a pale yellow solid. LCMS (ESI, m / z): 653 [M+H]+

[0195] Step 6: tert-Butyl (S)-(1-(2-(1-(Cyclopropylmethyl)-7-hydroxy-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate A solution of tert-butyl (S)-(1-(2-(7-(Benzyloxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (2.4 g, 3.7 mmol) was reacted according to General Procedure 9. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:3) to give the title compound (1.5 g, 73% yield) as a light brown solid. LCMS (ESI, m / z): 563 [M+H]+

[0196] Intermediate 6. 3-Amino-2-(methylamino)-7,8-dihydro-1,6-naphthyridin-5(6H)-one [Chemical formula] To a solution of Intermediate 3 (13 g, 58.5 mmol) in methanol (300 mL) was added a solution of NH4Cl (31.3 g, 585 mmol) in water (100 mL), and then Zn (38 g, 585 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The solid was filtered off, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by flash column chromatography (C18 silica) to give the title compound (3 g, 27%) as a yellow solid. LCMS (ESI, m / z): 193 [M+H]+

[0197] Intermediate 7. tert-Butyl (S)-(1-(3-Amino-2-(methylamino)-5-oxo-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3-fluoropropan-2-yl)carbamate [Chemical formula] To a solution of tert-butyl (S)-(1-fluoro-3-(2-(methylamino)-3-nitro-5-oxo-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)propan-2-yl)carbamate (10 g, 22.6 mmol) in methanol (200 mL) was added a solution of NH4Cl (12.1 g, 226 mmol) in water (50 mL), followed by the slow addition of Zn (14.5 g, 226 mmol) portionwise. The mixture was stirred at room temperature for 2 hours. The solid was filtered off and the solvent was distilled off under reduced pressure. The resulting crude product was purified by flash column chromatography (C18 silica) to give the title compound (7.6 g, 92%) as a pale yellow solid. LCMS (ESI, m / z): 368 [M+H]+

[0198] Example 1. (S)-7-(2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical formula

[0199] Step 1: Synthesis of 1-(cyclopropylmethyl)-7-methoxy-1H-indole 7-Methoxy-1H-indole (1 g, 6.79 mmol) was reacted with bromomethylcyclopropane (1.3 g, 10.19 mmol) according to General Procedure 7. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100:1) to give 1-(cyclopropylmethyl)-7-methoxy-indole (1.35 g, 99%) as a yellow oil. LCMS (ESI, m / z): 202 [M+H]+

[0200] Step 2: Synthesis of 1-(cyclopropylmethyl)-7-methoxy-1H-indole-2-carbaldehyde To a solution of 1-(cyclopropylmethyl)-7-methoxy-indole (500 mg, 2.48 mmol) in THF (20 mL) was added dropwise n-butyllithium (2.5 M, n-hexane solution, 1.97 mL, 4.97 mmol) little by little at -78 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. To the above mixture was added dropwise DMF (0.38 mL, 4.97 mmol) at -78 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. Then saturated aqueous NH4Cl solution (20 mL) was added at -58 °C to quench the reaction, and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 15:1) to give the title compound (133 mg, 23%) as a yellow oil. LCMS (ESI, m / z): 230 [M+H]+

[0201] Step 3: Synthesis of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate Intermediate 2 (50 mg, 0.13 mmol) was reacted with 1-(cyclopropylmethyl)-7-methoxy-indole-2-carbaldehyde (29 mg, 0.13 mmol) according to General Procedure 6. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:3) to give the title compound (32 mg, 44%) as a pale yellow solid. LCMS (ESI, m / z): 577 [M+H]+

[0202] Step 4: Synthesis of (S)-7-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl (S)-(1-(2-(1-(Cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (32 mg, 0.06 mmol) was reacted according to General Procedure 2. The crude product obtained was purified by preparative HPLC (Method A) to give the title compound (14.3 mg, 53%) as a white solid. LCMS (ESI, m / z): 477 [M+H]+; LCMS RT: 1.942 min (Method B)

[0203] The compounds of Examples 2 to 16 in Table 1 were obtained using appropriate alkylating agents in Step 1 in the same procedure as for the preparation of the compound of Example 1.

Table 3

Table 4

Table 5

Table 6

Table 7

[0204] Example 17. (S)-7-(2-Amino-3-fluoropropyl)-2-(1-(isoxazol-5-ylmethyl)-7-methyl-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chem.

[0205] Step 1: Synthesis of (7-Methyl-1H-indol-2-yl)methanol 7-Methyl-1H-indole-2-carboxylate (1 g, 4.9 mmol) was reacted according to General Procedure 3. The crude product obtained was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound (700 mg, 88%) as a yellow solid. LCMS (ESI, m / z): 162 [M+H]+

[0206] Step 2: Synthesis of 7-methyl-1H-indole-2-carbaldehyde (7-Methyl-1H-indol-2-yl)methanol (700 mg, 4.3 mmol) was reacted according to General Procedure 4. The crude product obtained was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound (500 mg, 73%) as a yellow solid. LCMS (ESI, m / z): 160 [M+H]+

[0207] Step 3: Synthesis of 1-(isoxazol-5-ylmethyl)-7-methyl-1H-indole-2-carbaldehyde 7-Methyl-1H-indole-2-carbaldehyde (100 mg, 0.63 mmol) was reacted with 5-(bromomethyl)isoxazole (204 mg, 1.26 mmol) according to General Procedure 5 and stirred at 50 °C for 2 h. The reaction was monitored by LCMS. Then water was added (30 mL) to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL), washed with water (2 x 30 mL) and brine (2 x 30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title compound (95 mg, 63%) as a yellow oil. LCMS (ESI, m / z): 241 [M+H]+

[0208] Step 4: Synthesis of tert-butyl (S)-(1-fluoro-3-(2-(1-(isoxazol-5-ylmethyl)-7-methyl-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)propan-2-yl)carbamate 1-(Isoxazol-5-ylmethyl)-7-methyl-1H-indole-2-carbaldehyde (95 mg, 0.39 mmol) was reacted with Intermediate 2 (186 mg, 0.47 mmol) according to General Procedure 6. The crude product obtained was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (80 mg, 34%) as a yellow solid. LCMS (ESI, m / z): 588 [M+H]+

[0209] Step 5: Synthesis of (S)-7-(2-amino-3-fluoropropyl)-2-(1-(isoxazol-5-ylmethyl)-7-methyl-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl (S)-(1-fluoro-3-(2-(1-(isoxazol-5-ylmethyl)-7-methyl-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)propan-2-yl)carbamate (80 mg, 0.14 mmol) was reacted according to General Procedure 2. The crude product obtained was purified by preparative HPLC (Method E) to give the title compound (16.1 mg, 24%) as a white solid. LCMS (ESI, m / z): 488 [M+H]+; LCMS RT: 1.467 min (Method B)

[0210] The compounds of Examples 18 - 21 in Table 2 were obtained in the same procedure as the preparation of the compound of Example 17, using appropriate indole-2-carbaldehyde and alkylating agent in Step 3.

Table 8

Table 9

[0211] Example 22. (S)-7-(2-Amino-3-fluoropropyl)-2-(5-fluoro-1-(isoxazol-5-ylmethyl)-7-methoxy-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical formula

[0212] Step 1: Synthesis of ethyl 5-fluoro-7-methoxy-1H-indole-2-carboxylate To a solution of 4-fluoro-2-methoxy-aniline (2.8 g, 19.8 mmol) in DMSO (200 mL) were added ethyl 2-oxopropanoate (4.6 g, 39.6 mmol), Pd(OAc)2 (889 mg, 3.97 mmol) and AcOH (1.2 mL, 19.8 mmol) under a nitrogen atmosphere, and the mixture was stirred at 70 °C overnight under an oxygen atmosphere. The reaction was monitored by LCMS. Then water (600 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (600 mL), washed with water (2 x 600 mL) and brine (2 x 600 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (2.5 g, 53%) as a yellow solid. LCMS (ESI, m / z): 238 [M+H]+

[0213] Step 2: Synthesis of (5-fluoro-7-methoxy-1H-indol-2-yl)methanol A solution of ethyl 5-fluoro-7-methoxy-1H-indole-2-carboxylate (200 mg, 0.84 mmol) was reacted according to General Procedure 3. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (120 mg, 73%) as a yellow oil. LCMS (ESI, m / z): 196 [M+H]+

[0214] Step 3: Synthesis of 5-fluoro-7-methoxy-1H-indole-2-carbaldehyde (5-Fluoro-7-methoxy-1H-indol-2-yl)methanol (164 mg, 0.84 mmol) was reacted according to General Procedure 4. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (100 mg, 62%) as a yellow solid. LCMS (ESI, m / z): 194 [M+H]+

[0215] Step 4: Synthesis of 5-fluoro-1-(isoxazol-5-ylmethyl)-7-methoxy-1H-indole-2-carbaldehyde 5-Fluoro-7-methoxy-1H-indole-2-carbaldehyde (100 mg, 0.52 mmol) was reacted with 5-(bromomethyl)isoxazole (126 mg, 0.78 mmol) according to General Procedure 5. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (120 mg, 84%) as a yellow solid. LCMS (ESI, m / z): 275 [M+H]+

[0216] Step 5: Synthesis of tert-butyl (S)-(1-fluoro-3-(2-(5-fluoro-1-(isoxazol-5-ylmethyl)-7-methoxy-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)propan-2-yl)carbamate 5-Fluoro-1-(isoxazol-5-ylmethyl)-7-methoxy-1H-indole-2-carbaldehyde (50 mg, 0.18 mmol) was reacted with Intermediate 2 (144 mg, 0.36 mmol) according to General Procedure 6. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (60 mg, 53%) as a yellow solid. LCMS (ESI, m / z): 622 [M+H]+

[0217] Step 6: Synthesis of (S)-7-(2-amino-3-fluoropropyl)-2-(5-fluoro-1-(isoxazol-5-ylmethyl)-7-methoxy-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl (S)-(1-fluoro-3-(2-(5-fluoro-1-(isoxazol-5-ylmethyl)-7-methoxy-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)propan-2-yl)carbamate (50 mg, 0.08 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method F) to give the title compound (21.7 mg, 50%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.52 (s, 1H), 8.33 - 8.30 (m, 4H), 7.32 (s, 1H), 7.09 (d, J = 7.0 Hz, 1H), 6.86 (d, J = 7.0 Hz, 1H), 6.30 (s, 2H), 5.99 (d, J = 1.8 Hz, 1H), 4.82 - 4.57 (m, 2H), 3.95 (d, J = 1.9 Hz, 6H), 3.89 - 3.80 (m, 2H), 3.78 - 3.69 (m, 3H), 3.33 (t, J = 6.4 Hz, 2H); LCMS (ESI, m / z): 522 [M+H]+; LCMS RT: 1.489 min (Method B)

[0218] Example 23. (S)-7-(2-Amino-3-fluoropropyl)-2-(6-fluoro-1-(isoxazol-5-ylmethyl)-7-methoxy-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one Example 23 was synthesized in the same synthetic route as Example 22, starting from 4-fluoro-2-methoxy-aniline in Step 1. The obtained crude product was purified by preparative HPLC (Method F) to give the title compound (15.8 mg, 36%) as a white solid. LCMS (ESI, m / z): 522 [M+H]+; LCMS RT: 1.491 min (Method D)

[0219] Example 24. (R)-7-(2-Aminopropyl)-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical Structure

[0220] Step 1: Synthesis of 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one Intermediate 3 (170 mg, 0.77 mmol) was reacted with 1-(cyclopropylmethyl)indole-2-carbaldehyde (168 mg, 0.84 mmol) according to General Procedure 6. The obtained residue was separated by preparative TLC (DCM:MeOH = 25:1) to give 2-[1-(cyclopropylmethyl)indol-2-yl]-3-methyl-6,7-dihydro-5H-imidazo[4,5-b][1,6]naphthyridin-8-one (170 mg, 60%) as a yellow oil. LCMS (ESI, m / z): 372 [M+H]+

[0221] Step 2: Synthesis of tert-butyl (R)-(1-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)propan-2-yl)carbamate 2-(1-(Cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one (60 mg, 0.16 mmol) was reacted with tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (58 mg, 0.24 mmol) according to General Procedure 1. The resulting residue was purified by preparative TLC (DCM:MeOH = 25:1) to give the title compound (50 mg, 57%) as a yellow solid. LCMS (ESI, m / z): 529 [M+H]+

[0222] Step 3: Synthesis of (R)-7-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl (R)-(1-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)propan-2-yl)carbamate (50 mg, 0.09 mmol) was reacted according to General Procedure 2. The resulting residue was purified by preparative HPLC (Method E) to give the title compound (27.1 mg, 67%) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.88 (s, 3H), 7.72 (dd, J = 8.1 Hz, J = 6.6 Hz, 2H), 7.36 - 7.30 (m, 1H), 7.26 (s, 1H), 7.19 - 7.14 (m, 1H), 4.59 (d, J = 7.0 Hz, 2H), 4.01 (s, 3H), 3.85 - 3.67 (m, 3H), 3.65 - 3.50 (m, 2H), 3.32 (t, J = 6.6 Hz, 2H), 1.26 (d, J = 6.2 Hz, 3H), 1.17 - 1.07 (m, 1H), 0.33 - 0.26 (m, 2H), 0.10 - 0.04 (m, 2H); LCMS (ESI, m / z): 429 [M+H]+; LCMS RT: 1.118 min (Method D)

[0223] Example 25. (R)-7-(2-Aminopropyl)-2-(7-methoxy-1-(oxazol-2-ylmethyl)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one [Chemical Structure Diagram] Example 25 was synthesized in the same synthetic route as Example 24 using an appropriate substituted indole (7-methoxy-1-(oxazol-2-ylmethyl)-1H-indole-2-carbaldehyde) in Step 1. The obtained crude product was purified by preparative HPLC (Method F) to give the title compound (10.3 mg, 62%) as a yellow solid. 11H NMR (400 MHz, methanol-d4) δ 8.62 (s, 1H), 7.68 (s, 1H), 7.33 (d, J = 8 Hz, 1H), 7.21 (s, 1H), 7.18 (t, J = 21.6 Hz, 1H), 6.92 (s, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.29 (s, 2H), 4.01 (s, 3H), 4.00 - 3.90 (m, 1H), 3.89 (s, 3H), 3.81 - 3.72 (m, 2H), 3.71 - 3.63 (m, 1H), 3.62 - 3.50 (m, 1H), 3.40 (t, J = 6.8 Hz, 2H), 1.40 (s, 3H); LCMS (ESI, m / z): 486 [M + H]+; LCMS RT: 0.815 min (Method D)

[0224] Example 26. (S)-2-(1-((1-Fluorocyclopropyl)methyl)-7-methoxy-1H-indol-2-yl)-3-methyl-7-(morpholin-3-ylmethyl)-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical formula

[0225] Step 1: Synthesis of Methyl (1-fluorocyclopropyl)methanesulfonate To a stirred solution of (1-fluorocyclopropyl)methanol (200 mg, 2.22 mmol) in DCM (10 mL) under a nitrogen atmosphere, Et3N (0.62 mL, 4.44 mmol) and MsCl (0.21 mL, 2.66 mmol) were added at 0 °C and stirred at room temperature for 1 hour. The reaction was monitored by TLC and LCMS. Water (20 mL) was added to quench the reaction and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (2 x 40 mL), dried over anhydrous sodium sulfate, concentrated, and the title compound (200 mg, 53%) was obtained as a yellow oil. LCMS (ESI, m / z): 169 [M + H]+

[0226] Step 2: Synthesis of 1-((1-fluorocyclopropyl)methyl)-7-methoxy-1H-indole-2-carbaldehyde 7-Methoxy-1H-indole-2-carbaldehyde (140 mg, 0.8 mmol) was reacted with methyl (1-fluorocyclopropyl)methanesulfonate (201 mg, 1.2 mmol) according to General Procedure 5. The resulting crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound (110 mg, 55%) as a yellow solid. LCMS (ESI, m / z): 248 [M+H]+

[0227] Step 3: Synthesis of 2-(1-((1-fluorocyclopropyl)methyl)-7-methoxy-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one Intermediate 3 (110 mg, 0.5 mmol) was reacted with 1-((1-fluorocyclopropyl)methyl)-7-methoxy-1H-indole-2-carbaldehyde (122 mg, 0.5 mmol) according to General Procedure 6. The resulting crude product was purified by preparative TLC (DCM / methanol = 30:1) to give the title compound (30 mg, 14%) as a yellow solid. LCMS (ESI, m / z): 420 [M+H]+

