Heterocyclic PAD4 inhibitors

Abstract

The present disclosure relates, in general, to compounds of formula I comprising 1, 6, 7, 8-tetrahydro-5H-imidazo [4, 5-g] [1, 2, 4] triazolo [1, 2, 3] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [ 6, 6] isoquinoline-5-ketone moieties.

Description

Cross-references

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 346,111, filed May 26, 2022, the entire contents of which are incorporated herein by reference. Sequence Listing is 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, is named 055920-607001WO_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 peptidylarginine deiminase (PAD) family of enzymes that catalyzes the conversion of arginine citrullination to citrulline in peptide sequences. PAD4 is responsible for the deimination or citrullination of a variety of proteins in vitro and in vivo, resulting in different functional responses in a variety of diseases (Jones JE et al., Curr. Opin. Drug Discov. Devel., 12(5), (2009), 616-627). Examples of exemplary diseases or conditions include rheumatoid arthritis, diseases in which neutrophils are involved in the pathogenesis (e.g., vasculitis, systemic lupus erythematosus, ulcerative colitis), and tumor indications. PAD4 inhibitors also have broader applicability as tools and treatments for human diseases and conditions through epigenetic mechanisms.

[0005] PAD4 inhibitors are effective for rheumatoid arthritis (RA). RA is an autoimmune disease that affects approximately 1% of the population (Wegner N. et al., Immunol. Rev., 233(1), (2010), 34-54). It is characterized by debilitating destruction of bones and cartilage by inflammation of the joints. In large population studies, 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 (along with its 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 leads to a breakdown of tolerance to citrullinated substrates, such as fibrinogen, vimentin, and collagen, in RA joints, and triggers an immune response to citrullinated substrates. These anti-citrullinated protein antibodies (ACPAs) contribute to disease pathogenesis and are also used as diagnostic tests for RA (e.g., the commercially available CCP2 or cyclic citrullinated protein 2 test). Furthermore, 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, such as fibrinogen, antithrombin, and multiple chemokines. Anti-PAD4 antibodies are 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) (an innate defense mechanism by which neutrophils can fix and kill pathogens) 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 et al., J. Allergy Clin. Immunol., 127(5), (2011), 1260-6), 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 (e.g., 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). DSS colitis reports 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 to treat 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 promoters of p53 target genes (such as p21), which are involved in cell cycle arrest and induction of apoptosis. From these 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 aforementioned role of PAD4 in the deimination of arginine residues in histones may suggest a role for PAD4 in epigenetic regulation of gene expression. PAD4 is the primary PAD family member observed to reside in the nucleus and cytoplasm. Early evidence that PAD4 may function as a histone demethyliminase and deimidase is inconsistent and unconfirmed. However, it may indirectly reduce histone arginine methylation (and, therefore, the epigenetic regulation associated with this mark) by consuming available arginine residues through conversion to citrulline. PAD4 inhibitors may be used as epigenetic tools or therapies to influence the expression of different target genes in other disease settings. Through these mechanisms, PAD4 inhibitors may also effectively control citrullination levels in stem cells and, therefore, may therapeutically influence the pluripotency and differentiation potential of a variety of stem cells, including but not limited to embryonic stem cells, neural stem cells, hematopoietic stem cells, and cancer stem cells. Accordingly, there remains an unmet need to identify and develop PAD4 inhibitors for the treatment of PAD4-mediated diseases or conditions. Summary of the Invention

[0010] Accordingly, the present disclosure provides compounds 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 compounds 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 enzymatic 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. Such diseases or conditions include, among others, rheumatoid arthritis, vasculitis, systemic lupus erythematosus, and ulcerative colitis. DETAILED DESCRIPTION 1. General Description of the 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 6 and N; X′ is selected from CR 6′ and N, where X and X′ are not both N; R 1 C 1-4 aliphatic; R 2 For 0-4 R 7 Substituted C 1-6 aliphatic; R 3 For 0-3 R 8 Substituted C 1-6 aliphatic; R 4 Halogen or C 1-4 aliphatic; R 5 is a halogen; Each R 6 and R 6′ Selected from hydrogen, C 1-6 Aliphatic, -L 1 (R 9 ) q and-OL 2 -(R 9 ) p ; R 7 is selected from halogen, -OR, -N(R)2 and -Cy; R 8 is selected from halogen, -OR, -N(R)2, -C(O)N(R)2 and -Cy; R 9 Selected from halogen, -CN, -OR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, -OC(O)N(R)2 and -Cy; L 1 Covalent bond or C 1-4 aliphatic; L 2 C 1-4 aliphatic; 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, a 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic 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 is selected from halogen, -OR, -N(R)2, -CN, -C(O)R, -C(O)OR, -C(O)N(R)2, oxo and an optionally substituted group 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 Each p and q is 1-4. 2. 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 this disclosure, chemical elements are identified according to the periodic table of the elements, 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 that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is non-aromatic (also referred to herein as a "carbocycle," "carbocyclic," "cycloaliphatic," or "cycloalkyl") that 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 may be fully saturated or which may contain one or more unsaturated units, but which is non-aromatic, having 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 cycloalkyl or heterocyclic rings through one or more spiro linkages. 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 a 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 + (eg, in N-substituted pyrrolidinyl groups.) In some embodiments, 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 as 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" is 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, and the like, which may bear 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, and the like.

