Heterocyclic PAD4 inhibitors

Abstract

The present disclosure relates generally to 3, 5, 6, 7-tetrahydro-8H-imidazo [4, 5-b] [1, 6] phthalazin-8-one compounds of formula I as PAD4 inhibitors, processes for preparing these compounds, pharmaceutical compositions comprising these compounds, and the use of these compounds in the treatment of diseases or conditions associated with PAD4 enzyme activity.

Description

Cross-references

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 365,370, filed on May 26, 2022, the entire contents of which are incorporated herein by reference. Sequence Listing Incorporated by Reference

[0002] The sequence listing section of this application contains a sequence listing, which is submitted in .XML format via EFS-WEB, and is incorporated herein by reference in its entirety. The .XML copy was created on May 26, 2023, named 055920-608001WO_SeqList_ST26.xml, and is 3KB in size. Technical Field

[0003] The present invention generally relates to substituted heterocyclic compounds, methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and the use of these compounds in treating diseases or disorders associated with PAD4 enzyme activity. Background Art

[0004] PAD4 (SEQ ID NO: 1) is a member of the peptidyl arginine deiminase (PAD) family of enzymes that can catalyze the arginine citrullination in peptide sequences to citrulline. PAD4 is responsible for the deimination or citrullination of multiple proteins in vitro and in vivo, producing different functional responses in multiple diseases (Jones JE et al., Curr. Opin. Drug Discov. Devel., 12 (5), (2009), 616-627). Examples of exemplary diseases or disorders include rheumatoid arthritis, diseases in which neutrophils participate in the onset of disease (e.g., vasculitis, systemic lupus erythematosus, ulcerative colitis), and tumor indications. Through epigenetic mechanisms, PAD4 inhibitors are also more widely applicable as tools and treatments for human diseases and disorders.

[0005] PAD4 inhibitors have therapeutic effects on rheumatoid arthritis (RA). RA is an autoimmune disease that affects about 1% of the population (Wegner N. et al., Immunol. Rev., 233 (1), (2010), 34-54). It is characterized by debilitating destruction of bones and cartilage caused by joint inflammation. In a large population study, although inconsistent, there is a weak genetic association between PAD4 polymorphism and RA susceptibility (Kochi Y. et al., Ann. Rheum. Dis., 70, (2011), 512-515). PAD4 (together with family member PAD2) has been detected in synovial tissue, where it is responsible for the degradation of multiple joint proteins. It is speculated that this process will lead to a breakdown of tolerance to citrullinated substrates, such as fibrinogen, vimentin and collagen, in RA joints, and induce an immune response to citrullinated substrates. These anti-citrullinated protein antibodies (ACPA) contribute to disease pathogenesis and can also be used as diagnostic tests for RA (e.g., the commercially available CCP2 or cyclic citrullinated protein 2 test). In addition, increased citrullination may also provide an additional direct contribution to disease pathogenesis through its ability to directly affect the function of several joint and inflammatory mediators (e.g., fibrinogen, antithrombin, and multiple chemokines). Anti-PAD4 antibodies can be detected in a small percentage of RA patients and may be associated with more severe forms of the disease.

[0006] PAD4 inhibitors can also be used to reduce pathological neutrophil activity in a variety of diseases. Studies have shown that the formation process of neutrophil extracellular traps (NETs) (neutrophils can fix and kill pathogens by this innate defense mechanism) is related to the citrullination of histones and is lacking 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). PAD4 inhibitors are therefore applicable to diseases in which NET formation in tissues leads to local damage and disease pathology. 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 SR et al., Nat. Med., 13(4), (2007), 463-9), appendicitis (Brinkmann V. et al., Science, 303, (2004), 1532-5) and stroke. In addition, there is evidence that NETs may contribute to the pathology of diseases affecting the skin, such as cutaneous lupus erythematosus (Villanueva E. et al., J. Immunol., 187(1), (2011), 538-52) and psoriasis (Lin AM et al., J. Immunol., 187(1), (2011), 490-500), and PAD4 inhibitors may show benefits in addressing NET skin diseases when administered by systemic or cutaneous routes. PAD4 inhibitors may affect other functions of neutrophils and have broader applicability to neutrophil diseases.

[0007] Studies have demonstrated the effectiveness of tool PAD inhibitors such as chloramidine in a number of animal disease models, including collagen-induced arthritis (Willis VC et al., J. Immunol., 186(7), (2011), 4396-4404), dextran sulfate sodium (DSS)-induced experimental colitis (Chumanevich AA 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). The DSS colitis report also demonstrated that chloramidine can drive apoptosis of inflammatory cells both in vitro and in vivo, suggesting that PAD4 inhibitors may be more generally effective in a wide range of inflammatory diseases.

[0008] PAD4 inhibitors can also be used for the treatment of cancer (Slack JL et al., Cell. Mol. Life Sci., 68 (4), (2011), 709-720). Overexpression of PAD4 has been confirmed in a variety of cancers (Chang X. et al., BMC Cancer, 9, (2009), 40). PAD4 citrullinates arginine residues in histones at the promoter of p53 target genes (such as p21), which are involved in cell cycle arrest and induction of apoptosis. From the above observations, it has been shown that PAD4 inhibitors have anti-proliferative effects (Li P. et al., Mol. Cell Biol., 28 (15), (2008), 4745-4758).

[0009] The above-mentioned role of PAD4 in the deimination of arginine residues in histones can indicate the role of PAD4 in epigenetic regulation of gene expression.PAD4 is the main PAD family member observed to reside in the nucleus and cytoplasm.The early evidence that PAD4 can act as histone demethyliminase and deiminase is inconsistent and unconfirmed.However, it can indirectly reduce histone arginine methylation (and thus reduce epigenetic regulation associated with this mark) by consuming available arginine residues through conversion to citrulline.PAD4 inhibitors can be used as epigenetic tools or therapies for affecting the expression of different target genes in other disease environments.Through these mechanisms, PAD4 inhibitors can also effectively control the citrullination level in stem cells, and therefore can affect the pluripotent state and differentiation potential of multiple stem cells in treatment, including but not limited to embryonic stem cells, neural stem cells, hematopoietic stem cells and cancer stem cells.Accordingly, the needs of identifying and developing PAD4 inhibitors for treating diseases or conditions mediated by PAD4 remain unmet. Summary of the invention

[0010] Accordingly, the present disclosure provides a compound of formula I

[0011] and pharmaceutically acceptable salts, isomers, enantiomers or tautomers thereof, wherein each X, X′, R 1 , R 2 , R 3 , R 4 , R 5 , m and n are as defined below and described herein.

[0012] In another aspect, the present disclosure provides a compound of formula I' and pharmaceutically acceptable salts, isomers, enantiomers or tautomers thereof, wherein each X, X′, R 1 , R 2 , R 3 , R 4 , R 5 , m and n are as defined below and described herein.

[0013] 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 pharmaceutical composition provided is suitable for oral, parenteral, mucosal, transdermal or topical administration.

[0014] In another aspect, the present disclosure provides a method of inhibiting a PAD4 enzyme or a mutant thereof, the method comprising contacting a biological sample with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0015] In another aspect, the present disclosure provides a method for treating a disease or condition associated with PAD4 enzyme activity, comprising administering a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. The disease or condition includes, among others, rheumatoid arthritis, vasculitis, systemic lupus erythematosus, and ulcerative colitis. DETAILED DESCRIPTION General Description of Compounds of the Disclosure:

[0016] In some embodiments, the present disclosure provides compounds of Formula I: or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof, wherein: X is selected from CR 6and N; X′ is selected from CR 6′ and N, where X and X′ are not N at the same time; R 1 C 1-4 Fat; R 2 For 0-4 R 7 Substituted C 1-6 Fat; R 3 For 0-3 R 8 Substituted C 1-6 Fat; R 4 is a halogen; R 5 is a halogen; Each R 6 and R 6′ is selected from 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 Fat; R 7 Selected from halogen, -OR, -N(R) 2 and -Cy; R 8 Selected from halogen, -OR, -N(R) 2 and -Cy; R 9 Selected from halogen, -OR, -N(R) 2 and -Cy; L is a covalent bond or C 1-4 Fat; Cy is selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a phenyl group, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy is surrounded by 0-3 R 10 replace; R 10 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 selected from C 1-6 aliphatic and 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; R is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each m and n is 0 or 1; and p is 1-4. 1. Definition:

[0017] Compounds of the present disclosure include those generally described above, and are further illustrated by classes, subclasses, and specific compounds disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present disclosure, chemical elements are identified according to the periodic table, CAS version, 75th edition of the Handbook of Chemistry and Physics. In addition, the general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999 and March Advanced Organic Chemistry, 5th edition, Smith, MB and March, J., John, Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0018] As used herein, the term "aliphatic" or "aliphatic group" means a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain, which is fully saturated or contains one or more unsaturated units, or a monocyclic hydrocarbon or a bicyclic hydrocarbon, which is fully saturated or contains one or more unsaturated units, but which is non-aromatic (also referred to herein as "carbocycle", "carbocyclic", "cycloaliphatic" or "cycloalkyl"), which has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In yet other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 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.

[0019] In some embodiments, "carbocycle" (or "cycloaliphatic" or "carboncycle" or "cycloalkyl") refers to a C3-C8 hydrocarbon, which may be monocyclic or polycyclic, which is fully saturated or which contains one or more unsaturated units, but which is non-aromatic, and which has a single point of attachment to the rest of the molecule. The ring of a polycyclic carbocyclic compound may be fused, bridged and / or connected to one or two aromatic cycloalkyls or heterocycles through one or more spiro connections. Typical, non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, and the like.

[0020] The term "heteroatom" means one or more oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; any quaternized form of basic nitrogen; a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (such as in N-substituted pyrrolidinyl)). In some embodiments, the oxidized forms of sulfur include S=O and S(=O) 2 .

[0021] As used herein, the term "unsaturated" means that the moiety has one or more units of unsaturation.

[0022] The term "halogen" means F, Cl, Br or I.

[0023] The term "aryl", used alone or as part of a larger moiety in "aralkyl", "aralkyloxy" or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system, and exemplary groups include phenyl, biphenyl, naphthyl, anthracenyl, etc., which may carry one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthalimidyl, or tetrahydronaphthyl, etc.

[0024] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms or 5, 6 or 9 ring atoms; having 6, 10 or 14 π electrons shared in the ring array; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Exemplary heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl rings, cycloaliphatic rings, or heterocyclic rings, wherein the radical or point of attachment is on the heteroaromatic ring. Exemplary groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, and tetrahydroisoquinolyl. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," wherein any of the terms include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl group, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0025] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more or one to four heteroatoms as defined above in addition to carbon atoms. When used to refer to the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolidinyl), NH (as in pyrrolidinyl) or + NR (as in N-substituted pyrrolidinyl).

[0026] The heterocycle can be attached to its side group at any heteroatom or carbon atom to form a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclic ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherein the radical or point of attachment is on the heterocycle. The heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions are independently optionally substituted.

[0027] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0028] As described herein, compounds of the present disclosure may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. "Substituted" applies to one or more hydrogens from a structure, whether explicit or implicit (e.g., means at least as well as means at least ). Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents at each position may be the same or different. Combinations of substituents contemplated by the present disclosure are those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that do not substantially change when subjected to conditions that allow their production, detection, and in certain embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0029] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are independently halogen; -(CH 2 ) 0–4 R o ; –(CH 2 ) 0–4 OR o ; -O(CH 2 ) 0-4 R o 、–O–(CH 2 ) 0–4 C(O)OR o ; –(CH 2 ) 0–4 CH(OR o ) 2 ; –(CH 2 ) 0– 4 SR o ; –(CH 2 ) 0–4 Ph, which can be o Substitution; –(CH 2 ) 0–4 O(CH 2 ) 0–1 Ph, which can be o Substitution; –CH=CHPh, which can be replaced by R o Substitution; –(CH 2 ) 0–4 O(CH 2 ) 0–1 -pyridyl, which may be R o Replace; –NO 2 ;–CN;–N 3 ;-(CH 2 ) 0–4 N(R o ) 2 ; –(CH 2 ) 0–4 N(R o )C(O)R o ; –N(R o )C(S)R o ; –(CH 2 ) 0–4 N(R o )C(O)NR o 2 ;-N(R o )C(S)NR o 2 ; –(CH 2 ) 0–4 N(R o )C(O)ORo ;–N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2 ;-N(R o )N(R o )C(O)OR o ;–(CH 2 ) 0–4 C(O)R o ;–C(S)R o ;–(CH 2 ) 0–4 C(O)OR o ;–(CH 2 ) 0–4 C(O)SR o ;-(CH 2 ) 0–4 C(O)OSiR o 3 ;–(CH 2 ) 0–4 OC(O)R o ;–OC(O)(CH 2 ) 0–4 SR o ;–(CH 2 ) 0–4 SC(O)R o ;–(CH 2 ) 0–4 C(O)NR o 2 ;–C(S)NR o 2 ;–C(S)SR o ;–SC(S)SR o 、-(CH 2 ) 0– 4 OC(O)NR o 2 ;-C(O)N(OR o )R o ;–C(O)C(O)R o ;–C(O)CH 2 C(O)R o ;–C(NOR o )R o ;-(CH 2 ) 0–4 SSR o ;-(CH 2) 0–4 S(O) 2 R o ; –(CH 2 ) 0–4 S(O) 2 OR o ; –(CH 2 ) 0–4 OS(O) 2 R o ; –S(O) 2 NR o 2 ;-(CH 2 ) 0–4 S(O)R o ;-N(R o )S(O) 2 NR o 2 ; –N(R o )S(O) 2 R o ;–N(OR o )R o ; –C(NH)NR o 2 ; –P(O) 2 R o ;-P(O)R o 2 ;-OP(O)R o 2 ;–OP(O)(OR o ) 2 ;SiR o 3 ;–(C 1-4 Straight or branched alkylene)O–N(R o ) 2 or –(C 1-4 Straight or branched alkylene)C(O)ON(R o ) 2 , where each R o may be substituted as defined below and are independently hydrogen, C 1-6 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, -CH 2 -(5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 members independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of R o, together with their central atoms, form a 3-12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0030] R o A suitable monovalent substituent (or two independent occurrences of R o Together with their central atoms to form a ring) are independently halogen, –(CH 2 ) 0–2 R ● 、–(halogenated R ● ),–(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR ● ,–(CH 2 ) 0–2 CH(OR · ) 2 、-O(halogenated R ● ),–CN,–N 3 ,–(CH 2 ) 0–2 C(O)R ● ,–(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR ● ,–(CH 2 ) 0–2 SR ● ,–(CH 2 ) 0– 2 SH, –(CH 2 ) 0–2 NH 2 ,–(CH 2 ) 0–2 NHR ● ,–(CH 2 ) 0–2 NR ● 2 ,–NO 2 、–SiR ● 3 ,–OSiR ● 3 、-C(O)SR · ,–(C 1–4 Straight or branched alkylene)C(O)OR ● or –SSR · , where each R ● Each R which is unsubstituted or preceded by "halo"● is substituted only by one or more halogens and is independently selected from C 1-4 Aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph or a 5-6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0031] Suitable divalent substituents on a substitutable carbon atom of an "optionally substituted" group include the following: =0 ("oxo"), =S, =NNR * 2 、=NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O) 2 R * , =NR * , =NOR * , –O(C(R * 2 )) 2–3 O–or–S(C(R * 2 )) 2–3 S–, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6 an aliphatic or unsubstituted 5-6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bound to adjacent substitutable carbons of an "optionally substituted" group include: -O(CR * 2 ) 2– 3 O-, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 Aliphatic or unsubstituted 5-6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0032] R * Suitable substituents on the aliphatic group include halogen, –R ● 、-(halogenated R ● ), -OH, –OR · 、–O(halogenated R · ), –CN, –C(O)OH, –C(O)OR · , –NH 2 , –NHR · ,–NR ·2 or –NO 2 , where each R · Each R which is unsubstituted or preceded by "halo" · is substituted only by one or more halogens and is independently C 1-4 Aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph or a 5-6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0033] Suitable substituents on the substitutable nitrogen of an "optionally substituted" group include - or Each of these are independently hydrogen, C which may be substituted as defined below 1-6 aliphatic, unsubstituted -OPh or unsubstituted 5-6-membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent occurrences of Together with their central atoms, they form an unsubstituted 3-12-membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0034] Suitable substituents on the aliphatic group are independently halogen, -R ● 、-(halogenated R ● ), –OH, –OR ● 、–O(halogenated R ● ), –CN, –C(O)OH, –C(O)OR ● , –NH 2 , –NHR ● ,–NR · 2 or-NO 2 , where each R · Each R which is unsubstituted or preceded by "halo" · is substituted only by one or more halogens and is independently C 1-4 Aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph or a 5-6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0035] As used herein, the term "subject" refers to and includes any human or non-human organism that may benefit from treatment with a PAD4 inhibitor. Exemplary subjects include humans and animals.

[0036] As used herein, the term "treating" or "treatment" refers to and includes treatment of a disease state in a subject (e.g., a human or an animal), and includes: (a) inhibiting the disease state, i.e., arresting its development; (b) alleviating the disease state, i.e., causing regression of the disease state; and / or (c) preventing the disease state from occurring in a subject.

[0037] As used herein, the term "preventing" or "prevention" refers to and includes the prophylactic treatment (i.e., prevention and / or risk reduction) of a subclinical disease state in a subject (e.g., a human or animal) for the purpose of reducing the likelihood of the clinical disease state occurring. A subject may be selected for prophylactic treatment based on factors known to increase the risk of developing a clinical disease state compared to the general population. "Prophylactic" treatment can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment of a subject who has not yet developed a clinical disease state, while secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.

[0038] The term "therapeutically effective amount" refers to and includes an amount of a compound or composition according to the present disclosure that is effective in preventing or treating a disease or condition associated with PAD4 enzyme activity when administered alone or in combination. When applied to a combination, the term refers to the combined amounts of the active ingredients that produce a preventive or therapeutic effect, whether administered in combination, serially or simultaneously.

[0039] "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to humans and / or animals. Pharmaceutically acceptable carriers are formulated according to many factors within the knowledge of those of ordinary skill in the art. These factors include, but are not limited to, the type and nature of the active agent to be formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the compound or composition, and the therapeutic indication for which it is intended. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media. In addition to the active agent, such carriers may include many different ingredients and additives, which are included in the formulation for a variety of reasons known to those of ordinary skill in the art, such as, stabilizing active agents, adhesives, etc. Typical, non-limiting examples of such carriers include diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, flavoring agents, antibacterial agents, antifungal agents, lubricants, dispersants, coating agents, etc. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, can be found in a variety of readily available resources, such as, for example, Allen, 1v, Jr. et al., Remington: The Science and Practice of Pharmacy (Vol. 2), 22nd Edition, Pharmaceutical Press (2012).

[0040] The present disclosure is intended to include all isotopes of atoms occurring in the disclosed compounds. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and not limitation, isotopes of hydrogen include deuterium (symbol D or 2 H) and tritium (symbol T or 3 H). For example, a methyl group may be represented by CH 3 or CD 3 Indicates. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.

[0041] The salts formed by the compounds of formula I are also within the scope of the present disclosure. Unless otherwise indicated, references to compounds of formula I should be understood to include references to their salts. As used herein, the term "salt" means an acid addition salt and / or a base addition salt formed with an inorganic acid and / or an organic acid and an inorganic base and / or an organic base. In addition, when the compound of formula I contains both a basic part and an acidic part, a zwitterion ("inner salt") can be formed and is included in the term "salt" as used herein. Pharmaceutically acceptable salts include those generally acceptable salts for use in subjects (including humans and animals) in the pharmaceutical field. Typically, pharmaceutically acceptable salts are nontoxic and physiologically acceptable salts. According to the salt of the compound of the present disclosure, for example, the compound can be reacted with a certain amount of acid or base, such as an equivalent amount of acid or base, in a medium such as a salt precipitated therein or in an aqueous medium and then lyophilized to form.

[0042] Compounds of Formula I containing a basic moiety can form salts with various organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acids (e.g., trifluoroacetic acid)), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), hydrobromide (formed with hydrobromic acid), hydroiodide.

[0013] Examples of the invention include succinates, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, fruit salts, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates (such as tosylates), undecanoates, and the like.

[0043] Compounds of Formula I containing an acidic moiety can form salts with a variety of organic and inorganic bases. Exemplary base addition salts include ammonium salts, alkali metal salts (such as sodium, lithium and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), and organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydrabamine (formed with N, N-di(dehydroabietyl)-ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.

[0044] The present disclosure encompasses compounds of Formula I or pharmaceutically acceptable salts thereof, methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and uses of these compounds in treating diseases or conditions associated with PAD4 enzyme activity. 2. Description of Exemplary Embodiments:

[0045] In some embodiments, the present disclosure provides compounds of Formula I: or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof, wherein: X is selected from CR 6 and N; X′ is selected from CR 6′ and N, where X and X′ are not N at the same time; R 1 C 1-4 Fat; R 2 For 0-4 R 7 Substituted C 1-6 Fat; R 3 For 0-3 R 8 Substituted C 1-6 Fat; R 4 is a halogen; R 5 is a halogen; Each R 6 and R 6′ are independently selected from 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 Fat; Each R 7 independently selected from halogen, -OR, -N(R) 2 and -Cy; Each R 8 independently selected from halogen, -OR, -N(R) 2 and -Cy; Each R 9 independently selected from halogen, -OR, -N(R) 2 and -Cy; L 1 For covalent bonds or C 1-4 Fat; Each Cy is independently selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a phenyl group, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy is surrounded by 0-3 R 10 replace; Each R 10 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 selected from C 1-6 aliphatic and 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each m and n is independently 0 or 1; and Each p is independently 1-4.