[0228] Step 4: Synthesis of (S)-3-((2-(1-((1-fluorocyclopropyl)methyl)-7-methoxy-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)methyl)morpholine-4-sulfonic acid 2-(1-((1-Fluorocyclopropyl)methyl)-7-methoxy-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one (30 mg, 0.07 mmol) was reacted with intermediate 4 (15 mg, 0.09 mmol) according to General Procedure 1. The resulting crude product was purified by flash chromatography to give the title compound (40 mg, 93%) as a yellow solid. LCMS (ESI, m / z): 599 [M+H]+

[0229] Step 5: Synthesis of (S)-2-(1-((1-Fluorocyclopropyl)methyl)-7-methoxy-1H-indol-2-yl)-3-methyl-7-(morpholin-3-ylmethyl)-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one (S)-3-((2-(1-((1-Fluorocyclopropyl)methyl)-7-methoxy-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)methyl)morpholine-4-sulfonic acid (40 mg, 0.07 mmol) was reacted according to General Procedure 8. The resulting crude product was purified by preparative HPLC (Method F) to give the title compound (21.8 mg, 62%) as a white solid. 1 1H NMR (400 MHz, DMSO-d6 + D2O): δ 8.53 (s, 1H), 7.34 - 7.29 (m, 1H), 7.24 (s, 1H), 7.11 (t, J = 7.9 Hz, 1H), 6.91 - 6.84 (m, 1H), 5.36 (d, J = 21.6 Hz, 2H), 4.04 - 3.99 (m, 1H), 3.93 (d, J = 1.7 Hz, 7H), 3.82 - 3.65 (m, 4H), 3.63 - 3.47 (m, 3H), 3.34 - 3.24 (m, 3H), 3.12 - 3.01 (m, 1H), 0.79 - 0.67 (m, 2H), 0.53 - 0.45 (m, 2H); LCMS (ESI, m / z): 519 [M+H]+; LCMS RT: 1.550 min (Method B)

[0230] The compounds of Examples 27 and 28 in Table 3 were obtained in the same procedure as the preparation of the compound of Example 26 using an appropriate alkylating agent in Step 2. [Table 10]

[0231] Example 29. (S)-2-(7-(1-Acetylpiperidin-4-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-7-(2-amino-3-fluoropropyl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one [Chemical formula]

[0232] Step 1: Synthesis of Ethyl 7-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate To a solution of ethyl 7-bromo-1-(cyclopropylmethyl)indole-2-carboxylate (150 mg, 0.47 mmol) and tert-butyl 4-iodopiperidine-1-carboxylate (145 mg, 0.47 mmol) in DMF (6 mL) were added Ir[dF(CF3)ppy]2(dtbbpy)PF6 (52.7 mg, 0.05 mmol), NiCl2·dimethoxyethane adduct (5.17 mg, 0.02 mmol), dtbbpy (6.3 mg, 0.02 mmol), (TMS)3SiH (116 mg, 0.47 mmol) and Na2CO3 (98.7 mg, 0.93 mmol). The reaction mixture was stirred and irradiated with a blue LED light overnight under a nitrogen atmosphere (irradiated at a distance of 7 cm, and the reaction temperature was maintained at 25 °C with a cold air blower). The reaction was monitored by LCMS. Then water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL), washed with water (2 x 20 mL) and brine (2 x 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (30 mg, 15%) as a pale yellow solid. LCMS (ESI, m / z): 427 [M+H]+

[0233] Step 2: Synthesis of tert-butyl 4-(1-(cyclopropylmethyl)-2-(hydroxymethyl)-1H-indol-7-yl)piperidine-1-carboxylate To a solution of ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (110 mg, 0.26 mmol) in THF (3 mL) was added LiBH4 (0.02 mL, 1.03 mmol) at 0 °C, and the mixture was stirred at 50 °C overnight. The reaction was monitored by LCMS. Then water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 x 10 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (40 mg, 40%) as a pale yellow solid. LCMS (ESI, m / z): 385 [M+H]+

[0234] Step 3: Synthesis of tert-butyl 4-(1-(cyclopropylmethyl)-2-formyl-1H-indol-7-yl)piperidine-1-carboxylate tert-Butyl 4-(1-(cyclopropylmethyl)-2-(hydroxymethyl)-1H-indol-7-yl)piperidine-1-carboxylate (55 mg, 0.14 mmol) was reacted according to General Procedure 4. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 6:1) to give the title compound (50 mg, 91%) as a pale yellow solid. LCMS (ESI, m / z): 383 [M+H]+

[0235] Step 4: Synthesis of 1-(cyclopropylmethyl)-7-(piperidin-4-yl)-1H-indole-2-carbaldehyde tert-Butyl 4-(1-(cyclopropylmethyl)-2-formyl-1H-indol-7-yl)piperidine-1-carboxylate (50 mg, 0.13 mmol) was reacted according to General Procedure 2. The resulting solution was concentrated under reduced pressure to give the title compound (35 mg, 95%) as a pale yellow solid. LCMS (ESI, m / z): 283 [M+H]+

[0236] Step 5: Synthesis of 7-(1-acetylpiperidin-4-yl)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde To a solution of 1-(cyclopropylmethyl)-7-(piperidin-4-yl)-1H-indole-2-carbaldehyde (50 mg, 0.18 mmol) in DCM (5 mL) were added acetyl chloride (27.8 mg, 0.35 mmol) and DIEA (0.05 mL, 0.71 mmol), and the mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. Then water (10 mL) was added to quench the reaction, and the mixture was extracted with DCM (3 x 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography to afford the title compound (30 mg, 52%) as a pale yellow solid. LCMS (ESI, m / z): 325 [M+H]+

[0237] Step 6: Synthesis of tert-butyl (S)-(1-(2-(7-(1-acetylpiperidin-4-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate 7-(1-Acetylpiperidin-4-yl)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (55 mg, 0.17 mmol) was reacted with intermediate 2 (61.3 mg, 0.15 mmol) according to General Procedure 6. The resulting crude product was purified by column chromatography (DCM / MeOH = 20:1) to afford the title compound (25 mg, 24%) as a pale yellow solid. LCMS (ESI, m / z): 672 [M+H]+

[0238] Step 7: Synthesis of (S)-2-(7-(1-acetylpiperidin-4-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-7-(2-amino-3-fluoropropyl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl (S)-(1-(2-(7-(1-acetylpiperidin-4-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (20 mg, 0.03 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method F) to give the title compound (12.1 mg, 68%) as a white solid. LCMS (ESI, m / z): 572 [M+H]+; LCMS RT: 2.489 min (Method B)

[0239] The compounds of Examples 30 - 32 in Table 4 were obtained in a similar procedure to the preparation of the compound of Example 29 using the appropriate acylating agent in Step 5.

Table 11

[0240] Example 33. (S)-7-(2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chem.

[0241] Step 1: Synthesis of methyl 6-acetyl-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridine-2-carboxylate Methyl 6-chloro-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridine-2-carboxylate (264 mg, 1 mmol) and tributyl(1-ethoxyvinyl)stannane (720 mg, 1.9 mmol) in 1,4-dioxane (10 mL) were added with Davephos (78 mg, 0.2 mmol) and Pd(dppf)Cl2 (73 mg, 0.1 mmol) under a nitrogen atmosphere, and the mixture was stirred at room temperature for 0.5 h. To the above mixture, HCl (1 M aqueous solution) was added at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the title compound (130 mg, 47.8%) as a yellow oil. LCMS (ESI, m / z): 273 [M+H]+

[0242] Step 2: Synthesis of methyl 1-(cyclopropylmethyl)-6-(1-hydroxy-1-methyl-ethyl)pyrrolo[2,3-b]pyridine-2-carboxylate To a solution of methyl 6-acetyl-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridine-2-carboxylate (130 mg, 0.5 mmol) in THF (5 mL), methylmagnesium bromide (3 M, diethyl ether solution, 0.3 mL, 0.9 mmol) was added at 0 °C, and the mixture was stirred from 0 °C to room temperature for 4 h. Then saturated NH4Cl aqueous solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL), washed with water (2×10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound (110 mg, 79.9%) as a pale yellow solid. LCMS (ESI, m / z): 289 [M+H]+

[0243] Step 3: Synthesis of 2-[1-(cyclopropylmethyl)-2-(hydroxymethyl)pyrrolo[2,3-b]pyridin-6-yl]propan-2-ol Methyl 1-(cyclopropylmethyl)-6-(1-hydroxy-1-methylethyl)pyrrolo[2,3-b]pyridine-2-carboxylate (80 mg, 0.3 mmol) was reacted according to General Procedure 3. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (70 mg, 96.9%) as a pale yellow solid. LCMS (ESI, m / z): 261 [M+H]+

[0244] Step 4: Synthesis of 1-(cyclopropylmethyl)-6-(1-hydroxy-1-methylethyl)pyrrolo[2,3-b]pyridine-2-carbaldehyde 2-[1-(Cyclopropylmethyl)-2-(hydroxymethyl)pyrrolo[2,3-b]pyridin-6-yl]propan-2-ol (70 mg, 0.3 mmol) was reacted according to General Procedure 4. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (50 mg, 71.9%) as a pale yellow solid. LCMS (ESI, m / z): 259 [M+H]+

[0245] Step 5: Synthesis of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate 1-(Cyclopropylmethyl)-6-(1-hydroxy-1-methylethyl)pyrrolo[2,3-b]pyridine-2-carbaldehyde (40 mg, 0.15 mmol) was reacted with Intermediate 2 (74 mg, 0.2 mmol) according to General Procedure 6. The resulting crude product was purified by column chromatography (ethyl acetate) to give the title compound (30 mg, 31.9%) as a pale yellow solid. LCMS (ESI, m / z): 606 [M+H]+

[0246] Step 6: Synthesis of (S)-7-(2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl (S)-(1-(2-(1-(cyclopropylmethyl)-6-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropyl)carbamate (30 mg, 0.05 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method F) to give the title compound (15.6 mg, 61.6%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.29 (s, 3H), 8.11 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 5.28 (s, 1H), 4.81 - 4.70 (m, 1H), 4.72 - 4.60 (m, 3H), 4.04 (s, 3H), 3.88 - 3.70 (m, 5H), 3.4 - 3.3 (m, 2H), 1.55 (s, 6H), 1.29 - 1.25 (m, 1H), 0.37 - 0.23 (m, 4H); LCMS (ESI, m / z): 506 [M+H]+; LCMS RT: 0.819 min (Method B)

[0247] Example 34. (S)-5-(((2-(7-((S)-2-Amino-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)oxazolidin-2-one

Chemical Structure

[0248] Step 1: Synthesis of tert-butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-(((S)-2-oxooxazolidin-5-yl)methoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate Intermediate 5 (50 mg, 0.09 mmol) was reacted with (S)-5-(chloromethyl)oxazolidin-2-one (23 mg, 0.17 mmol) according to General Procedure 5. The crude product obtained was purified by column chromatography (DCM / MeOH = 10:1) to give the title compound (40 mg, 68%) as a yellow oil. LCMS (ESI, m / z): 662 [M+H]+

[0249] Step 2: Synthesis of (S)-5-(((2-(7-((S)-2-amino-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)oxazolidin-2-one tert-Butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-(((S)-2-oxooxazolidin-5-yl)methoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (40 mg, 0.06 mmol) was reacted according to General Procedure 4. The crude product obtained was purified by preparative HPLC (Method E) to give the title compound (12.5 mg, 36%) as a pale yellow solid. 11H NMR (400 MHz, DMSO-d6): δ 8.53 (s, 1H), 8.29 (s, 3H), 7.66 (s, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.21 (s, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 5.10 - 5.00 (m, 1H), 4.84 - 4.58 (m, 4H), 4.44 - 4.38 (m, 1H), 4.34 - 4.28 (m, 1H), 3.97 (s, 3H), 3.93 - 3.81 (m, 2H), 3.81 - 3.67 (m, 4H), 3.55 - 3.42 (m, 1H), 3.34 (t, J = 6.6 Hz, 2H), 1.02 - 0.93 (m, 1H), 0.26 - 0.13 (m, 2H), -0.07 - -0.16 (m, 2H); LCMS (ESI, m / z): 562 [M+H]+; LCMS RT: 1.385 min (Method B)

[0250] Example 35. 7 - ((S)-2 - Amino - 3 - fluoropropyl)-2-(1-(cyclopropylmethyl)-7 - ((2,2 - dimethyl - 5 - oxopyrrolidin - 3 - yl)methoxy)-1H - indol - 2 - yl)-3 - methyl - 3,5,6,7 - tetrahydro - 8H - imidazo[4,5 - b][1,6]naphthyridin - 8 - one

Chemical Structure

[0251] Step 1: Synthesis of 4 - (hydroxymethyl)-5,5 - dimethyl - pyrrolidin - 2 - one To a stirred solution of ethyl 2,2-dimethyl-5-oxopyrrolidine-3-carboxylate (100 mg, 0.54 mmol) in THF (5 mL) was added dropwise LiBH4 (2 M, THF solution, 0.1 mL, 2.16 mmol) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere, and the reaction was monitored by TLC and LCMS. The reaction was quenched by adding saturated aqueous NH4Cl solution. The resulting mixture was concentrated under reduced pressure and purified by flash column chromatography to give the title compound (80 mg, 103.5%) as a white solid. LCMS (ESI, m / z): 144 [M+H] +

[0252] Step 2: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-((2,2-dimethyl-5-oxopyrrolidin-3-yl)methoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate Intermediate 5 (50 mg, 0.09 mmol) was reacted with 4-(hydroxymethyl)-5,5-dimethyl-pyrrolidin-2-one (64 mg, 0.44 mmol) according to General Procedure 10. The resulting crude product was purified by preparative TLC to give the title compound (40 mg, 65.4%) as a yellow oil. LCMS (ESI, m / z): 688 [M+H] +

[0253] Step 3: Synthesis of 7-((S)-2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-((2,2-dimethyl-5-oxopyrrolidin-3-yl)methoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl ((2S)-1-(2-(1-(Cyclopropylmethyl)-7-((2,2-dimethyl-5-oxopyrrolidin-3-yl)methoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (40 mg, 0.306 mmol) was reacted according to General Procedure 2. The resulting crude material was purified by preparative HPLC (Method E) to give the title compound (28.5 mg, 82.7%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.39 - 8.22 (m, 3H), 7.78 (s, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.19 (s, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 4.84 - 4.71 (m, 2H), 4.70 - 4.59 (m, 1H), 4.40 - 4.34 (m, 1H), 4.14 - 4.07 (m, 2H), 3.97 (s, 3H), 3.91 - 3.82 (m, 2H), 3.79 - 3.70 (m, 3H), 3.33 (t, J = 6.6 Hz, 2H), 2.69 - 2.59 (m, 1H), 2.45 - 2.39 (m, 1H), 2.38 - 2.29 (m, 1H), 1.35 (s, 3H), 1.21 (s, 3H), 1.06 - 0.92 (m, 1H), 0.25 - 0.15 (m, 2H), -0.11--0.27 (m, 2H); LCMS (ESI, m / z): 588 [M+H]+; LCMS RT: 1.447 min (Method D)

[0254] The compounds of Examples 36 - 58 in Table 5 were obtained in the same procedure as the preparation of the compound of Example 35 using appropriate ester or alcohol starting materials.