[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 pi 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, as well as any quaternized form of a 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 heteroaryl ring is fused to one or more aryl rings, cycloaliphatic rings, or heterocyclic rings, wherein the radical or point of attachment is on the heteroaryl ring. Exemplary groups include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. The heteroaryl group can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," wherein any of these 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- to 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. The term "nitrogen" when used to refer to a ring atom of a heterocycle 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] Heterocycle can be connected to its side group at any heteroatom or carbon atom, thereby forming a stable structure, and any ring atom can be optionally substituted.The example of such saturated or partially unsaturated heterocyclic radical comprises tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepinyl (diazepinyl), oxazepinyl (oxazepinyl), thiazepinyl (thiazepinyl), morpholinyl and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl 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. A heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the alkyl and heterocyclyl moieties 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

[0029] 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 undergo substantial 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.

[0030] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are independently halogen; -(CH2) 0–4 R o ; –(CH2) 0–4 OR o ;-O(CH2) 0-4 R o 、–O–(CH2) 0–4 C(O)OR o ; –(CH2) 0–4 CH(OR o )2;–(CH2) 0– 4SR o ; –(CH2) 0–4 Ph, which can be R o Substitution; –(CH2) 0–4 O(CH2) 0–1 Ph, which can be R o Substitution; –CH=CHPh, which can be replaced by R o Substitution; –(CH2) 0–4 O(CH2) 0–1 -pyridyl, which may be R o Substitution; –NO2; –CN; –N3; -(CH2) 0–4 N(R o )2;–(CH2) 0–4 N(R o )C(O)R o ;–N(R o )C(S)R o ; –(CH2) 0–4 N(R o )C(O)NR o 2;-N(R o)C(S)NR o 2;–(CH2) 0–4 N(R o )C(O)OR o ;–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 ;–(CH2) 0–4 C(O)R o ;–C(S)R o ;–(CH2) 0–4 C(O)OR o ;–(CH2) 0–4 C(O)SR o ;-(CH2) 0–4 C(O)OSiR o 3;–(CH2) 0–4 OC(O)R o ;–OC(O)(CH2) 0–4 SR o ;–(CH2) 0–4 SC(O)R o ;–(CH2) 0–4 C(O)NR o 2;–C(S)NR o 2;–C(S)SR o ;–SC(S)SR o 、-(CH2) 0– 4OC(O)NR o 2;-C(O)N(OR o )R o ;–C(O)C(O)R o ;–C(O)CH2C(O)R o ;–C(NOR o )R o ;-(CH2) 0–4 SSR o ;-(CH2) 0–4 S(O)2R o ;–(CH2) 0–4 S(O)2OR o ;–(CH2) 0–4 OS(O)2R o ;–S(O)2NR o 2;-(CH2)0–4 S(O)R o ;-N(R o )S(O)2NR o 2;–N(R o )S(O)2R o ;–N(OR o )R o ;–C(NH)NR o 2;–P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;–OP(O)(OR o )2;SiR o 3;–(C 1-4 linear or branched alkylene)O–N(R o )2 or –(C 1-4 linear 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, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 atoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independently occurring 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.