[0046] In some embodiments, the present disclosure provides compounds of Formula I: or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof, wherein: X is selected from CR 6 and N; X′ is selected from CR 6′ and N, where X and X′ are not N at the same time; R 1 C 1-4 Fat; R 2 For 0-4 R 7 Substituted C 1-6 Fat; R 3 For 0-3 R 8 Substituted C 1-6 Fat; R 4 is a halogen; R 5 is a halogen; Each R 6 and R 6′ are independently selected from hydrogen, halogen, -OR, -N(R) 2 , -OC(O)R, -N(R)C(O)R, -N(R)C(O)-L-(R 9 ) p 、-OL-(R 9 ) p , -Cy, optionally substituted C 1-6 Aliphatic and C 1-6 Aliphatic -OH; Each R 7 independently selected from halogen, -OR, -N(R) 2 and -Cy; Each R 8 independently selected from halogen, -OR, -N(R) 2 and -Cy; Each R 9 independently selected from halogen, -OR, -N(R) 2 and -Cy; L 1 For covalent bonds or C 1-4 Fat; Each Cy is independently selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a phenyl group, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy is surrounded by 0-3 R 10 replace; Each R 10 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 selected from C 1-6 aliphatic and 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each m and n is independently 0 or 1; and p is independently 1-4.

[0047] In some embodiments, the present disclosure provides a compound selected from any one of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, and Ih:

[0048] or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the present disclosure provides a compound selected from the group consisting of compounds of any one of Formulas Iai, Ibi, Ici, Idi, Iei, Ifi, Igi, and Ihi:

[0050] or a pharmaceutically acceptable salt thereof.

[0051] As generally defined above, X is selected from CR 6 and N. In some embodiments of Formula I, X is CR 6 In some embodiments of any of Formula I, X is N.

[0052] As generally defined above, X' is selected from CR 6′ and N, wherein X and X' are not N at the same time. In some embodiments of Formula I, X' is CR 6′ In some embodiments of Formula I, X′ is N.

[0053] In some embodiments of Formula I, X is CR 6 And X′ is CR 6′ In some embodiments of Formula I, X is N and X′ is CR 6′ In some embodiments of Formula I, X is CR 6 And X′ is N′.

[0054] As generally defined above, R 1 C 1-4 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 1 It is methyl.

[0055] As generally defined above, R 2 0-4 R 7 Substituted C 1-6 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 2 0-4 R 7 Substituted C 1-4 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 2 0-4 R 7 Substituted C 1-2 Fatty.

[0056] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 2 For 1-2 R 7 Substituted C 1-6 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 2 For 1-2 R 7 Substituted C 1-4 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 2For 1-2 R 7 Substituted C 1-2 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 2 For 3-4 R 7 Substituted C 1-6 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 2 For 3-4 R 7 Substituted C 1-4 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 2 For 3-4 R 7 Substituted C 1-2 Fatty.

[0057] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 2 Selected from:

[0058] As generally defined above, R 3 0-3 R 8 Substituted C 1-6 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 3 0-3 R 8 Substituted C 1-4 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R3 0-3 R 8 Substituted C 1-2 Fatty.

[0059] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 3 For 1-3 R 8 Substituted C 1-6 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 3 For 1-3 R 8 Substituted C 1-4 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 3 For 1-3 R 8 Substituted C 1-2 Fatty.

[0060] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 3 Selected from: –CH 2 -R 8 -CH 2 CH 2 R 8

[0061] As generally defined above, R 4 In various embodiments, any suitable position of the fused bicyclic moiety of Formulas I, I', Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih and Ihi may be substituted by R 4In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 4 It is fluorine or chlorine.

[0062] As generally defined above, R 5 In some embodiments of any of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, or Ih, R 5 For fluorine.

[0063] As generally defined above, each R 6 and R 6′ Selected from 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 In some embodiments of Formula I, R 6 For hydrogen.

[0064] In some embodiments of any of Formulas I, Ia, Iai, Ic, Ici, Ig, and Igi, R 6 In some embodiments of any one of Formulas I, Ia, Iai, Ic, Ici, Ig, and Igi, R 6 For fluorine.

[0065] In some embodiments of any of Formulas I, Ia, Iai, Ic, Ici, Ig, and Igi, R 6 is –OR.

[0066] In some embodiments of any of Formulas I, Ia, Iai, Ic, Ici, Ig, and Igi, R 6 for –N(R) 2 .

[0067] In some embodiments of any of Formulas I, Ia, Iai, Ic, Ici, Ig, and Igi, R 6 is –OC(O)R.

[0068] In some embodiments of any of Formulas I, Ia, Iai, Ic, Ici, Ig, and Igi, R 6is -N(R)C(O)R. In some embodiments of any one of Formulas I, Ia, Iai, Ic, Ici, Ig, and Igi, R 6 In some such embodiments of any of Formulas I, Ia, Iai, Ic, Ici, Ig, and Igi, R is optionally substituted with R o Substituted C 1-6 In some embodiments of any one of Formulas I, Ia, Iai, Ic, Ici, Ig, and Igi, R 6 is -NHC(O)R, wherein R is optionally o Substituted C 1-6 Aliphatic, where R o is a 5- to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0069] In some embodiments of any of Formulas I, Ia, Iai, Ic, Ici, Ig, and Igi, R 6 For –Cy.

[0070] In some embodiments of any of Formulas I, Ia, Iai, Ic, Ici, Ig, and Igi, R 6 for-OL-(R 9 ) p .

[0071] In some embodiments of any of Formulas I, Ia, Iai, Ic, Ici, Ig, and Igi, R 6 is an optionally substituted C 1-6 In some such embodiments of any of Formulas I, Ia, Iai, Ic, Ici, Ig, and Igi, R 6 For –CH 3 .

[0072] In some embodiments of any of Formulas I, Ia, Iai, Ic, Ici, Ig, and Igi, R 6 Selected from –CH 3 、-OCH 3 ,

[0073] In some embodiments of Formula I, R 6′ For hydrogen.

[0074] In some embodiments of any of Formulas I, Ib, Ibi, Ic, Ici, Ie, and Iei, R 6′ In some such embodiments, R 6′ For fluorine.

[0075] In some embodiments of any of Formulas I, Ib, Ibi, Ic, Ici, Ie, and Iei, R 6′ is an optionally substituted C 1-6 In some embodiments of any one of Formulas I, Ib, Ibi, Ic, Ici, Ie, and Iei, R 6′ is an optionally substituted C 1-4 In some embodiments of any one of Formulas I, Ib, Ibi, Ic, Ici, Ie, and Iei, R 6′ is an optionally substituted C 1-2 In some embodiments of any one of Formulas I, Ib, Ibi, Ic, Ici, Ie, and Iei, R 6′ is an optionally substituted C 2-3 In some such embodiments of any of Formulas I, Ib, Ibi, Ic, Ici, Ie, and Iei, R 6′ For –C(CH 3 ) 2 OH.

[0076] In some embodiments of any of Formulas I, Ib, Ibi, Ic, Ici, Ie, and Iei, R 6′ is –OR.

[0077] In some embodiments of any of Formulas I, Ib, Ibi, Ic, Ici, Ie, and Iei, R 6′ for –N(R) 2 .

[0078] In some embodiments of any of Formulas I, Ib, Ibi, Ic, Ici, Ie, and Iei, R 6′ is –OC(O)R.

[0079] In some embodiments of any of Formulas I, Ib, Ibi, Ic, Ici, Ie, and Iei, R 6′ is –N(R)C(O)R.

[0080] In some embodiments of any one of Formulas I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6′ is –Cy.

[0081] In some embodiments of any one 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 .

[0082] In some embodiments of any one of Formulas I, I-b, I-b-i, I-c, I-c-i, I-e, and I-e-i, R 6′ is selected from fluorine, -OCH 3 and -C(CH 3 ) 2 OH.

[0083] As defined generally above, R 7 is selected from halogen, -OR, -N(R) 2 and –Cy. In some embodiments of any one 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 such embodiments of any one 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 fluorine. In some embodiments of any one 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 –OR. In some embodiments of any one 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 -N(R) 2。In some such embodiments of any one 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. Accordingly, in some embodiments of any one 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 -NH 2 。In some embodiments of any one 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 –Cy. In some embodiments of any one 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 selected from fluorine, -NH 2 and –Cy.

[0084] In some embodiments of any one 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 selected from

[0085] as defined generally above, R 8 is selected from halogen, -OR, -N(R) 2 , -C(O)N(R) 2 and –Cy. In some embodiments of any one 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 one 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 8is –OR. In some embodiments of any one 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 such embodiments of any one 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 fluorine.

[0086] In some embodiments of any one 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 selected from

[0087] As defined generally above, R 9 is selected from halogen, -OR, -N(R) 2 and –Cy. In some embodiments of any one 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 halogen. In some embodiments of any one 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 fluorine. In some embodiments of any one 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 one 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 such embodiments of any one 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. Accordingly, in some embodiments of any one 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 one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Ie, Iei, Ig, and Igi, R 9 For –Cy.

[0088] As generally defined above, L is a covalent bond or C 1-4 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Ie, Iei, and Ie-ii, Ig, and Igi, L is a covalent bond. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Ie, Iei, and Ie-ii, Ig, and Igi, L is C 1-4 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Ie, Iei and Ie-ii, Ig and Igi, L is C 1-3 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Ie, Iei and Ie-ii, Ig and Igi, L is C 1-2 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Ie, Iei and Ie-ii, Ig and Igi, L 1 C 2-3 Fatty.

[0089] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Ie, Iei and Ie-ii, Ig and Igi, -L-(R 9 ) p Selected from

[0090] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Ie, Iei and Ie-ii, Ig and Igi, R 9 Selected from fluorine,

[0091] As generally defined above, Cy is selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a phenyl ring, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy is surrounded by 0-3 R 10 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is replaced by 1-2 R 10 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is replaced by 1-3 R 10 replace.

[0092] In some embodiments of any one 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 3- to 7-membered saturated or partially unsaturated carbocycle. In some embodiments of any one 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 3-membered saturated carbocycle. In some embodiments of any one 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 4-membered saturated carbocycle. In some embodiments of any one 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 5-membered saturated or partially unsaturated carbocycle. In some embodiments of any one 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 5-membered saturated carbocycle. In some embodiments of any one 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 or partially unsaturated carbocycle. In some embodiments of any one 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 partially unsaturated carbocycle. In some embodiments of any one 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 carbocycle. In some embodiments of any one 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 carbocycle.

[0093] In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is a 3-membered saturated or partially unsaturated carbocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is a 5-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is a 5-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is a 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is a 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is a 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is a 7-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0094] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is phenyl.

[0095] In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is a 5-membered heteroaryl ring having 2-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0096] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is a 6-membered heteroaryl ring having 1-2 nitrogen atoms.

[0097] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, Cy is selected from

[0098] As generally defined above, R 10 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 selected from C 1-6 aliphatic and 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 It is fluorine or chlorine.

[0099] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is –OR.

[0100] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 for –N(R)2 。

[0101] In some embodiments of any one 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.

[0102] In some embodiments of any one 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 –C(O)R. In some such embodiments of any one 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 C 1-6 aliphatic. In some embodiments of any one 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 –C(O)R, wherein R is C 1-6 aliphatic. In some embodiments of any one 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 –C(O)R, wherein R is C 1-4 aliphatic. In some embodiments of any one 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 –C(O)R, wherein R is C 1-2 aliphatic.

[0103] In some embodiments of any one 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 –C(O)R, wherein R is optionally substituted C 1-6In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is -C(O)R, wherein R is optionally substituted with -OR o Substituted C 1-6 In some such embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R o is hydrogen or C 1-6 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is -C(O)R, wherein R is optionally substituted with -OR o Substituted C 1-4 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is -C(O)R, wherein R is optionally substituted with -OR o Substituted C 1-2 Fatty.

[0104] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is –C(O)OR.

[0105] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 for –C(O)N(R) 2 .

[0106] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 For oxygen.

[0107] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is an optionally substituted C 1-6 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is an optionally substituted C 1-4 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is an optionally substituted C 1-2 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 For –CH 3 .

[0108] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10is an optionally substituted 3-membered saturated or partially unsaturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is an optionally substituted 4-membered saturated or partially unsaturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is an optionally substituted 5-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is an optionally substituted 5-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is an optionally substituted 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is an optionally substituted 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10is an optionally substituted 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 is an optionally substituted 7-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0109] In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R 10 Selected from oxo, fluoro, chloro, -CN, –CH 3 ,

[0110] As generally defined above, R is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih and Ihi, R is hydrogen. In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih and Ihi, R is an optionally substituted group selected from C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R is an optionally substituted C 1-6In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R is optionally halogenated or -OR o Substituted C 1-6 In some such embodiments of any of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R o is hydrogen or C 1-6 In some embodiments of any one of Formulas I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, R is optionally halogenated or -OR o Substituted C 1-6 Aliphatic, where R o is hydrogen or C 1-6 Fatty.

[0111] As generally defined above, each m and n is 0 or 1. In some embodiments of any of Formula I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, m is 0. In some embodiments of any of Formula I, Ia, Iai, Ib, Ibi, Ic, Ici, Id, Idi, Ie, Iei, If, Ifi, Ig, Igi, Ih, and Ihi, m is 1. In some embodiments of any of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, and Ih, n is 0. In some embodiments of any of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, and Ih, n is 1. In some embodiments of Formula I, m is 1 and n is 0. In some embodiments of Formula I, each m and n is 0.

[0112] As defined generally above, p is from 1 to 4. In some embodiments of any one 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, p is 1. In some embodiments of any one 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, p is from 1 to 2. In some embodiments of any one 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, p is 2. In some embodiments of any one 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, p is 3.

[0113] In some embodiments, the compound of Formula I is selected from

[0114] or a pharmaceutically acceptable salt thereof. 4. Pharmaceutical Composition

[0115] In some embodiments, the present disclosure provides a composition comprising a compound or a pharmaceutically acceptable salt thereof provided by the present disclosure, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the composition of the present disclosure is such that it effectively and measurably suppresses the amount of PAD4 in a biological sample or in a patient. In some embodiments, the amount of the compound in the composition of the present disclosure is such that it effectively and measurably suppresses the amount of PAD4 in a biological sample or in a patient. In some embodiments, the composition provided by the present disclosure is formulated for administration to a patient in need of the composition. In some embodiments, the composition provided by the present disclosure is formulated for oral administration to a patient.

[0116] As used herein, the term "subject" is used interchangeably with the term "patient" and refers to an animal or mammal. In some embodiments, the subject or patient is a human. In other embodiments, the subject (or patient) is a veterinary subject (or patient). In some embodiments, the veterinary subject (or patient) is a canine, feline, or equine subject.

[0117] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or carrier that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions provided by the present disclosure include, but are not limited to, ion exchangers, aluminum oxide, 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 sulfatinamine, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0118] The compositions provided by the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or by an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. The compositions can be administered orally, intraperitoneally or intravenously. The sterile injection form of the compositions provided by the present disclosure can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injection preparation can also be a sterile injection solution or suspension in a non-toxic parenteral acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are typically used as solvents or suspending media.

[0119] For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and glyceride derivatives thereof can be used for the preparation of injections, as pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially its polyoxyethylene amidated form. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants, which are generally used in the preparation of pharmaceutically acceptable dosage forms including emulsions and suspensions. For formulation purposes, other conventional surfactants can also be used, such as tweens, spans and other emulsifiers or bioavailability enhancers, which are generally used in the preparation of pharmaceutically acceptable solids, liquids or other dosage forms.

[0120] The pharmaceutically acceptable compositions provided by the present disclosure can be orally administered in any oral acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. For oral administration in the form of capsules, useful diluents include lactose and dry corn starch. When an aqueous suspension for oral use is needed, the active ingredient is used in combination with an emulsifier and a suspending agent. If necessary, certain sweeteners, flavorings or coloring agents may also be added.

[0121] Alternatively, the pharmaceutically acceptable compositions provided by the present disclosure can be used for rectal administration in the form of suppositories. These can be prepared by mixing with suitable non-irritating excipients, which are solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycol.

[0122] The pharmaceutically acceptable compositions provided by the present disclosure can also be applied topically, especially when the target of treatment includes an area or organ that is easily reached by topical application, including diseases of the eyes, skin or lower intestinal tract. For each of these areas or organs, suitable topical preparations can be easily prepared. Topical application for the lower intestinal tract can be played in rectal suppository preparations (see above) or in suitable enema preparations. Local transdermal patches can also be used. For topical application, the pharmaceutically acceptable compositions provided can be formulated into a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. The carriers for topical application of compounds provided by the present disclosure include but are not limited to mineral oil, liquid vaseline, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.

[0123] Alternatively, the pharmaceutically acceptable compositions provided can be formulated into suitable lotions or creams containing active ingredients 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 esters wax, stearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0124] For ophthalmic use, provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or as solutions in isotonic, pH-adjusted sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated as ointments such as petrolatum.

[0125] The pharmaceutically acceptable compositions provided by the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons and / or other conventional solubilizing agents or dispersants.

[0126] In addition, the pharmaceutically acceptable compositions provided by the present disclosure can be formulated for oral administration. Such preparations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions provided by the present disclosure are not administered with food. In other embodiments, the pharmaceutically acceptable compositions provided by the present disclosure are administered with food.

[0127] The pharmaceutically acceptable compositions provided by the present disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (such as by powder, ointment or drops), buccally, as an oral or nasal spray or the like as needed. In certain embodiments, the compounds provided by the present disclosure can be administered orally or parenterally once or more per day 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 of the subject's body weight per day to obtain the desired therapeutic effect.

[0128] 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, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, the oral composition may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and aromatics.

[0129] Injection preparations such as sterile aqueous or oily suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injection preparations can also be sterile injection solutions, suspensions or emulsions in nontoxic parenteral acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution (USP) and isotonic sodium chloride solution. In addition, sterile fixed oils are generally used as solvents or suspending media. For this purpose, any mild fixed oil including synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid can also be used for the preparation of injections.

[0130] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0131] In order to prolong the effect of the compound provided by the invention, it is usually necessary to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. Then, the absorption rate of the compound depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of the compound form for parenteral administration is achieved by dissolving or suspending the compound in an oil vehicle. The injectable reservoir form is made by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactic acid-polyglycolic acid. The rate at which the compound is released can be controlled according to the ratio of the compound to the polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injection preparations are also prepared by embedding the compound in a liposome or microemulsion compatible with body tissues.

[0132] Compositions for rectal or vaginal administration may be suppositories, which can be prepared by mixing a compound provided by the present disclosure with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0133] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and pellets. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dibasic calcium phosphate and / or (a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia, (c) humectants such as glycerol, (d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, (e) solution retarders such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glyceryl monostearate, (h) absorbents such as kaolin and bentonite, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0134] Solid compositions of similar types may also use excipients such as lactose or milk sugar and high molecular weight polyethylene glycol as fillers in soft and hard filled gelatin capsules. Solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shells such as coatings known in the art of enteric coatings and pharmaceutical preparations. They may optionally contain an opacifying agent and may also be a composition that releases the active ingredient only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of usable embedded compositions include polymeric substances and waxes. Solid compositions of similar types may also use excipients such as lactose or milk sugar and high molecular weight polyethylene glycol as fillers in soft and hard filled capsules.

[0135] The active compound can also be in the form of a microcapsule with one or more of the above-mentioned excipients. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells (such as coatings known in the field of enteric coatings and pharmaceutical preparations). In such dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also include other substances other than inert diluents according to common practice, for example, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can also include a buffer.

[0136] The dosage form of the compound for topical or transdermal administration provided by the present disclosure includes ointment, paste, cream, emulsion, gel, powder, solution, spray, inhalant or patch. The active ingredient is mixed with a pharmaceutically acceptable carrier and a preservative or buffer that may be needed under aseptic conditions. Ophthalmic preparations, ear drops and eye drops are also encompassed within the scope of the present disclosure. In addition, the present disclosure encompasses the purposes of transdermal patches, which have the additional advantage that the compound is controlled to be delivered to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or a gel.

[0137] The amount of the disclosed compounds that can be combined with the carrier materials to produce a single dosage composition can vary depending on the host being treated, the particular mode of administration. Provided compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0138] The compounds of the present disclosure may be administered alone or in combination with one or more other therapeutic compounds, with possible combination therapies being in the form of a fixed combination or staggered administration of the compounds of the present disclosure and one or more other therapeutic compounds or given independently of one another, or in combination with a fixed combination and one or more other therapeutic compounds. Exemplary such other therapeutic agents include corticosteroids, rolipram, carvstatin, cytokine suppressive anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide and other immunosuppressants; nuclear translocation inhibitors such as deoxyspergualin (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugs such as azathioprine and cyclophosphamide; TNF-α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptors and rapamycin (sirolimus or Rapamune) or its derivatives. In addition, the compounds of the present disclosure can be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention or a combination of these, especially for tumor therapy. As mentioned above, long-term therapy is also possible as adjuvant therapy in the context of other treatment strategies. Other possible treatments are therapies that maintain the patient's status after tumor regression, or even chemoprevention, for example in patients at risk.

[0139] As part of a multiple dose regimen, those additional agents may be administered separately from the composition containing the disclosed compounds. Alternatively, these agents may be part of a single dosage form, mixed together with the disclosed compounds in a single composition. If administered as part of a multiple dose regimen, the two active agents may be presented simultaneously, sequentially, or within a period of time of each other (usually within 5 hours of each other).

[0140] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, a compound of the present disclosure may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a compound of the present disclosure, the other therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0141] The amount of both the provided compound and the additional therapeutic agent (in those compositions comprising the additional therapeutic agent as described above) that can be combined with the carrier material to provide a single dosage form will vary depending on the subject being treated and the particular mode of administration. The compositions of the present disclosure should be formulated so that a provided compound can be administered at a dosage of between 0.01-100 mg / kg body weight / day.

[0142] In those compositions comprising an additional therapeutic agent, the additional therapeutic agent and the compounds of the present disclosure may act synergistically. Thus, the amount of the additional therapeutic agent in such compositions will be less than that required in a monotherapy using only that therapeutic agent.

[0143] The amount of additional therapeutic agent present in the compositions of the present disclosure will not exceed the amount normally administered in a composition comprising the therapeutic agent as the only active agent. The amount of additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of that normally present in a composition comprising the agent as the only therapeutically active agent.

[0144] It is also understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the attending physician and the severity of the specific disease or condition being treated. The amount of the compound of the present disclosure in the composition will also depend on the specific compound in the composition. 5. Uses of the compound

[0145] The compounds and compositions described herein are generally useful for the inhibition of PAD4.