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

[0255] Example 59. 7-((S)-2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(((S)-5-oxopyrrolidin-3-yl)methoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical Structure

[0256] Step 1: Synthesis of [7-benzyloxy-1-(cyclopropylmethyl)indol-2-yl]methanol To a solution of 7-benzyloxy-1-(cyclopropylmethyl)indole-2-carbaldehyde (5.0 g, 16.37 mmol) in methanol (150 mL) was added sodium borohydride (0.62 g, 16.37 mmol) portionwise at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 0 °C for 4 h. The reaction was monitored by TLC and LCMS. Water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 × 80 mL). The combined organic extracts were washed with water (2 × 100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the title compound (4.8 g, 95%) as a brown oil. LCMS (ESI, m / z): 308 [M+H]+

[0257] Step 2: Synthesis of [7-benzyloxy-1-(cyclopropylmethyl)indol-2-yl]methoxy-tert-butyl-dimethyl-silane To a solution of [7-benzyloxy-1-(cyclopropylmethyl)indol-2-yl]methanol (4.8 g, 15.62 mmol) in DCM (100 mL) was added imidazole (3.19 g, 46.85 mmol) at room temperature, and then tert-butylchlorodimethylsilane (2.82 g, 18.74 mmol) was added at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC and LCMS. Water (100 mL) was added to quench the reaction, and the mixture was extracted with DCM (2 × 70 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the title compound (6.0 g, 91%) as a brown oil. LCMS (ESI, m / z): 422 [M+H]+

[0258] Step 3: Synthesis of 2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(cyclopropylmethyl)indol-7-ol [7-Benzyloxy-1-(cyclopropylmethyl)indol-2-yl]methoxy-tert-butyl-dimethylsilane (3.5 g, 8.3 mmol) / ethyl acetate (30 mL) and methanol (70 mL) were reacted according to General Procedure 9. The resulting residue was purified by flash column chromatography to give the title compound (2.5 g, 91%) as a brown oil. LCMS (ESI, m / z): 332 [M+H]+

[0259] Step 4: Synthesis of (4S)-4-[[2-[[tert-Butyl(dimethyl)silyl]oxymethyl]-1-(cyclopropylmethyl)indol-7-yl]oxymethyl]pyrrolidin-2-one 2-[[tert-Butyl(dimethyl)silyl]oxymethyl]-1-(cyclopropylmethyl)indol-7-ol (2.1 g, 6.33 mmol) and (S)-4-(hydroxymethyl)pyrrolidin-2-one (2.19 g, 19 mmol) were reacted according to General Procedure 10. The resulting crude product was purified by flash column chromatography to give the title compound (2.1 g, 77%) as a brown oil. LCMS (ESI, m / z): 429 [M+H]+

[0260] Step 5: Synthesis of (4S)-4-[[1-(cyclopropylmethyl)-2-(hydroxymethyl)indol-7-yl]oxymethyl]pyrrolidin-2-one To a stirred solution of (4S)-4-[[2-[[tert-Butyl(dimethyl)silyl]oxymethyl]-1-(cyclopropylmethyl)indol-7-yl]oxymethyl]pyrrolidin-2-one (2.1 g, 4.9 mmol) / acetonitrile (20 mL), hydrochloric acid (1 M, 10 mL, 4.9 mmol) was added at room temperature and the mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with ethyl acetate (2 × 60 mL). The organic layer was washed with brine (2 × 70 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (1.25 g, 81%) as a brown solid. LCMS (ESI, m / z): 315 [M+H]+

[0261] Step 6: Synthesis of 1-(Cyclopropylmethyl)-7-[[(3S)-5-oxopyrrolidin-3-yl]methoxy]indole-2-carbaldehyde (4S)-4-[[1-(Cyclopropylmethyl)-2-(hydroxymethyl)indol-7-yl]oxymethyl]pyrrolidin-2-one (1.25 g, 3.98 mmol) was reacted according to General Procedure 4. The resulting crude product was purified by preparative TLC (DCM / MeOH = 15:1) to give the title compound (0.80 g, 64%) as a yellow oil. LCMS (ESI, m / z): 313 [M+H]+

[0262] Step 7: Synthesis of tert-butyl ((S)-1-(2-(1-(Cyclopropylmethyl)-7-(((S)-5-oxopyrrolidin-3-yl)methoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate Intermediate 2 (550 mg, 1.38 mmol) and 1-(Cyclopropylmethyl)-7-[[(3S)-5-oxopyrrolidin-3-yl]methoxy]indole-2-carbaldehyde (475 mg, 1.52 mmol) were reacted according to General Procedure 6. The resulting crude product was purified by preparative TLC (DCM / MeOH = 12:1) to give the title compound (450 mg, 49%) as a yellow solid. LCMS (ESI, m / z): 660 [M+H]+

[0263] Step 8: Synthesis of 7-((S)-2-Amino-3-fluoropropyl)-2-(1-(Cyclopropylmethyl)-7-(((S)-5-oxopyrrolidin-3-yl)methoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-(((S)-5-oxopyrrolidin-3-yl)methoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropyl)-2-yl)carbamate (450 mg, 0.68 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method A) to give the title compound (191 mg, 48.2%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.16 (s, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 4.72 (d, J = 6.9 Hz, 2H), 4.44 - 4.37 (m, 1H), 4.33 - 4.26 (m, 1H), 4.18 (d, J = 6.5 Hz, 2H), 3.95 (s, 3H), 3.82 - 3.70 (m, 2H), 3.64 - 3.57 (m, 1H), 3.55 - 3.43 (m, 2H), 3.28 (d, J = 13.3 Hz, 2H), 3.26 - 3.18 (m, 2H), 2.04 - 1.94 (m, 1H), 2.46 - 2.37 (m, 1H), 2.22 - 2.12 (m, 1H), 1.04 - 0.91 (m, 1H), 0.25 - 0.14 (m, 2H), -0.09 - -0.20 (m, 2H); LCMS (ESI, m / z): 560 [M+H]+; LCMS RT: 1.320 min (Method D)

[0264] Example 60. 7-((S)-2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(((R)-5-oxopyrrolidin-3-yl)methoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical Structure

[0265] Examples 61a and 61b. 7-((S)-2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-((S)-2-hydroxy-2-(oxazol-5-yl)ethoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one and 7-((S)-2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-((R)-2-hydroxy-2-(oxazol-5-yl)ethoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical Structure

[0266] Step 1: Synthesis of 2-benzyloxy-1-(2-triisopropylsilyloxyoxazol-5-yl)ethanol Triisopropyl(oxazol-2-yl)silane (1 g, 4.4 mmol) and a solution of 2-benzyloxyacetaldehyde (1 g, 6.6 mmol) / THF (50 mL) were added dropwise with n-butyllithium (2.5 M, n-hexane solution, 4.4 mL, 11.1 mmol) at -10 °C under a nitrogen atmosphere, and stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. Then, saturated aqueous NH4Cl solution (150 mL) was added at 0 °C to quench the reaction, and extracted with ethyl acetate (2 × 150 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound (747 mg, 44.8%) as a pale yellow solid. LCMS (ESI, m / z): 376 [M+H]+

[0267] Step 2: Synthesis of 2-(benzyloxy)-1-(2-(triisopropylsilyl)oxazol-5-yl)ethyl acetate TEA (1 mL, 5.4 mmol) was added to a solution of 2-benzyloxy-1-(2-triisopropylsilyloxyoxazol-5-yl)ethanol (670 mg, 1.8 mmol) / DCM (2 mL), and a solution of acetyl chloride (168 mg, 2.1 mmol) / DCM (0.5 mL) was added dropwise at 0 °C under a nitrogen atmosphere, stirred at room temperature for 2 hours under a nitrogen atmosphere, and the reaction was monitored by LCMS. Saturated aqueous NH4Cl solution (5 mL) was added at 0 °C to quench the reaction, and extracted with DCM (2 × 5 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the title compound (450 mg, 60.4%) as a pale yellow oil. LCMS (ESI, m / z): 418 [M+H]+

[0268] Step 3: Synthesis of 2-(hydroxy)-1-(2-(triisopropylsilyl)oxazol-5-yl)ethyl acetate 2-(Benzyloxy)-1-(2-(triisopropylsilyl)oxazol-5-yl)ethyl acetate (400 mg, 1.0 mmol) / methanol (10 mL) was reacted according to General Procedure 9. The crude product obtained was purified by flash column chromatography (C18 silica) to give the title compound (160 mg, 51.0%) as a pale yellow solid. LCMS (ESI, m / z): 328 [M+H]+

[0269] Step 4: Synthesis of 2-((2-(7-((S)-2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-1-(oxazol-5-yl)ethyl acetate 2-(Hydroxy)-1-(2-(triisopropylsilyl)oxazol-5-yl)ethyl acetate (142 mg, 0.4 mmol) was reacted with Intermediate 5 (163 mg, 0.3 mmol) according to General Procedure 10. The crude product obtained was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound as a mixture of diastereomers (80 mg, 38.6%) as a pale yellow solid. LCMS (ESI, m / z): 716 [M+H]+

[0270] Step 5: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(2-hydroxy-2-(oxazol-5-yl)ethoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropyl)carbamate A solution of 2-((2-(7-((S)-2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-1-(oxazol-5-yl)ethyl acetate (75 mg, 0.1 mmol) in THF (1 mL) and water (0.2 mL) was added with LiOH (12.5 mg, 0.5 mmol), and stirred at 50 °C for 16 h. The reaction was monitored by LCMS. This mixed product was adjusted to pH 2 with hydrochloric acid (1 M) and stirred at room temperature for 0.5 h. The mixture was extracted with ethyl acetate (2 × 10 mL), the combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by flash column chromatography (C18 silica) to give a diastereomeric mixture of the title compound (70 mg, 99.1%) as a pale yellow solid. LCMS (ESI, m / z): 674 [M+H]+

[0271] Step 6: Synthesis of 7-((S)-2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(2-hydroxy-2-(oxazol-5-yl)ethoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl ((2S)-1-(2-(1-(Cyclopropylmethyl)-7-(2-hydroxy-2-(oxazol-5-yl)ethoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (65 mg, 0.01 mmol) was reacted according to General Procedure 2. The crude product obtained was purified by chiral preparative HPLC [Column: Chiralpak IF, 2 × 25 cm, 5 μm; Mobile phase A: MTBE (0.5% 2M NH3 / MeOH), Mobile phase B: MeOH:DCM (1:1) (0.1% 2M NH3 / MeOH); Flow rate: 14 mL / min; Isocratic gradient: Elute 30% B for 32 minutes; Detection: UV (220 / 254 nm)] to give a single stereoisomer with an undetermined stereocenter of the alcohol. Example 61a (Isomer 1): Chiral HPLC retention time: 19.2 minutes; 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 7.37 (s, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.14 (s, 1H), 7.01 (d, J = 7.6 Hz, 2H), 5.74 (t, J = 6.4 Hz, 1H), 5.29 (t, J = 6.4 Hz, 1H), 4.83 - 4.82 (m, 1H), 4.70 - 4.68 (m, 1H), 4.43 - 4.42 (m, 1H), 4.33 - 4.30 (m, 1H), 4.07 - 4.03 (m, 1H), 3.96 - 3.94 (m, 4H), 3.81 - 3.72 (m, 2H), 3.64 - 3.46 (m, 5H), 1.02 - 1.0 (m, 1H), 0.19 - 0.17 (m, 2H), -0.04 - -0.13 (m, 2H); LCMS (ESI, m / z): 574 [M + H]+; LCMS RT: 0.803 minutes (Method D) Example 61b (Isomer 2): Chiral HPLC retention time: 28.11 minutes; 11H NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 8.38 (s, 1H), 7.37 (s, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.14 (s, 1H), 7.01 (d, J = 7.6 Hz, 2H), 5.74 (t, J = 6.4 Hz, 1H), 5.29 (t, J = 6.4 Hz, 1H), 4.83 - 4.82 (m, 1H), 4.70 - 4.68 (m, 1H), 4.43 - 4.42 (m, 1H), 4.33 - 4.30 (m, 1H), 4.07 - 4.03 (m, 1H), 3.96 - 3.94 (m, 4H), 3.81 - 3.72 (m, 2H), 3.64 - 3.46 (m, 5H), 1.02 - 1.0 (m, 1H), 0.19 - 0.17 (m, 2H), -0.04 - -0.13 (m, 2H); LCMS (ESI, m / z): 574 [M+H]+; LCMS RT: 1.033 min (Method D)

[0272] Example 62. 2-(7-(((R)-1-(1H-Imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-7-((S)-2-amino-3-fluoropropyl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical Structure

[0273] Step 1: Synthesis of Ethyl (R)-7-((1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (S)-1-((tert-butyldiphenylsilyl)oxy)propan-2-ol (1.8 g, 5.72 mmol) was reacted with ethyl 1-(cyclopropylmethyl)-7-hydroxy-indole-2-carboxylate (300 mg, 1.16 mmol) according to General Procedure 10. The resulting crude product was purified by flash column chromatography (DCM / MeOH = 10:1) to give the title compound (500 mg, 16%) as a yellow oil. LCMS (ESI, m / z): 556 [M+H]+

[0274] Step 2: Synthesis of ethyl (R)-1-(cyclopropylmethyl)-7-((1-hydroxypropan-2-yl)oxy)-1H-indole-2-carboxylate To a solution of ethyl (R)-7-((1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (550 mg, 0.99 mmol) in THF (10 mL) was added TBAF (10 mL) at 0 °C and the mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. Then water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL), washed with water (5 × 20 mL) and brine (5 × 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (DCM / MeOH = 10:1) to give the title compound (300 mg, 80%) as a yellow oil. LCMS (ESI, m / z): 318 [M+H]+

[0275] Step 3: Synthesis of ethyl (R)-1-(cyclopropylmethyl)-7-((1-((methylsulfonyl)oxy)propan-2-yl)oxy)-1H-indole-2-carboxylate (R)-Ethyl 1-(cyclopropylmethyl)-7-((1-hydroxypropan-2-yl)oxy)-1H-indole-2-carboxylate (200 mg, 0.63 mmol) / DCM (6 mL) was reacted with TEA (0.16 mL, 1.15 mmol) and MsCl (88 mg, 0.77 mmol) according to General Procedure 13 to give the title compound (200 mg, 80%) as a pale yellow oil. LCMS (ESI, m / z): 396 [M+H]+

[0276] Step 4: Synthesis of (R)-Ethyl 7-((1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (R)-Ethyl 1-(cyclopropylmethyl)-7-((1-((methylsulfonyl)oxy)propan-2-yl)oxy)-1H-indole-2-carboxylate (254 mg, 0.64 mmol) was reacted with 1H-imidazole (435 mg, 6.39 mmol) according to General Procedure 14. The crude product obtained was purified by column chromatography (DCM / MeOH = 10:1) to give the title compound (165 mg, 70%) as a yellow oil. LCMS (ESI, m / z): 368 [M+H]+

[0277] Step 5: Synthesis of (R)-(7-((1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol (R)-Ethyl 7-((1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (80 mg, 0.36 mmol) was reacted according to General Procedure 3. The crude product obtained was purified by column chromatography (DCM / MeOH = 10:1) to give the title compound (60 mg, 85%) as a yellow oil. LCMS (ESI, m / z): 326 [M+H]+

[0278] Step 6: Synthesis of (R)-7-((1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (R)-(7-((1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol (80 mg, 0.25 mmol) was reacted according to General Procedure 4. The resulting crude product was purified by column chromatography (DCM / MeOH = 20:1) to give the title compound (45 mg, 57%) as a yellow oil. LCMS (ESI, m / z): 324 [M+H]+

[0279] Step 7: Synthesis of tert-butyl ((S)-1-(2-(7-(((R)-1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (R)-7-((1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (45 mg, 0.14 mmol) was reacted with Intermediate 2 (66 mg, 0.17 mmol) according to General Procedure 6. The resulting crude product was purified by column chromatography (DCM / MeOH = 10:1) to give the title compound (35 mg, 37%) as a yellow oil. LCMS (ESI, m / z): 671 [M+H]+

[0280] Step 8: Synthesis of 2-(7-(((R)-1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-7-((S)-2-amino-3-fluoropropyl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl ((S)-1-(2-(7-(((R)-1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (35 mg, 0.05 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method G) to give the title compound (21.2 mg, 73%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.24 (s, 1H), 8.50 (s, 1H), 8.36 (s, 2H), 7.88 (t, J = 1.7 Hz, 1H), 7.73 (t, J = 1.6 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.19 (s, 1H), 7.09 (t, J = 7.9 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 5.32 - 5.24 (m, 1H), 4.84 - 4.58 (m, 6H), 3.96 (s, 3H), 3.91 - 3.71 (m, 5H), 3.34 (t, J = 6.5 Hz, 2H), 1.39 (d, J = 6.4 Hz, 3H), 0.87 - 0.74 (m, 1H), 0.22 - 0.10 (m, 2H), -0.21 - -0.34 (m, 2H); LCMS (ESI, m / z): 571 [M+H]+; LCMS RT: 1.258 min (Method B)

[0281] Example 63. 2-(7-(((S)-1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-7-((S)-2-amino-3-fluoropropyl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical Structure

[0282] Example 64. 7-((S)-2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-5-fluoro-7-((1-(oxazol-5-yl)propan-2-yl)oxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical formula

[0283] Step 1: Synthesis of 2-(benzyloxy)-4-fluoronitrobenzene To a solution of 5-fluoro-2-nitro-phenol (15.7 g, 99.9 mmol) in DMF (500 mL) was added (bromomethyl)benzene (25.6 g, 150 mmol) and K2CO3 (41.4 g, 299 mmol) at room temperature under a nitrogen atmosphere, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. Then water (1.5 L) was added to quench the reaction, and the mixture was extracted with ethyl acetate (1.5 L), washed with water (2 × 500 mL) and brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (24.5 g, 99.1%) as a pale yellow solid. LCMS (ESI, m / z): 248 [M+H]+