[0031] R o Suitable monovalent substituents (or two independent occurrences of R o together with their central atoms to form a ring) are independently halogen, –(CH2) 0–2 R ● 、–(halogenated R ● ),–(CH2) 0–2 OH, –(CH2) 0–2 OR ● 、–(CH2) 0–2 CH(OR · )2、-O(halogenated R ● ), –CN, –N3, –(CH2) 0–2 C(O)R ● 、–(CH2) 0–2 C(O)OH, –(CH2) 0–2 C(O)OR ● 、–(CH2) 0–2SR ● 、–(CH2) 0– 2SH, –(CH2) 0–2 NH2, –(CH2) 0–2 NHR · 、–(CH2) 0–2 NR · 2. –NO2, –SiR · 3. –OSiR · 3. -C(O)SR · 、–(C 1–4 linear or branched alkylene)C(O)OR · or –SSR · , where each R · Each R that is unsubstituted or preceded by "halo" · is substituted only with one or more halogens and is independently selected from C 1-4 Aliphatic, –CH2Ph, –O(CH2) 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. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0032] 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)2R * 、=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– 3O-, 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.

[0033] R * Suitable substituents on the aliphatic group include halogen, –R ● 、-(halogenated R ● ),-OH, –OR · 、–O(halogenated R · ), –CN, –C(O)OH, –C(O)OR · , –NH2, –NHR · ,–NR ● 2 or –NO2, where each R ● Each R that is unsubstituted or preceded by "halo" ● is substituted only with one or more halogens and is independently C 1-4 Aliphatic, –CH2Ph, –O(CH2) 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.

[0034] Suitable substituents on the substitutable nitrogen of an "optionally substituted" group include or Each of these are independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh or unsubstituted 5-6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independently occurring 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.

[0035] Suitable substituents on the aliphatic group are independently halogen, -R ● 、-(halogenated R ● ),–OH,–OR ● 、–O(halogenated R ● ), –CN, –C(O)OH, –C(O)OR ● , –NH2, –NHR ● ,–NR · 2 or -NO2, where each R · Each R that is unsubstituted or preceded by "halo" · is substituted only with one or more halogens and is independently C 1-4 Aliphatic, –CH2Ph, –O(CH2) 0–1Ph or a 5-6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0036] 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.

[0037] As used herein, the term "treating" or "treatment" refers to and includes the treatment of a disease state in a subject (e.g., a human or animal), and includes: (a) inhibiting the disease state, i.e., arresting its development; (b) relieving the disease state, i.e., causing the regression of the disease state; and / or (c) preventing the disease state from occurring in a subject.

[0038] As used herein, the terms "preventing" or "prevention" refer to and include prophylactic treatment (i.e., preventing and / or reducing the risk) 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.

[0039] The term "therapeutically effective amount" refers to and includes an amount of a compound or composition according to the present disclosure that, when administered alone or in combination, is effective to prevent or treat a disease or condition associated with PAD4 enzyme activity. When applied to a combination, the term refers to combined amounts of the active ingredients that produce the prophylactic or therapeutic effect, whether administered in combination, serially or simultaneously.

[0040] "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 based on 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 well known to those of ordinary skill in the art, for example, to stabilize the active agent, adhesives, etc. Typical, non-limiting examples of such carriers include diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, fragrances, 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 ed., Pharmaceutical Press (2012).

[0041] 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 can be represented by CH3 or CD3. 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.

[0042] The salts formed by the compounds of formula I are also within the scope of the present disclosure. Unless otherwise indicated, reference to compounds of formula I should be understood to include reference to their salts. As used herein, the term "salt" refers to acid addition salts and / or base addition salts formed with inorganic acids and / or organic acids and inorganic bases and / or organic bases. In addition, when the compound of formula I contains both a basic moiety and an acidic moiety, a zwitterion ("inner salt") can be formed and 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 non-toxic and physiologically acceptable salts. According to the salts of the compounds of the present disclosure, for example, the compound can be reacted with an amount of acid or base, such as an equal amount of acid or base, in a medium such as a salt precipitated therein or in an aqueous medium and then lyophilized to form.

[0043] 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, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), hydrobromide (formed with hydrobromic acid), hydroiodide, Examples of the present invention include but are not limited to succinates, hydroxybenzoates, benzoic acid ...

[0044] 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), salts formed with 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 reagents 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.