[0146] The activity of the compounds used in the present disclosure as PAD4 inhibitors can be determined in vivo, in vitro or in a cell line. In vitro assays include assays to determine PAD4 inhibition. Detailed conditions for determining the compounds used in the present disclosure as PAD4 inhibitors are listed in the examples below. In some embodiments, the compounds provided selectively inhibit PAD4 compared to PAD2.

[0147] As used herein, the terms "treatment", "treat" and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of, a disease or disorder or one or more symptoms thereof as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also continue after symptoms subside, e.g., to prevent or delay their recurrence.

[0148] The provided compounds are PAD4 inhibitors and are therefore useful for treating one or more diseases or conditions associated with PAD4 enzyme activity. Therefore, in certain embodiments, the present disclosure provides a method for treating a disease or condition associated with PAD4 enzyme activity, comprising the step of administering a compound of the present disclosure or a pharmaceutically acceptable composition thereof to a patient in need thereof.

[0149] In one embodiment, the disease or condition associated with PAD4 enzyme activity is a disease, condition or disorder mediated by inappropriate PAD4 activity. In some embodiments, the disease or condition 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 another embodiment, the disease or condition associated with PAD4 enzyme activity is rheumatoid arthritis. In another embodiment, the disease or condition associated with PAD4 enzyme activity is systemic lupus erythematosus. In another embodiment, the disease or condition associated with PAD4 enzyme activity is vasculitis. In another embodiment, the disease or condition associated with PAD4 enzyme activity is cutaneous lupus erythematosus. In another embodiment, the disease or condition associated with PAD4 enzyme activity is psoriasis.

[0150] In one embodiment, a method for treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis is provided, the method comprising administering a therapeutically effective amount of a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof to a human subject in need thereof.

[0151] In one embodiment, a method for treating rheumatoid arthritis is provided, comprising administering a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof to a human subject in need thereof. In one embodiment, a method for treating systemic lupus erythematosus is provided, comprising administering a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof to a human subject in need thereof. In one embodiment, a method for treating vasculitis is provided, comprising administering a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof to a human subject in need thereof. In one embodiment, a method for treating cutaneous lupus erythematosus is provided, comprising administering a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof to a human subject in need thereof. In one embodiment, a method of treating psoriasis is provided, the method comprising administering a therapeutically effective amount of a provided compound, a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof to a human subject in need thereof.

[0152] In some embodiments, the disease or condition associated with PAD4 enzyme activity is selected from the group consisting of acid-induced lung injury, acne (PAPA), acute lymphoblastic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopneumonia, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, weight loss, angina pectoris, angioedema, anhidrotic ectodermal dysplasia with immunodeficiency (anhidroticecodermal dysplasia-ID), ankylosing spondylitis, anterior segment (anterior segment), inflammation, antiphospholipid syndrome, oral ulcers, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, inflammation caused by bee stings, Bechet's disease, Bechet's syndrome, Bell's palsy Palsey), beryllium poisoning, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysms, inflammation caused by chemical irritants, chorioretinitis, 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, cold pyrin-associated periodic syndrome, cryptococcal meningitis, cystic fibrosis, interleukin-1 receptor antagonist (DIRA) deficiency, dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse intrinsic pontine glioma glioma), endometriosis, endotoxemia, epicondylitis, erythrocytopenia, familial amyloid polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, intestinal disease, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Schonlein purpura, hepatitis, hereditary periodic fever syndromes, herpes zoster and herpes simplex, HIV-1, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia type D with periodic fever (HIDS), hypoplastic and other anemias, hypoplastic anemia, idiopathic thrombocytopenic purpura, incontinence pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, inflammation caused by insect bites, iritis, inflammation caused by irritants, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney damage caused by parasitic infection,Kidney transplant rejection prevention, leptospirosis, leukemia, Loeffler syndrome, lung injury, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria, deafness, amyloidosis), multiple sclerosis, muscle wasting syndrome, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungoides, myelodysplastic syndrome, myositis, sinusitis, necrotizing enterocolitis, neonatal multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neurosis Pathological diseases, non-allergenic asthma, obesity, eye allergies, optic neuritis, organ transplantation, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, whooping cough, pharyngitis and adenitis (PFAPA syndrome), inflammation caused by plant irritants, pneumonia, pneumonitis, pulmonary system infections, inflammation caused by poison ivy / urushiol oil, polyarteritis nodosa , polychondritis, polycystic kidney disease, polymyositis, psoriasis, psychosocial stress disorders, lung diseases, pulmonary hypertension, pulmonary fibrosis, pustular gangrene, suppurative sterile arthritis, kidney disease, retinal diseases, rheumatic carditis, rheumatic diseases, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell disease, sickle cell anemia, silica-induced diseases, Sergulin syndrome, skin diseases, sleep apnea, 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, Wegener's granulomatosis, interstitial lung disease, psoriatic arthritis, juvenile idiopathic arthritis, Sergulin's syndrome, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, antiphospholipid antibody syndrome, sepsis, deep vein thrombosis, fibrosis, Alzheimer's disease, scleroderma, and CREST syndrome.

[0153] In one embodiment, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof for use in therapy. In another embodiment, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof for use in treating a disease or condition mediated by inappropriate PAD4 activity. In another embodiment, the present disclosure provides a compound or a stereoisomer, enantiomer, diastereomer, tautomer or a pharmaceutically acceptable salt thereof for use in treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus or psoriasis. In another embodiment, the present disclosure provides a compound or a stereoisomer, enantiomer, diastereomer, tautomer or a pharmaceutically acceptable salt thereof for use in treating rheumatoid arthritis. In another embodiment, the present disclosure provides a compound or a stereoisomer, enantiomer, diastereomer, tautomer or a pharmaceutically acceptable salt thereof for use in treating systemic lupus erythematosus. In another embodiment, the present disclosure provides a compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt for treating vasculitis. In another embodiment, the present disclosure provides a compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt for treating cutaneous lupus erythematosus. In another embodiment, the present disclosure provides a compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt for treating psoriasis. In another embodiment, the present disclosure provides a compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt for preparing a medicament for treating a disease mediated by inappropriate PAD4 activity. In another embodiment, the present disclosure provides the use of a compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt in the preparation of a medicament for treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus. In another embodiment, the present disclosure provides the use of a compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt in the preparation of a medicament for treating rheumatoid arthritis. In another embodiment, the present disclosure provides the use of a compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt in the preparation of a medicament for treating systemic lupus erythematosus. In another embodiment, the present disclosure provides the use of a compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt in the preparation of a medicament for treating vasculitis.In another embodiment, the present disclosure provides the use of a compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt in the preparation of a medicament for treating cutaneous lupus erythematosus. In another embodiment, the present disclosure provides the use of a compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt in the preparation of a medicament for treating psoriasis. In another embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing a disease or condition mediated by inappropriate PAD4 activity, the composition comprising a provided compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt. In another embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus or psoriasis, the composition comprising the provided compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt. In another embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, the composition comprising the provided compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt. In another embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing systemic lupus erythematosus, the composition comprising the provided compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt. In another embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing vasculitis, the composition comprising a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing vasculitis, the composition comprising a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing cutaneous lupus erythematosus, the composition comprising a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing psoriasis, the composition comprising a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer or a pharmaceutically acceptable salt thereof.

[0154] All features of each aspect of the present invention are applicable to all other aspects when necessary. In order to more fully understand the invention described herein, the following examples are listed. It should be understood that these examples are only for illustrative purposes and should not be considered to limit the present invention in any way. 6. Examples

[0155] The following examples were prepared, isolated, and characterized using the methods disclosed herein.The following examples demonstrate part of the scope of the present disclosure and are not intended to limit the scope of the present disclosure. Example abbreviation AcOH or HOAc Acetic acid ACN, MeCN or CH 3 CN Acetonitrile Bn Benzyl Boc tert-Butyloxycarbonyl Cbz benzyloxycarbonyl CDCl 3 Deuterated chloroform CD 3 OD or methanol-d 4 Deuterated methanol CCl 4 Carbon tetrachloride CH 2 Cl 2 Dichloromethane CH 3 CN Acetonitrile CHCl 3 Chloroform Cs 2 CO 3 Cesium carbonate DCM Dichloromethane DEA Diethanolamine DIEA,DIPEA or DIPEA diisopropylethylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide DMSO-d 6 Hexa-deuterated dimethyl sulfoxide DTBAD Di-tert-butyl azodicarboxylate ESI Electrospray ionization E 3 N or TEA Triethylamine E 2 O Ether EtOAc Ethyl acetate EtOH HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HCl HPLC High Performance Liquid Chromatography IPA Isopropyl Alcohol Ir(dF(CF 3 )ppy)2(dtbbpy)PF 6 (4,4'-Bis-tert-butyl-2,2'-bipyridyl)bis[3,5-difluoro-2-(5-trifluoromethyl-2-pyridyl-kN)phenyl-kC]iridium(III) hexafluorophosphate H 2 SO 4 sulfuric acid K 2 CO 3 Potassium carbonate KNO 3 Potassium Nitrate LCMS Liquid chromatography mass spectrometry LiAlH 4 Lithium aluminum hydride LqCy 4 Lithium borohydride MeOH or CH 3 OH Methanol MgSO 4 Magnesium sulfate MHz Megahertz mL milliliters mm Millimeters mM millimolar concentration μm or uM micrometer MnO 2 Manganese dioxide min or min. Minutes MS MsOH or MSA methanesulfonic acid MsCl Methanesulfonyl chloride NaCl Sodium chloride Na 2 CO 3 Sodium carbonate NaH Sodium hydride NaHCO 3 Sodium bicarbonate NaIO 4 Sodium periodate NaOH Sodium hydroxide Na 2 SO 4 Sodium sulfate Na 2 S 2 O 4 Sodium thionate NH 3 ammonia NH 4 Cl Ammonium chloride NH 4 OAc Ammonium acetate nm nanometer Pd / C Palladium / Carbon Pd(OAc) 2 Palladium(II) acetate Pd(dppf)Cl 2 [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride Pd(PPh 3 ) 4 Tetrakis(triphenylphosphine)palladium(0) PPh 3 Triphenylphosphine i-PrOH or IPA Isopropyl alcohol Rt or RT retention time RuCl 3 Ruthenium trichloride SFC Supercritical Fluid Chromatography TBAI Tetrabutylammonium iodide TBAF Tetrabutylammonium fluoride TBME or MTBE tert-butyl methyl ether TBSCl tert-Butyldimethylsilyl chloride TsCl 4-Toluenesulfonyl chloride THF Tetrahydrofuran UV

[0156] Description of Preparative HPLC and Analytical LCMS Methods:

[0157] Method A: Preparative HPLC. Column: XBridge C18 OBD Prep, 10 μm, 19 mm x 250 mm; mobile phase A: water + 0.05% TFA, mobile phase B: ACN; flow rate: 25 mL / min.; gradient: 35% B to 60% B in 4.8 min; detection: UV (210 / 254 nm).

[0158] Method B: Analytical LCMS. Column: Shim-pack XR-ODS, 3x50 mm, 2.2 μm; Mobile phase A: water + 0.05% TFA, Mobile phase B: ACN + 0.05% TFA; Flow rate: 1.2 mL / min.; Gradient: 5% B to 95% B in 2 min, maintained at 95% for 0.7 min., 95% B to 5% B in 0.05 min; Detection: MS and UV (254 nm).

[0159] Method C: Analytical LCMS. Column: L-column 3C18, 3.0 mm x 30 mm, 2.0 μm particles; Mobile phase A: water + 5 mM ammonium bicarbonate, Mobile phase B: ACN; Flow rate: 1.5 mL / min.; Gradient: 10% B to 95% B over 1.2 min, then hold at 95% B for 0.6 min; Detection: UV (254 / 210 nm).

[0160] Method D: Analytical LCMS. Column: HALO C18, 3x30 mm, 2.7 μm; Mobile phase A: water + 0.05% TFA, Mobile phase B: acetonitrile + 0.05% TFA; Flow rate: 1.5 mL / min; Gradient: 5% B to 95% B in 2.5 min; Hold at 95% for 1 min, 95% B to 5% B in 0.05 min; Detection: MS and UV (254 nm).

[0161] Method E: Preparative HPLC. Column: XSelect CSH Prep C18 OBD, 19x250 mm; 5 um; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 22% B to 50% B in 5.5 min; Detection: UV (254 nm).

[0162] Method F: Preparative HPLC. Column: SunFire C18 OBD Prep 19x150 mm; 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min.; Gradient: 30% B to 55% B in 5.5 min; Detection: UV (254 nm).

[0163] Method G: Preparative HPLC. Column: Atlantis Prep T3 OBD column, 19x150 mm; 10 um; Mobile phase A: water + 0.05% TFA, Mobile phase B: ACN; Flow rate: 20 mL / min.; Gradient: 20% B to 50% B, 50% B in 6 min; Detection: UV (210 / 254 nm).

[0164] Method H: Analytical LCMS. Column: YMC MeteoricCore C18 BIO column 3x50 mm, 2.6 μm; Mobile phase A: water + 5 mM NH 4 HCO 3, mobile phase B: ACN; flow rate: 1.2 mL / min.; gradient: 10% B to 95% B in 1.20 min., hold at 95% for 0.68 min., 95% B to 10% B in 0.05 min.; detection: UV (254 nm).

[0165] Method I: Analytical LCMS. Column: HALO C18, 3x30 mm, 2.7 mm; Mobile phase A: water + 0.05% TFA, Mobile phase B: acetonitrile + 0.05% TFA; Flow rate: 1.5000 mL / min; Gradient: 5% B to 100% B in 1.3 min, hold at 100% for 0.5 min, 100% B to 5% B in 0.03 min; Detection: UV (254 nm).

[0166] Method J: Column: Waters BEH C18, 2.1x50mm, 1.7μm; Mobile phase A: 95% / 5% water / ACN+10mMol ammonium acetate, Mobile phase B: 5% / 95% acetonitrile: water+10mM ammonium acetate; Flow rate: 0.8mL / min.; Gradient: 5% B to 95% B in 1.5min, maintained at 95% for 0.50min., 95% B to 5% B in 0.1min; Detection: PDA (210 to 400nm) / MS (total ion count positive / negative mode).

[0167] 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: 0.8mL / min.; Gradient: 5% B to 95% B in 1.5min, maintained at 95% for 0.50min., 95% B to 5% B in 0.1min; Detection: PDA (210 to 400nm) / MS (total ion count positive / negative mode). Synthesis Example General Procedure 1: Alkylation of lactams with cyclic sulfamidates

[0168] To a stirred solution of lactam (1.0 eq.) in DMF was added NaH (60%) (2.0 eq.) and cyclic aminosulfonate (1.4 eq.) at 0°C. The reaction was warmed to room temperature over 2 h. TLC showed the reaction was complete, and the mixture was quenched with water and extracted with ethyl acetate (×3). The organic layer was washed with brine (×2), concentrated and purified by column chromatography to give the desired product. General procedure 2: N-Boc deprotection with TFA

[0169] A solution of N-Boc amine (1.0 equiv.) in DCM:TFA (3:1, 0.02 M) was stirred at room temperature for 30 min. TLC showed that the reaction was complete, and the mixture was concentrated. The product was purified by preparative HPLC or column chromatography. General Procedure 3: Reduction of Esters or Acids with Lithium Aluminum Hydride

[0170] To a stirred solution of the acid or ester (1.0 eq) in THF (0.3 M) was added LiAlH 4 (2.0 equivalents). The resulting solution was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction was then quenched by water (0.5 mL) / NaOH (15%) (1:4 ratio) and stirred at room temperature for 20 min. The solid was filtered out and the resulting solution was concentrated under vacuum. The crude product was purified by column chromatography. General Procedure 4: Oxidation of Alcohols with Manganese Dioxide

[0171] To a stirred solution of alcohol (1.0 eq.) in DCM (0.1 M) was added MnO at room temperature under nitrogen atmosphere. 2 (10 eq.). The resulting mixture was stirred at room temperature for 12 h. LCMS showed that the reaction was complete and the solid was filtered off. The resulting mixture was concentrated to give the crude product, which was used without further purification or purified by column chromatography. General Procedure 5: Alkylation of heterocyclic NH or phenolic OH with cesium carbonate base

[0172] To a stirred solution of the substituted indole (1.0 eq., 250 mg, 1.47 mmol) in DMF (0.2 M) was added Cs 2 CO 3 (3.0 eq.), TBAI (0.1 eq.) and alkyl electrophile (1.5 eq.) were added and warmed to 50°C for 1.5 h. TLC showed that the reaction was complete, and the mixture was quenched with water (20 mL) and extracted with ethyl acetate (×3). The combined organic layers were washed with brine (×2), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography. General Procedure 6: Cyclization from nitroaniline to form tricyclic benzimidazoles

[0173] To a stirred solution of aldehyde (1.0 eq.) in alcohol:water (2:1, 0.08 M) was added aniline (1.0 eq.) and Na 2 S 2 O 4(3.0 equivalents) and warmed to 90 ° C over 2h. TLC showed that the reaction was complete. The reaction mixture was concentrated under vacuum to remove ethanol and diluted with water (20mL), then extracted with DCM / MeOH (10: 1) (x3). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by preparative TLC or column chromatography. General Procedure 7: Alkylation of Indole NH with Sodium Hydride Base

[0174] Under nitrogen atmosphere, NaH (1.5 equivalents) was added in batches to a solution of the stirring of the substituted indole (1.0 equivalents) in DMF (0.15M) at 0°C and warmed to room temperature. The resulting mixture was stirred at room temperature for 0.5h. Then, under nitrogen atmosphere, alkyl electrophilic reagents (1.5 equivalents) were added in batches at 0°C and warmed to room temperature. The resulting mixture was stirred at room temperature for 2h. The reaction was monitored by TLC or LCMS. The reaction was then quenched by adding water and extracted with ethyl acetate (x2). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography. General Procedure 8: Deprotection of N-sulfonic Acids with HCl

[0175] To a stirred solution of N-sulfonic acid (60 mg, 0.09 mmol) in THF (2 mL) was added 2M HCl (1 mL). The mixture was stirred at 50°C for 30 min. LCMS showed the reaction was complete and the final compound was purified as described in the examples. General Procedure 9: Deprotection of benzyloxy ethers via hydrogenation

[0176] To a stirred solution of benzyloxy ether (1.0 eq.) in a solvent mixture (0.02-0.1 M) was added Pd / C (1.0 eq.) in portions at room temperature under nitrogen atmosphere. The resulting solution was stirred at room temperature overnight under hydrogen atmosphere. The reaction was monitored by TLC and LCMS. The solid was filtered off and the resulting mixture was concentrated. The crude product was used without further purification or purified by column chromatography. General Procedure 10: Mitsunobu Reaction

[0177] To a solution of phenol (2.1 g, 6.33 mmol, 1.0 eq.) and alcohol (3.0 eq.) in toluene (0.15 M) was added PPh 3 (2.0 equiv.) and DTBAD (2.0 equiv.). The resulting mixture was stirred at 80 °C for 6 h. The reaction was monitored by TLC and LCMS. The reaction was quenched by adding water and extracted with ethyl acetate (x2). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified as described in a separate procedure. General Procedure 11: Cyclization from dianiline to form tricyclic benzimidazoles

[0178] To the solution of aldehyde (1 equivalent) and dianiline (1 equivalent) in DMF: water (30: 1, 0.25M), potassium monopersulfate (Oxone) (4.6 g, 7.5 mmol) was added. The resulting solution was stirred at room temperature for 16 h. The reaction was then quenched by adding water and extracted with ethyl acetate (x2). The combined organic extracts were washed with water (x2) and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified as described in the separate continuous. General Procedure 12: Alkylation of Phenols via Epoxide Ring Opening

[0179] To a solution of phenol (1 eq.) in alcohol (0.05-0.3 M) was added epoxide (3-10 eq.) and TEA (5 eq.). The mixture was irradiated with microwave radiation at 100 °C for 2 h. The reaction was monitored by LCMS. The mixture was concentrated under vacuum. The crude product was purified as described in a separate procedure. General Procedure 13: Activation of alcohols with sulfonyl chlorides

[0180] To a solution of alcohol (x eq) in DCM (0.01-0.2 M) was added TEA (2-4 eq) and sulfonyl chloride (1.2-2.0 eq) at 0°C. The resulting solution was stirred at room temperature for 1-2 h. The reaction was monitored by LCMS. The reaction was then heated to 40°C by the addition of saturated NH 4 The mixture was quenched with aqueous Cl solution and extracted with DCM (x3). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum at 0 °C to give the title compound. General Procedure 14: Alkylation of Imidazole NH with Cesium Carbonate Base

[0181] To a solution of substituted indole (1 eq.) in DMF (0.1 M) was added imidazole reagent (1-9 eq.) and cesium carbonate (3 eq.). The reaction 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 vacuum. The crude product was purified as described in a separate procedure. Intermediate 1. (S)-tert-Butyl 4-(fluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide Step 1: Synthesis of methyl (S)-2-((tert-butyloxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)propanoate

[0182] To a solution of (2S)-2-(tert-butyloxycarbonylamino)-3-hydroxy-propionic acid methyl ester (90 g, 410 mmol) and imidazole (30.7 g, 452 mmol) in DCM (900 mL) was added TBSCl (80.4 g, 534 mmol) at 0°C. After addition, the reaction mixture was stirred at 20°C for 2 h. TLC showed that the starting material was completely consumed. The reaction was quenched with water (1 L) at 0°C and extracted with DCM (800 mL x3). The combined organic layers were washed with brine (1 L x 2) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to give the title compound as a light yellow oil (140 g, crude). 1 H NMR (400 MHz, CDCl 3 )δ:5.34(d,J=8.4Hz,1H),4.36(d,J=8.8Hz,1H),4.06(d,J=2.4Hz,1H),4.03( d,J=2.4Hz,1H),3.75(s,3H),1.46(s,9H),0.87(s,9H),0.03(d,J=5.2Hz,6H). Step 2: Synthesis of methyl N-[(1R)-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-hydroxy-ethyl]carbamate