[0284] Step 2: Synthesis of 2-(benzyloxy)-4-fluoroaniline To a solution of 2-(benzyloxy)-4-fluoro-1-nitrobenzene (24.4 g, 98.7 mmol) in methanol (600 mL) was added NH4Cl (53.3 g, 987 mmol) / water (100 mL) and Zn (64.2 g, 987 mmol) at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. The solid was filtered off and the solvent was distilled off under reduced pressure. The resulting crude product was diluted with ethyl acetate (600 mL). The combined organic extracts were washed with water (2 × 500 mL) and brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the title compound (16.3 g, 76%) as a pale yellow oil. LCMS (ESI, m / z): 218 [M+H]+

[0285] Step 3: Synthesis of ethyl 7-(benzyloxy)-5-fluoro-1H-indole-2-carboxylate To a solution of 2-(benzyloxy)-4-fluoroaniline (8 g, 36.8 mmol) in DMSO (100 mL) were added Pd(OAc)2 (1.7 g, 7.3 mmol) and AcOH (2.1 mL, 36.8 mmol) at room temperature under a nitrogen atmosphere. The nitrogen gas was refilled three times and then oxygen gas was filled three times. The mixture was stirred at 70 °C overnight under an oxygen atmosphere, and the reaction was monitored by LCMS. Then water (300 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (500 mL). The combined organic extracts were washed with water (2 × 300 mL) and brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (3.8 g, 33%) as a pale yellow solid. LCMS (ESI, m / z): 314 [M+H]+

[0286] Step 4: Synthesis of (7-(benzyloxy)-5-fluoro-1H-indol-2-yl)methanol Ethyl 7-(benzyloxy)-5-fluoro-1H-indole-2-carboxylate (3.5 g, 11.2 mmol) was reacted according to General Procedure 3. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound (2.9 g, 95.6%) as a pale yellow solid. LCMS (ESI, m / z): 272 [M+H]+

[0287] Step 5: Synthesis of 7-(benzyloxy)-5-fluoro-1H-indole-2-carbaldehyde (7-(benzyloxy)-5-fluoro-1H-indol-2-yl)methanol (3.4 g, 12.5 mmol) was reacted according to General Procedure 4. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (1.9 g, 56%) as a pale yellow solid. LCMS (ESI, m / z): 270 [M+H]+

[0288] Step 6: Synthesis of 7-(Benzyloxy)-1-(cyclopropylmethyl)-5-fluoro-1H-indole-2-carbaldehyde 7-(Benzyloxy)-5-fluoro-1H-indole-2-carbaldehyde (1 g, 3.7 mmol) was reacted with bromomethylcyclopropane (602 mg, 4.4 mmol) according to General Procedure 5. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound (1.0 g, 83%) as a pale yellow solid. LCMS (ESI, m / z): 324 [M+H]+

[0289] Step 7: Synthesis of tert-Butyl (S)-(1-(2-(7-(Benzyloxy)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate 7-(Benzyloxy)-1-(cyclopropylmethyl)-5-fluoro-1H-indole-2-carbaldehyde (388 mg, 1.2 mmol) was reacted with Intermediate 2 (476 mg, 1.2 mmol) according to General Procedure 6. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (370 mg, 45.9%) as a pale yellow solid. LCMS (ESI, m / z): 671 [M+H]+

[0290] Step 8: Synthesis of tert-Butyl (S)-(1-(2-(1-(Cyclopropylmethyl)-5-fluoro-7-hydroxy-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate tert-Butyl (S)-(1-(2-(7-(benzyloxy)-1-(cyclopropylmethyl)-5-fluoro-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (370 mg, 0.5 mmol) was reacted according to General Procedure 9. The crude product obtained was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (270 mg, 84.3%) as a pale yellow solid. LCMS (ESI, m / z): 581 [M+H]+

[0291] Step 9: Synthesis of 2-(triisopropylsilyl)oxazole To a stirred solution of oxazole (6 g, 86.9 mmol) / THF (40 mL) was added n-butyllithium (21.8 g, 130.3 mmol) portionwise at -10 °C under a nitrogen atmosphere, and the mixture was stirred at -10 °C for 30 minutes under a nitrogen atmosphere. Triisopropylsilyl trifluoromethanesulfonate (31.9 g, 104.3 mmol) was added dropwise to the above mixture at -10 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. Then water (120 mL) was added at 0 °C to quench the reaction, and the mixture was extracted with ethyl acetate (2 × 200 mL). The combined organic extracts were washed with brine (120 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (5 g, 25.5%) as a pale yellow solid. LCMS (ESI, m / z): 226 [M+H]+

[0292] Step 10: Synthesis of 1-(2-(triisopropylsilyl)oxazol-5-yl)propan-2-ol To a stirred solution of 2-(triisopropylsilyl)oxazole (1 g, 4.4 mmol) in THF (40 mL), n-butyllithium (1.9 g, 11 mmol) was added portionwise at -10 °C under a nitrogen atmosphere. The mixture was stirred at -10 °C for 30 minutes under a nitrogen atmosphere, and 2-methyloxirane (515 mg, 8.8 mmol) was added dropwise at -10 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS, then water (120 mL) was added to quench the reaction at 0 °C, and the mixture was extracted with ethyl acetate (2 × 200 mL). The combined organic extracts were washed with brine (120 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain the title compound (800 mg, 63.6%) as a pale yellow oil. LCMS (ESI, m / z): 284 [M+H]+

[0293] Step 11: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-5-fluoro-7-((1-(2-(triisopropylsilyl)oxazol-5-yl)propan-2-yl)oxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate tert-Butyl (S)-(1-(2-(1-(cyclopropylmethyl)-5-fluoro-7-hydroxy-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (200 mg, 0.3 mmol) and 1-(2-triisopropylsilyloxazol-5-yl)propan-2-ol (292 mg, 1 mmol) were reacted according to General Procedure 10. The resulting crude product was purified by flash column chromatography (C18 silica) to obtain the title compound (140 mg, 48%) as a pale yellow solid. LCMS (ESI, m / z): 847 [M+H]+

[0294] Step 12: Synthesis of 7-((S)-2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-5-fluoro-7-((1-(oxazol-5-yl)propan-2-yl)oxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one HF (2 mL) was added to a solution of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-5-fluoro-7-((1-(2-(triisopropylsilyl)oxazol-5-yl)propan-2-yl)oxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropyl)carbamate (140 mg, 0.17 mmol) in DCM (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS, and the mixture was concentrated under reduced pressure. The obtained crude product was purified by preparative HPLC (Method F) to give the title compound (23.6 mg, 23.3%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.28 (s, 1H), 7.12 (s, 1H), 7.04 - 7.01 (m, 2H), 6.89 - 6.86 (m, 1H), 5.08 - 5.07 (m, 1H), 4.64 - 4.62 (m, 2H), 4.42 (m, 1H), 4.30 (m, 1H), 3.93 (s, 3H), 3.85 - 3.58 (m, 4H), 3.28 - 3.2 (m, 5H), 1.42 (d, J = 8.0 Hz, 3H), 0.92 - 0.89 (m, 1H), 0.18 - 0.16 (m, 2H), -0.18 - -0.01 (m, 2H); LCMS (ESI, m / z): 590 [M+H]+; LCMS RT: 0.909 min (Method B)

[0295] The compounds of Examples 65a and 65b in Table 6 were obtained as a single isomer of undetermined configuration of the methyl group according to the chiral separation of Example 64 [column: Chiralpak IF, 2×25 cm, 5 μm; mobile phase A: hexane:DCM (3:1) (0.5% 2M NH3 / MeOH); mobile phase B: MeOH; flow rate: 20 mL / min; isocratic gradient: elution with 50% B for 17 minutes; detection: UV (220 / 254 nm)].

Table 21

[0296] Example 66. 7-((S)-2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(((S)-1-(4-fluoro-1H-imidazol-1-yl)propan-2-yl)oxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chem.

[0297] Step 1: Synthesis of (R)-1-(4-fluoro-1H-imidazol-1-yl)propan-2-ol 4-Fluoro-1H-imidazole (600 mg, 6.97 mmol), (R)-2-methyloxirane (485 mg, 8.37 mmol) and potassium tert-butoxide (2.15 mL, 13.9 mmol) were dissolved in THF (4 mL) and tert-butanol (4 mL), and stirred at 70 °C for 1 hour. The reaction was monitored by LCMS and the mixture was concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (C18 silica) to give the title compound (430 mg, 42.6%) as a colorless oil. LCMS (ESI, m / z): 145 [M+H]+

[0298] Step 2: Synthesis of tert-butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-(((S)-1-(4-fluoro-1H-imidazol-1-yl)propan-2-yl)oxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate Intermediate 5 (50 mg, 0.09 mmol) was reacted with (R)-1-(4-fluoro-1H-imidazol-1-yl)propan-2-ol (64 mg, 0.44 mmol) according to General Procedure 10. The resulting crude product was purified by flash column chromatography (C18 silica) to give the title compound (50 mg, 81.7%) as a yellow solid. LCMS (ESI, m / z): 689 [M+H]+

[0299] Step 3: Synthesis of 7-((S)-2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(((S)-1-(4-fluoro-1H-imidazol-1-yl)propan-2-yl)oxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-(((S)-1-(4-fluoro-1H-imidazol-1-yl)propan-2-yl)oxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (60 mg, 0.09 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by Method G to give the title compound (29.8 mg, 57.8%) as a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.41 - 8.29 (m, 3H), 7.42 (s, 1H), 7.17 - 7.07 (m, 1H), 7.05 (s, 1H), 7.03 (t, J = 14 Hz, 1H), 6.99 (d, J = 6.8 Hz, 1H), 6.89 - 6.88 (m, 1H), 5.11 - 5.10 (m, 1H), 4.75 - 4.63 (m, 4H), 4.36 - 4.31 (m, 2H), 3.95 (s, 3H), 3.87 - 3.72 (m, 2H), 3.54 - 3.35 (m, 3H), 3.33 - 3.32 (m, 2H), 1.33 (s, 3H), 0.95 - 0.75 (m, 1H), 0.25 - 0.15 (m, 2H), -0.15 - -0.35 (m, 2H); LCMS (ESI, m / z): 589 [M + H]+; LCMS RT: 0.866 min (Method D)

[0300] The compounds of Examples 67 - 77 in Table 7 were obtained according to the same procedure as the preparation of the compound of Example 66 using appropriate starting materials.

Table 22

Table 23

[0301] Examples 73a and 73b. 7 - ((S)-2 - Amino - 3 - fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(1 - fluoro - 2-(4 - fluoro - 1H - imidazol - 1 - yl)ethoxy)-1H - indol - 2 - yl)-3 - methyl - 3,5,6,7 - tetrahydro - 8H - imidazo[4,5 - b][1,6]naphthyridin - 8 - one

Chemical Structure

[0302] Step 1: Synthesis of ethyl 2-((2-(7-((S)-2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-2-fluoroacetate To a solution of Intermediate 5 (300 mg, 0.53 mmol) in DMF (5 mL) were added ethyl 2-bromo-2-fluoroacetate (148 mg, 0.8 mmol) and Cs2CO3 (520 mg, 1.6 mmol), and the mixture was stirred at 50 °C for 2 h, and the reaction was monitored by LCMS. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with water (15 mL) and brine (2 × 15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give a diastereomeric mixture (280 mg, 78.7%) of the title compound as a pale yellow solid. LCMS (ESI, m / z): 667 [M+H]+

[0303] Step 2: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-hydroxyethoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropyl)carbamate A solution of ethyl 2-((2-(7-((S)-2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-2-fluoroacetate (238 mg, 0.36 mmol) in ethanol (5 mL) was added with NaBH4 (40.5 mg, 1.07 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS, and the solvent was distilled off under reduced pressure. The obtained residue was diluted with water (10 mL), extracted with DCM (3 × 10 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a diastereomeric mixture of the title compound (200 mg, 89.6%) as a pale yellow solid. LCMS (ESI, m / z): 625 [M+H]+

[0304] Step 3: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-iodoethoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropyl)carbamate To a solution of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-hydroxyethoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (100 mg, 0.02 mmol) in DCM (3 mL), iodine (81.3 mg, 0.03 mmol), imidazole (27.2 mg, 0.04 mmol), and PPh3 (84 mg, 0.03 mmol) were added, and the mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS, and water (30 mL) was added to quench the reaction. The mixture was extracted with DCM (3 × 30 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give a diastereomeric mixture of the title compound (30 mg, 28.9%) as a pale yellow solid. LCMS (ESI, m / z): 735 [M+H]+

[0305] Step 4: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-(4-fluoro-1H-imidazol-1-yl)ethoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate tert-Butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-iodoethoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (30 mg, 0.04 mmol) / DMF (3 mL) was reacted with 4-fluoro-1H-imidazole (3.87 mg, 0.04 mmol) and Cs2CO3 (39.8 mg, 0.12 mmol) according to General Procedure 14. The crude product obtained was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give a diastereomeric mixture of the title compound (10 mg, 35.3%) as a pale yellow solid. LCMS (ESI, m / z): 693 [M+H]+

[0306] Step 5: Synthesis of 7-((S)-2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-(4-fluoro-1H-imidazol-1-yl)ethoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-(4-fluoro-1H-imidazol-1-yl)ethoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (30 mg, 0.04 mmol) was reacted according to General Procedure 2. The crude material was purified by preparative HPLC (Method F) to give a diastereomeric mixture of the title compound. This was separated by chiral preparative HPLC [column: Chiralpak ID, 2 × 25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH3 / MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; isocratic gradient: eluted with 50% B for 11 min; detection: UV (254 / 220 nm)] to give a single stereoisomer of undetermined configuration of fluorine. Example 73a (isomer 1): Chiral HPLC retention time: 5.85 min; 1 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.52 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H) 6.61 (d, J = 60 Hz, 1H), 4.67 - 4.31 (m, 6H), 3.95 (s, 3H), 3.78 - 3.29 (m, 4H), 3.25 - 3.21 (m, 3H), 0.93 - 0.91 (m, 1H), 0.25 - 0.17 (m, 2H), -0.18 - -0.28 (m, 2H); LCMS (ESI, m / z): 593 [M+H]+; LCMS RT: 0.878 min (method D) Example 73b (isomer 2): Chiral HPLC retention time: 8.44 min; 1 1H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1H), 7.52 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H) 6.61 (d, J = 60 Hz, 1H), 4.67 - 4.31 (m, 6H), 3.95 (s, 3H), 3.78 - 3.29 (m, 4H), 3.25 - 3.21 (m, 3H), 0.92 - 0.89 (m, 1H), 0.21 - 0.17 (m, 2H), -0.18 - -0.23 (m, 2H); LCMS (ESI, m / z): 593 [M+H]+; LCMS RT: 0.878 min (method D)

[0307] The compounds of Examples 74 - 77 in Table 8 were obtained using appropriate starting materials in the same procedure as the preparation of the compounds of Example 73. [Table 24] [Table 25]

Table 26

Table 27

[0308] Examples 78a, 78b, 78c, and 78d. 7-((S)-2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-(1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chem.