[0045] The present disclosure encompasses compounds of Formula I or pharmaceutically acceptable salts thereof, methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and the use of these compounds in treating diseases or conditions associated with PAD4 enzyme activity. 3. Description of Exemplary Embodiments

[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 both N; R 1 C 1-4 aliphatic; R 2 For 0-4 R 7 Substituted C 1-6 aliphatic; R 3 For 0-3 R 8 Substituted C 1-6 aliphatic; R 4 Halogen or C 1-4 aliphatic; R 5 is a halogen; Each R 6 and R 6′ are independently selected from hydrogen, C 1-6 Aliphatic, -L1 (R 9 ) q and-OL 2 -(R 9 ) p ; R 7 is selected from halogen, -OR, -N(R)2 and -Cy; R 8 is selected from halogen, -OR, -N(R)2, -C(O)N(R)2 and -Cy; R 9 Selected from halogen, -CN, -OR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, -OC(O)N(R)2 and -Cy; L 1 Covalent bond or C 1-4 aliphatic; L 2 C 1-4 aliphatic; 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, a 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic 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 of p and q is independently 1-4.

[0047] 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 both N; R 1 C 1-4 aliphatic; R 2 For 0-4 R 7 Substituted C 1-6 aliphatic; R 3 For 0-3 R 8 Substituted C 1-6 aliphatic; R 4 Halogen or C 1-4 aliphatic; R 5 is a halogen; Each R 6 and R 6′ are independently selected from hydrogen, C 1-6 Aliphatic, -L 1 (R 9 ) q and-OL 2 -(R 9 ) p ; Each R 7 independently selected from halogen, -OR, -N(R)2 and -Cy; Each R 8 independently selected from halogen, -OR, -N(R)2, -C(O)N(R)2, and -Cy; Each R 9 independently selected from halogen, -CN, -OR, -N(R), -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R), -N(R)C(O)R, -N(R)C(O)OR, -OC(O)N(R), and -Cy; L 1 Covalent bond or C 1-4 aliphatic; L 2 C 1-4 aliphatic; 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, a 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic 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, wherein R 10 Replaced by 0-3 Rs; Each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, oxo, -CH2OCH3, 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 R is replaced by 0-3 halogen, C 1-6 aliphatic or -OH substituted; Each m and n is independently 0 or 1; and Each of p and q is independently 1-4.

[0048] In some embodiments, the present disclosure provides a compound selected from compounds of any one of Formulas Ia, Ib, Ic, Id, Ie, If, Ig, and Ih: 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, Ia-ii, Ibi, Ib-ii, Ici, Ic-ii, Idi, Id-ii, Iei, Ie-ii, Ifi, If-ii, Igi, Ig-ii, Ihi, and Ih-ii: or a pharmaceutically acceptable salt thereof.

[0050] 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.

[0051] As generally defined above, X' is selected from CR 6′ and N, wherein X and X' are not simultaneously N. In some embodiments of Formula I, X' is CR 6′ In some embodiments of Formula I, X′ is N.

[0052] 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′.

[0053] As generally defined above, R 1 C 1-4 In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R 1 is –CH3.

[0054] 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, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R 2 0-4 R 7 Substituted C 1-4Aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R 2 is C 7 aliphatic substituted with 0 - 4 R 1-2 .

[0055] Aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R 2 is C 7 aliphatic substituted with 1 - 2 R 1-6 . Aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R 2 is C 7 aliphatic substituted with 1 - 2 R[[ID=​​​​​​Aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 2 is C 7 substituted with 3 - 4 R 1-6 Aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 2 is C 7 substituted with 3 - 4 R 1-4 Aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 2 is C 7 substituted with 3 - 4 R 1-2 Aliphatic.

[0056] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 2 is selected from: –CH2-R 7

[0057] As defined generally above, R 3 is C 8 substituted with 0 - 3 R 1-6Aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 3 is C 8 substituted with 0 - 3 R 1-4 Aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 3 is C 8 substituted with 0 - 3 R 1-2 Aliphatic.

[0058] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 3 is C 8 substituted with 1 - 3 R 1-6 Aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 3 is C 8 substituted with 1 - 3 R 1-4Aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 3 is C 8 aliphatic substituted with 1-3 R 1-2 groups.

[0059] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 3 is selected from: –CH2-R 8

[0060] As defined generally above, R 4 is halogen or C 1-4 aliphatic. In various embodiments, any substitutable position of the fused bicyclic moiety of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii may be substituted with R 4 groups. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 4 is halogen. In some such embodiments, R 4In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R 4 C 1-4 In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R 4 C 1-2 In some such embodiments, R 4 is –CH3.

[0061] As generally defined above, R 5 In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R 5 For fluorine.

[0062] As generally defined above, each R 6 and R 6′ Selected from hydrogen, C 1-6 Aliphatic, -L 1 (R 9 ) q and-OL 2 -(R 9 ) p In some embodiments of Formula I, R 6 For hydrogen.