[0183] At 0℃, LiAlH 4 To a suspension of (27.9 g, 734 mmol) in THF (1.2 L) was added a solution of (S)-methyl 2-((tert-butyloxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)propanoate (144 g, 432 mmol) in THF (300 mL). After addition, the reaction mixture was then stirred at 0 °C for 1 h. TLC showed that the starting material was completely consumed. The reaction was heated to saturated NH 4 The filtrate was quenched with aqueous Cl solution (800 mL) and filtered. Ethyl acetate (800 mL x 2) was added to the filtrate and washed with brine (800 mL). 2 SO 4 Dry.The mixture was filtered and concentrated to give the title compound as a light yellow oil (110 g, crude). 1 H NMR (400 MHz, CDCl 3 )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). Step 3: Synthesis of (3R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-oxo-oxathiazolidine-3-carboxylic acid tert-butyl ester

[0184] To a solution of imidazole (147 g, 2.16 mol) in DCM (700 mL) was added SOCl at 0 °C 2 (77.1g, 648mmol) in DCM (400mL). After addition, the reaction mixture was stirred at 18 ° C for 1h. Then a solution of tert-butyl N-[(1R)-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-hydroxy-ethyl]carbamate (110g, 360mmol) in DCM (600mL) was added to the reaction at -10 ° C. After addition, the reaction mixture was stirred at 18 ° C for 1h. TLC showed that the starting material was completely consumed. The reaction was quenched with aqueous citric acid (10%, 800mL) and extracted with DCM (1L x 2). The combined organic layer was washed with water (1L x 2) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate to give the title compound as a light yellow oil (104 g, crude). 1 H NMR (400 MHz, CDCl 3 )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). Step 4: Synthesis of (3R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-oxathiazolidine-3-carboxylic acid tert-butyl ester

[0185] To a solution of (3R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-oxo-oxathiazolidine-3-carboxylic acid tert-butyl ester (52 g, 148 mmol) in MeCN (1000 mL) was added RuCl at 18 °C. 3 (30.7 mg, 148 umol) and NaIO 4 (31.6 g, 148 mmol) in H 2 O (500mL). After addition, the reaction mixture was stirred at 18 ° C for 1h. TLC showed that the starting material was completely consumed. The two batches of reaction were combined and diluted with water (1L). The aqueous phase was extracted with DCM (1L x 2). The combined organic layer was washed with water (500mL x 2) and washed with anhydrous Na 2 SO 4Dry, filter and concentrate to give the title compound as a light yellow solid (80 g, crude). 1 H NMR (400 MHz, CDCl 3 )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). Step 5: Synthesis of tert-butyl N-[(1S)-1-(fluoromethyl)-2-hydroxy-ethyl]carbamate

[0186] To a solution of (4S)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-oxathiazolidine-3-carboxylic acid tert-butyl ester (85 g, 231 mmol) in THF (850 mL) was added TBAF (1 M, 277 mL) and stirred at 20°C for 1 hr. TLC showed complete consumption of the starting material. The reaction was heated with saturated NH 4 The precipitate was quenched with aqueous Cl solution (100 ml) and extracted with ethyl acetate (800 mL x 2). The combined organic layers were washed with water (500 mL x 2) and washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated.The residue was purified by MPLC (petroleum ether / ethyl acetate=2 / 1) to give the title compound (20 g, 45% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ:5.05(d,J=7.6Hz,2H),4.57-4.44(m,2H),3.81-3.73(m,3H),1.45(s,9H). Step 6: Synthesis of (4S)-4-(fluoromethyl)-2-oxo-oxathiazolidine-3-carboxylic acid tert-butyl ester

[0187] To a solution of imidazole (42.3 g, 621 mmol) in DCM (200 mL) was added SOCl dropwise at 0 °C 2 (22.2g, 186mmol) in DCM (200mL), then the reaction mixture was stirred at 20°C for 1hr, then N-[(1S)-1-(fluoromethyl)-2-hydroxy-ethyl]carbamic acid tert-butyl ester (20g, 103mmol) dissolved in DCM (200mL) was added dropwise at -10°C, and the reaction mixture was finally stirred at 20°C for 1hr. TLC showed that the starting material was completely consumed. The reaction was quenched with aqueous citric acid (10%) to pH = 5 and extracted with DCM (300mL x 3). The combined organic layers were washed with brine (200mL x 2) and washed with anhydrous Na2 SO 4 Dry, filter and concentrate to give the title compound as a yellow oil (22 g, crude). 1 HNMR (400MHz, CDCl 3 )δ:5.29-4.97(m,2H),4.86-4.57(m,2H),4.42-4.10(m,3H),1.52(s,9H). Step 7: Synthesis of (S)-tert-butyl 4-(fluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

[0188] To a solution of (4S)-4-(fluoromethyl)-2-oxo-oxathiazolidine-3-carboxylic acid tert-butyl ester (22 g, 91.9 mmol) in MeCN (440 mL) was added RuCl 3 (191mg, 919umol), then in N 2 NaIO was added dropwise 4 (19.7 g, 91.9 mmol) in water (220 mL). The reaction mixture was finally stirred at 20 ° C for 1 hr. TLC showed 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 to the mixture, and then separated, the combined organic layer was washed with water (300 mL x 2), brine (200 mL x 2), and anhydrous Na 2 SO 4 Dry, filter and concentrate to give the title compound as a yellow solid (17.5 g, crude). 1 HNMR (400MHz, CDCl 3 )δ:4.73-4.53(m,5H),1.57(s,9H). Intermediate 2. (S)-tert-butyl (1-fluoro-3-(2-(methylamino)-3-nitro-5-oxo-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)propan-2-yl)carbamate Step 1: Synthesis of tert-butyl 2-chloro-5-oxo-7,8-dihydro-1,6-naphthyridine-6-carboxylate

[0189] Two batches were carried out in parallel. 2-Chloro-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylic acid tert-butyl ester (25 g, 93.0 mmol) was dissolved in CCl 4 NaIO was added to a solution of 1% ethanol (250 mL) and MeCN (25 mL). 4A solution of (59.7 g, 279 mmol) in water (175 mL) was then stirred under N 2 Add RuCl 3 (193 mg, 930 umol). The reaction mixture was finally stirred at 15 °C for 16 hr. The two batches were combined; the mixture was filtered and concentrated to remove the solvent. Water (800 mL) was added to the residue and extracted with ethyl acetate (400 mL x 3), and the combined organic layers were washed with Na 2 SO aqueous solution (500 mL), brine (300 mL x 2), and anhydrous Na 2 SO 4 Dry, filter and concentrate to give the title compound as a grey solid (40 g, crude). 1 HNMR (400 MHz, DMSO-d 6 )δ: 8.28 (d, J = 8.0Hz, 1H), 7.60 (d, J = 8.4Hz, 1H), 3.98 (t, J = 6.0Hz, 2H), 3.13 (t, J = 6.4Hz, 2H), 1.46 (s, 9H). Step 2: Synthesis of tert-butyl 2-[benzyl(methyl)amino]-5-oxo-7,8-dihydro-1,6-naphthyridine-6-carboxylate

[0190] Two batches were carried out in parallel. To a solution of tert-butyl 2-chloro-5-oxo-7,8-dihydro-1,6-naphthyridine-6-carboxylate (20 g, 70.7 mmol) in tert-butyl alcohol (400 mL) and ethylene glycol (400 mL) was added N-methyl-1-phenyl-methylamine (42.9 g, 354 mmol), and the mixture was stirred at 50 ° C for 16 hr. TLC showed that the starting material was completely consumed and new spots appeared. The reaction mixture was concentrated to remove tert-butyl alcohol. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 30: 1 to 5: 1) to obtain the title compound (40 g, 77% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ:7.40(d,J=9.2Hz,1H),7.35-7.21(m,5H),6.67(d,J=9.2Hz,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). Step 3: Synthesis of 2-[Benzyl(methyl)amino]-7,8-dihydro-6H-1,6-naphthyridin-5-one

[0191] 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 TFA (158 g, 1.39 mol) dropwise at 0°C and then stirred at 20°C for 1 hr. TLC showed that the starting material was completely consumed and new spots appeared. The reaction mixture was concentrated, the residue was diluted with DCM (200 mL), and Na 2 CO 3 The aqueous solution was adjusted to pH = 8. The solution was extracted with DCM (200 mL x 2) and washed with brine (400 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to give the title compound as a yellow solid (17.5 g, 86% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ:7.83(d,J=8.8Hz,1H),7.54(s,1H),7.33-7.20(m,5H),6.58(d,J=8.8H z,1H),4.84(s,2H),3.38-3.35(m,2H),3.07(s,3H),2.81(t,J=6.8Hz,2H). 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

[0192] 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) according to General Procedure 1. The residue was purified by silica gel column (DCM:MeOH=50:1 to 20:1) to give the title compound (9.7 g, 76% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 )δ:7.87(d,J=8.8Hz,1H),7.33-7.29(m,2H),7.24-7.19(m,3H),6.94(d,J=8.8Hz,1H),6.25( d,J=8.8Hz,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). 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

[0193] Two batches were run in parallel. At 0°C, 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) was added to H 2 SO 4 KNO (110 g, 60 mL) was added dropwise to the solution 3 (5.50 g, 54.4 mmol), and then the mixture was stirred at 20°C for 3 hr. LCMS showed that the starting material was completely consumed. The two batches were poured into ice water (1 L) and extracted with ethyl acetate (300 mL x 2). The aqueous phase was washed with Na 2 CO 3 The mixture was slowly alkalized to pH = 9-10, and then THF (1.2 L), Boc 2 The mixture was stirred at 25 °C for 16 hours at 37 °C for 1 h. The reaction mixture was extracted with ethyl acetate (2 L x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 10: 1 to 1: 1) to give the title compound (4.13 g, 38% yield) as a yellow solid. 1 HNMR (400 MHz, DMSO-d 6 )δ:8.86(d,J=4.8Hz,1H),8.65(s,1H),6.98(d,J=8.8Hz,1H),4.45(d,J=5.6Hz,1H),4 .35(d,J=5.2Hz,1H),3.68-3.32(m,4H),3.08(s,3H),3.07-3.02(m,2H),1.31(s,9H). Intermediate 3. 2-(Methylamino)-3-nitro-7,8-dihydro-1,6-naphthyridin-5(6H)-one Step 1: Synthesis of tert-butyl 2-chloro-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0194] To tert-butyl 2-chloro-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate (500 mg, 1.86 mmol) in CCl 4To a stirred solution of 1% ethanol (7.5 mL) and MeCN (0.75 mL) was added NaIO 4 (1.2 g, 5.58 mmol) and water (2.5 mL). Then RuCl 3 .H 2 O (126 mg, 0.56 mmol), and then the reaction mixture was vigorously stirred at room temperature for 2 hours. LCMS showed that the reaction was complete, and the mixture was filtered and extracted with DCM (3x20 mL). The organic matter was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was passed through silica gel (petroleum ether: ethyl acetate = 2: 1) to give the title compound (447 mg, 85%) as a white solid. LCMS (ESI, m / z): 283 [M+H] + . Step 2: Synthesis of 2-chloro-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0195] 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 directly in the next step without further purification. LCMS (ESI, m / z): 183 [M+H] + . Step 3: Synthesis of 2-(methylamino)-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0196] Methylamine (2M in THF) (2.8 mL, 5.48 mmol) was added to a solution of 2-chloro-7,8-dihydro-1,6-naphthyridin-5(6H)-one (200 mg, 1.1 mmol) in ethylene glycol (7 mL) and tert-butanol (7 mL). The resulting mixture was stirred at 220 ° C for 2 h. LCMS showed that the reaction was complete, and the mixture was quenched with water (20 mL) and extracted with ethyl acetate (3x20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 2) to give the title compound as a white solid (170 mg, 88%). LCMS (ESI, m / z): 178 [M + H] + . Step 4: Synthesis of 2-(methylamino)-3-nitro-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0197] At 0°C, 2-(methylamino)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (170 mg, 0.96 mmol) was added to H 2 SO 4To the stirred solution of 2 mL of KNO was added 3 (194 mg, 1.92 mmol). The resulting solution was stirred at room temperature for 2 h. LCMS showed that the reaction was complete, and the mixture was quenched with water (20 mL) at 0 ° C. The resulting solution was adjusted to pH 8-9 with sodium bicarbonate and then extracted with ethyl acetate (3x30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The 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] + . Intermediate 4. (R)-Tetrahydro-3H-[1,2,3]oxathiazo[4,3-c][1,4]oxazine 1,1-dioxide Step 1: Synthesis of (3aR)-tetrahydro-3H-[1,2,3]oxathiazo[4,3-c][1,4]oxazine 1-oxide

[0198] To a solution of imidazole (17.4 g, 256 mmol) in DCM (40 mL) was added SOCl dropwise at room temperature under nitrogen atmosphere. 2 (9.14g, 76.82mmol) in DCM (80mL). The resulting mixture was stirred at room temperature for 1h. A solution of (S)-morpholine-3-ylmethanol (5g, 42.68mmol) in DCM (80mL) was added dropwise to the above mixture under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The resulting mixture was diluted with water (200mL) and acidified to pH 6 with citric acid. The reaction was then extracted with DCM (3x200 mL). The combined organic extracts were washed with brine (200mL), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the title compound (6g, 86%) as a yellow oil. LCMS (ESI, m / z): 164 [M+H] +. Step 2: Synthesis of (R)-tetrahydro-3H-[1,2,3]oxathiazo[4,3-c][1,4]oxazine 1,1-dioxide

[0199] Under nitrogen atmosphere, (3aR)-tetrahydro-3H-[1,2,3]oxathiazo[4,3-c][1,4]oxazine 1-oxide and RuCl were added at room temperature. 3 (938 mg, 3.68 mmol) was added to a solution of MeCN (200 mL) with NaIO 4(8.65g, 40.44mmol) in water (200mL). The mixture was stirred at room temperature for 0.5h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture solution was concentrated under vacuum. The crude product was extracted with ethyl acetate (2x300 mL). The combined organic extracts were washed with brine (300mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:1) to obtain the title compound (3.2g, 48%) as a white solid. LCMS (ESI, m / z): 180[M+H]+. Intermediate 5. (S)-tert-butyl (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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate Step 1: Ethyl 7-benzyloxy-1H-indole-2-carboxylate

[0200] 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) was added AcOH (4.52 g, 75.3 mmol) and Pd(OAc) under nitrogen atmosphere. 2 (1.7 g, 7.5 mmol). The resulting solution was stirred at 70 ° C for 16 h under an oxygen atmosphere. The mixture was then quenched by adding water (1 L) and 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 vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10: 1) to give the title compound (8 g, 35.9%) as a light yellow solid. LCMS (ESI, m / z): 296 [M + H] +. Step 2: (7-(Benzyloxy)-1H-indol-2-yl)methanol

[0201] Ethyl 7-benzyloxy-1H-indole-2-carboxylate (8 g, 27.1 mmol) was reacted according to General Procedure 3. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=3:1) to give the title compound (4.5 g, 62%) as a light yellow solid. LCMS (ESI, m / z): 254 [M+H]+. Step 3: 7-(Benzyloxy)-1H-indole-2-carbaldehyde

[0202] (7-Benzyloxy-1H-indol-2-yl)methanol (4.5 g, 17.7 mmol) was reacted according to General Procedure 4. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=5:1) to give the title compound (4 g, 90%) as a light yellow solid. LCMS (ESI, m / z): 252 [M+H]+. Step 4: 7-(Benzyloxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde

[0203] 7-(Benzyloxy)-1H-indole-2-carbaldehyde (4 g, 15.9 mmol) and Cs 2 CO 3 (15.6 g, 47.7 mmol) and bromomethylcyclopropane (3.2 g, 23.9 mmol) were reacted according to General Procedure 5. The 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]+. Step 5: (S)-tert-butyl (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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0204] A solution of 7-(benzyloxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (2.3 g, 7.5 mmol) and intermediate 7 (3 g, 7.5 mmol) were reacted according to general procedure 11. The crude material was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (2.4 g, 49%) as a light yellow solid. LCMS (ESI, m / z): 653 [M+H]+. Step 6: (S)-tert-butyl (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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0205] A solution of (S)-tert-butyl(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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (2.4 g, 3.7 mmol) was reacted according to General Procedure 9. The 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]+. Intermediate 6. 3-Amino-2-(methylamino)-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0206] To a solution of intermediate 3 (13 g, 58.5 mmol) in methanol (300 mL) was added NH 4 A solution of Cl (31.3 g, 585 mmol) in water (100 mL). Zn (38 g, 585 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 h. The solid was filtered off and the solvent was evaporated under vacuum. The crude product was purified by flash column chromatography on C18 silica gel to give the title compound (3 g, 27%) as a yellow solid. LCMS (ESI, m / z): 193 [M+H]+. Intermediate 7. (S)-tert-butyl (1-(3-amino-2-(methylamino)-5-oxo-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3-fluoropropan-2-yl)carbamate

[0207] To a solution of (S)-tert-butyl (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 NH 4 A solution of Cl (12.1 g, 226 mmol) in water (50 mL) was added. Zn (14.5 g, 226 mmol) was slowly added to the mixture in batches. The mixture was stirred at room temperature for 2 h. The solid was filtered off and the solvent was evaporated under vacuum. The crude product was purified by flash column chromatography on C18 silica gel to give the title compound (7.6 g, 92%) as a light yellow solid. LCMS (ESI, m / z): 368 [M+H]+. 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]phthalazin-8-one Step 1: Synthesis of 1-(cyclopropylmethyl)-7-methoxy-1H-indole

[0208] 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 crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100: 1) to give 1-(cyclopropylmethyl)-7-methoxy-1H-indole (1.35 g, 99%) as a yellow oil. LCMS (ESI, m / z): 202 [M+H]+. Step 2: Synthesis of 1-(cyclopropylmethyl)-7-methoxy-1H-indole-2-carbaldehyde

[0209] Under nitrogen atmosphere, n-butyl lithium (2.5M in n-hexane) (1.97 mL, 4.97 mmol) was added in batches to a solution of 1-(cyclopropylmethyl)-7-methoxy-1H-indole (500 mg, 2.48 mmol) in THF (20 mL) at -78 ° C. The mixture was stirred at room temperature for 1 h. Under nitrogen atmosphere, DMF (0.38 mL, 4.97 mmol) was added dropwise to the above mixture at -78 ° C. The mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction was then reacted by adding saturated NH 4 The product was quenched with Cl aqueous solution (20 mL) and extracted with ethyl acetate (2x20 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The 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]+. 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0210] Intermediate 2 (50 mg, 0.13 mmol) was reacted with 1-(cyclopropylmethyl)-7-methoxy-1H-indole-2-carbaldehyde and 1-(cyclopropylmethyl)-7-methoxy-indole-2-carbaldehyde (29 mg, 0.13 mmol) according to General Procedure 6. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:3) to give the title compound (32 mg, 44%) as a light yellow solid. LCMS (ESI, m / z): 577 [M+H]+. 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]phthalazin-8-one

[0211] (S)-tert-Butyl(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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (32 mg, 0.06 mmol) was reacted according to General Procedure 2. The crude product 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).

[0212] The compounds of Examples 2 to 16 in Table 1 were obtained following a procedure similar to that of preparing the compound of Example 1 in Step 1 using an appropriate alkylating agent. Table 1 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]phthalazin-8-one Step 1: Synthesis of (7-methyl-1H-indol-2-yl)methanol

[0213] Ethyl 7-methyl-1H-indole-2-carboxylate (1 g, 4.9 mmol) was reacted according to General Procedure 3. The crude product 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]+. Step 2: Synthesis of 7-methyl-1H-indole-2-carbaldehyde

[0214] (7-Methyl-1H-indol-2-yl)methanol (700 mg, 4.3 mmol) was reacted according to General Procedure 4. The crude product 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]+. Step 3: Synthesis of 1-(isoxazol-5-ylmethyl)-7-methyl-1H-indole-2-carbaldehyde

[0215] 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. The resulting solution was stirred at 50 ° C for 2 h. The reaction was monitored by LCMS. The reaction was then quenched by adding water (30 mL) and extracted with ethyl acetate (30 mL), washed with water (2x30 mL) and brine (2x30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product 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] +. 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]phthalazin-7-yl)propan-2-yl)carbamate

[0216] 1-(Isoxazolyl-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 was purified by column chromatography (petroleum ether / ethyl acetate=1:2) to give the title compound (80 mg, 34%) as a yellow oil. LCMS (ESI, m / z): 588 [M+H]+. 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]phthalazin-8-one

[0217] (S)-tert-Butyl(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]phthalazin-7-yl)propan-2-yl)carbamate (80 mg, 0.14 mmol) was reacted according to General Procedure 2. The crude product was purified by preparative HPLC (Method E) to give the title compound as a white solid (16.1 mg, 24%). LCMS (ESI, m / z): 488 [M+H]+. LCMS RT: 1.467 min. (Method B).