[0309] Step 1: Synthesis of 2-((2-(7-((S)-2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-2-fluoroacetic acid To a solution of Intermediate 5 (1.5 g, 2.67 mmol) in DMF (26 mL) was added ethyl 2-bromo-2-fluoroacetate (740 mg, 4.00 mmol) and Cs2CO3 (2.61 g, 8.00 mmol) under a nitrogen atmosphere. The mixture was stirred at 50 °C for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS, and water (50 mL) was added to the above mixture. The solution was stirred at room temperature for 0.5 hour, and the reaction was monitored by LCMS. The mixture was extracted with ethyl acetate (80 mL), washed with water (2 × 80 mL) and brine (2 × 80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (ethyl acetate) to give a diastereomeric mixture (1 g, 58%) of the title compound as a yellow solid. LCMS (ESI, m / z): 639 [M+H]+

[0310] Step 2: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-(methoxy(methyl)amino)-2-oxoethoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate To a solution of 2-((2-(7-((S)-2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-2-fluoroacetic acid (1 g, 1.57 mmol) and DIEA (1.02 g, 7.83 mmol) in DMF (15 mL), HATU (1.19 g, 3.13 mmol) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 10 minutes under a nitrogen atmosphere. Then, a solution of N,O-dimethylhydroxylamine hydrochloride (764 mg, 7.83 mmol) in DMF (1 mL) was added dropwise at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere, and the reaction was monitored by LCMS. Then, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL). The combined organic extracts were washed with water (2 × 60 mL) and brine (2 × 60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (C18 silica) to obtain a diastereomeric mixture (1 g, 93%) of the title compound as a brown solid. LCMS (ESI, m / z): 682 [M+H]+

[0311] Step 3: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoropropoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate The diastereomer tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-(methoxy(methyl)amino)-2-oxoethoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (1 g) was separated by preparative SFC [(column: Chiralpak IH, 5 × 25 cm, 5 mm; mobile phase A: CO2, mobile phase B: IPA (0.5% 2M NH3 / MeOH); flow rate: 200 mL / min; isocratic gradient: 35% B; column temperature: 35 °C; back pressure: 100 bar; detection: UV (220 nm)] to obtain a single stereoisomer with undetermined configuration of fluorine (RT of isomer 1: 5.84 min; RT of isomer 2: 8.08 min ). To a solution of isomer 1 (250 mg, 0.37 mmol) in THF (4 mL) was added methylmagnesium bromide (0.73 mL, 2.19 mmol) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. Then water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with brine (3 × 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (230 mg, 98%). LCMS (ESI, m / z): 637 [M+H]+

[0312] Step 4: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-hydroxypropoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate A solution of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-oxopropoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (230 mg, 0.37 mmol) in ethanol (4 mL) was added with NaBH4 (138 mg, 3.66 mmol) at 0 °C under a nitrogen atmosphere, and stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. Then, acetone (5 mL) was added to quench the reaction, and the mixed solution was concentrated under reduced pressure. The obtained crude product was purified by flash column chromatography (C18 silica), and the title compound as a diastereomer mixture at the alcohol stereocenter (180 mg, 77%) was obtained as a yellow oil. LCMS (ESI, m / z): 639 [M+H]+

[0313] Step 5: Synthesis of 1-((2-(7-((S)-2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-1-fluoropropan-2-yl trifluoromethanesulfonate A solution of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-hydroxypropoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (160 mg, 0.25 mmol) in DCM (2.5 mL) was added with Tf2O (0.06 mL, 0.38 mmol) and pyridine (0.06 mL, 0.75 mmol) at 0 °C under a nitrogen atmosphere, and stirred at 0 °C for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. Then saturated aqueous NH4Cl solution (1 mL) was added at 0 °C to quench the reaction, and extracted with DCM (3 × 10 mL). The combined organic extracts were washed with brine (3 × 10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 20:1) to obtain the title compound as a yellow oil, a diastereomer mixture at the stereocenter of the triflate (120 mg, 62%). LCMS (ESI, m / z): 771 [M+H]+

[0314] Step 6: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-(1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate 1-((2-(7-((S)-2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-1-fluoropropan-2-yl trifluoromethanesulfonate (120 mg, 0.16 mmol) / DMF (2 mL) was reacted with 1H-imidazole (104 mg, 1.53 mmol) and Cs2CO3 (152 mg, 0.47 mmol) according to General Procedure 14. The reaction mixture was purified by flash column chromatography (C18 silica) to give the title compound as a yellow oil (100 mg, 93%) as a diastereomeric mixture at the imidazolyl stereocenter. LCMS (ESI, m / z): 689 [M+H]+

[0315] Step 7: Synthesis of 7-((S)-2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-(1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-(1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropyl)carbamate (100 mg, 0.14 mmol) was reacted according to General Procedure 2. The crude product obtained was purified by preparative HPLC (Method F) to give the title compound as a white solid (70 mg, 82%) as a diastereomeric mixture at the imidazolyl stereocenter. LCMS (ESI, m / z): 589 [M+H]+ The diastereomers were separated by preparative chiral HPLC (column: CHIRAL ART Cellulose-SB, 4.6×100 mm, 3 μm; mobile phase A: MTBE(0.1% DEA):EtOH(1:1); flow rate: 1 mL / min; isocratic gradient: 0% B) to obtain a single stereoisomer with undetermined configurations of fluorine and imidazolyl. Example 78a (Isomer 1): Chiral HPLC retention time: 2.23 min; 1 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.85 (s, 1H), 7.48 (dd, J = 2.0, 6.8 Hz, 1H), 7.39 (s, 1H), 7.23 (s, 1H), 7.15 - 7.12 (m, 2H), 6.98 (s, 1H), 6.64 (dd, J = 3.2, 57.2 Hz, 1H), 5.05 - 4.90 (m, 1H), 4.55 - 4.38 (m, 4H), 3.95 (s, 3H), 3.77 - 3.65 (m, 2H), 3.63 - 3.58 (m, 2H), 3.41 - 3.31 (m, 1H), 3.29 - 3.08 (m, 2H), 1.66 (d, J = 7.1 Hz, 3H), 0.84 - 0.80 (m, 1H), 0.19 - 0.14 (m, 2H), -0.26 - -0.31 (m, 2H); LCMS (ESI, m / z): 589 [M+H]+; LCMS RT: 1.219 min (Method D) Example 78b (Isomer 2): Chiral HPLC retention time: 2.60 min; 11H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1H), 7.84 (s, 1H), 7.48 (dd, J = 1.2, 7.2 Hz, 1H), 7.40 (s, 1H), 7.22 (s, 1H), 7.14 - 7.08 (m, 2H), 6.97 (s, 1H), 6.45 (dd, J = 4.0, 56.8 Hz, 1H), 5.05 - 4.95 (m, 1H), 4.57 - 4.49 (m, 1H), 4.47 - 4.44 (m, 2H), 4.34 - 4.31 (m, 1H), 3.95 (s, 3H), 3.79 - 3.74 (m, 2H), 3.63 - 3.59 (m, 1H), 3.53 - 3.51 (m, 1H), 3.32 - 3.28 (m, 3H), 1.69 (d, J = 7.2 Hz, 3H), 0.94 - 0.92 (m, 1H), 0.21 - 0.19 (m, 2H), -0.18 - -0.22 (m, 2H); LCMS (ESI, m / z): 589 [M + H]+; LCMS RT: 0.766 min (Method D)

[0316] The compounds of Examples 78c and 78d in Table 9 were obtained in the same procedure as the compounds of Examples 78a and 78b, using isomer 2 as the starting material in Step 3. [Table 28]

[0317] Examples 79a and 79b. 7 - ((S) - 2 - Amino - 3 - fluoropropyl) - 2 - (1 - (cyclopropylmethyl) - 7 - (2 - fluoro - 2 - (1H - imidazol - 1 - yl)ethoxy) - 1H - indol - 2 - yl) - 3 - methyl - 3,5,6,7 - tetrahydro - 8H - imidazo[4,5 - b][1,6]naphthyridin - 8 - one [Chemical Structure]

[0318] Step 1: Synthesis of ethyl 2 - fluoro - 2 - imidazol - 1 - yl - acetate To a solution of 1H-imidazole (1 g, 14.7 mmol) in MeCN (20 mL) was added ethyl 2-bromo-2-fluoroacetate (1.36 g, 7.34 mmol) under a nitrogen atmosphere, and the mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The reaction was monitored by LCMS, and the resulting solution was concentrated under reduced pressure. The obtained crude product was purified by column chromatography (ethyl acetate) to give the title compound (880 mg, 34.7%) as a pale yellow oil. LCMS (ESI, m / z): 173 [M+H]+

[0319] Step 2: Synthesis of 2-fluoro-2-imidazol-1-yl-ethanol To a solution of ethyl 2-fluoro-2-imidazol-1-ylacetate (4.9 g, 28.5 mmol) in THF (230 mL) was added LiBH4 (46 mL, 113 mmol) dropwise at 0 °C under a nitrogen atmosphere. The solution was stirred at room temperature for 1 hour under a nitrogen atmosphere, and the reaction was monitored by LCMS. Then acetone (60 mL) was added to quench the reaction, and the mixed solution was concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (2.2 g, 59.4%) as a colorless oil. LCMS (ESI, m / z): 131 [M+H]+

[0320] Step 3: Synthesis of (2-fluoro-2-imidazol-1-yl-ethyl)methanesulfonic acid 2-Fluoro-2-imidazol-1-yl-ethanol (1 g, 7.69 mmol) / DCM (70 mL) was reacted with TEA (3.14 mL, 23.1 mmol) and MsCl (0.89 mL, 11.5 mmol) according to General Procedure 13 to give the title compound (1.14 g, 71%) as a yellow oil. LCMS (ESI, m / z): 209 [M+H]+

[0321] Step 4: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(2-fluoro-2-(1H-imidazol-1-yl)ethoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate Intermediate 5 (150 mg, 0.27 mmol) / DMF (3 mL) was reacted with (2-fluoro-2-imidazol-1-yl-ethyl)methanesulfonic acid (370 mg, 1.78 mmol) according to General Procedure 5. The crude product obtained was purified by flash column chromatography (C18 silica) to give a diastereomeric mixture of the title compound (110 mg, 62%) as a brown oil. LCMS (ESI, m / z): 675 [M+H]+

[0322] Step 5: Synthesis of 7-((S)-2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(2-fluoro-2-(1H-imidazol-1-yl)ethoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(2-fluoro-2-(1H-imidazol-1-yl)ethoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (110 mg, 0.16 mmol) was reacted according to General Procedure 2. The crude product obtained was purified by preparative HPLC (Method F) to give a diastereomeric mixture of the title compound (75 mg, 80%) as a white solid. LCMS (ESI, m / z): 575 [M+H]+ The diastereomers were separated by chiral preparative HPLC [column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH3 / MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; isocratic gradient: eluted with 30% B for 15 minutes; detection: UV (220 / 254 nm)] to obtain a single stereoisomer with an undetermined configuration of fluorine. Example 79a (isomer 1): Chiral HPLC retention time: 8.5 minutes; 1 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.16 (s, 1H), 7.70 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.17 (s, 1H), 7.11 - 7.07 (m, 2H), 7.01 - 6.85 (m, 2H), 4.99 - 4.97 (m, 1H), 4.79 - 4.59 (m, 1H), 4.59 - 4.55 (m, 1H), 4.55 - 4.42 (m, 2H), 4.33 - 4.30 (m, 1H), 3.93 (s, 3H), 3.78 - 3.73 (m, 2H), 3.63 - 3.60 (m, 1H), 3.58 - 3.46 (m, 1H), 3.32 - 3.27 (m, 3H), 0.89 - 0.80 (m, 1H), 0.14 - 0.01 (m, 2H), -0.18 - -0.22 (m, 2H); LCMS (ESI, m / z): 575 [M+H]+; LCMS RT: 1.179 minutes (method D) Example 79b (isomer 2): Chiral HPLC retention time: 11.33 minutes; 11H NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 8.16 (s, 1H), 7.70 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.17 - 6.85 (m, 5H), 5.02 - 4.98 (m, 1H), 4.95 - 4.81 (m, 1H), 4.79 - 4.41 (m, 3H), 4.31 - 4.29 (m, 1H), 3.93 (s, 3H), 3.80 - 3.71 (m, 2H), 3.63 - 3.45 (m, 2H), 3.32 - 3.28 (m, 3H), 2.15 (s, 2H), 0.87 (s, 1H), 0.15 - 0.01 (m, 2H), -0.20 - -0.32 (m, 2H); LCMS (ESI, m / z): 575 [M + H]+; LCMS RT: 1.174 min (Method D)

[0323] Example 80. 2-(7-((S)-2-(1H-Imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-7-((S)-2-amino-3-fluoropropyl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical Structure

[0324] Step 1: Synthesis of Ethyl (R)-1-(cyclopropylmethyl)-7-(2-hydroxypropoxy)-1H-indole-2-carboxylate Ethyl 1-(cyclopropylmethyl)-7-hydroxy-indole-2-carboxylate (100 mg, 0.39 mmol) / ethanol (2 mL) was reacted with (2R)-2-methyloxirane (224 mg, 3.86 mmol) and TEA (0.34 mL, 1.93 mmol) according to General Procedure 12. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (90 mg, 73.5%) as a pale yellow solid. LCMS (ESI, m / z): 318 [M + H]+

[0325] Step 2: Synthesis of Ethyl (R)-1-(Cyclopropylmethyl)-7-(2-((Methylsulfonyl)oxy)propoxy)-1H-indole-2-carboxylate Ethyl (R)-1-(Cyclopropylmethyl)-7-(2-hydroxypropoxy)-1H-indole-2-carboxylate (90 mg, 0.28 mmol) / DCM (4 mL) was reacted with TEA (0.2 mL, 1.13 mmol) and MsCl (0.04 mL, 0.57 mmol) according to General Procedure 13 to give the title compound (90 mg, 80%) as a pale yellow oil. LCMS (ESI, m / z): 396 [M+H]+

[0326] Step 3: Synthesis of Ethyl (S)-7-(2-(1H-Imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate To a solution of ethyl (R)-1-(cyclopropylmethyl)-7-(2-((methylsulfonyl)oxy)propoxy)-1H-indole-2-carboxylate (90 mg, 0.23 mmol) / DMF (3 mL) were added 1H-imidazole (23.3 mg, 0.34 mmol) and Cs2CO3 (222 mg, 0.68 mmol), and the mixture was stirred at 50 °C overnight. The reaction was monitored by LCMS. Then water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL), washed with water (5×10 mL) and brine (5×10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (70 mg, 83.7%) as a pale yellow solid. LCMS (ESI, m / z): 368 [M+H]+

[0327] Step 4: Synthesis of (S)-(7-(2-(1H-Imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol (S)-Ethyl 7-(2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (70 mg, 0.19 mmol) was reacted according to General Procedure 3. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (50 mg, 81%) as a pale yellow solid. LCMS (ESI, m / z): 326 [M+H]+

[0328] Step 5: Synthesis of (S)-7-(2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (S)-(7-(2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol (50 mg, 0.15 mmol) was reacted according to General Procedure 4. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (40 mg, 80%) as a pale yellow solid. LCMS (ESI, m / z): 324 [M+H]+

[0329] Step 6: Synthesis of tert-butyl ((S)-1-(2-(7-((S)-2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (S)-7-(2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (40 mg, 0.12 mmol) and Intermediate 2 (49.2 mg, 0.12 mmol) were reacted according to General Procedure 6. The obtained crude product was purified by column chromatography (DCM / MeOH = 15:1) to give the title compound (30 mg, 36%) as a pale yellow solid. LCMS (ESI, m / z): 671 [M+H]+

[0330] Step 7: Synthesis of 2-(7-((S)-2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-7-((S)-2-amino-3-fluoropropyl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl ((S)-1-(2-(7-((S)-2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (30 mg, 0.04 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method F) to give the title compound (15 mg, 58%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.41 (s, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.16 (s, 1H), 7.07 (t, J = 7.9 Hz, 1H), 6.95 (s, 1H), 6.88 (d, J = 7.8 Hz, 1H), 4.86 - 4.83 (m, 1H), 4.82 - 4.70 (m, 1H), 4.66 - 4.55 (m, 1H), 4.53 - 4.41 (m, 4H), 3.94 (s, 3H), 3.81 - 3.73 (m, 4H), 3.32 (s, 3H), 1.58 (d, J = 6.9 Hz, 3H), 0.81 - 0.79 (m, 1H), 0.18 - 0.12 (m, 2H), -0.24 - -0.33 (m, 2H); LCMS (ESI, m / z): 571 [M+H]+; LCMS RT: 1.202 min (Method B)

[0331] Example 8 1. 7-((R)-2-Aminopropyl)-2-(1-(cyclopropylmethyl)-7-((R)-2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical formula

[0332] Step 1: Synthesis of ethyl (S)-1-(cyclopropylmethyl)-7-(2-hydroxypropoxy)-1H-indole-2-carboxylate Ethyl 1-(cyclopropylmethyl)-7-hydroxy-indole-2-carboxylate (1 g, 3.86 mmol) / ethanol (12.5 mL) was reacted with (2S)-2-methyloxirane (672 mg, 11.5 mmol) and TEA (3.36 mL, 19.3 mmol) according to General Procedure 12. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (1 g, 81%) as a peach-colored solid. LCMS (ESI, m / z): 318 [M+H]+

[0333] Step 2: Synthesis of ethyl (S)-1-(cyclopropylmethyl)-7-(2-((methylsulfonyl)oxy)propoxy)-1H-indole-2-carboxylate (S)-Ethyl 1-(cyclopropylmethyl)-7-(2-hydroxypropoxy)-1H-indole-2-carboxylate (2 g, 6.3 mmol) / DCM (50 mL) was reacted with TEA (3.3 mL, 18.9 mmol) and MsCl (866 mg, 7.56 mmol) according to General Procedure 13 to give the title compound (2 g, 80%) as a yellow oil. LCMS (ESI, m / z): 396 [M+H]+

[0334] Step 3: Synthesis of Ethyl (R)-1-(Cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indole-2-carboxylate (S)-Ethyl 1-(Cyclopropylmethyl)-7-(2-((methylsulfonyl)oxy)propoxy)-1H-indole-2-carboxylate (2 g, 5.06 mmol) / DMF (50 mL) was reacted with 4-Fluoro-1H-imidazole (522 mg, 6.07 mmol) and Cs2CO3 (4.95 g, 15.2 mmol) according to General Procedure 14. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (1.7 g, 87%) as a yellow solid. LCMS (ESI, m / z): 386 [M+H]+