[0063] In some embodiments of any of Formulas I, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, R 6In some such embodiments of any of Formulas I, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, R 6 For fluorine.

[0064] In some embodiments of any of Formulas I, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, R 6 -L 1 (R 9 ) q .

[0065] In some embodiments of any of Formulas I, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, R 6 For-OL 2 -(R 9 ) p .

[0066] In some embodiments of any of Formulas I, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, R 6 C 1-6 In some such embodiments of any of Formulas I, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, R 6 It is –CH3, –CH2CH3, –CH(CH3)2 or –C(CH3)3.

[0067] In some embodiments of any of Formulas I, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, R 6 Selected from C 1-6 Aliphatic, halogen, -CN, -OR, -N(R)2, -Cy, -(C 1-4 Aliphatic)-Cy, -(C 1-4 Aliphatic)-halogen, -O(C 1-4 Aliphatic)-Cy, -O(C 1-4 Aliphatic)-OR, -O(C 1-4 Aliphatic)-N(R)2、-O(C 1-4 Aliphatic)-N(R)C(O)OR and -O(C 1-4 Aliphatic)-OC(O)N(R)2.

[0068] In some embodiments of any of Formulas I, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, R 6 Selected from C 1-6 Aliphatic, -R 9 、

[0069] In some embodiments of any of Formulas I, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, R 6 Selected from -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CN, halogen, -OCH3, -N(CH3)2,

[0070] In some embodiments of Formula I, R 6′ For hydrogen.

[0071] In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ic, Ici, Ic-ii, Ie, Iei, Ie-ii, R 6′ In some such embodiments of any of Formulas I, Ia, Iai, Ia-ii, Ic, Ici, Ic-ii, Ie, Iei, Ie-ii, R 6′ is fluorine or chlorine.

[0072] In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ic, Ici, Ic-ii, Ie, Iei, Ie-ii, R 6′ for –L 1 -(R 9 ) p .

[0073] In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ic, Ici, Ic-ii, Ie, Iei, Ie-ii, R 6′ For-OL 2 -(R 9 ) p .

[0074] In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ic, Ici, Ic-ii, Ie, Iei, Ie-ii, R 6′ C 1-6 In some such embodiments of any of Formulas I, Ia, Iai, Ia-ii, Ic, Ici, Ic-ii, Ie, Iei, Ie-ii, R 6′ It is –CH3, –CH2CH3, –CH(CH3)2 or –C(CH3)3.

[0075] In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ic, Ici, Ic-ii, Ie, Iei, Ie-ii, R 6′ Selected from C 1-6 Aliphatic, halogen, -CN, -OR, -Cy, -(C 1-4 Aliphatic)-(Halogen) 1-3 , –C(O)N(R)2 and -CO2R.

[0076] In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ic, Ici, Ic-ii, Ie, Iei, Ie-ii, R 6′ Selected from C 1-6 Aliphatic, -R 9 、

[0077] In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ic, Ici, Ic-ii, Ie, Iei, Ie-ii, R 6′ Selected from C 1-6 Aliphatic, -R 9 、

[0078] As generally defined above, R 7 is selected from halogen, -OR, -N(R)2, and -Cy. In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R 7is a halogen. In some such embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R 7 is fluorine. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R 7 is –OR. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R 7 is -N(R)2. In some such embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R is hydrogen. Accordingly, in some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R 7is -NH2. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R 7 is –Cy. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R 7 is selected from fluorine, -NH2 and –Cy.

[0079] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R 2 is selected from

[0080] 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-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R 8 is –Cy. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R[[ID=--19]] 8is –OR. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 8 is halogen. In some such embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 8 is fluorine. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 8 is –C(O)N(R)2.

[0081] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 3 is selected from –CH2CH3, -CH(CH3)2,

[0082] As defined generally above, R 9Selected from halogen, -CN, -OR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, -OC(O)N(R)2 and –Cy. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i and I-e-ii, R 9 is halogen. In some such embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i and I-e-ii, R 9 is fluorine or chlorine. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i and I-e-ii, R 9 is –OR. In some such embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i and I-e-ii, R is hydrogen or –CH3. Accordingly, in some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i and I-e-ii, R 9 is –OH or –CH3. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i and I-e-ii, R 9is –N(R)2. In some such embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, R is hydrogen. Accordingly, in some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, R 9 is –NH2.

[0083] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, R 9 is –CN.