[0218] The compounds of Examples 18 to 21 in Table 2 were obtained following procedures similar to those for the preparation of the compound of Example 17 using the appropriate indole-2-carboxaldehyde and an alkylating agent in step 3. Table 2 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]phthalazin-8-one Step 1: Synthesis of ethyl 5-fluoro-7-methoxy-1H-indole-2-carboxylate

[0219] 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) and 4-fluoro-2-methoxy-aniline (2.8 g, 19.8 mmol) under nitrogen atmosphere. 2(889mg, 3.97mmol) and AcOH (1.2mL, 19.8mmol). The resulting mixture was stirred at 70 ° C overnight under an oxygen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (600mL) and extracted with ethyl acetate (600mL), washed with water (2x600 ml) and brine (2x600 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=5:1) to obtain the title compound (2.5g, 53%) as a yellow solid. LCMS (ESI, m / z): 238[M+H]+. Step 2: Synthesis of (5-fluoro-7-methoxy-1H-indol-2-yl)methanol

[0220] 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 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]+. Step 3: Synthesis of 5-fluoro-7-methoxy-1H-indole-2-carbaldehyde

[0221] (5-Fluoro-7-methoxy-1H-indol-2-yl)methanol (164 mg, 0.84 mmol) was reacted according to General Procedure 4. The 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]+. Step 4: Synthesis of 5-fluoro-1-(isoxazol-5-ylmethyl)-7-methoxy-1H-indole-2-carbaldehyde

[0222] 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 crude material 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]+. 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]phthalazin-7-yl)propan-2-yl)carbamate

[0223] 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 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]+. 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]phthalazin-8-one

[0224] (S)-tert-Butyl(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]phthalazin-7-yl)propan-2-yl)carbamate (50 mg, 0.08 mmol) was reacted according to General Procedure 2. The 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 (400MHz, DMSO-d6): δ8.52(s,1H),8.33–8.30(m,4H),7.32(s,1H),7.09(d,J=7.0Hz,1H),6.86(d,J=7.0Hz,1H),6.30(s,2H ),5.99(d,J=1.8Hz,1H),4.82–4.57(m,2H),3.95(d,J=1.9Hz,6H),3.89–3.80(m,2H),3.78–3.69(m,3H),3.33(t,J=6.4Hz,2H). LCMS(ESI,m / z):522[M+H]+. LCMS RT:1.489min. (Method B). 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]phthalazin-8-one

[0225] Example 23 was synthesized via a synthetic route similar to that of Example 22, starting from 4-fluoro-2-methoxy-methylamine in step 1. The crude product was purified by preparative HPLC (Method F) to give the title compound as a white solid (15.8 mg, 36%). LCMS (ESI, m / z): 522 [M+H]+. LCMS RT: 1.491 min. (Method D). 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]phthalazin-8-one 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]phthalazin-8-one

[0226] 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 residue was purified by preparative TLC (DCM:MeOH=25:1) to give 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]phthalazin-8-one (170 mg, 60%) as a yellow oil. LCMS (ESI, m / z): 372 [M+H]+. 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]phthalazin-7-yl)propan-2-yl)carbamate

[0227] 2-(1-(Cyclopropylmethyl)-1H-indol-2-yl)-3-methyl-3,5,6,7-tetrahydro-8H-imidazo[4,5-b][1,6]phthalazin-8-one (60 mg, 0.16 mmol) was reacted with (R)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (58 mg, 0.24 mmol) according to General Procedure 1. The 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]+. 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]phthalazin-8-one

[0228] (R)-tert-Butyl(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 residue was purified by preparative HPLC (Method E) to give the title compound (27.1 mg, 67%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.51(s,1H),7.88(s,3H),7.72(dd,J=8.1Hz,J=6.6Hz,2H),7.36–7.3 0(m,1H),7.26(s,1H),7.19–7.14(m,1H),4.59(d,J=7.0Hz,2H),4.01(s, 3H),3.85–3.67(m,3H),3.65–3.50(m,2H),3.32(t,J=6.6Hz,2H),1.26(d ,J=6.2Hz,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). 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]phthalazin-8-one

[0229] Example 25 was synthesized via a synthetic route similar to Example 24 using the appropriate substituted indole (7-methoxy-1-(oxazol-2-ylmethyl)-1H-indole-2-carbaldehyde) in step 1. The crude product was purified by preparative HPLC (Method F) to give the title compound (10.3 mg, 62%) as a yellow solid. 1H NMR (400MHz, methanol-d4) δ8.62(s,1H),7.68(s,1H),7.33(d,J=8Hz,1H),7.21(s,1H),7.18(t,J=21.6Hz,1H),6.92(s,1H),6.87(d,J=7.6Hz,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=6.8Hz,2H),1.40(s,3H). LCMS(ESI,m / z):486[M+H]+. LCMS RT: 0.815 min. (Method D). Example 26. (S)-2-(1-((1-fluorocycloalkyl)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]phthalazin-8-one Step 1: Synthesis of (1-fluorocyclopropyl)methyl methanesulfonate

[0230] To a stirred solution of (1-fluorocyclopropyl)methanol (200 mg, 2.22 mmol) in DCM (10 mL) was added Et 3 N (0.62mL, 4.44mmol) and MsCl (0.21mL, 2.66mmol). The resulting mixture was stirred at room temperature for 1h. The reaction was monitored by TLC and LCMS. The reaction was quenched by adding water (20mL) and extracted with ethyl acetate (3x20 mL). The combined organic layer was washed with brine (2x40 mL), dried over anhydrous sodium sulfate and concentrated to give the title compound (200mg, 53%) as a yellow oil. LCMS (ESI, m / z): 169[M+H]+. Step 2: Synthesis of 1-((1-fluorocyclopropyl)methyl)-7-methoxy-1H-indole-2-carbaldehyde

[0231] 7-Methoxy-1H-indole-2-carbaldehyde (140 mg, 0.8 mmol) was reacted with (1-fluorocyclopropyl)methyl methanesulfonate (201 mg, 1.2 mmol) according to General Procedure 5. The crude product was chromatographed on a silica gel column (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]+. 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]phthalazin-8-one

[0232] 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 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]+. 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

[0233] 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]phthalazin-8-one (30 mg, 0.07 mmol) was reacted with Intermediate 4 (15 mg, 0.09 mmol) according to General Procedure 1. The crude material was purified by flash chromatography to give the title compound as a yellow solid (40 mg, 93%). LCMS (ESI, m / z): 599 [M+H]+. 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]phthalazin-8-one

[0234] (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 crude material was purified by preparative HPLC (Method F) to give the title compound (21.8 mg, 62%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 +D 2O): δ8.53(s,1H),7.34–7.29(m,1H),7.24(s,1H),7.11(t,J=7.9Hz,1H),6.91–6.84(m,1H),5.36(d,J=21.6Hz,2H),4.04–3.99(m,1H),3 .93(d,J=1.7Hz,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).

[0235] The compounds of Examples 27 and 28 in Table 3 were obtained following a procedure similar to that for the compound of Example 26 using an appropriate alkylating agent in step 2. Table 3 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]phthalazin-8-one Step 1: Synthesis of ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0236] 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) was added Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (52.7mg, 0.05mmol), NiCl 2 -dme(5.17mg,0.02mmol),dtbbpy(6.3mg,0.02mmol),(TMS) 3 SiH (116 mg, 0.47 mmol) and Na 2 CO 3(98.7 mg, 0.93 mmol). The reaction was stirred under a nitrogen atmosphere and irradiated overnight with a blue LED lamp (7 cm away, equipped with a cooling fan to maintain the reaction temperature at 25 ° C). The reaction was monitored by LCMS. The reaction was then quenched by adding water (20 mL) and extracted with ethyl acetate (20 mL), washed with water (2x20 mL) and brine (2x20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=5:1) to give the title compound (30 mg, 15%) as a light yellow solid. LCMS (ESI, m / z): 427 [M+H] +. Step 2: Synthesis of tert-butyl 4-(1-(cyclopropylmethyl)-2-(hydroxymethyl)-1H-indol-7-yl)piperidine-1-carboxylate

[0237] To a solution of ethyl-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (110 mg, 0.26 mmol) in THF (3 mL) at 0°C was added LiBH 4 (0.02mL, 1.03mmol). The resulting solution was stirred at 50 ° C overnight. The reaction was monitored by LCMS. The reaction was then quenched by adding water (10mL) and extracted with ethyl acetate (2x10mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=5:1) to give the title compound (40mg, 40%) as a light yellow solid. LCMS (ESI, m / z): 385[M+H]+. Step 3: Synthesis of tert-butyl 4-(1-(cyclopropylmethyl)-2-formyl-1H-indol-7-yl)piperidine-1-carboxylate

[0238] 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 crude product was purified by column chromatography (petroleum ether / ethyl acetate=6:1) to give the title compound (50 mg, 91%) as a light yellow solid. LCMS (ESI, m / z): 383 [M+H]+. Step 4: Synthesis of 1-(cyclopropylmethyl)-7-(piperidin-4-yl)-1H-indole-2-carbaldehyde

[0239] 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 vacuum to give the title compound as a light yellow solid (35 mg, 95%). LCMS (ESI, m / z): 283 [M+H]+. Step 5: Synthesis of 7-(1-acetylpiperidin-4-yl)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde

[0240] To a solution of 1-(cyclopropylmethyl)-7-(piperidin-4-yl)-1H-indole-2-carbaldehyde (50 mg, 0.18 mmol) in DCM (5 mL) was added acetyl chloride (27.8 mg, 0.35 mmol) and DIEA (0.05 mL, 0.71 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction was then quenched by adding water (10 mL) and extracted with DCM (3x10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography to obtain the title compound (30 mg, 52%) as a light yellow solid. LCMS (ESI, m / z): 325 [M+H]+. 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

[0241] 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 crude product was purified by column chromatography (DCM / MeOH=20:1) to give the title compound (25 mg, 24%) as a light yellow solid. LCMS (ESI, m / z): 672 [M+H]+. 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]phthalazin-8-one

[0242] (S)-tert-Butyl(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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (20 mg, 0.03 mmol) was reacted according to General Procedure 2. The 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).

[0243] The compounds of Examples 30 to 32 in Table 4 were obtained by following a procedure similar to that for the compound of Example 29 using an appropriate acylating agent in step 5. Table 4 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]phthalazin-8-one Step 1: Synthesis of methyl 6-acetyl-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridine-2-carboxylate

[0244] To a solution of 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) was added Davephos (78 mg, 0.2 mmol) and Pd(dppf)Cl under nitrogen atmosphere. 2 (73 mg, 0.1 mmol). The mixture was stirred at room temperature for 0.5 h. HCl (1 M aqueous solution) was added to the above mixture at 0 ° C. The mixture was stirred at room temperature for 2 h. The reaction was concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=3:1) to give the title compound (130 mg, 47.8%) as a yellow oil. LCMS (ESI, m / z): 273 [M+H] +. Step 2: Synthesis of methyl 1-(cyclopropylmethyl)-6-(1-hydroxy-1-methyl-ethyl)pyrrolo[2,3-b]pyridine-2-carboxylate

[0245] 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) was added methylmagnesium bromide (3 M in diethyl ether, 0.3 mL, 0.9 mmol) at 0°C. The mixture was stirred at room temperature at 0°C for 4 h. The reaction was then stirred by adding saturated NH 4 The mixture was quenched with aqueous Cl solution (10 mL) and extracted with ethyl acetate (20 mL), washed with water (2×10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:1) to give the title compound (110 mg, 79.9%) as a light yellow solid. LCMS (ESI, m / z): 289 [M+H]+. Step 3: Synthesis of 2-[1-(cyclopropylmethyl)-2-(hydroxymethyl)pyrrolo[2,3-b]pyridin-6-yl]propan-2-ol

[0246] 1-(Cyclopropylmethyl)-6-(1-hydroxy-1-methyl-ethyl)pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester (80 mg, 0.3 mmol) was reacted according to General Procedure 3. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:1) to give the title compound (70 mg, 96.9%) as a light yellow solid. LCMS (ESI, m / z): 261 [M+H]+. Step 4: Synthesis of 1-(cyclopropylmethyl)-6-(1-hydroxy-1-methyl-ethyl)pyrrolo[2,3-b]pyridine-2-carbaldehyde

[0247] 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 crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:1) to give the title compound (50 mg, 71.9%) as a light yellow solid. LCMS (ESI, m / z): 259 [M+H]+. 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

[0248] 1-(Cyclopropylmethyl)-6-(1-hydroxy-1-methyl-ethyl)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 crude product was purified by column chromatography (ethyl acetate) to give the title compound (30 mg, 31.9%) as a light yellow solid. LCMS (ESI, m / z): 606 [M+H]+. 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]phthalazin-8-one

[0249] (S)-tert-Butyl(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 (30 mg, 0.05 mmol) was reacted according to General Procedure 2. The 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-d 6 )δ8.54(s,1H),8.29(s,3H),8.11(d,J=8.0Hz,1H),7.57(d,J=8.0Hz,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). 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]phthalazin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)oxazolidin-2-one 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

[0250] 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 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]+. 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]phthalazin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)oxazolidin-2-one

[0251] 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 was purified by preparative HPLC (Method E) to give the title compound (12.5 mg, 36%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6): δ8.53(s,1H),8.29(s,3H),7.66(s,1H),7.33(d,J=7.9Hz,1H),7.21(s,1H),7.08(t,J =7.8Hz,1H),6.90(d,J=7.8Hz,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). 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]phthalazin-8-one Step 1: Synthesis of 4-(hydroxymethyl)-5,5-dimethyl-pyrrolidin-2-one

[0252] To a solution of 2,2-dimethyl-5-oxo-pyrrolidine-3-carboxylic acid ethyl ester (100 mg, 0.54 mmol) in THF (5 mL) was added LiBH dropwise at 0°C under nitrogen atmosphere. 4 (2M in THF, 0.1 mL, 2.16 mmol). The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was monitored by TLC and LCMS. The reaction was concentrated by adding saturated NH 4 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] + . 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0253] 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 crude product was purified by preparative TLC to give the title compound as a yellow oil (40 mg, 65.4%). LCMS (ESI, m / z): 688 [M+H] + . 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]phthalazin-8-one

[0254] 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (40 mg, 0.306 mmol) was reacted according to General Procedure 2. The 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-d 6 )δ8.51(s,1H),8.39–8.22(m,3H),7.78(s,1H),7.31(d,J=7.9Hz,1H),7.19(s,1H),7.08(t,J=7.8Hz,1H) ,6.94(d,J=7.8Hz,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=6.6Hz,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).

[0255] The compounds of Examples 36-58 in Table 5 were obtained following procedures similar to those for the preparation of the compound of Example 35 using appropriate ester or alcohol starting materials. Table 5 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]phthalazin-8-one Step 1: Synthesis of [7-benzyloxy-1-(cyclopropylmethyl)indol-2-yl]methanol

[0256] Under nitrogen atmosphere, sodium borohydride (0.62 g, 16.37 mmol) was added to a solution of 7-benzyloxy-1-(cyclopropylmethyl)indole-2-carboxaldehyde (5.0 g, 16.37 mmol) in methanol (150 mL) at 0 ° C. The resulting mixture was stirred at 0 ° C for 4 h. The reaction was monitored by TLC and LCMS. The reaction was quenched by adding water (100 mL) and 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 and concentrated under vacuum to give the title compound (4.8 g, 95%) as a brown oil. LCMS (ESI, m / z): 308 [M+H] +. Step 2: Synthesis of [7-benzyloxy-1-(cyclopropylmethyl)indol-2-yl]methoxy-tert-butyl-dimethyl-silane

[0257] 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. Under a nitrogen atmosphere, tert-butylchlorodimethylsilane (2.82 g, 18.74 mmol) was added to the above mixture at 0 ° C. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC and LCMS. The reaction was quenched by adding water (100 mL) and 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, and concentrated under vacuum to give the title compound (6.0 g, 91%) as a brown oil. LCMS (ESI, m / z): 422 [M+H]+. Step 3: Synthesis of 2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(cyclopropylmethyl)indol-7-ol

[0258] [7-Benzyloxy-1-(cyclopropylmethyl)indol-2-yl]methoxy-tert-butyl-dimethyl-silane (3.5 g, 8.3 mmol) was reacted in ethyl acetate (30 mL) and methanol (70 mL) according to General Procedure 9. The residue was purified by flash column chromatography to give the title compound as a brown oil (2.5 g, 91%). LCMS (ESI, m / z): 332 [M+H]+. Step 4: Synthesis of (4S)-4-[[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(cyclopropylmethyl)indol-7-yl]oxymethyl]pyrrolidin-2-one

[0259] 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 crude product was purified by flash column chromatography to give the title compound as a brown oil (2.1 g, 77%). LCMS (ESI, m / z): 429 [M+H]+. Step 5: Synthesis of (4S)-4-[[1-(cyclopropylmethyl)-2-(hydroxymethyl)indol-7-yl]oxymethyl]pyrrolidin-2-one

[0260] 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) in acetonitrile (20 mL) was added aqueous HCl (1 M, 10 mL, 4.9 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The mixture was washed with saturated NaHCO 3 The mixture was quenched with aqueous solution (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 vacuum to give the title compound (1.25 g, 81%) as a brown solid. LCMS (ESI, m / z): 315 [M+H]+. Step 6: Synthesis of 1-(cyclopropylmethyl)-7-[[(3S)-5-oxopyrrolidin-3-yl]methoxy]indole-2-carbaldehyde

[0261] (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 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]+. 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

[0262] 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 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]+. 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]phthalazin-8-one

[0263] 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (450 mg, 0.68 mmol) was reacted according to General Procedure 2. The crude product was purified by preparative HPLC (Method A) to give the title compound (191 mg, 48.2%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.48(s,1H),7.29(d,J=7.9Hz,1H),7.16(s,1H),7.06(t,J=7.8Hz,1H),6.86(d,J=7.8Hz,1H),4.72( d,J=6.9Hz,2H),4.44–4.37(m,1H),4.33–4.26(m,1H),4.18(d,J=6.5Hz,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=13.3Hz,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: 1.320min (Method D). 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]phthalazin-8-one

[0264] Example 60 Synthesis was performed using a synthetic route similar to Example 59 using (R)-4-(hydroxymethyl)pyrrolidin-2-one in step 4 to give the title compound as a white solid (17.7 mg, 19.77%). LCMS (ESI, m / z): 560 [M+H]+. LCMS RT: 1.628 min (Method D). 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]phthalazin-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]phthalazin-8-one Step 1: Synthesis of 2-benzyloxy-1-(2-triisopropylsilyloxazol-5-yl)ethanol

[0265] Under nitrogen atmosphere, n-butyl lithium (2.5M in n-hexane, 4.4 mL, 11.1 mmol) was added dropwise to a solution of triisopropyl(oxazol-2-yl)silane (1 g, 4.4 mmol) and 2-benzyloxyacetaldehyde (1 g, 6.6 mmol) in THF (50 mL) at -10 °C. The mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then heated to 40 °C by adding saturated NH 4 The mixture was quenched with aqueous Cl solution (150 mL) 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 vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:1) to give the title compound (747 mg, 44.8%) as a light yellow solid. LCMS (ESI, m / z): 376 [M+H]+. Step 2: Synthesis of 2-(benzyloxy)-1-(2-(triisopropylsilyl)oxazol-5-yl)ethyl acetate

[0266] To 2-benzyloxy-1-(2-triisopropylsilyloxazol-5-yl)ethanol (670 mg, 1.8 mmol) in DCM (2 mL) was added TEA (1 mL, 5.4 mmol). Under a nitrogen atmosphere, a solution of acetyl chloride (168 mg, 2.1 mmol) in DCM (0.5 mL) was added to the above mixture at 0 °C. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was concentrated by adding saturated NH 4The product was quenched with Cl aqueous solution (5 mL) 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 vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=3:1) to give the title compound (450 mg, 60.4%) as a light yellow oil. LCMS (ESI, m / z): 418 [M+H]+. Step 3: Synthesis of 2-(hydroxy)-1-(2-(triisopropylsilyl)oxazol-5-yl)ethyl acetate

[0267] 2-(Benzyloxy)-1-(2-(triisopropylsilyl)oxazol-5-yl)ethyl acetate (400 mg, 1.0 mmol) was reacted in methanol (10 mL) according to General Procedure 9. The crude product was purified by flash column chromatography on C18 silica gel to give the title compound as a light yellow solid (160 mg, 51.0%). LCMS (ESI, m / z): 328 [M+H]+. Step 4: Synthesis of 2-((2-(7-((S)-2-((tert-butyloxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]phthalazin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-1-(oxazol-5-yl)ethyl acetate

[0268] Acetic acid 2-(hydroxy)-1-(2-(triisopropylsilyl)oxazol-5-yl)ethyl ester (142 mg, 0.4 mmol) was reacted with intermediate 5 (163 mg, 0.3 mmol) according to general procedure 10. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:1) to give the title compound (80 mg, 38.6%) as a pale yellow solid, which was a mixture of diastereomers. LCMS (ESI, m / z): 716 [M+H]+. 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0269] 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]phthalazin-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 LiOH (12.5 mg, 0.5 mmol). The resulting solution was stirred at 50 °C for 16 h. The reaction was monitored by LCMS. The mixture product was adjusted to pH 2 with aqueous HCl (1 M). The resulting solution was 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 vacuum. The crude product was purified by flash column chromatography on C18 silica gel to give the title compound (70 mg, 99.1%) as a pale yellow solid as a mixture of diastereomers. LCMS (ESI, m / z): 674 [M+H] + . 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]phthalazin-8-one

[0270] 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (65 mg, 0.01 mmol) was reacted according to General Procedure 2. The crude product was purified by chiral preparative HPLC [column: CHIRALPAK IF, 2×25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH 3 / MeOH), mobile phase B: MeOH: DCM (1:1) (0.1% 2M NH 3 / MeOH); flow rate: 14 mL / min; gradient: isocratic in 32 min, 30% B.; detection: UV (220 / 254 nm)] to give a single stereoisomer as an unknown configuration at the alcohol stereocenter.

[0271] Example 61a. Isomer 1: Chiral HPLC RT: 19.2min. 1 H NMR (400 MHz, DMSO-d6 )δ8.48(d,J=1.6Hz,1H),8.38(s,1H),7.37(s,1H),7.28(d,J=7.2Hz,1H),7.14(s,1H),7.0 1(d,J=7.6Hz,2H),5.74(t,J=6.4Hz,1H),5.29(t,J=6.4Hz,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 min. (Method D).