[0335] Step 4: Synthesis of (R)-(1-(Cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)methanol (R)-Ethyl 1-(Cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indole-2-carboxylate (2 g, 5.19 mmol) was reacted according to General Procedure 3. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (1.5 g, 84%) as a yellow oil. LCMS (ESI, m / z): 344 [M+H]+

[0336] Step 5: Synthesis of (R)-1-(Cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indole-2-carbaldehyde (R)-(1-(Cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)methanol (2 g, 5.82 mmol) was reacted according to General Procedure 4. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (1.4 g, 70%) as a pale green solid. LCMS (ESI, m / z): 342 [M+H]+

[0337] Step 6: Synthesis of (R)-2-(1-(Cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one Intermediate 6 (212 mg, 1.1 mmol) and (R)-1-(Cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indole-2-carbaldehyde (342 mg, 1.1 mmol) were reacted according to General Procedure 11. The reaction mixture was then purified by flash column chromatography (C18 silica) to give the title compound (160 mg, 31%) as a yellow solid. LCMS (ESI, m / z): 514 [M+H]+

[0338] Step 7: Synthesis of tert-butyl ((R)-1-(2-(1-(Cyclopropylmethyl)-7-((R)-2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)propan-2-yl)carbamate (R)-2-(1-(Cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one (200 mg, 0.39 mmol) was reacted with tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (277 mg, 1.17 mmol) according to General Procedure 1. The resulting crude product was purified by column chromatography (DCM / MeOH = 10:1) to give the title compound (110 mg, 42%) as a yellow solid. LCMS (ESI, m / z): 671 [M+H]+

[0339] Step 8: Synthesis of 7-((R)-2-aminopropyl)-2-(1-(cyclopropylmethyl)-7-((R)-2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl ((R)-1-(2-(1-(cyclopropylmethyl)-7-((R)-2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)propan-2-yl)carbamate (100 mg, 0.15 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method F) to give the title compound (33.6 mg, 39%) as a pale yellow solid. 11H NMR (400 MHz, DMSO-d6): δ 8.52 (s, 1H), 7.87 (s, 3H), 7.53 (s, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.17 - 7.12 (m, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 4.79 - 4.78 (m, 1H), 4.57 - 4.40 (m, 4H), 3.96 (s, 3H), 3.82 - 3.71 (m, 3H), 3.59 - 3.53 (m, 2H), 3.32 (t, J = 6.8 Hz, 2H), 1.55 (d, J = 6.8 Hz, 3H), 1.26 (d, J = 6.4 Hz, 3H), 0.79 (s, 1H), 0.15 - 0.12 (m, 2H), -0.29 - -0.31 (m, 2H); LCMS (ESI, m / z): 571 [M + H]+; LCMS RT: 1.390 min (Method D)

[0340] Example 82. 7 - ((S)-2 - Amino - 3 - fluoropropyl)-2-(1-(cyclopropylmethyl)-7 - (((S)-5 - oxopyrrolidin - 3 - yl)methoxy)-1H - pyrrolo[2,3 - c]pyridin - 2 - yl)-3 - methyl - 3,5,6,7 - tetrahydro - 8H - imidazo[4,5 - b][1,6]naphthyridin - 8 - one

Chemical Structure

[0341] Step 1: Synthesis of Ethyl 7 - chloro - 1-(cyclopropylmethyl)pyrrolo[2,3 - c]pyridine - 2 - carboxylate Ethyl 7 - chloro - 1H - pyrrolo[2,3 - c]pyridine - 2 - carboxylate (250 mg, 1.11 mmol) was reacted with bromomethylcyclopropane (225 mg, 1.67 mmol) according to General Procedure 5. The resulting crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 1:2) to give the title compound (240 mg, 77.37%) as a white solid. LCMS (ESI, m / z): 279 [M + H]+

[0342] Step 2: Synthesis of [7-chloro-1-(cyclopropylmethyl)pyrrolo[2,3-c]pyridin-2-yl]methanol Ethyl 7-chloro-1-(cyclopropylmethyl)pyrrolo[2,3-c]pyridine-2-carboxylate (240 mg, 0.86 mmol) was reacted according to General Procedure 3. The resulting crude product was purified by preparative TLC (DCM / MeOH = 15:1) to give the title compound (80 mg, 39.25%) as a yellow solid. LCMS (ESI, m / z): 237 [M+H]+

[0343] Step 3: Synthesis of 7-chloro-1-(cyclopropylmethyl)pyrrolo[2,3-c]pyridine-2-carbaldehyde [7-chloro-1-(cyclopropylmethyl)pyrrolo[2,3-c]pyridin-2-yl]methanol (80 mg, 0.34 mmol) was reacted according to General Procedure 4. The resulting crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 1:1) to give the title compound (50 mg, 63.04%) as a yellow oil. LCMS (ESI, m / z): 235 [M+H]+

[0344] Step 4: Synthesis of (S)-1-(cyclopropylmethyl)-7-((5-oxopyrrolidin-3-yl)methoxy)-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde To a solution of 7-chloro-1-(cyclopropylmethyl)pyrrolo[2,3-c]pyridine-2-carbaldehyde (50 mg, 0.21 mmol) in THF (2 mL) were added (4S)-4-(hydroxymethyl)pyrrolidin-2-one (73 mg, 0.64 mmol), Cs2CO3 (208 mg, 0.64 mmol), Dave Phos (14 mg, 0.04 mmol) and DavePhos Pd G3 (16 mg, 0.02 mmol) at room temperature under a nitrogen atmosphere, and the mixture was stirred at 90 °C for 6 h. The reaction was monitored by TLC and LCMS. The reaction was quenched by adding water (15 mL), and the mixture was extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative TLC (DCM / MeOH = 15:1) to give the title compound (20 mg, 29.96%) as a yellow oil. LCMS (ESI, m / z): 314 [M+H]+

[0345] Step 5: Synthesis of tert-butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-(((S)-5-oxopyrrolidin-3-yl)methoxy)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate Intermediate 2 (28 mg, 0.07 mmol) and (S)-1-(cyclopropylmethyl)-7-((5-oxopyrrolidin-3-yl)methoxy)-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde (19 mg, 0.06 mmol) were reacted according to General Procedure 6. The obtained crude product was purified by preparative TLC (DCM / MeOH = 10:1) to give the title compound (15 mg, 32.22%) as a yellow solid. LCMS (ESI, m / z): 661 [M+H]+

[0346] Step 6: Synthesis of 7-((S)-2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(((S)-5-oxopyrrolidin-3-yl)methoxy)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-(((S)-5-oxopyrrolidin-3-yl)methoxy)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropyl)-2-yl)carbamate (15 mg, 0.02 mmol) was reacted according to General Procedure 2. The resulting crude orange sticky oil was purified by preparative HPLC (Method F) to give the title compound (10.2 mg, 78.2%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.27 (s, 3H), 7.76 (d, J = 5.6 Hz, 1H), 7.61 (s, 1H), 7.32 (d, J = 5.6 Hz, 1H), 7.23 (s, 1H), 4.82 - 4.74 (m, 1H), 4.71 (d, J = 7.1 Hz, 2H), 4.68 - 4.61 (m, 1H), 4.55 - 4.47 (m, 2H), 3.96 (s, 3H), 3.90 - 3.81 (m, 2H), 3.80 - 3.70 (m, 3H), 3.50 (t, J = 8.9 Hz, 1H), 3.35 (t, J = 6.6 Hz, 2H), 3.25 - 3.17 (m, 1H), 3.02 - 2.92 (m, 1H), 2.45 - 2.36 (m, 1H), 2.21 - 2.12 (m, 1H), 1.12 - 1.01 (m, 1H), 0.31 - 0.19 (m, 2H), -0.03 - -0.13 (m, 2H); LCMS (ESI, m / z): 561 [M+H]+; LCMS RT: 1.608 min (Method D)

[0347] Example 83 in Table 10 was obtained in the same procedure as the production of Example 82.

Table 29

[0348] Example 84. (S)-2-(7-(2-(1H-Imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7-(2-amino-3-fluoropropyl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical formula

[0349] Step 1: Synthesis of ethyl 1-(cyclopropylmethyl)-7-(2-imidazol-1-yl ethoxy)pyrrolo[2,3-c]pyridine-2-carboxylate To a solution of ethyl 7-chloro-1-(cyclopropylmethyl)pyrrolo[2,3-c]pyridine-2-carboxylate (100 mg, 0.36 mmol) in THF (4 mL) were added Cs2CO3 (350 mg, 1.08 mmol), 2-imidazol-1-yl ethanol (80 mg, 0.72 mmol), DavePhos (28 mg, 0.07 mmol) and DavePhos Pd G3 (27 mg, 0.04 mmol) at room temperature under a nitrogen atmosphere, and the mixture was stirred at 90 °C for 1 hour. The reaction was monitored by TLC and LCMS. The reaction was quenched by adding water (10 mL), and the mixture was extracted with EtOAc (2 × 20 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by preparative TLC (petroleum ether / EtOAc = 5:1) to give the title compound (110 mg, 86.5%) as a yellow oil. LCMS (ESI, m / z): 355 [M+H]+

[0350] Step 2: Synthesis of [1-(cyclopropylmethyl)-7-(2-imidazol-1-yl ethoxy)pyrrolo[2,3-c]pyridin-2-yl]methanol Ethyl 1-(cyclopropylmethyl)-7-(2-imidazol-1-ylethoxy)pyrrolo[2,3-c]pyridine-2-carboxylate (100 mg, 0.28 mmol) was reacted according to General Procedure 3. The resulting mixture was purified by flash column chromatography (C18 silica, mobile phase A: water (0.5% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: eluted with 45% B for 7 minutes; 254 / 210 nm) to give the title compound (80 mg, 90.7%) as a white solid. LCMS (ESI, m / z): 313 [M+H]+

[0351] Step 3: Synthesis of 1-(cyclopropylmethyl)-7-(2-imidazol-1-ylethoxy)pyrrolo[2,3-c]pyridine-2-carbaldehyde [1-(Cyclopropylmethyl)-7-(2-imidazol-1-ylethoxy)pyrrolo[2,3-c]pyridin-2-yl]methanol (80 mg, 0.26 mmol) was reacted according to General Procedure 4. The filtrate was concentrated under reduced pressure to give the title compound (60 mg, 75.4%) as a yellow oil. LCMS (ESI, m / z): 311 [M+H]+

[0352] Step 4: Synthesis of tert-butyl (S)-(1-(2-(7-(2-(1H-imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate 1-(Cyclopropylmethyl)-7-(2-imidazol-1-ylethoxy)pyrrolo[2,3-c]pyridine-2-carbaldehyde (11 mg, 0.04 mmol) and Intermediate 2 (50 mg, 0.13 mmol) were reacted according to General Procedure 6. The resulting crude product was purified by flash column chromatography (C18 silica) to give the title compound (60 mg, 72.5%) as a yellow solid. LCMS (ESI, m / z): 658 [M+H]+

[0353] Step 5: Synthesis of (S)-2-(7-(2-(1H-imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-7-(2-amino-3-fluoropropyl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl (S)-(1-(2-(7-(2-(1H-imidazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (50 mg, 0.08 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method F) to give the title compound (14.4 mg, 33.6%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6 + D2O): δ 9.26 (s, 1H), 8.54 (s, 1H), 7.93 (t, J = 1.8 Hz, 1H), 7.77 (d, J = 5.6 Hz, 1H), 7.72 (t, J = 1.8 Hz, 1H), 7.36 (d, J = 5.6 Hz, 1H), 7.23 (s, 1H), 4.98 (t, J = 5.0 Hz, 2H), 4.77 (d, J = 9.4, 4.6 Hz, 2H), 4.75 - 4.58 (m, 2H), 4.51 (d, J = 7.0 Hz, 2H), 3.93 (s, 3H), 3.91 - 3.78 (m, 3H), 3.76 (t, J = 6.7 Hz, 2H), 3.34 (t, J = 6.6 Hz, 2H), 0.82 - 0.67 (m, 1H), 0.24 - 0.09 (m, 2H), -0.23--0.39 (m, 2H); LCMS (ESI, m / z): 558 [M + H]+; LCMS RT: 0.672 min (Method D)

[0354] Example 85. 7-((S)-2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-((R)-2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical Structure

[0355] Step 1: Synthesis of tert-butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-((S)-2-hydroxypropoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate Intermediate 5 (50 mg, 0.09 mmol) / ethanol (2 mL) was reacted with (2S)-2-methyloxirane (51.6 mg, 0.89 mmol) and TEA (0.06 mL, 0.44 mmol) according to General Procedure 12. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:5) to give the title compound (45 mg, 81.8%) as a yellow solid. LCMS (ESI, m / z): 419 [M+H] +

[0356] Step 2: Synthesis of (S)-1-((2-(7-((S)-2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)propan-2-yl methanesulfonate tert-Butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-((S)-2-hydroxypropoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (45 mg, 0.07 mmol) / DCM (5 mL) was reacted with TEA (0.03 mL, 0.22 mmol) and MsCl (12.5 mg, 0.11 mmol) according to General Procedure 13 to give the title compound (50 mg, 98.8%) as a pale yellow oil. LCMS (ESI, m / z): 699 [M+H] +

[0357] Step 3: Synthesis of tert-Butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-((R)-2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate Methanesulfonic acid (S)-1-((2-(7-((S)-2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)propan-2-yl (60 mg, 0.09 mmol) / DMF (1 mL) was reacted with 4-fluoro-1H-imidazole (50 mg, 0.58 mmol) and Cs2CO3 (110 mg, 0.34 mmol) according to General Procedure 14. The crude product obtained was purified by column chromatography (petroleum ether / ethyl acetate = 1:3) to give the title compound (25 mg, 58.9%) as a yellow solid. LCMS (ESI, m / z): 689 [M+H] +

[0358] Step 4: Synthesis of 7-((S)-2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-((R)-2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-((R)-2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropyl)-2-yl)carbamate (20 mg, 0.03 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method F) to give the title compound (10.3 mg, 60.5%) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ 8.65 (s, 1H), 7.54 (s, 1H), 7.34 (d, J = 8 Hz, 1H), 7.12 (t, J = 8 Hz, 1H), 7.09 (s, 1H), 6.99 (d, J = 2 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 4.88 - 4.82 (m, 3H), 4.75 - 4.44 (m, 4H), 4.41 - 3.42 (m, 8H), 3.43 (d, J = 6.8 Hz, 2H), 1.67 (s, 3H), 0.81 - 0.80 (m, 1H), 0.21 - 0.19 (m, 2H), -0.33 - -0.34 (m, 2H); LCMS (ESI, m / z): 589 [M+H]+; LCMS RT: 0.881 min (Method D)

[0359] The compounds of Examples 86 - 94 in Table 11 were obtained using appropriate starting materials in the same procedure as for the preparation of the compound of Example 85.