[0084] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, R 9 is -C(O)N(R)2.

[0085] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, R 9 is -N(R)C(O)R.

[0086] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, R 9 is -N(R)C(O)OR.

[0087] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, R 9 is –CO2R.

[0088] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, R 9 is -OC(O)N(R)2.

[0089] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, R 9 is –Cy.

[0090] As defined generally above, L 1 is a covalent bond or C 1-4 aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, L 1 is a covalent bond. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, L 1 is C 1-4 aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, L 1 is C 1-3 aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, L 1 is C 1-2 aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, L1 is C 2-3 aliphatic.

[0091] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, -L 1 -(R 9 ) p is selected from

[0092] As defined generally above, L 2 is C 1-4 aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, L 2 is C 1-3 aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, L 2 is C 1-2 aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, L 2 is C 2-3 aliphatic.

[0093] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, and I-e-ii, -L 2 -(R 9 ) p is selected from

[0094] In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, and Ie-ii, R 9 Selected from fluorine, chlorine, -CN, -OR, -N(R)2, -C(O)N(R)2, -CO2R, -OC(O)N(R)2, -N(R)C(O)OR,

[0095] As generally defined above, 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, a 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic 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, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, Cy is replaced by 1-2 R 10 In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, Cy is replaced by 1-3 R 10 replace.

[0096] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, 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-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, Cy is a 3-membered saturated carbocycle. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, Cy is a 4-membered saturated carbocycle. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, 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-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, Cy is a 5-membered saturated carbocycle. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, 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-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, Cy is a 6-membered partially unsaturated carbocycle. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, 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-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, Cy is a 7-membered saturated carbocycle.

[0097] In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, 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, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, 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, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, Cy is a 4-membered saturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, 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 of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, Cy is a 5-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.In some embodiments of any of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, 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, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, Cy is a 6-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, 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 of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, Cy is a 7-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0098] In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, Cy is phenyl.

[0099] In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, 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, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, Cy is a 5-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, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, Cy is a 5-membered heteroaryl ring having 2-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, Cy is a 5-membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0100] In some embodiments of any of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, Cy is a 6-membered heteroaryl ring having 1-2 nitrogen atoms.

[0101] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, Cy is selected from

[0102] As defined generally above, R 10 is selected from halogen, -OR, -N(R)2, -CN, -C(O)R, -C(O)OR, -C(O)N(R)2, oxo and an optionally substituted group selected from C 1-6 aliphatic and 3- to 7-membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R 10 is halogen.In some such embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R 10 is fluorine or chlorine.

[0103] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i and I-h-ii, R 10 is –OR.

[0104] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is –N(R)2.

[0105] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is –CN.

[0106] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is –C(O)R. In some such embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R is C 1-6 aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is –C(O)R, wherein R is C 1-6Aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is –C(O)R, where R is C 1-4 Aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is –C(O)R, where R is C 1-2 Aliphatic.

[0107] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is –C(O)R, where R is optionally substituted C 1-6 Aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is –C(O)R, where R is optionally substituted with -OR o substituted C 1-6 Aliphatic. In some such embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, Ro is hydrogen or C 1-6 is aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is –C(O)R, where R is optionally C o substituted with -OR 1-4 is aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is –C(O)R, where R is optionally C o substituted with -OR 1-2 is aliphatic.

[0108] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is –C(O)OR.

[0109] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is –C(O)N(R)2.

[0110] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is oxo.

[0111] In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is optionally substituted C 1-6 aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is optionally substituted C 1-4 aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is optionally substituted C 1-2 aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R 10 is –CH3 or -CH2CH3.

[0112] In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R 10 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. In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R 10 is 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, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, 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, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, 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, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R 10is 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, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, 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, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, 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, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R 10 is 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, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R 10 is an optionally substituted 7-membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0113] In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R 10 Selected from oxo, fluoro, chloro, -CN, -CH3, -CH2CH3, -NH2, -OH, -OCH3,

[0114] As generally defined above, R is hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 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. In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R is hydrogen. In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R is an optionally substituted group selected from C 1-6 aliphatic, a 3- to 7-membered saturated or partially unsaturated carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 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. In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, R is an optionally substituted C 1-6Aliphatic. In some such embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R is optionally halogen- or -OR o substituted C 1-6 Aliphatic. In some such embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R is hydrogen or C 1-6 Aliphatic. In some embodiments of any one of Formulas I, I-a, I-a-i, I-a-ii, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, I-d-ii, I-e, I-e-i, I-e-ii, I-f, I-f-i, I-f-ii, I-g, I-g-i, I-g-ii, I-h, I-h-i, and I-h-ii, R is optionally halogen- or -OR o substituted C 1-6 Aliphatic, wherein R o is hydrogen or C 1-6 Aliphatic.