[0272] Example 61b. Isomer 2: Chiral HPLC RT: 28.11min. 1 H NMR (400 MHz, DMSO-d 6 ): δ8.48(s,1H),8.38(s,1H),7.37(s,1H),7.28(d,J=7.2Hz,1H),7.14(s,1H),7.01(d,J= 7.6Hz,2H),5.74(t,J=6.4Hz,1H),5.29(t,J=6.4Hz,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: 1.033min. (Method D). Example 62. 2-(7-(((R)-1-(1H-imidazo-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]phthalazin-8-one Step 1: Synthesis of ethyl (R)-7-((1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0273] (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 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]+. Step 2: Synthesis of ethyl (R)-1-(cyclopropylmethyl)-7-((1-hydroxypropan-2-yl)oxy)-1H-indole-2-carboxylate

[0274] To a solution of (R)-7-((1-((tert-butyldiphenylsilyl)oxy)propane-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylic acid ethyl ester (550 mg, 0.99 mmol) in THF (10 mL) was added TBAF (10 mL) at 0°C. The resulting solution was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The reaction was then quenched by adding water (20 mL) and 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 vacuum. The 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]+. Step 3: Synthesis of ethyl (R)-1-(cyclopropylmethyl)-7-((1-((methylsulfonyl)oxy)propan-2-yl)oxy)-1H-indole-2-carboxylate

[0275] (R)-ethyl 1-(cyclopropylmethyl)-7-((1-hydroxypropan-2-yl)oxy)-1H-indole-2-carboxylate (200 mg, 0.63 mmol) in 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 light yellow oil. LCMS (ESI, m / z): 396 [M+H]+. Step 4: Synthesis of (R)-ethyl 7-((1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0276] (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 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]+. Step 5: Synthesis of (R)-(7-((1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol

[0277] (R)-7-((1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylic acid ethyl ester (80 mg, 0.36 mmol) was reacted according to General Procedure 3. The crude product 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]+. Step 6: Synthesis of (R)-7-((1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde

[0278] (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 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]+. 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

[0279] (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 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]+. 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]phthalazin-8-one

[0280] 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 crude product was purified by preparative HPLC (Method G) to give the title compound (21.2 mg, 73%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ9.24(s,1H),8.50(s,1H),8.36(s,2H),7.88(t,J=1.7Hz,1H),7.73(t,J=1.6Hz,1H ),7.31(d,J=7.8Hz,1H),7.19(s,1H),7.09(t,J=7.9Hz,1H),6.90(d,J=7.9Hz,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). 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]phthalazin-8-one

[0281] Example 63 The synthesis was carried out according to a synthetic route similar to that of Example 62, starting from (R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-ol. 1 H NMR (400 MHz, DMSO-d 6 )δ9.22(s,1H),8.50(s,1H),8.34(s,3H),7.87(s,1H),7.72(s,1H),7.30 (d,J=8.0Hz,1H),7.18–76.9(m,2H),6.88(s,1H),5.28(d,J=4.0Hz,1H),4 .78–4.61(m,6H),3.95(s,3H),3.89–3.74(m,5H),3.34(t,J=6.4Hz,2H),1 .39(d,J=6.0Hz,3H),0.80(s,1H),0.19–0.03(m,2H),-0.23–-0.3(m,2H). LCMS (ESI, m / z): 571 [M+H]+. LCMS RT: 1.256 min. (Method D). 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]phthalazin-8-one Step 1: Synthesis of 2-(benzyloxy)-4-fluoro-1-nitrobenzene

[0282] 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 K under nitrogen at room temperature. 2 CO 3(41.4g, 299mmol). The mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (1.5L) and extracted with ethyl acetate (1.5L), washed with water (2×500mL) and brine (500mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=5:1) to give the title compound (24.5g, 99.1%) as a light yellow solid. LCMS (ESI, m / z): 248[M+H]+. Step 2: Synthesis of 2-(benzyloxy)-4-fluoroaniline

[0283] To a solution of 2-(benzyloxy)-4-fluoro-1-nitrobenzene (24.4 g, 98.7 mmol) in methanol (600 mL) was added NH 2 O in water (100 mL) at room temperature under a nitrogen atmosphere. 4 Cl (53.3 g, 987 mmol) and Zn (64.2 g, 987 mmol). The mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS. The solid was filtered off and the solvent was evaporated under vacuum. The 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 vacuum. The crude material was passed through column chromatography (petroleum ether / ethyl acetate=3:1) to obtain the title compound (16.3 g, 76%) as a light yellow oil. LCMS (ESI, m / z): 218 [M+H]+. Step 3: Synthesis of ethyl 7-(benzyloxy)-5-fluoro-1H-indole-2-carboxylate

[0284] To a solution of 2-(benzyloxy)-4-fluoroaniline (8 g, 36.8 mmol) in DMSO (100 mL) was added Pd(OAc) at room temperature under nitrogen atmosphere. 2 (1.7g, 7.3mmol) and AcOH (2.1mL, 36.8mmol). The reaction mixture was refilled three times with nitrogen and then three times with oxygen. The mixture was stirred at 70 ° C overnight under an oxygen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (300mL) and extracted with ethyl acetate (500mL). The combined organic extracts were washed with water (2×300mL) and brine (300mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=5:1) to obtain the title compound (3.8g, 33%) as a light yellow solid. LCMS (ESI, m / z): 314[M+H]+. Step 4: Synthesis of (7-(benzyloxy)-5-fluoro-1H-indol-2-yl)methanol

[0285] Ethyl 7-(benzyloxy)-5-fluoro-1H-indole-2-carboxylate (3.5 g, 11.2 mmol) was reacted according to General Procedure 3. The 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 light yellow solid. LCMS (ESI, m / z): 272 [M+H]+. Step 5: Synthesis of 7-(benzyloxy)-5-fluoro-1H-indole-2-carbaldehyde

[0286] (7-(Benzyloxy)-5-fluoro-1H-indol-2-yl)methanol (3.4 g, 12.5 mmol) was reacted according to General Procedure 4. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=3:1) to give the title compound (1.9 g, 56%) as a light yellow solid. LCMS (ESI, m / z): 270 [M+H]+. Step 6: Synthesis of 7-(benzyloxy)-1-(cyclopropylmethyl)-5-fluoro-1H-indole-2-carbaldehyde

[0287] 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 crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound (1.0 g, 83%) as a light yellow solid. LCMS (ESI, m / z): 324 [M+H]+. 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0288] 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 crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:1) to give the title compound (370 mg, 45.9%) as a light yellow solid. LCMS (ESI, m / z): 671 [M+H]+. 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0289] (S)-tert-Butyl(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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (370 mg, 0.5 mmol) was reacted according to General Procedure 9. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:2) to give the title compound (270 mg, 84.3%) as a light yellow solid. LCMS (ESI, m / z): 581 [M+H]+. Step 9: Synthesis of 2-(triisopropylsilyl)oxazole

[0290] Under a nitrogen atmosphere, n-butyl lithium (21.8 g, 130.3 mmol) was added in batches to a stirred solution of oxazole (6 g, 86.9 mmol) in THF (40 mL) at -10 ° C. Under a nitrogen atmosphere, the mixture was stirred for 30 min at -10 ° C. Under a nitrogen atmosphere, trifluoromethanesulfonic acid triisopropylsilyl ester (31.9 g, 104.3 mmol) was added dropwise to the above mixture at -10 ° C. Under a nitrogen atmosphere, the mixture was stirred for 2 h at room temperature. The reaction was monitored by LCMS. The reaction was then quenched by adding water (120 mL) at 0 ° C and 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 vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1: 2) to obtain the title compound (5 g, 25.5%) as a light yellow solid. LCMS (ESI, m / z): 226 [M+H]+. Step 10: Synthesis of 1-(2-(triisopropylsilyl)oxazol-5-yl)propan-2-ol

[0291] Under nitrogen atmosphere, n-butyl lithium (1.9 g, 11 mmol) was added in batches to a stirred solution of 2-(triisopropylsilyl)oxazole (1 g, 4.4 mmol) in THF (40 mL) at -10 ° C. Under nitrogen atmosphere, the mixture was stirred for 30 min at -10 ° C. Under nitrogen atmosphere, 2-methyloxirane (515 mg, 8.8 mmol) was added dropwise to the above mixture at -10 ° C. The mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (120 mL) at 0 ° C and 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 vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1: 2) to obtain the title compound (800 mg, 63.6%) as a light yellow oil. LCMS (ESI, m / z): 284 [M+H]+. 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

[0292] (S)-tert-Butyl(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]phthalazin-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 crude product was purified by flash column chromatography on C18 silica gel to give the title compound (140 mg, 48%) as a light yellow solid. LCMS (ESI, m / z): 847 [M+H]+. 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]phthalazin-8-one

[0293] 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (140 mg, 0.17 mmol) in DCM (5 mL) was added HF (2 mL). The mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The mixture was concentrated under vacuum. The 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-d 6 )δ8.48(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=8.0Hz,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).

[0294] The compounds of Examples 65a and 65b in Table 6 were obtained from the chiral separation of Example 64 [column: CHIRALPAK IF, 2×25 cm, 5 μm; mobile phase A: hexane: DCM (3:1) (0.5% 2MNH 3 / MeOH); mobile phase B: MeOH; flow rate: 20 mL / min.; gradient: isocratic 50% B for 17 min.; detection: UV (220 / 254 nm)] to obtain a single isomer of unknown configuration at the stereogenic methyl group. Table 6 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]phthalazin-8-one Step 1: Synthesis of (R)-1-(4-fluoro-1H-imidazol-1-yl)propan-2-ol

[0295] 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). The mixture was stirred at 70 ° C for 1 h. The reaction was monitored by LCMS. The mixture was concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica gel to give the title compound (430 mg, 42.6%) as a colorless oil. LCMS (ESI, m / z): 145 [M+H] +. 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

[0296] 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 crude product was purified by flash column chromatography on C18 silica gel to give the title compound as a yellow solid (50 mg, 81.7%). LCMS (ESI, m / z): 689 [M+H]+. 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]phthalazin-8-one

[0297] 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (60 mg. 0.09 mmol) was reacted according to General Procedure 2. The crude product was purified by (Method G) to give the title compound (29.8 mg, 57.8%) as a yellow solid. 1H NMR (400 MHz, DMSO-d 6 )δ8.52(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=14Hz,1H),6.99(d,J=6.8Hz,1H),6.89–6.88(m,1H),5.11–5.10(m,1H),4.75–4.6 3 (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).

[0298] The compounds of Examples 67 to 77 in Table 7 were obtained following procedures similar to those for the compound of Example 66 using appropriate starting reagents. Table 7 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]phthalazin-8-one Step 1: Synthesis of ethyl 2-((2-(7-((S)-2-((tert-butyloxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]phthalazin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-2-fluoroacetate

[0299] To a solution of intermediate 5 (300 mg, 0.53 mmol) in DMF (5 mL) was added ethyl 2-bromo-2-fluoro-acetate (148 mg, 0.8 mmol) and Cs 2 CO 3(520mg, 1.6mmol). The reaction was stirred at 50 ° C for 2h. The reaction was monitored by LCMS. The mixture was quenched with water (15mL) and extracted with ethyl acetate (15mL). The organic layer was washed with water (15mL) and brine (2×15mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=2:1) ​​to give the title compound (280mg, 78.7%) as a light yellow solid, which is a mixture of diastereomers. LCMS (ESI, m / z): 667[M+H]+. 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0300] To 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]phthalazin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-2-fluoroacetate (238 mg, 0.36 mmol) in ethanol (5 mL) was added NaBH at 0°C. 4 (40.5mg, 1.07mmol). The reaction was stirred at room temperature for 2h. The reaction was monitored by LCMS. The solvent was evaporated under vacuum. The residue was diluted with water (10mL) and extracted with DCM (3×10mL), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:1) to give the title compound (200mg, 89.6%) as a light yellow solid, which was a mixture of diastereomers. LCMS (ESI, m / z): 625[M+H]+. 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0301] 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (100 mg, 0.02 mmol) in DCM (3 mL) was added iodine (81.3 mg, 0.03 mmol), imidazole (27.2 mg, 0.04 mmol) and PPh 3 (84mg, 0.03mmol). The reaction was stirred at room temperature for 2h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was quenched by adding water (30mL) and extracted with DCM (3×30mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:1) to give the title compound (30mg, 28.9%) as a light yellow solid, which was a mixture of diastereomers. LCMS (ESI, m / z): 735[M+H]+. 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

[0302] 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (30 mg, 0.04 mmol) was mixed with 4-fluoro-1H-imidazole (3.87 mg, 0.04 mmol) and Cs 2 CO 3 (39.8 mg, 0.12 mmol) was reacted according to General Procedure 14. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:1) to give the title compound (10 mg, 35.3%) as a pale yellow solid, which was a mixture of diastereomers. LCMS (ESI, m / z): 693 [M+H]+. 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]phthalazin-8-one

[0303] 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]phthalazin-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 the title compound as a mixture of diastereomers which was purified by chiral preparative HPLC [column: CHIRALPAK ID, 2×25 cm, 5 μm; mobile phase A: MTBE (0.5% 2M NH 3 / MeOH), mobile phase B: MeOH; flow rate: 20 mL / min.; gradient: isocratic 50% B for 11 min.; detection: UV (254 / 220 nm)] to obtain a single stereoisomer of unknown configuration at the fluorine center.

[0304] Example 73a. Isomer 1: Chiral HPLC RT: 5.85min. 1 H NMR (400 MHz, DMSO-d 6 )δ8.50(s,1H),7.52(s,1H),7.48(d,J=8.0Hz,1H),7.22(s,1H),7.13(d,J=8.0Hz,1H),7.05(s,1H),7.04(d,J=8.0Hz,1H)6.61(d,J=60H z,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 RT: 8.44min. 1 H NMR (400 MHz, DMSO-d 6): δ8.49(s,1H),7.52(s,1H),7.49(d,J=8.0Hz,1H),7.22(s,1H),7.13(d,J=8.0Hz,1H),7.05(s,1H),7.04(d,J=8.0Hz,1H)6.61(d,J=60H z,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).

[0305] The compounds of Examples 74 to 77 in Table 8 were obtained following procedures similar to those for the preparation of the compound of Example 73 using appropriate starting reagents. Table 8 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]phthalazin-8-one Step 1: Synthesis of 2-((2-(7-((S)-2-((tert-butyloxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]phthalazin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-2-fluoroacetic acid

[0306] To a solution of intermediate 5 (1.5 g, 2.67 mmol) in DMF (26 mL) was added ethyl 2-bromo-2-fluoro-acetate (740 mg, 4.00 mmol) and Cs 2 CO 3(2.61g, 8.00mmol). The resulting solution was stirred at 50 ° C for 1h under a nitrogen atmosphere. The reaction was monitored by LCMS. Water (50mL) was added to the above mixture. The resulting solution was stirred at room temperature for 0.5h. The reaction was monitored by LCMS. The mixture was extracted with ethyl acetate (80mL), washed with water (2×80mL) and brine (2×80mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (ethyl acetate) to obtain the title compound (1g, 58%) as a yellow solid, which is a mixture of diastereomers. LCMS (ESI, m / z): 639[M+H]+. 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0307] 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) was added HATU (1.19 g, 3.13 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 10 min under nitrogen atmosphere. Then, to the above obtained mixture was added a solution of N,O-dimethylhydroxylamine (764 mg, 7.83 mmol) in DMF (1 mL) dropwise at room temperature under nitrogen atmosphere. The obtained mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (20 mL) and 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 vacuum. The crude product was purified by flash column chromatography on C18 silica gel to obtain the title compound (1 g, 93%) as a brown solid, which is a mixture of diastereomers. LCMS (ESI, m / z): 682 [M + H] +. Step 3: Synthesis 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0308] The diastereomers 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (1 g) were determined by preparative SFC [(column: CHIRALPAKIH, 5×25 cm, 5 mm; mobile phase A: CO 2 , mobile phase B: IPA (0.5% 2M NH 3 / MeOH); Flow rate: 200 mL / min.; Gradient: isocratic 35% B; Column temperature: 35°C; Back pressure: 100 bar; Detection: UV (220 nm)] to obtain a single stereoisomer of unknown configuration at the fluorine center. Isomer 1 RT: 5.84 min.; Isomer 2 RT: 8.08 min.

[0309] Under nitrogen atmosphere, methylmagnesium bromide (0.73mL, 2.19mmol) was added to a solution of isomer 1 (250mg, 0.37mmol) in THF (4mL) at 0°C. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (10mL) and extracted with ethyl acetate (3×10mL). The combined organic extracts were washed with brine (3×10mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (230mg, 98%). LCMS (ESI, m / z): 637[M+H]+. 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0310] To 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (230 mg, 0.37 mmol) in ethanol (4 mL) was added NaBH at 0°C under a nitrogen atmosphere. 4 The mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding acetone (5 mL). The mixture solution was concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica gel to obtain the title compound (180 mg, 77%) as a yellow oil, which is a mixture of diastereomers at the center of the alcohol. LCMS (ESI, m / z): 639 [M+H] +. Step 5: Synthesis of 1-((2-(7-((S)-2-((tert-butyloxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]phthalazin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-1-fluoropropane-2-yl trifluoromethanesulfonate

[0311] To 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (160 mg, 0.25 mmol) in DCM (2.5 mL) was added Tf at 0 °C under nitrogen atmosphere. 2 O (0.06 mL, 0.38 mmol) and pyridine (0.06 mL, 0.75 mmol). The resulting solution was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then reacted by adding saturated NH 4 The mixture was quenched with aqueous Cl solution (1 mL) 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 vacuum and purified by column chromatography (DCM / MeOH=20:1) to give the title compound (120 mg, 62%) as a yellow oil, which is a mixture of diastereomers at the triflate center. LCMS (ESI, m / z): 771 [M+H]+. 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

[0312] Trifluoromethanesulfonic acid 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]phthalazin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-1-fluoropropane-2-ester (120 mg, 0.16 mmol) was mixed with 1H-imidazole (104 mg, 1.53 mmol) and Cs 2 CO 3 (152 mg, 0.47 mmol) was reacted according to General Procedure 14. The reaction mixture was purified by flash column chromatography on C18 silica gel to give the title compound (100 mg, 93%) as a yellow oil as a mixture of diastereomers at the imidazolyl center. LCMS (ESI, m / z): 689 [M+H]+. 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]phthalazin-8-one

[0313] 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (100 mg, 0.14 mmol) was reacted according to General Procedure 2. The crude product was purified by preparative HPLC (Method F) to give the title compound (70 mg, 82%) as a white solid as a mixture of diastereomers at the imidazolyl center. 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; gradient: isocratic 0% B) to give single stereoisomers of unknown configuration at the fluoro and imidazolyl centers.

[0314] Example 78a. Isomer 1: Chiral HPLC RT: 2.23 min. 1 H NMR (400 MHz, DMSO-d 6 )δ8.50(s,1H),7.85(s,1H),7.48(dd,J=2.0,6.8Hz,1H),7.39(s,1H),7.23(s,1H),7.15 -7.12(m,2H),6.98(s,1H),6.64(dd,J=3.2,57.2Hz,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).

[0315] Example 78b. Isomer 2: Chiral HPLC RT: 2.60 min. 1 H NMR (400 MHz, DMSO-d 6): δ8.49(s,1H),7.84(s,1H),7.48(dd,J=1.2,7.2Hz,1H),7.40(s,1H),7.22(s,1H),7.14–7.08(m ,2H),6.97(s,1H),6.45(dd,J=4.0,56.8Hz,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 step 3 starting from Isomer 2 by a procedure analogous to that of the compounds of Examples 78a and 78b. Table 9 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]phthalazin-8-one Step 1: Synthesis of ethyl 2-fluoro-2-imidazol-1-yl-acetate

[0317] To a solution of 1H-imidazole (1 g, 14.7 mmol) in MeCN (20 mL) was added 2-bromo-2-fluoro-ethyl acetate (1.36 g, 7.34 mmol) under a nitrogen atmosphere. The resulting solution was stirred at 80 ° C overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting solution was concentrated under vacuum. The crude product was purified by column chromatography (ethyl acetate) to give the title compound (880 mg, 34.7%) as a light yellow oil. LCMS (ESI, m / z): 173 [M + H] +. Step 2: Synthesis of 2-fluoro-2-imidazol-1-yl-ethanol

[0318] To a solution of ethyl 2-fluoro-2-imidazol-1-yl-acetate (4.9 g, 28.5 mmol) in THF (230 mL) was added LiBH at 0°C under nitrogen atmosphere. 4 (46mL, 113mmol). The resulting solution was stirred at room temperature for 1h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding acetone (60mL). The mixture solution was concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:2) to give the title compound (2.2g, 59.4%) as a colorless oil. LCMS (ESI, m / z): 131[M+H]+. Step 3: Synthesis of methanesulfonic acid (2-fluoro-2-imidazol-1-yl-ethyl) ester

[0319] 2-Fluoro-2-imidazol-1-yl-ethanol (1 g, 7.69 mmol) in 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 as a yellow oil (1.14 g, 71%). LCMS (ESI, m / z): 209 [M+H]+. 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

[0320] Intermediate 5 (150 mg, 0.27 mmol) was reacted in DMF (3 mL) with methanesulfonic acid (2-fluoro-2-imidazol-1-yl-ethyl) ester (370 mg, 1.78 mmol) according to General Procedure 5. The crude product was purified by flash column chromatography on C18 silica gel to give the title compound as a mixture of diastereomers as a brown oil (110 mg, 62%). LCMS (ESI, m / z): 675 [M+H]+. 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]phthalazin-8-one

[0321] 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 was purified by preparative HPLC (Method F) to give the title compound as a mixture of diastereomers as a white solid (75 mg, 80%). 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 NH 3 / MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: isocratic 30% B for 15 min.; detection: UV (220 / 254 nm)] to obtain a single stereoisomer of unknown configuration at the fluorine center.

[0322] Example 79a. Isomer 1: Chiral HPLC RT: 8.5 min. 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, 1 H), 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 min (Method D).