Table 30

Table 31

Table 32

Table 33

[0360] Example 95. (S)-2-(7-(2-(1H-Imidazol-1-yl)ethoxy-1,1,2,2-d4)-1-(cyclopropylmethyl)-1H-indol-2-yl)-7-(2-amino-3-fluoropropyl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical formula

[0361] Step 1: Synthesis of ethane-1,2-diyl-d4 bis(4-methylbenzenesulfonate) Ethane-d4-1,2-diol (100 mg, 1.51 mmol) / DCM (10 mL) was reacted with TEA (459 mg, 4.54 mmol) and TsCl (433 mg, 2.27 mmol) according to General Procedure 13 to give the title compound as a pale yellow oil. LCMS (ESI, m / z): 375 [M+H]+

[0362] Step 2: Synthesis of (S)-2-((2-(7-(2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)ethyl-1,1,2,2-d4 4-methylbenzenesulfonate Intermediate 5 (40 mg, 0.07 mmol) / DMF (2 mL) was reacted with ethane-1,2-diyl-bis(4-methylbenzenesulfonate)-d4 (39.9 mg, 0.11 mmol) according to General Procedure 5. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound (30 mg, 55.1%) as a pale yellow solid. LCMS (ESI, m / z): 765 [M+H]+

[0363] Step 3: Synthesis of tert-butyl (S)-(1-(2-(7-(2-(1H-imidazol-1-yl)ethoxy-1,1,2,2-d4)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate 4-Methylbenzenesulfonic acid (S)-2-((2-(7-(2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)ethyl-1,1,2,2-d4 (30 mg, 0.04 mmol) / DMF (2 mL) was reacted with 1H-imidazole (4.01 mg, 0.06 mmol) and Cs2CO3 (38.3 mg, 0.12 mmol) according to General Procedure 14. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound (20 mg, 70.7%) as a pale yellow solid. LCMS (ESI, m / z): 661 [M+H]+

[0364] Step 4: Synthesis of (S)-2-(7-(2-(1H-imidazol-1-yl)ethoxy-1,1,2,2-d4)-1-(cyclopropylmethyl)-1H-indol-2-yl)-7-(2-amino-3-fluoropropyl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl (S)-(1-(2-(7-(2-(1H-imidazol-1-yl)ethoxy-1,1,2,2-d4)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (20 mg, 0.03 mmol) was reacted according to General Procedure 2. The reaction mixture was purified by preparative HPLC (Method F) to give the title compound (7.2 mg, 42%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.37 (s, 1H), 8.20 (s, 2H), 7.64 (s, 1H), 7.38 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.65 - 4.39 (m, 2H), 3.82 (s, 3H), 3.75 - 3.63 (m, 5H), 3.42 - 3.38 (m, 2H), 0.62 - 0.61 (s, 1H), 0.00 - 0.02 (m, 2H), -0.45 - -0.46 (m, 2H); LCMS (ESI, m / z): 561 [M+H]+; LCMS RT: 0.719 min (Method D)

[0365] Example 96. (S)-2-(7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-7-(2-amino-3-fluoropropyl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical Structure

[0366] Step 1: Synthesis of methyl 2-(1H-imidazol-1-yl)-2-methylpropanoate To a solution of 1H-imidazole (1 g, 14.6 mmol) in MeCN (20 mL) was added methyl 2-bromo-2-methylpropanoate (1.3 g, 7.34 mmol) at room temperature, and the mixture was stirred at 80 °C overnight. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure and purified by flash column chromatography (C18 silica) to afford the title compound (900 mg, 36.4%) as a colorless oil. LCMS (ESI, m / z): 169 [M+H]+

[0367] Step 2: Synthesis of 2-(1H-imidazol-1-yl)-2-methylpropan-1-ol To a solution of methyl 2-imidazol-1-yl-2-methyl-propanoate (900 mg, 5.35 mmol) in THF (20 mL) was added dropwise LiBH4 (2.5 M, THF solution, 10.8 mL, 21.4 mmol) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. Then MeOH was added to quench the reaction, and the mixture was stirred at room temperature for 20 min and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (C18 silica) to afford the title compound as a white solid. LCMS (ESI, m / z): 141 [M+H]+

[0368] Step 3: Synthesis of 1-(1-(3-iodo-2-nitrophenoxy)-2-methylpropan-2-yl)-1H-imidazole To a solution of 2-(1H-imidazol-1-yl)-2-methylpropan-1-ol (350 mg, 2.5 mmol) in DMF (15 mL) was added NaH (60%, 5.4 mL, 4.99 mmol) portionwise at 0 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 0.5 h. The resulting mixture was stirred at room temperature for 2 h, and the reaction was monitored by LCMS. The reaction was quenched by adding water (50 mL), and the mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with water (2 × 100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title compound (600 mg, 62.1%) as a brown oil. LCMS (ESI, m / z): 388 [M+H]+

[0369] Step 4: Synthesis of 2-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-6-iodoaniline To a solution of 1-(1-(3-iodo-2-nitrophenoxy)-2-methylpropan-2-yl)-1H-imidazole (600 mg, 1.55 mmol) in AcOH (4 mL, 69.8 mmol) and ethanol (8 mL) was added iron (865 mg, 15.5 mmol) at room temperature, and the mixture was stirred at 85 °C for 1 h. The reaction was monitored by TLC and LCMS. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure and purified by flash column chromatography (C18 silica) to give the title compound (550 mg, 99.4%) as a brown oil. LCMS (ESI, m / z): 358 [M+H]+

[0370] Step 5: Synthesis of methyl 7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1H-indole-2-carboxylate To a solution of 2-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-6-iodoaniline (550 mg, 1.54 mmol) in DMF (10 mL) was added (3-methoxy-3-oxoprop-1-ynyl)copper (293 mg, 2 mmol) at room temperature, and the mixture was stirred at 50 °C for 1.5 h. The reaction was monitored by TLC and LCMS. Then water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 × 30 mL). The combined organic extracts were washed with water (2 × 60 mL) and brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (70 mg, 14.5%) as a brown oil. LCMS (ESI, m / z): 314 [M+H]+

[0371] Step 6: Synthesis of methyl 7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate Methyl 7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1H-indole-2-carboxylate (40 mg, 0.13 mmol) was reacted with bromomethylcyclopropane (34 mg, 0.26 mmol) according to General Procedure 5. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (20 mg, 42.6%) as a yellow oil. LCMS (ESI, m / z): 368 [M+H]+

[0372] Step 7: Synthesis of (7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol Methyl 7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (20 mg, 0.05 mmol) was reacted according to General Procedure 3. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (20 mg, 98.2%) as a yellow oil. The resulting crude product was used directly in the next step. LCMS (ESI, m / z): 340 [M+H]+

[0373] Step 8: Synthesis of 7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol (20 mg, 0.06 mmol) was reacted according to General Procedure 4. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (18 mg, 90.5%) as a yellow oil. LCMS (ESI, m / z): 338 [M+H]+

[0374] Step 9: Synthesis of tert-butyl (S)-(1-(2-(7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate 7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (18 mg, 0.05 mmol) and Intermediate 2 (25 mg, 0.06 mmol) were reacted according to General Procedure 6. The crude material was purified by preparative TLC (DCM / MeOH = 20 / 1) to give the title compound (25 mg, 68.4%) as a yellow oil. LCMS (ESI, m / z): 685 [M+H]+

[0375] Step 10: Synthesis of (S)-2-(7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-7-(2-amino-3-fluoropropyl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl (S)-(1-(2-(7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (25 mg, 0.04 mmol) was reacted according to General Procedure 2. The crude material was purified by preparative HPLC (Method F) to give the title compound (6 mg, 27.7%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.48 (s, 1H), 8.33 (s, 3H), 8.14 (s, 1H), 7.81 (s, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.19 (s, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H), 4.82 - 4.58 (m, 4H), 4.43 (d, J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.86 - 3.73 (m, 5H), 3.33 (t, J = 6.6 Hz, 2H), 1.82 (s, 6H), 0.72 - 0.59 (m, 1H), 0.15 - 0.05 (m, 2H), -0.35 - -0.47 (m, 2H); LCMS (ESI, m / z): 585 [M+H]+; LCMS RT: 0.711 min (Method D)

[0376] Example 97. (S,E)-7-(2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(3-(4-fluoro-1H-imidazol-1-yl)prop-1-en-1-yl)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chemical formula

[0377] Step 1: Synthesis of ethyl 7-bromo-1-(cyclopropylmethyl)-1H-indole-2-carboxylate Ethyl 7-bromo-1H-indole-2-carboxylate (500 mg, 1.86 mmol) was reacted with (bromomethyl)cyclopropane (510 mg, 3.7 mmol) according to General Procedure 5. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 6:1) to give the title compound (480 mg, 81%) as a pale yellow solid. LCMS (ESI, m / z): 322 [M+H]+

[0378] Step 2: Synthesis of (7-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol Ethyl 7-bromo-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (480 mg, 1.49 mmol) was reacted according to General Procedure 3. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (400 mg, 91%) as a pale yellow solid. LCMS (ESI, m / z): 294 [M+H]+

[0379] Step 3: Synthesis of 7-bromo-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (7-Bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol (400 mg, 1.36 mmol) was reacted according to General Procedure 4. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (300 mg, 78%) as a pale yellow solid. LCMS (ESI, m / z): 278 [M+H]+

[0380] Step 4: Synthesis of (E)-7-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde To a solution of 7-bromo-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (300 mg, 1.07 mmol) and (E)-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)boronic acid (350 mg, 1.60 mmol) in dioxane (10 mL) and water (2 mL), K3PO4 (580 mg, 3.21 mmol) and AmPhos-PdCl2 (85 mg, 0.1 mmol) were added under a nitrogen atmosphere, and the mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. Then water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 × 30 mL), washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title compound (320 mg, 81%) as a pale yellow solid. LCMS (ESI, m / z): 370 [M+H]+

[0381] Step 5: Synthesis of (E)-1-(cyclopropylmethyl)-7-(prop-1-en-1-yl)-1H-indole-2-carbaldehyde A solution of (E)-7-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxaldehyde (320 mg, 0.8 mmol) in THF (10 mL) was added with TBAF (5 mL) under a nitrogen atmosphere and stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. Then water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL), washed with water (5×30 mL) and brine (5×30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (180 mg, 90%) as a pale yellow solid. LCMS (ESI, m / z): 239 [M+H]+

[0382] Step 6: Synthesis of (E)-7-(3-chloroprop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxaldehyde (E)-1-(Cyclopropylmethyl)-7-(prop-1-en-1-yl)-1H-indole-2-carboxaldehyde (180 mg, 0.75 mmol) / DCM (10 mL) was reacted with TEA (228 mg, 2.1 mmol) and MsCl (165 mg, 1.5 mmol) according to General Procedure 13 to give the title compound (180 mg, 90%) as a pale yellow oil. LCMS (ESI, m / z): 274 [M+H]+

[0383] Step 7: Synthesis of (E)-1-(cyclopropylmethyl)-7-(3-(4-fluoro-1H-imidazol-1-yl)prop-1-en-1-yl)-1H-indole-2-carboxaldehyde (E)-7-(3-Chloroprop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (180 mg, 0.65 mmol) / DMF (10 mL) was reacted with 4-fluoro-1H-imidazole (111 mg, 1.3 mmol) and Cs2CO3 (635 mg, 1.95 mmol) according to General Procedure 14. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (150 mg, 71%) as a pale yellow solid. LCMS (ESI, m / z): 323 [M+H]+

[0384] Step 8: Synthesis of tert-butyl (S,E)-(1-(2-(1-(cyclopropylmethyl)-7-(3-(4-fluoro-1H-imidazol-1-yl)prop-1-en-1-yl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate 1-(Isoxazol-5-ylmethyl)-7-methyl-1H-indole-2-carbaldehyde (100 mg, 0.22 mmol) and Intermediate 7 (60 mg, 0.15 mmol) were reacted according to General Procedure 11. The reaction mixture was purified by flash column chromatography (C18 silica) to give the title compound (70 mg, 79%) as a yellow solid. LCMS (ESI, m / z): 671[M+H]+

[0385] Step 9: Synthesis of (S,E)-7-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(3-(4-fluoro-1H-imidazol-1-yl)prop-1-en-1-yl)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl (S,E)-(1-(2-(1-(Cyclopropylmethyl)-7-(3-(4-fluoro-1H-imidazol-1-yl)prop-1-en-1-yl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (25 mg, 0.04 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method E) to give (S,E)-7-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(3-(4-fluoro-1H-imidazol-1-yl)prop-1-en-1-yl)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one (8.1 mg, 79%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.28 (s, 3H), 7.67 (d, J = 2.4 Hz, 1H), 7.59 (s, 1H), 7.14 (s, 3H), 7.24 (s, 1H), 7.09 - 7.02 (m, 1H), 6.32 (d, J = 15.2 Hz, 1H), 4.78 - 4.62 (m, 2H), 4.43 (d, J = 6.4 Hz, 2H), 4.45 - 3.72 (m, 10H), 3.35 - 3.32 (m, 2H), 0.72 (s, 1H), 0.16 - 0.13 (m, 2H), -0.31 - -0.34 (m, 2H); LCMS (ESI, m / z): 571 [M+H]+; LCMS RT: 0.896 min (Method I)

[0386] Example 98 in Table 12 was obtained using the positional isomer of the imidazole intermediate in Step 7 in the same procedure as the preparation of Example 97.

Table 34

[0387] Example 99. (S)-7-(2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(3-(4-fluoro-1H-imidazol-1-yl)propyl)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one

Chem.

[0388] Step 1: Synthesis of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-7-(3-(4-fluoro-1H-imidazol-1-yl)propyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate tert-Butyl (S,E)-(1-(2-(1-(cyclopropylmethyl)-7-(3-(4-fluoro-1H-imidazol-1-yl)prop-1-en-1-yl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (65 mg, 0.77 mmol) / methanol (30 mL) was reacted according to General Procedure 9. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (30 mg, 80.5%) as a pale yellow solid. LCMS (ESI, m / z): 673 [M+H]+

[0389] Step 2: Synthesis of (S)-7-(2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(3-(4-fluoro-1H-imidazol-1-yl)propyl)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]naphthyridin-8-one tert-Butyl (S)-(1-(2-(1-(cyclopropylmethyl)-7-(3-(4-fluoro-1H-imidazol-1-yl)propyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (30 mg, 0.04 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method E) to give the title compound (19.3 mg, 79%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.30 (s, 3H), 7.60 (d, J = 2.4 Hz, 1H), 7.59 (s, 1H), 7.14 (s, 1H), 7.24 (s, 2H), 7.09 - 7.02 (m, 1H), 4.78 - 4.62 (m, 2H), 4.43 (d, J = 6.4 Hz, 2H), 4.45 - 3.72 (m, 10H), 3.35 - 3.32 (m, 2H), 3.06 - 3.02 (m, 2H), 2.17 - 2.13 (m, 2H), 0.72 (s, 1H), 0.16 - 0.13 (m, 2H), -0.43 - -0.47 (m, 2H); LCMS (ESI, m / z): 573 [M+H]+; LCMS RT: 0.896 min (Method I)

[0390] Example 100. (S)-N-(2-(7-(2-Amino-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)-2-(1H-imidazol-1-yl)acetamide

Chem.

[0391] Step 1: Synthesis of ethyl 1-(cyclopropylmethyl)-7-nitro-1H-indole-2-carboxylate Ethyl 7-nitro-1H-indole-2-carboxylate (5 g, 21.4 mmol) / DMF (100 mL) was reacted with bromomethylcyclopropane (4.32 g, 32 mmol) according to General Procedure 5. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (5 g, 81.2%) as a yellow solid. LCMS (ESI, m / z): 289 [M+H]+

[0392] Step 2: Synthesis of (1-(cyclopropylmethyl)-7-nitro-1H-indol-2-yl)methanol To a solution of ethyl 1-(cyclopropylmethyl)-7-nitro-1H-indole-2-carboxylate (2 g, 6.94 mmol) / THF (1.5 mL) was added dropwise LiBH4 (2 M, THF solution, 302 mg, 13.9 mmol) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. Then water (0.7 mL) / NaOH(aq) (2 mL) / water (0.7 mL) was added to quench the reaction, and the mixture was stirred at room temperature for 20 min and dried over anhydrous sodium sulfate. The solid was filtered and the solvent was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (647 mg, 38%) as a yellow solid. LCMS (ESI, m / z): 247 [M+H]+

[0393] Step 3: Synthesis of 1-(cyclopropylmethyl)-7-nitro-1H-indole-2-carbaldehyde (1-(cyclopropylmethyl)-7-nitro-1H-indol-2-yl)methanol (670 mg, 2.07 mmol) was reacted according to General Procedure 4. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title compound (460 mg, 69.1%) as a yellow solid. LCMS (ESI, m / z): 245 [M+H]+

[0394] Step 4: Synthesis of tert-butyl (S)-(1-(2-(7-amino-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate Intermediate 2 (400 mg, 1 mmol) and 1-(cyclopropylmethyl)-7-nitro-1H-indole-2-carbaldehyde (367 mg, 1.5 mmol) were reacted according to General Procedure 6. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (30 mg, 5%) as a yellow solid. LCMS (ESI, m / z): 562 [M+H]+

[0395] Step 5: Synthesis of tert-butyl (S)-(1-(2-(7-(2-(1H-imidazol-1-yl)acetamido)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate To a solution of 2-(1-imidazolyl)acetic acid (82 mg, 0.65 mmol) and DIEA (0.06 mL, 0.65 mmol) in DMF (1 mL) was added HATU (74.1 mg, 0.19 mmol) at room temperature, and the mixture was stirred at room temperature for 10 minutes. Then the resulting mixture was added dropwise at room temperature to a solution of tert-butyl (S)-(1-(2-(7-amino-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (73 mg, 0.13 mmol) in DMF (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. Then water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL). The combined organic extracts were washed with water (3 x 10 mL) and brine (3 x 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (30 mg, 35%) as a yellow solid. LCMS (ESI, m / z): 670 [M+H]+

[0396] Step 6: Synthesis of (S)-N-(2-(7-(2-Amino-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]naphthyridin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)-2-(1H-imidazol-1-yl)acetamide tert-Butyl (S)-(1-(2-(7-(2-(1H-imidazol-1-yl)acetamido)-1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-8-oxo-3,5,6,8-tetrahydro-7H-imidazo[4,5-b][1,6]naphthyridin-7-yl)-3-fluoropropan-2-yl)carbamate (30 mg, 0.04 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method F) to give the title compound (6.9 mg, 26%) as a yellow solid. 11H NMR (400 MHz, methanol-d4) δ 9.10 (s, 1H), 8.66 (s, 1H), 7.76 - 7.75 (m, 2H), 7.66 (s, 1H), 7.30 - 7.28 (m, 3H), 5.45 (s, 2H), 4.90 - 4.82 (m, 2H), 4.53 (d, J = 6.4 Hz, 2H), 4.10 - 4.08 (m, 1H), 4.04 (s, 3H), 3.93 - 3.80 (m, 4H), 3.46 - 3.43 (m, 2H), 0.90 - 0.88 (m, 1H), 0.25 - 0.23 (m, 2H), -0.24 - -0.28 (m, 2H); LCMS (ESI, m / z): 570 [M + H]+; LCMS RT: 1.079 min (Method D)

[0397] Biological assay For the compounds of the present disclosure, assays as PAD4 inhibitors were performed using the following assay protocols.