[0115] As generally defined above, each m and n is 0 or 1. In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, m is 0. In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, Ie-ii, If, Ifi, If-ii, Ig, Igi, Ig-ii, Ih, Ihi, and Ih-ii, m is 1. In some embodiments of any of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, n is 0. In some embodiments of any of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, n is 1. In some embodiments of Formula I, m is 1 and n is 0. In some embodiments of Formula I, each of m and n is 0.

[0116] As generally defined above, p is 1-4. In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, and Ie-ii, p is 1. In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, and Ie-ii, p is 1-2. In some embodiments of any one of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, and Ie-ii, p is 2. In some embodiments of any of Formulas I, Ia, Iai, Ia-ii, Ib, Ibi, Ib-ii, Ic, Ici, Ic-ii, Id, Idi, Id-ii, Ie, Iei, and Ie-ii, p is 3.

[0117] In some embodiments, the compound of formula I is selected from or a pharmaceutically acceptable salt thereof. 4. Pharmaceutical Compositions

[0118] In some embodiments, the present disclosure provides a composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof, 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 inhibits 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 inhibits 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.

[0119] 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.

[0120] The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle 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 herein 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.

[0121] The compositions provided herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via 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 injectable forms of the compositions provided herein can be aqueous or oily suspensions. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions 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, fixed oils are commonly used as solvents or suspending media.

[0122] 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 their polyoxyethylene amidated forms. 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 (Tweens), Spans (Spans) and other emulsifiers or bioavailability enhancers, which are generally used in the preparation of pharmaceutically acceptable solids, liquids or other dosage forms.

[0123] The pharmaceutically acceptable compositions provided herein can be orally administered in any orally 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 typically added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an aqueous suspension for oral use is desired, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings, or coloring agents may also be added.

[0124] 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.

[0125] The pharmaceutically acceptable compositions provided by the present disclosure can also be topically applied, especially when the target of treatment includes an area or organ easily accessible by topical application, including diseases of the eyes, skin or lower intestinal tract. For each in these areas or organs, suitable topical preparations can be easily prepared. Topical application for the lower intestinal tract can be performed 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 carrier for the topical application of the compound provided by the present disclosure includes but is not limited to mineral oil, liquid vaseline, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.

[0126] Alternatively, provided pharmaceutically acceptable compositions can be formulated into suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, stearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0127] 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.

[0128] The pharmaceutically acceptable compositions provided herein can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0129] In addition, the pharmaceutically acceptable compositions provided by the present disclosure can be formulated for oral administration. Such formulations 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.

[0130] The pharmaceutically acceptable compositions provided by the present disclosure can be administered orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powder, ointment, or drops), buccally, as an oral or nasal spray, or the like to humans and other animals 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.

[0131] 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, isopropyl alcohol, 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, flavorings and aromatics.

[0132] Injectable 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 injectable preparations can also be sterile injectable 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.

[0133] 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.

[0134] In order to prolong the effect of the compound provided by the present invention, it is generally 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. The absorption rate of the compound then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of the compound form administered parenterally can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactic acid-polyglycolic acid. The rate of compound release 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 formulations are also prepared by encapsulating the compound in a liposome or microemulsion compatible with body tissues.

[0135] Compositions for rectal or vaginal administration can be suppositories, which can be prepared by mixing a compound provided herein 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.

[0136] 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, polyvinylpyrrolidone, sucrose and acacia, (c) humectants such as glycerol, (d) disintegrants such as agar, calcium carbonate, potato 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 glycerol 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.

[0137] Solid compositions of similar types can also use excipients such as lactose (lactose) or milk sugar (milk sugar) and high molecular weight polyethylene glycol as fillers in soft-filled and hard-filled gelatin capsules. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells (coatings such as those known in the field of enteric coatings and pharmaceutical preparations). They can optionally contain an opacifying agent (opacifying agent) and can also be a composition that only or preferentially releases the active ingredient in a certain part of the intestinal tract, optionally in a delayed manner. Examples of spendable embedded compositions include polymeric substances and waxes. Solid compositions of similar types can also use excipients such as lactose (lactose) or milk sugar (milk sugar) and high molecular weight polyethylene glycol as fillers in soft-filled and hard-filled capsules.