[0323] Example 79b. Isomer 2: Chiral HPLC RT: 11.33min. 1 H NMR (400 MHz, DMSO-d 6): δ8.48(s,1H),8.16(s,1H),7.70(s,1H),7.34(d,J=7.6Hz,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). 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]phthalazin-8-one Step 1: Synthesis of ethyl (R)-1-(cyclopropylmethyl)-7-(2-hydroxypropoxy)-1H-indole-2-carboxylate

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

[0325] (R)-ethyl 1-(cyclopropylmethyl)-7-(2-hydroxypropoxy)-1H-indole-2-carboxylate (90 mg, 0.28 mmol) in 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 light yellow oil. LCMS (ESI, m / z): 396 [M+H]+. Step 3: Synthesis of ethyl (S)-7-(2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0326] To a solution of (R)-1-(cyclopropylmethyl)-7-(2-((methylsulfonyl)oxy)propoxy)-1H-indole-2-carboxylic acid ethyl ester (90 mg, 0.23 mmol) in DMF (3 mL) were added 1H-imidazole (23.3 mg, 0.34 mmol) and Cs 2 CO 3 (222mg, 0.68mmol). The reaction was stirred at 50 °C overnight. The reaction was monitored by LCMS. The reaction was then quenched by adding water (10mL) and extracted with ethyl acetate (10mL), washed with water (5×10mL) and brine (5×10mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:1) to give the title compound (70mg, 83.7%) as a light yellow solid. LCMS (ESI, m / z): 368[M+H]+. Step 4: Synthesis of (S)-(7-(2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol

[0327] (S)-7-(2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylic acid ethyl ester (70 mg, 0.19 mmol) was reacted according to General Procedure 3. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:1) to give the title compound (50 mg, 81%) as a light yellow solid. LCMS (ESI, m / z): 326 [M+H]+. Step 5: Synthesis of (S)-7-(2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde

[0328] (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 crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:1) to give the title compound (40 mg, 80%) as a light yellow solid. LCMS (ESI, m / z): 324 [M+H]+. 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

[0329] (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 crude product was purified by column chromatography (DCM / MeOH=15:1) to give the title compound (30 mg, 36%) as a light yellow solid. LCMS (ESI, m / z): 671 [M+H]+. 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]phthalazin-8-one

[0330] 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 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-d 6)δ8.51(s,1H),8.15(s,1H),7.83(s,1H),7.41(s,1H),7.30(d,J=7.9Hz,1H),7.16(s,1H ),7.07(t,J=7.9Hz,1H),6.95(s,1H),6.88(d,J=7.8Hz,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=6.9Hz,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). Example 81. 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]phthalazin-8-one Step 1: Synthesis of (S)-1-(cyclopropylmethyl)-7-(2-hydroxypropoxy)-1H-indole-2-carboxylic acid ethyl ester

[0331] 1-(Cyclopropylmethyl)-7-hydroxy-indole-2-carboxylic acid ethyl ester (1 g, 3.86 mmol) was reacted in ethanol (12.5 mL) with (2S)-2-methyloxirane (672 mg, 11.5 mmol) and TEA (3.36 mL, 19.3 mmol) according to General Procedure 12. The crude material was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (1 g, 81%) as a pink solid. LCMS (ESI, m / z): 318 [M+H]+. Step 2: Synthesis of ethyl (S)-1-(cyclopropylmethyl)-7-(2-((methylsulfonyl)oxy)propoxy)-1H-indole-2-carboxylate

[0332] (S)-1-(Cyclopropylmethyl)-7-(2-hydroxypropoxy)-1H-indole-2-carboxylic acid ethyl ester (2 g, 6.3 mmol) in 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 as a yellow oil (2 g, 80%). LCMS (ESI, m / z): 396 [M+H]+. Step 3: Synthesis of ethyl (R)-1-(cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indole-2-carboxylate

[0333] (S)-1-(Cyclopropylmethyl)-7-(2-((methylsulfonyl)oxy)propoxy)-1H-indole-2-carboxylic acid ethyl ester (2 g, 5.06 mmol) was mixed with 4-fluoro-1H-imidazole (522 mg, 6.07 mmol) and Cs 2 CO 3 (4.95 g, 15.2 mmol) The reaction was carried out according to General Procedure 14. The 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] +. Step 4: Synthesis of (R)-(1-(cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)methanol

[0334] (R)-1-(Cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indole-2-carboxylic acid ethyl ester (2 g, 5.19 mmol) was reacted according to General Procedure 3. The 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]+. Step 5: Synthesis of (R)-1-(cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indole-2-carbaldehyde

[0335] (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 crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:1) to give the title compound (1.4 g, 70%) as a light green solid. LCMS (ESI, m / z): 342 [M+H]+. 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]phthalazin-8-one

[0336] 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 on C18 silica gel to give the title compound as a yellow solid (160 mg, 31%). LCMS (ESI, m / z): 514 [M+H]+. 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

[0337] (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]phthalazin-8-one (200 mg, 0.39 mmol) was reacted with (R)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (277 mg, 1.17 mmol) according to General Procedure 1. The 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]+. 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]phthalazin-8-one

[0338] 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 crude product was purified by preparative HPLC (Method F) to give the title compound (33.6 mg, 39%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ8.52(s,1H),7.87(s,3H),7.53(s,1H),7.29(d,J=7.6Hz,1H),7.17–7.12(m,2H), 7.07(t,J=7.6Hz,1H),6.88(d,J=7.6Hz,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). 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]phthalazin-8-one Step 1: Synthesis of ethyl 7-chloro-1-(cyclopropylmethyl)pyrrolo[2,3-c]pyridine-2-carboxylate

[0339] 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 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]+. Step 2: Synthesis of [7-chloro-1-(cyclopropylmethyl)pyrrolo[2,3-c]pyridin-2-yl]methanol

[0340] 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 crude product was purified by (DCM / MeOH=15:1) to give the title compound (80 mg, 39.25%) as a yellow solid. LCMS (ESI, m / z): 237 [M+H]+. Step 3: Synthesis of 7-chloro-1-(cyclopropylmethyl)pyrrolo[2,3-c]pyridine-2-carbaldehyde

[0341] [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 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]+. Step 4: Synthesis of (S)-1-(cyclopropylmethyl)-7-((5-oxopyrrolidin-3-yl)methoxy)-1H-pyrrolo[2,3-c]pyridine-2-carbaldehyde

[0342] To a solution of 7-chloro-1-(cyclopropylmethyl)pyrrolo[2,3-c]pyridine-2-carbaldehyde (50 mg, 0.21 mmol) in THF (2 mL) was added (4S)-4-(hydroxymethyl)pyrrolidin-2-one (73 mg, 0.64 mmol), Cs 2 CO 3 (208mg, 0.64mmol), Dave Phos (14mg, 0.04mmol) and DavePhos Pd G3 (16mg, 0.02mmol). The resulting mixture was stirred at 90 °C for 6h. The reaction was monitored by TLC and LCMS. The reaction was quenched by adding water (15mL) and extracted with ethyl acetate (2×30mL). The combined organic extracts were washed with water (50mL) and brine (50mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by preparative TLC (DCM / MeOH=15:1) to give the title compound (20mg, 29.96%) as a yellow oil. LCMS (ESI, m / z): 314[M+H]+. 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

[0343] 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 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]+. 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]phthalazin-8-one

[0344] 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 (15 mg, 0.02 mmol) was reacted according to General Procedure 2. The resulting crude orange viscous oil was purified by preparative HPLC (Method F) to give the title compound (10.2 mg, 78.2%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6)δ8.55(s,1H),8.27(s,3H),7.76(d,J=5.6Hz,1H),7.61(s,1H),7.32(d,J=5.6Hz,1H),7.23(s,1H),4. 82–4.74(m,1H),4.71(d,J=7.1Hz,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=8.9Hz,1H),3.35(t,J=6.6Hz,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).

[0345] Example 83 in Table 10 was obtained following a preparation method similar to that of Example 82. Table 10 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]phthalazin-8-one Step 1: Synthesis of ethyl 1-(cyclopropylmethyl)-7-(2-imidazol-1-ylethoxy)pyrrolo[2,3-c]pyridine-2-carboxylate

[0346] 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) was added Cs(II) at room temperature under a nitrogen atmosphere. 2 CO 3(350mg, 1.08mmol), 2-imidazole-1-ylethanol (80mg, 0.72mmol), DavePhos (28mg, 0.07mmol) and DavePhos Pd G3 (27mg, 0.04mmol). The resulting mixture was stirred at 90 ° C for 1h. The reaction was monitored by TLC and LCMS. The reaction was quenched by adding water (10mL) and extracted with EtOAc (2×20ml). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / EtOAc=5:1) to give the title compound (110mg, 86.5%) as a yellow oil. LCMS (ESI, m / z): 355[M+H]+. Step 2: Synthesis of [1-(cyclopropylmethyl)-7-(2-imidazol-1-ylethoxy)pyrrolo[2,3-c]pyridin-2-yl]methanol

[0347] 1-(Cyclopropylmethyl)-7-(2-imidazol-1-ylethoxy)pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (100 mg, 0.28 mmol) was reacted according to General Procedure 3. The resulting mixture was purified by flash column chromatography on C18 silica gel (mobile phase A: water (0.5% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 45% B to 45% B in 7 min; 254 / 210 nm) to give the title compound (80 mg, 90.7%) as a white solid. LCMS (ESI, m / z): 313 [M+H]+. Step 3: Synthesis of 1-(cyclopropylmethyl)-7-(2-imidazol-1-ylethoxy)pyrrolo[2,3-c]pyridine-2-carbaldehyde

[0348] [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 as a yellow oil (60 mg, 75.4%). LCMS (ESI, m / z): 311 [M+H]+. 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

[0349] 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 crude material was purified by flash column chromatography on C18 silica gel to give the title compound as a yellow solid (60 mg, 72.5%). LCMS (ESI, m / z): 658 [M+H]+. 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]phthalazin-8-one

[0350] (S)-tert-Butyl(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 crude material was purified by preparative HPLC (Method F) to give the title compound as a yellow solid (14.4 mg, 33.6%). 1 H NMR (400 MHz, DMSO-d 6 +D 2 O): δ9.26(s,1H),8.54(s,1H),7.93(t,J=1.8Hz,1H),7.77(d,J=5.6Hz,1H),7.72(t,J=1.8 Hz,1H),7.36(d,J=5.6Hz,1H),7.23(s,1H),4.98(t,J=5.0Hz,2H),4.77(d,J=9.4,4.6Hz,2 H),4.75–4.58(m,2H),4.51(d,J=7.0Hz,2H),3.93(s,3H),3.91–3.78(m,3H),3.76(t,J=6. 7Hz,2H),3.34(t,J=6.6Hz,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: 0.672min (Method D). 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]phthalazin-8-one 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0351] Intermediate 5 (50 mg, 0.09 mmol) was reacted in ethanol (2 mL) with (2S)-2-methyloxirane (51.6 mg, 0.89 mmol) and TEA (0.06 mL, 0.44 mmol) according to General Procedure 12. The 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] + . Step 2: Synthesis of (S)-1-((2-(7-((S)-2-((tert-butyloxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]phthalazin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)propane-2-methanesulfonate

[0352] 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) in 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 light yellow oil. LCMS (ESI, m / z): 699 [M+H] + . 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

[0353] (S)-1-((2-(7-((S)-2-((tert-Butyloxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]phthalazin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)propane-2-methanesulfonate (60 mg, 0.09 mmol) was mixed with 4-fluoro-1H-imidazole (50 mg, 0.58 mmol) and Cs 2 CO 3 (110 mg, 0.34 mmol) was reacted according to General Procedure 14. The crude product 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] + . 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]phthalazin-8-one

[0354] 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 (20 mg, 0.03 mmol) was reacted according to General Procedure 2. The 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-d 4)δ8.65(s,1H),7.54(s,1H),7.34(d,J=8Hz,1H),7.12(t,J=8Hz,1H),7.09(s,1H),6.99(d,J=2Hz,1H),6.91(d,J=7.6Hz,1H),4.88–4.82(m ,3H),4.75–4.44(m,4H),4.41–3.42(m,8H),3.43(d,J=6.8Hz,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).

[0355] The compounds in Examples 86 to 94 in Table 11 were prepared in a manner similar to that of the compound in Example 85 using appropriate starting reagents. Table 11 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]phthalazin-8-one Step 1: Synthesis of 1,2-diyl-bis(4-methylbenzenesulfonate)ethane

[0356] Ethane-d4-1,2-diol (100 mg, 1.51 mmol) in 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]+. Step 2: Synthesis of (S)-2-((2-(7-(2-((tert-butyloxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]phthalazin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)ethyl-1,1,2,2-d4 4-methylbenzenesulfonate

[0357] Intermediate 5 (40 mg, 0.07 mmol) was reacted with bis(4-methylbenzenesulfonic acid)ethane-1,2-diyl-d4 ester (39.9 mg, 0.11 mmol) in DMF (2 mL) according to General Procedure 5. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=2:1) ​​to give the title compound (30 mg, 55.1%) as a light yellow solid. LCMS (ESI, m / z): 765 [M+H]+. 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

[0358] (S)-2-((2-(7-(2-((tert-Butyloxycarbonyl)amino)-3-fluoropropyl)-3-methyl-8-oxo-5,6,7,8-tetrahydro-3H-imidazo[4,5-b][1,6]phthalazin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)ethyl-1,1,2,2-d4-methylbenzylsulfonate (30 mg, 0.04 mmol) was reacted with 1H-imidazole (4.01 mg, 0.06 mmol) and Cs 2 CO 3 (38.3 mg, 0.12 mmol) was reacted according to General Procedure 14. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=4:1) to give the title compound (20 mg, 70.7%) as a light yellow solid. LCMS (ESI, m / z): 661 [M+H]+. 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]phthalazin-8-one

[0359] (S)-tert-Butyl(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 system 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-d 6 )δ8.70(s,1H),8.37(s,1H),8.20(s,2H),7.64(s,1H),7.38(s,1H),7.19(d,J=8.0Hz,1H),7.04(s,1H),6.95(d,J=8.0Hz,1H),6.78(d,J=8. 0Hz,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). 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]phthalazin-8-one Step 1: Synthesis of methyl 2-(1H-imidazol-1-yl)-2-methylpropanoate

[0360] To a solution of 1H-imidazole (1 g, 14.6 mmol) in MeCN (20 mL) was added 2-bromo-2-methylpropionic acid methyl ester (1.3 g, 7.34 mmol) at room temperature. The resulting 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 on C18 silica gel to give the title compound (900 mg, 36.4%) as a colorless oil. LCMS (ESI, m / z): 169 [M + H] +. Step 2: Synthesis of 2-(1H-imidazol-1-yl)-2-methylpropan-1-ol

[0361] To a solution of methyl 2-(1H-imidazol-1-yl)-2-methylpropanoate (900 mg, 5.35 mmol) in THF (20 mL) was added LiBH dropwise at 0°C under nitrogen atmosphere. 4 (2.5M in THF) (10.8mL, 21.4mmol). The resulting solution was stirred at room temperature for 2h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding MeOH and stirred at room temperature for 20min and concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica gel to obtain the title compound as a white solid. LCMS (ESI, m / z): 141 [M+H]+. Step 3: Synthesis of 1-(1-(3-iodo-2-nitrophenoxy)-2-methylpropan-2-yl)-1H-imidazole

[0362] Under nitrogen atmosphere, NaH (60%) (5.4 mL, 4.99 mmol) was added in batches to a solution of 2-(1H-imidazole-1-yl)-2-methylpropane-1-ol (350 mg, 2.5 mmol) in DMF (15 mL) at 0 ° C. The mixture was stirred at room temperature for 0.5 h. The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by LCMS. The reaction was quenched by adding water (50 mL) and 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 vacuum. The 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]+. Step 4: Synthesis of 2-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-6-iodoaniline

[0363] To a solution of 1-(1-(3-iodo-2-nitrophenoxy)-2-methylpropane-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 stirred at 85 ° C for 1 h. The reaction was monitored by TLC and LCMS. The mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure and purified by flash column chromatography on C18 silica gel to give the title compound (550 mg, 99.4%) as a brown oil. LCMS (ESI, m / z): 358 [M+H] +. Step 5: Synthesis of methyl 7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1H-indole-2-carboxylate

[0364] To a solution of 2-(2-(1H-imidazole-1-yl)-2-methylpropoxy)-6-iodoaniline (550 mg, 1.54 mmol) in DMF (10 mL) was added (3-methoxy-3-oxo-prop-1-ynyl) copper (293 mg, 2 mmol) at room temperature. The mixture was stirred at 50 ° C for 1.5 h. The reaction was monitored by TLC and LCMS. The reaction was then quenched by adding water (30 mL) and 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 vacuum. The 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] +. Step 6: Synthesis of methyl 7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0365] 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 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]+. Step 7: Synthesis of (7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol

[0366] 7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylic acid methyl ester (20 mg, 0.05 mmol) was reacted according to General Procedure 3. The 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 crude product was used directly in the next step. LCMS (ESI, m / z): 340 [M+H]+. Step 8: Synthesis of 7-(2-(1H-imidazol-1-yl)-2-methylpropoxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde

[0367] (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 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]+. 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0368] 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] + . 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]phthalazin-8-one

[0369] (S)-tert-Butyl(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-d 6)δ9.37(s,1H),8.48(s,1H),8.33(s,3H),8.14(s,1H),7.81(s,1H),7.34(d,J= 7.9Hz,1H),7.19(s,1H),7.10(t,J=7.9Hz,1H),6.93(d,J=7.9Hz,1H),4.82–4.5 8(m,4H),4.43(d,J=6.8Hz,2H),3.95(s,3H),3.86–3.73(m,5H),3.33(t,J=6.6H z,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). 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]phthalazin-8-one Step 1: Synthesis of ethyl 7-bromo-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0370] 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 crude product was purified by column chromatography (petroleum ether / ethyl acetate=6:1) to give the title compound (480 mg, 81%) as a light yellow solid. LCMS (ESI, m / z): 322 [M+H]+. Step 2: Synthesis of (7-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol

[0371] Ethyl 7-bromo-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (480 mg, 1.49 mmol) was reacted according to General Procedure 3. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=3:1) to give the title compound (400 mg, 91%) as a light yellow solid. LCMS (ESI, m / z): 294 [M+H]+. Step 3: Synthesis of 7-bromo-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde

[0372] (7-Bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol (400 mg, 1.36 mmol) was reacted according to General Procedure 4. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=5:1) to give the title compound (300 mg, 78%) as a light yellow solid. LCMS (ESI, m / z): 278 [M+H]+. Step 4: Synthesis of (E)-7-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde

[0373] 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) was added K under nitrogen atmosphere. 3 PO 4 (580mg, 3.21mmol) and AmPhos-PdCl2 (85mg, 0.1mmol). The mixture was stirred at 80 ° C for 2h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (30mL) and extracted with ethyl acetate (2×30mL), washed with water (50mL) and brine (50mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=10:1) to give the title compound (320mg, 81%) as a light yellow solid. LCMS (ESI, m / z): 370[M+H]+. Step 5: Synthesis of (E)-1-(cyclopropylmethyl)-7-(prop-1-en-1-yl)-1H-indole-2-carbaldehyde

[0374] To a solution of (E)-7-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (320 mg, 0.8 mmol) in THF (10 mL) was added TBAF (5 mL) under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (30 mL) and 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 vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=5:1) to give the title compound (180 mg, 90%) as a light yellow solid. LCMS (ESI, m / z): 239[M+H]+. Step 6: Synthesis of (E)-7-(3-chloroprop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde

[0375] (E)-1-(Cyclopropylmethyl)-7-(prop-1-en-1-yl)-1H-indole-2-carbaldehyde (180 mg, 0.75 mmol) in 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 light yellow oil. LCMS (ESI, m / z): 274 [M+H]+. Step 7: Synthesis of (E)-1-(cyclopropylmethyl)-7-(3-(4-fluoro-1H-imidazol-1-yl)prop-1-en-1-yl)-1H-indole-2-carbaldehyde

[0376] (E)-7-(3-chloroprop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (180 mg, 0.65 mmol) was dissolved in DMF (10 mL) and 4-fluoro-1H-imidazole (111 mg, 1.3 mmol) and Cs 2 CO 3 (635 mg, 1.95 mmol) The reaction was carried out according to General Procedure 14. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=5:1) to give the title compound (150 mg, 71%) as a light yellow solid. LCMS (ESI, m / z): 323 [M+H]+. 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

[0377] 1-(Isoxazolyl-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 on C18 silica gel to give the title compound as a yellow solid (70 mg, 79%). LCMS (ESI, m / z): 671 [M+H]+. 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]phthalazin-8-one

[0378] 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 crude product was purified by preparative HPLC (Method E) to give 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 as a yellow solid (8.1 mg, 79%). 1 HNMR (400 MHz, DMSO-d 6 )δ8.52(s,1H),8.28(s,3H),7.67(d,J=2.4Hz,1H),7.59(s,1H),7.14(s,3H),7.24(s,1H),7.09–7.02(m,1H),6.32(d,J=15.2Hz,1H), 4.78–4.62(m,2H),4.43(d,J=6.4Hz,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]+. LCMSRT: 0.896min (Method I).

[0379] Example 98 in Table 12 was obtained following a procedure similar to the preparation of Example 97 from the regioisomeric imidazole intermediate used in Step 7. Table 12 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]phthalazin-8-one 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

[0380] (S,E)-tert-Butyl(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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate (65 mg, 0.77 mmol) was reacted in methanol (30 mL) according to General Procedure 9. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (30 mg, 80.5%) as a light yellow solid. LCMS (ESI, m / z): 673 [M+H]+. 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]phthalazin-8-one

[0381] (S)-tert-Butyl(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 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-d 6)δ8.51(s,1H),8.30(s,3H),7.60(d,J=2.4Hz,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 .4Hz,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). 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]phthalazin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)-2-(1H-imidazol-1-yl)acetamide Step 1: Synthesis of ethyl 1-(cyclopropylmethyl)-7-nitro-1H-indole-2-carboxylate

[0382] Ethyl 7-nitro-1H-indole-2-carboxylate (5 g, 21.4 mmol) was reacted with bromomethylcyclopropane (4.32 g, 32 mmol) in DMF (100 mL) according to General Procedure 5. The 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]+. Step 2: Synthesis of (1-(cyclopropylmethyl)-7-nitro-1H-indol-2-yl)methanol

[0383] To a solution of ethyl 1-(cyclopropylmethyl)-7-nitro-1H-indole-2-carboxylate (2 g, 6.94 mmol) in THF (1.5 mL) was added LiBH dropwise at 0°C under nitrogen atmosphere. 4(2M in THF) (302mg, 13.9mmol). The resulting solution was stirred at room temperature for 2h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (0.7mL) / NaOH (aq) (2mL) / water (0.7mL) and stirred at room temperature for 20 minutes, dried over anhydrous sodium sulfate. The solid was filtered out and the solvent was concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=3:1) to give the title compound (647mg, 38%) as a yellow solid. LCMS (ESI, m / z): 247 [M+H]+. Step 3: Synthesis of 1-(cyclopropylmethyl)-7-nitro-1H-indole-2-carbaldehyde

[0384] (1-(Cyclopropylmethyl)-7-nitro-1H-indol-2-yl)methanol (670 mg, 2.07 mmol) was reacted according to General Procedure 4. The 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]+. 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]phthalazin-7-yl)-3-fluoropropan-2-yl)carbamate

[0385] 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 crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:2) to give the title compound as a yellow solid (30 mg, 5%). LCMS (ESI, m / z): 562 [M+H]+. Step 5: Synthesis of tert-butyl (S)-(1-(2-(7-(2-(1H-imidazol-1-yl)acetylamino)-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

[0386] To a solution of 2-imidazole-1-yl 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. The mixture was stirred at room temperature for 10 minutes, and then a solution of (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]phthalazin-7-yl)-3-fluoropropane-2-yl)carbamic acid tert-butyl ester (73 mg, 0.13 mmol) in DMF (1 mL) was added dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction was monitored by LCMS. The reaction was then quenched by adding water (10 mL) and extracted with ethyl acetate (10 mL). The combined organic extracts were washed with water (3x10 mL) and brine (3x10 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The 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]+. 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]phthalazin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)-2-(1H-imidazol-1-yl)acetamide

[0387] (S)-tert-Butyl(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 crude product was purified by preparative HPLC (Method F) to give the title compound (6.9 mg, 26%) as a yellow solid. 1 H NMR (400 MHz, methanol-d 4)δ9.10(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=6.4Hz,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). Biological assays

[0388] Compounds of the present disclosure were assayed as PAD4 inhibitors using the assay protocol described below. RFMS measurement 1 conditions

[0389] Compounds were dissolved in 100% DMSO to achieve a compound concentration of 10 mM. Compound stock solutions were stored at room temperature. A series of dilutions were prepared in DMSO and mixed 8 times with a mixing volume of 20 μL. The final maximum concentration of compound in the assay was 50 μM. The final assay conditions were as follows: 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: pre-incubate compound and enzyme at 37°C for 30 min, enzyme / substrate reaction for 90 min. min, and reacted with phenyl glyoxal at 37°C for 30 min Stop solution: 40 μl 5% TCA / ACN

[0390] To 13 μL of 10 nM PAD4 in assay buffer was added 0.13 μL of compound solution. After 30 min, 13 μL of 500 μM BAEE in 25 mM hepes, pH 7.5, 5 mM NaCl, 1 mM DTT, 0.2 mg / ml BSA, 0.01% CHAPS, 50 μM calcium, 5 μM TPEN was added and the reaction was incubated at 37°C for 90 min. The enzymatic reaction was quenched by adding 15 μL of 6.1NTCA, 100%. The final concentration was 20%, and then 35 μL of 8.5 mM phenylpropanol hydrate (final concentration was 4 mM) was added and the reaction was incubated at 37°C for 30 min.