[0398] RFMS assay 1 conditions The compounds were dissolved in 100% DMSO to a concentration of 10 mM. The stock solutions of the compounds were stored at room temperature. Dilution series were prepared in DMSO and mixed 8 times with a total volume of 20 μL. The final highest concentration of the compounds in this assay was 50 μM. The final assay conditions are shown below. Reaction volume: 26 μL Assay buffer: 25 mM HEPES (pH 7.5), 5 mM NaCl, 1 mM DTT, 0.2 mg / mL BSA, 0.01% CHAPS, 50 μM calcium, and 5 μM TPEN Final concentration: 5 nM hPAD4 enzyme, 250 μM BAEE, and 0.5% DMSO Total incubation time: 30 min (The compounds and the enzyme were pre-incubated at 37 °C for 90 min for the enzyme / substrate reaction and reacted with phenylglyoxal at 37 °C for 30 min) Stop solution: 40 μL 5% TCA / ACN A compound solution (0.13 μL) was added to 13 μL of PAD4 / assay buffer (10 nM). After adding 13 μL of BAEE (500 μM) to 25 mM HEPES (pH 7.5), 5 mM NaCl, 1 mM DTT, 0.2 mg / mL BSA, 0.01% CHAPS, 50 μM calcium, and 5 μM TPEN, the reaction was incubated at 37 °C for 90 minutes. 15 μL of TCA (6.1 N) was added to stop the enzyme reaction (the final concentration of 100% was 20%), and then 35 μL of 8.5 mM phenylglyoxal (final concentration 4 mM) was added, and the reaction was incubated at 37 °C for 30 minutes. After 30 minutes, the plate was centrifuged to remove all precipitates. The enzyme reaction was quenched with methanol containing the same volume of internal standard (modified citrulline). The sample was loaded onto a Rapid Fire RF300 (Agilent). Here, the sample was first loaded for 1000 milliseconds, and then directly loaded onto a C18 separation cartridge with a mixed solution of acetonitrile containing 0.01% formic acid for 3000 milliseconds for desalting. The flow rate of the mobile phase was 1.5 mL / min. Once the sample was eluted from the cartridge, the mobile phase of acetonitrile containing 0.01% formic acid transferred the sample to the mass spectrometer in 4000 milliseconds (flow rate: 1.25 mL / min). A Sciex API5500 triple quadrupole mass spectrometer (Applied Biosystems) equipped with ESI was used for the analysis of peptidylcitrulline and internal standard ions. The MRM transitions of the product and the internal standard were observed at m / z 424.5~350.4 and m / z 293~247, respectively. The dwell time for each transition was set to 200 milliseconds, the ESI voltage was 5500, and the heat source was used at 400 °C. The ion peaks of each extracted transition were integrated using software (Rapid Fire Integrator). The peak area of the analyte was normalized with the internal standard.

[0399] RFMS assay 2 conditions Preparation of the compound: The stock compound was dissolved in 100% DMSO and stored. The compound solution was prepared by serial dilution three times in DMSO. The highest concentration of the compound in each assay was 20 μM. The compound solution (0.25 μL) was transferred from the compound plate to the assay plate using an acoustic dispenser. Final assay conditions: Total reaction volume: 25 μL Assay buffer: 100 mM HEPES (pH 7.4), 200 mM NaCl, 2 mM CaCl2, 5 mM DTT 35 nM recombinant human PAD4 500 μM TSTGGRQGSHH peptide (SEQ ID NO: 1) 1.2% DMSO Stop solution: 10% formic acid The reaction mixture was incubated at room temperature for 30 minutes. Each reaction mixture (10 μL) was then mixed with 10% formic acid (40 μL) in a microtiter plate. The plate was frozen at -80 °C and then taken out on dry ice for mass spectrometry (RapidFire). The thawed sample was loaded onto a Rapid Fire 300 (Agilent). Here, the sample was first loaded for 250 milliseconds and then loaded for 3000 milliseconds with a mobile phase of water (containing 0.09% formic acid / 0.01% trifluoroacetic acid) onto a "C" (C18) cartridge (Agilent) for desalting. The flow rate was 1.5 mL / min. Once the sample was loaded and eluted, the mobile phase of acetonitrile (containing 0.09% formic acid / 0.01% trifluoroacetic acid) directly transferred the sample to a Sciex API4000 triple quadrupole mass spectrometer for 3000 milliseconds (flow rate: 1.25 mL / min). The MRM transitions of the substrate and product were observed at m / z = 562.3 / 969.7 and m / z = 562.8 / 541.3, respectively, in positive mode ESI. The dwell time for each transition was set to 100 milliseconds, and the ESI voltage was 5500 and the heat source was 650 °C were used. The ion peaks of each extracted transition were integrated using software (Rapid Fire Integrator).

[0400] For the obtained example compounds, the following table shows the IC of human PAD4 (hPAD4) in the Rapid Fire mass spectrometry (RFMS) assay. 50 is shown.

[0401] Table 13 below shows the activities of selected compounds of the present invention in the PAD4 assay described above. Compounds indicated as "A" have an IC 50 ≦10 nM activity, compounds indicated as "B" have an IC 50 = 11 - 100 nM activity, compounds indicated as "C" have an IC 50 = 101 - 500 nM activity, compounds indicated as "D" have an IC 50 = 501 - 1000 nM activity, and compounds indicated as "E" have an IC 50 > 1000 nM activity. [Table 35] [Table 36] [Table 37]

[0402] Embodiment Embodiment 1. Formula I: [Chemical formula] [wherein, X is selected from C-R 6 and N; X' is selected from C-R 6' and N, provided that X and X' are not simultaneously N; R 1 is C 1-4 aliphatic; R 2 is C 7 aliphatic substituted with 0 to 4 R 1-6 ; R 3is C substituted with 0 to 3 Rs 8 and is aliphatic; 1-6 R 4 is halogen; R 5 is halogen; Each R 6 and R 6' is independently selected from hydrogen, halogen, -OR, -N(R)2, -OC(O)R, -N(R)C(O)R, -O-L-(R 9 ) p -Cy, and optionally substituted C 1-6 aliphatic; Each R 7 is independently selected from halogen, -OR, -N(R)2, and -Cy; Each R 8 is independently selected from halogen, -OR, -N(R)2, and -Cy; Each R 9 is independently selected from halogen, -OR, -N(R)2, and -Cy; L is a covalent bond or C 1-4 and is aliphatic; Each Cy is independently selected from a 3- to 7-membered saturated or partially unsaturated carbocycle; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where Cy is substituted with 0 to 3 Rs 10 and is substituted; Each R 10 is independently selected from halogen, -OR, -N(R)2, -CN, -C(O)R, -C(O)OR, -C(O)N(R)2, oxo, and an optionally substituted group, where the optionally substituted group is selected from C 1-6 aliphatic; and a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or an optionally substituted group, where the optionally substituted group is C 1-6 ​Selected from aliphatic; 3- to 7-membered saturated or partially unsaturated carbocyclic rings; phenyl; 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each m and n is independently 0 or 1; and p is independently 1 to 4] a compound of or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof. Embodiment 2. The compound is of formula I-a, I-b, I-c, I-d, I-e, I-f, I-g, and I-h:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Claims

1. Formula I: 【Chemistry 1】 [In the formula, X is CR 6 and selected from N; X' is CR 6' and are selected from N, where X and X' cannot be N at the same time; R 1 C 1-4 It is aliphatic; R 2 This includes 0 to 4 R 7 C replaced by 1-6 It is aliphatic; R 3 is C which is substituted with 0 to 3 R 8 and is aliphatic; 1-6 ​ R 4 It is a halogen; R 5 It is a halogen; Each R 6 and R 6' These are independently hydrogen, halogen, -OR, and -N(R) 2 , -OC(O)R, -N(R)C(O)R, -OL-(R 9 ) p -Cy, and C which may be substituted as appropriate. 1-6 Selected from aliphatic species; Each R 7 These are independently halogen, -OR, and -N(R) 2 Selected from , and -Cy; Each R 8 These are independently halogen, -OR, and -N(R) 2 Selected from , and -Cy; Each R 9 These are independently halogen, -OR, and -N(R) 2 Selected from , and -Cy; L is covalent or C 1-4 It is aliphatic; Each Cy is independently selected from 3-7 member saturated or partially unsaturated carbon rings; phenyl; 3-7 member saturated or partially unsaturated heterorings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 member heteroaryls having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where Cy has 0-3 R 10 Replaced by; Each R 10 These are independently halogen, -OR, and -N(R) 2 , -CN, -C(O)R, -C(O)OR, -C(O)N(R) 2 A group selected from , oxo, and optionally substituted groups, wherein the optionally substituted group is C 1-6 Aliphatic; as well as selected from 3- to 7-membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently a hydrogen or optionally substituted group, and the optionally substituted group is C 1-6 Aliphatic; 3- to 7-membered saturated or partially unsaturated carbon rings; phenyl; 3- to 7-membered saturated or partially unsaturated heterorings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and selected from 5- to 6-membered heteroaryls having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each m and n is independently 0 or 1; and p is independently 1 to 4. Compounds thereof or their pharmaceutically acceptable salts, isomers, enantiomers, or tautomers.

2. The compounds are those of formulas Ia, Ib, Ic, Id, Ie, If, Ig, and Ih: 【Chemistry 2】 A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof, selected from the above.

3. Compounds with formulas Iai, Ibi, Ici, Idi, Iei, Ifi, Igi, and Ihi: 【Transformation 3】 A compound according to claim 2, selected from the above, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

4. In the formula, R 1 ga-CH 3 The compound according to claim 1 or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

5. A compound according to claim 1, wherein m is 1, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

6. In the formula, R 4 The compound according to claim 5, wherein is fluoro or chloro, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

7. In the formula, R 4 C 1-6 An aliphatic compound as described in claim 1 or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

8. A compound according to claim 1, wherein m is 0, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

9. In the formula, R 2 1 to 4 R 7 C replaced by 1-6 An aliphatic compound as described in claim 1 or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

10. In the formula, R 2 1 to 2 R 7 C replaced by 1-4 The compound according to claim 9, which is aliphatic, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

11. In the formula, at least one R 7 The compound according to claim 1, wherein the halogen is a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

12. In the formula, at least one R 7 The compound according to claim 11, wherein is fluoro, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

13. In the formula, R 2 but, 【Chemistry 4】 A compound according to claim 1, selected from the group consisting of the above, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

14. In the formula, R 3 but, 【Transformation 5】 A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof, selected from the above.

15. In the formula, R 6 However, hydrogen, -CH 3 ,-OCH 3 , 【Transformation 6】 【Transformation 7】 A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof, selected from the above.

16. A pharmaceutically acceptable composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

17. A pharmaceutical composition for inhibiting PAD4, comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

18. A pharmaceutical composition for treating a PAD4-mediated disease, disorder, or symptom, comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

19. Diseases, disorders, or symptoms involving PAD4 include: acid-induced lung injury, acne (PAPA), acute lymphoblastic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenal insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergic asthma, allergic bronchopulmonary aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, weight loss, angina pectoris, angioedema, anhidrotic ectodermal dysplasia, ankylosing spondylitis, anterior segment inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, and arthritis. Asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, Behçet's disease, Bell's palsy, beryllium lung, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysms, inflammation due to chemical irritation, chorioretinitis, chronic heart failure, chronic lung disease in premature infants, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, Crohn's disease, cryopyrin-associated periodic fever syndrome, cryptococcosis, cystic fibrosis, interleukin-1 receptor Somatic antagonist deficiency (DIRA), dermatitis, cutaneous endotoxemia, dermatomyositis, diffuse pontine glioma, endometriosis, endotoxemia, epicondylitis, pure red cell aplasia, familial amyloid polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth restriction, glaucoma, glomerular disease, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, gastrointestinal disorders, head trauma, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Schönlein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster, herpes simplex, HIV-1, Hodgkin's disease, Huntington's disease, pulmonary hyaline membrane disease, hyperammonemia, hypercalcemia Ciumemia, hypercholesterolemia, hyper-IgD syndrome with periodic fever (HIDS), aplastic anemia, other anemias, idiopathic thrombocytopenic purpura, incontinentia pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, inflammation due to insect bites, iritis, inflammation due to irritation, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney damage due to parasitic infection, kidney transplant rejection, leptospirosis, leukemia, Loeffler's syndrome, lung injury, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Macklewells syndrome (urticaria,Hearing loss, amyloidosis, multiple sclerosis, muscle weakness, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungoides, myelodysplastic syndrome, myositis, sinusitis, necrotizing enterocolitis, neonatal-onset multiorgan inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological disorders, non-allergic asthma, obesity, ophthalmic allergies, optic neuritis, organ transplantation, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), plant-induced inflammation, pneumonia, lung infections, poison ivy / urushiol-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psychosomatic disorders, lung diseases, pulmonary hypertension A pharmaceutical composition according to claim 18, selected from the group consisting of pulmonary fibrosis, pyoderma gangrenosum, suppurative aseptic arthritis, kidney disease, retinal disease, rheumatic heart disease, rheumatic disease, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell anemia, sickle cell anemia, silica-induced disease, Sjögren's syndrome, skin disease, sleep apnea syndrome, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplantation, TNF receptor-associated periodic syndromes (TRAPS), toxoplasmosis, transplantation, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, and granulomatosis with polyangiitis.

20. Formula I': 【Transformation 8】 [In the formula, X is CR 6 and selected from N; X' is CR 6' and are selected from N, where X and X' cannot be N at the same time; R 1 C 1-4 It is aliphatic; R 2 This includes 0 to 4 R 7 C replaced by 1-6 It is aliphatic; R 3 This includes 0 to 3 R 8 C replaced by 1-6 It is aliphatic; R 4 It is a halogen; R 5 It is a halogen; Each R 6 and R 6' These are independently hydrogen, halogen, -OR, and -N(R) 2 , -OC(O)R, -N(R)C(O)R, -N(R)C(O)-L-(R 9 ) p , -OL-(R 9 ) p -Cy may be substituted as appropriate. 1-6 Aliphatic, and C 1-6 Selected from aliphatic -OH groups; Each R 7 These are independently halogen, -OR, and -N(R) 2 Selected from , and -Cy; Each R 8 These are independently halogen, -OR, and -N(R) 2 Selected from , and -Cy; Each R 9 These are independently halogen, -OR, and -N(R) 2 Selected from , and -Cy; L is covalent or C 1-4 It is aliphatic; Each Cy is independently selected from 3-7 member saturated or partially unsaturated carbon rings; phenyl; 3-7 member saturated or partially unsaturated heterorings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 member heteroaryls having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where Cy has 0-3 R 10 Replaced by; Each R 10 These are independently halogen, -OR, and -N(R) 2 , -CN, -C(O)R, -C(O)OR, -C(O)N(R) 2 A group selected from , oxo, and optionally substituted groups, wherein the optionally substituted group is C 1-6 Aliphatic; as well as selected from 3- to 7-membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently a hydrogen or optionally substituted group, and the optionally substituted group is C 1-6 Aliphatic; 3- to 7-membered saturated or partially unsaturated carbon rings; phenyl; 3- to 7-membered saturated or partially unsaturated heterorings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and selected from 5- to 6-membered heteroaryls having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where each R is independently 0-3 halogens, -OCH 3 , or substituted with -OH; Each m and n is independently 0 or 1; and p is independently 1 to 4. Compounds thereof or their pharmaceutically acceptable salts, isomers, enantiomers, or tautomers.

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