[0391] After 30 minutes, the disk was decelerated to remove all precipitates. The enzymatic reaction was quenched with an equal amount of methanol containing an internal standard (modified citrulline). The sample was loaded into a Rapid Fire RF300 system (Agilent), where the sample was first inhaled for 1000ms and directly loaded into a C18 separation column (cartridge), and a mixture of acetonitrile containing 0.01% formic acid was desalted for 3000ms. The flow rate of the mobile phase was 1.5ml / min. After the sample was eluted from the column, the sample was moved to a mass spectrometer using a mobile phase of acetonitrile containing 0.01% formic acid at a flow rate of 1.25ml / min over 4000ms. Peptidyl citrulline and internal standard ions were analyzed using a SciexAPI5500 triple quadrupole mass spectrometer (Applied Biosystems) equipped with ESI.

[0392] The MRM transitions of the product and internal standard were monitored in the range of m / z 424.5 to 350.4 and m / z 293 to 247, respectively. The dwell time of each transition was set to 200 ms, the ESI voltage was 5500, and the source temperature was 400°C. The ion peaks extracted for each transition were integrated using Rapid Fire Integrator software. The analyte peak areas were normalized using the internal standard. RFMS measurement 2 conditions

[0393] Compound preparation:

[0394] Stock compounds were dissolved and stored in 100% DMSO. In each assay, compound solutions were prepared via serial dilution in DMSO at 3-fold intervals, with the highest compound concentration being 20 μM. 0.25 μl of compound solution was transferred from the compound well plate to the assay well plate by using an acoustic dispenser. Final assay conditions: Total reaction volume: 25 μl Assay buffer: 100 HEPES pH 7.4, 200 mM NaCl, 2 mM CaCl2, 5 mM DTT ·35nM recombinant human PAD4 ·500μM TSTGGRQGSHH (SEQ ID NO:1) 1.2% DMSO Stop solution: 10% formic acid

[0395] The reaction mixtures were incubated at room temperature for 30 minutes. 10 μl of each reaction mixture was then mixed with 40 μl of 10% formic acid in a microplate. The plates were frozen at -80°C before shipping on dry ice for RapidFire mass spectrometry analysis.

[0396] The thawed samples were loaded into a Rapid Fire 300 system (Agilent), where they were first inhaled for 250 ms, then loaded into an Agilent "C" (C18) column using a mobile phase containing 0.09% formic acid / 0.01% trifluoroacetic acid, and desalted for 3000 ms at 1.5 ml / min. After sample loading and washing, the samples were directly eluted on a Sciex API4000 triple quadrupole mass spectrometer at a flow rate of 1.25 ml / min for 3000 ms using an acetonitrile mobile phase containing 0.09% formic acid / 0.01% trifluoroacetic acid.

[0397] The MRM transitions of substrate and product were monitored in positive ESI mode at m / z = 562.3 / 969.7 and m / z = 562.8 / 541.3, respectively. The dwell time of each transition was set to 100 ms, the ESI voltage was 5500, and the source temperature was 650°C. The ion peaks extracted from each transition were integrated using Rapid Fire Integrator software.

[0398] For a given compound example, the following table shows the human PAD4 (hPAD4) IC in a rapid-fire mass spectrometry (RFMS) assay: 50 .

[0399] Table 13 below shows the activity of selected compounds of the present invention in the above PAD4 assay. IC values ​​of compounds with activity indicated as "A" 50 ≤10nM; IC of compounds with activity marked as "B" 50 The IC values ​​of compounds marked with "C" are 11-100 nM. 50 The IC values ​​of compounds with activity marked as "D" are 101-500 nM. 50 The IC values ​​of compounds marked with "E" are 501-1000 nM. 50>1000nM. Table 13 Implementation Embodiment 1. Compound of formula I: or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof, wherein: X is selected from CR 6 and N; X′ is selected from CR 6′ and N, where X and X′ are not N at the same time; R 1 C 1-4 Fat; R 2 For 0-4 R 7 Substituted C 1-6 Fat; R 3 For 0-3 R 8 Substituted C 1-6 Fat; R 4 is a halogen; R 5 is a halogen; Each R 6 and R 6′ are independently selected from 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 Fat; Each R 7 independently selected from halogen, -OR, -N(R) 2 and -Cy; Each R 8 independently selected from halogen, -OR, -N(R) 2 and -Cy; Each R 9 independently selected from halogen, -OR, -N(R) 2 and -Cy; L 1 For covalent bonds or C 1-4 Fat; Each Cy is independently selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a phenyl group, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy is surrounded by 0-3 R 10 replace; Each R 10 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 selected from C 1-6 aliphatic and 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each m and n is independently 0 or 1; and p is independently 1-4. Embodiment 2. The compound according to Embodiment 1, wherein the compound is selected from the group consisting of compounds of Formula Ia, Ib, Ic, Id, Ie, If, Ig and Ih: or a pharmaceutically acceptable salt thereof. Embodiment 3. A compound according to any one of the preceding embodiments, wherein the compound is selected from the group consisting of Iai, Ibi, Ici, Idi, Iei, Ifi, Igi and Ihi: or a pharmaceutically acceptable salt thereof. Embodiment 4. A compound according to any one of the preceding embodiments, wherein R 1 -CH 3 . Embodiment 5. A compound according to any one of the preceding embodiments, wherein m is 1. Embodiment 6. A compound according to any one of the preceding embodiments, wherein R 4 It is fluorine or chlorine. Embodiment 7. A compound according to any one of the preceding embodiments, wherein R 4 C 1-6 Fatty. Embodiment 8. A compound according to any one of the preceding embodiments, wherein R 4 For –CH 3 . Embodiment 9. A compound according to any one of the preceding embodiments, wherein m is 0. Embodiment 10. A compound according to any one of the preceding embodiments, wherein R 2 For 1-4 R 7 Substituted C 1-6 Fatty. Embodiment 11. A compound according to any one of the preceding embodiments, wherein R 2 For 1-4 R 7 Substituted C 1-4 Fatty. Embodiment 12. A compound according to any one of the preceding embodiments, wherein R 2 For 1-2 R 7 Substituted C 1-4 Fatty. Embodiment 13. A compound according to any one of the preceding embodiments, wherein at least one R 7 It is a halogen. Embodiment 14. A compound according to any one of the preceding embodiments, wherein at least one R 7 For fluorine. Embodiment 15. A compound according to any one of the preceding embodiments, wherein at least one R 7 for –N(R) 2 . Embodiment 16. A compound according to any one of the preceding embodiments, wherein at least one R 7 Selected from – NH 2 and –NHR. Embodiment 17. A compound according to any one of the preceding embodiments, wherein R 2 is further substituted with at least one halogen. Embodiment 18. A compound according to any one of the preceding embodiments, wherein at least one R 7 For –Cy. Embodiment 19. A compound according to any one of the preceding embodiments, wherein R 2 Selected from the group consisting of: Embodiment 20. A compound according to any one of the preceding embodiments, wherein R 3 For 1-2 R 8 Substituted C 1-6 Fatty. Embodiment 21. A compound according to any one of the preceding embodiments, wherein R 3 For 1-2 R 8 Substituted C 1-4 Fatty. Embodiment 22. A compound according to any one of the preceding embodiments, wherein R 3 For 1 R 8 Substituted C 1-2 Fatty. Embodiment 23. A compound according to any one of the preceding embodiments, wherein R 8 It is -OR. Embodiment 24. A compound according to any one of the preceding embodiments, wherein R 8 For –Cy. Embodiment 25. A compound according to any one of the preceding embodiments, wherein R 8 It is a halogen. Embodiment 26. A compound according to any one of the preceding embodiments, wherein R 3 Selected from Embodiment 27. A compound according to any one of the preceding embodiments, wherein R 6 For hydrogen. Embodiment 28. A compound according to any one of the preceding embodiments, wherein R 6 It is -OR. Embodiment 29. A compound according to any one of the preceding embodiments, wherein R 6 is –N(R)C(O)R. Embodiment 30. A compound according to any one of the preceding embodiments, wherein R 6 is an optionally substituted C 1-6 Fatty. Embodiment 31. A compound according to any one of the preceding embodiments, wherein R 6 For –Cy. Embodiment 32. A compound according to any one of the preceding embodiments, wherein -Cy is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. Embodiment 33. A compound according to any one of the preceding embodiments, wherein -Cy is an optionally substituted 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. Embodiment 34. A compound according to any one of the preceding embodiments, wherein R 6 for-OL-(R 9 ) p . Embodiment 35. A compound according to any one of the preceding embodiments, wherein R 6 Selected from hydrogen, –CH 3 、-OCH 3 , Embodiment 36. A compound according to any one of the preceding embodiments, wherein R 6′ For hydrogen. Embodiment 37. A compound according to any one of the preceding embodiments, wherein R 6′ It is -OR. Embodiment 38. A compound according to any one of the preceding embodiments, wherein R 6′ It is a halogen. Embodiment 39. A compound according to any one of the preceding embodiments, wherein R 6′ is an optionally substituted C 1-6 Fatty. Embodiment 40. A compound according to any one of the preceding embodiments, wherein R 6′ Selected from hydrogen, fluorine, -OCH 3 and -C(CH 3 ) 2 OH. Embodiment 41. A pharmaceutically acceptable composition comprising a compound according to any one of the preceding embodiments and a pharmaceutically acceptable carrier, adjuvant or vehicle. Embodiment 42. A method of inhibiting PAD4 in a subject or in a biological sample, comprising the step of contacting said PAD4 with a compound according to any one of the preceding embodiments. Embodiment 43. A method for treating a PAD4-mediated disease, disorder or condition in a subject in need thereof, comprising the step of administering to the subject a composition according to any one of the preceding embodiments. Embodiment 44. The method according to any of the preceding embodiments, wherein the PAD4-mediated disease, disorder or condition is selected from the group consisting of 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 hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopneumonia, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, weight loss, angina pectoris, angioedema, anhidrotic ecodermal dysplasia-ID, ankylosing spondylitis, anterior segment (anterior segment), inflammation, antiphospholipid syndrome, mouth ulcers, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, inflammation caused by bee stings, Bechet's disease, Bechet's syndrome, Bell's palsy Palsey), beryllium poisoning, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysms, inflammation caused by chemical irritants, chorioretinitis, 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, cold pyrin-associated periodic syndrome, cryptococcal meningitis, cystic fibrosis, interleukin-1 receptor antagonist (DIRA) deficiency, dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse intrinsic pontine gliomaglioma), endometriosis, endotoxemia, epicondylitis, erythrocytopenia, familial amyloid polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, intestinal disease, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Schonlein purpura, hepatitis, hereditary periodic fever syndromes, herpes zoster and simplex, HIV-1, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia type D with periodic fever (HIDS), hypoplastic and other anemias, hypoplastic anemia, idiopathic thrombocytopenia Purpura hypoxica, incontinence pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, inflammation caused by insect bites, iritis, inflammation caused by irritants, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney damage caused by parasitic infection, kidney transplant rejection prevention, leptospirosis, leukemia, Loeffler syndrome, lung damage, lupus, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria, deafness, amyloidosis), multiple sclerosis, muscle wasting syndrome, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungoides fungiodes, mycosisfungoides, myelodysplastic syndrome, myositis, sinusitis, necrotizing enterocolitis, neonatal multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathic diseases, nonallergenic asthma, obesity, eye allergies, optic neuritis, organ transplantation, osteoarthritis, otitis media, Paget's diseasedisease), pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, whooping cough, pharyngitis and adenitis (PFAPA syndrome), inflammation caused by plant irritants, pneumonia, pneumonitis, pulmonary system infection, inflammation caused by poison ivy / urushiol oil, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psoriasis, psoriasis, psoriasis, psychosocial stress disorder, lung disease, pulmonary hypertension, pulmonary fibrosis, pustular gangrene, suppurative sterile arthritis, kidney disease, retinal disease disease, rheumatic carditis, rheumatic diseases, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell disease, sickle cell anemia, silica-induced diseases, Sergulin's syndrome, skin diseases, sleep apnea, 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, and Wegener's granulomatosis. Embodiment 45. The method according to any of the preceding embodiments, wherein the PAD4-mediated disease, disorder or condition is selected from the group consisting of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus and psoriasis. Embodiment 46. Compound of formula I': or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof, wherein: X is selected from CR 6 and N; X′ is selected from CR 6′ and N, where X and X′ are not N at the same time; R 1 C 1-4 Fat; R 2 For 0-4 R 7 Substituted C 1-6 Fat; R 3 For 0-3 R 8 Substituted C 1-6 Fat; R 4 is a halogen; R 5 is a halogen; Each R 6and R 6′ are independently selected from hydrogen, halogen, -OR, -N(R) 2 , -OC(O)R, -N(R)C(O)R, -N(R)C(O)-L-(R 9 ) p 、-OL-(R 9 ) p , -Cy, optionally substituted C 1-6 Aliphatic and C 1-6 Aliphatic -OH; Each R 7 independently selected from halogen, -OR, -N(R) 2 and -Cy; Each R 8 independently selected from halogen, -OR, -N(R) 2 and -Cy; Each R 9 independently selected from halogen, -OR, -N(R) 2 and –Cy; L is a covalent bond or C 1-4 Fat; Each Cy is independently selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a phenyl group, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy is surrounded by 0-3 R 10 replace; Each R 10 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 selected from C 1-6 aliphatic and 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each R is independently substituted by 0-3 halogen, -OCH 3 or -OH substitution; Each m and n is independently 0 or 1; and p is independently 1-4.

Claims

1. Compounds of formula I: or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof, wherein: X is selected from CR 6 and N; X′ is selected from CR 6′ and N, where X and X′ are not N at the same time; R 1 C 1-4 Fat; R 2 For 0-4 R 7 Substituted C 1-6 Fat; R 3 For 0-3 R 8 Substituted C 1-6 Fat; R 4 is a halogen; R 5 is a halogen; Each R 6 and R 6′ independently selected from 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 Fat; Each R 7 independently selected from halogen, -OR, -N(R)2 and -Cy; Each R 8 independently selected from halogen, -OR, -N(R)2 and -Cy; Each R 9 independently selected from halogen, -OR, -N(R)2 and -Cy; L 1 For covalent bonds or C 1-4 Fat; Each Cy is independently selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a phenyl group, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy is surrounded by 0-3 R 10 replace; Each R 10 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 selected from C 1-6 aliphatic and 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each m and n is independently 0 or 1; and p is independently 1-4.

2. The compound according to claim 1, wherein the compound is selected from the group consisting of compounds of Formula Ia, Ib, Ic, Id, Ie, If, Ig and Ih: or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, wherein the compound is selected from the group consisting of Iai, Ibi, Ici, Idi, Iei, Ifi, Igi and Ihi: or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3, wherein R 1 It is -CH3.

5. The compound according to any one of claims 1 to 4, wherein m is 1.

6. The compound according to claim 5, wherein R 4 It is fluorine or chlorine.

7. A compound according to any one of claims 1 to 5, wherein R 4 C 1-6 Fatty.

8. The compound according to any one of claims 1 to 4, wherein m is 0.

9. A compound according to any one of claims 1 to 8, wherein R 2 For 1-4 R 7 Substituted C 1-6 Fatty.

10. The compound according to claim 9, wherein R 2 For 1-2 R 7 Substituted C 1-4 Fatty.

11. A compound according to any one of claims 1 to 10, wherein at least one R 7 It is a halogen.

12. The compound according to claim 11, wherein at least one R 7 For fluorine.

13. A compound according to any one of claims 1 to 12, wherein R 2 Selected from the group consisting of:

14. A compound according to any one of claims 1 to 13, wherein R 3 Selected from 15. A compound according to any one of claims 1 to 14, wherein R 6 Selected from hydrogen, –CH3, -OCH3, 16. A pharmaceutically acceptable composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

17. A method of inhibiting PAD4 in a subject or in a biological sample, comprising the step of contacting the PAD4 with a compound according to any one of claims 1-15.

18. A method for treating a PAD4-mediated disease, disorder or condition in a subject in need thereof, comprising the step of administering the composition according to claim 16 to the subject.

19. The method of claim 18, wherein the PAD4-mediated disease, disorder or condition is selected from the group consisting of acid-induced lung injury, acne (PAPA), acute lymphoblastic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic hepatitis, alcoholic liver disease, allergen-induced asthma, allergic bronchopneumonia, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, weight loss, angina, angioedema, anhidrotic ecodermal dysplasia-ID, ankylosing spondylitis, anterior segment, inflammation, antiphospholipid syndrome, oral ulcers, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, inflammation caused by bee stings, Bechet's disease disease), Bechet's syndrome, Bell's palsy, beryllium poisoning, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysms, inflammation caused by chemical irritants, chorioretinitis, 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, cold pyrin-associated periodic syndrome, cryptococcal meningitis, cystic fibrosis, interleukin-1 receptor antagonist (DIRA) deficiency, dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse intrinsic pontine glioma diffuse intrinsic pontine gliomaglioma), endometriosis, endotoxemia, epicondylitis, erythrocytopenia, familial amyloid polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, intestinal disease, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Schonlein purpura, hepatitis, hereditary periodic fever syndromes, herpes zoster and simplex, HIV-1, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia type D with periodic fever (HIDS), hypoplastic and other anemias, hypoplastic anemia, idiopathic thrombocytopenia Purpura hypoxica, incontinence pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, inflammation caused by insect bites, iritis, inflammation caused by irritants, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney damage caused by parasitic infection, kidney transplant rejection prevention, leptospirosis, leukemia, Loeffler syndrome, lung damage, lupus, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria, deafness, amyloidosis), multiple sclerosis, muscle wasting syndrome, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungoides fungiodes, mycosis fungoides, myelodysplastic syndrome, myositis, sinusitis, necrotizing enterocolitis, neonatal multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathic diseases, nonallergenic asthma, obesity, ocular allergies, optic neuritis, organ transplantation, osteoarthritis, otitis media, Paget's diseasedisease), pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, whooping cough, pharyngitis and adenitis (PFAPA syndrome), inflammation caused by plant irritants, pneumonia, pneumonitis, pulmonary system infection, inflammation caused by poison ivy / urushiol oil, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psoriasis, psoriasis, psoriasis, psychosocial stress disorder, lung disease, pulmonary hypertension, pulmonary fibrosis, pustular gangrene, suppurative sterile arthritis, kidney disease, retinal disease disease, rheumatic carditis, rheumatic diseases, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell disease, sickle cell anemia, silica-induced diseases, Sergulin's syndrome, skin diseases, sleep apnea, 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, and Wegener's granulomatosis.

20. Compounds of formula I': or a pharmaceutically acceptable salt, isomer, enantiomer or tautomer thereof, wherein: X is selected from CR 6 and N; X′ is selected from CR 6′ and N, where X and X′ are not N at the same time; R 1 C 1-4 Fat; R 2 For 0-4 R 7 Substituted C 1-6 Fat; R 3 For 0-3 R 8 Substituted C 1-6 Fat; R 4 is a halogen; R 5 is a halogen; Each R 6 and R 6′ independently selected from hydrogen, halogen, -OR, -N(R)2, -OC(O)R, -N(R)C(O)R, -N(R)C(O)-L-(R 9 ) p 、-OL-(R 9 ) p , -Cy, optionally substituted C 1-6 Aliphatic and C 1-6 Aliphatic -OH; Each R 7 independently selected from halogen, -OR, -N(R)2 and -Cy; Each R 8 independently selected from halogen, -OR, -N(R)2 and -Cy; Each R 9 independently selected from halogen, -OR, -N(R)2 and -Cy; L is a covalent bond or C 1-4 Fat; Each Cy is independently selected from a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, a phenyl group, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy is surrounded by 0-3 R 10 replace; Each R 10 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 selected from C 1-6 aliphatic and 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein each R is independently substituted with 0-3 halogen, -OCH3 or -OH; Each m and n is independently 0 or 1; and p is independently 1-4.

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