[0138] The active compound can also be formed into 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 art 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.

[0139] 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 of controlled delivery of the compound 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.

[0140] The amount of the disclosed compounds that can be combined with the carrier materials to produce a single dosage form of the composition can vary depending on the host being treated, the particular mode of administration, and the 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.

[0141] 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 administered independently of one another, or in combination with one or more other therapeutic compounds. Exemplary of such other therapeutic agents include corticosteroids, rolipram, carferstatin, 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 thereof, particularly for tumor therapy. As described above, long-term therapy and adjuvant therapy in the context of other treatment strategies are also possible. Other possible treatments are therapies to maintain the patient's status after tumor regression, or even chemoprevention, for example in patients at risk.

[0142] As part of a multiple-dose regimen, those additional agents may be administered separately from the composition containing the compounds of the present disclosure. Alternatively, these agents may be part of a single dosage form, mixed together with the compounds of the present disclosure 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 (typically within 5 hours of each other).

[0143] 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 can be administered with another therapeutic agent simultaneously or sequentially 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.

[0144] The amount of both the provided compound and the additional therapeutic agent (in those compositions comprising additional therapeutic agents as described above) that can be combined with the carrier materials 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 dose of between 0.01-100 mg / kg body weight / day of the provided compound can be administered.

[0145] 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 additional therapeutic agent in such compositions will be less than that required in a monotherapy using only that therapeutic agent.

[0146] 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 that 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 that agent as the only therapeutically active agent.

[0147] It will also be 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, 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

[0148] The compounds and compositions described herein are generally useful for the inhibition of PAD4.

[0149] The activity of the compounds used in this disclosure as PAD4 inhibitors can be determined in vivo, in vitro, or in cell lines. In vitro assays include assays to determine PAD4 inhibition. Detailed conditions for determining the activity of the compounds used in this disclosure as PAD4 inhibitors are listed in the Examples below. In some embodiments, provided compounds selectively inhibit PAD4 compared to PAD2.

[0150] 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 condition as described herein, or one or more symptoms thereof. 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 before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other predisposing factors). Treatment may also continue after symptoms subside, e.g., to prevent or delay their recurrence.

[0151] The provided compounds are PAD4 inhibitors and are therefore useful for treating one or more diseases or conditions associated with PAD4 enzyme activity. Accordingly, in certain embodiments, the present disclosure provides a method for treating a disease or condition associated with PAD4 enzyme activity, comprising administering a compound of the present disclosure or a pharmaceutically acceptable composition thereof to a patient in need thereof.

[0152] In one embodiment, the disease or condition associated with PAD4 enzyme activity is a disease, condition, or illness 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.

[0153] 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, 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.

[0154] In one embodiment, a method for treating rheumatoid arthritis is provided, comprising administering a therapeutically effective amount of a provided compound, its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts 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, its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts 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, its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts 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, its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof to a human subject in need thereof. In one embodiment, provided is a method of treating psoriasis, comprising administering a therapeutically effective amount of a provided compound, stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof to a human subject in need thereof.

[0155] 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, adrenal 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 (ID), ankylosing spondylitis, anterior segment 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 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 Disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia type D with periodic fever (HIDS), hypoplastic and other anemias, hypoplastic anemia, idiopathic thrombocytopenic purpura, incontinentia 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, 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 disorder, lung disease, pulmonary hypertension, pulmonary fibrosis, pustular gangrene, suppurative sterile arthritis, kidney disease, retinal disease, rheumatic carditis, rheumatic disease, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell disease, sickle cell anemia, silica-induced disease, Sjögren's syndrome, skin disease, 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 mellitus, type 2 diabetes mellitus, ulcerative colitis, urticaria, uveitis, Wegener's granulomatosis, interstitial lung disease, psoriatic arthritis, juvenile idiopathic arthritis, Sjögren's syndrome, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, antiphospholipid antibody syndrome, sepsis, deep vein thrombosis, fibrosis, Alzheimer's disease, scleroderma, and CREST syndrome.

[0156] 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 use in treating vasculitis. In another embodiment, the present disclosure provides a compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt for use in treating cutaneous lupus erythematosus. In another embodiment, the present disclosure provides a compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt for use in treating psoriasis. In another embodiment, the present disclosure provides a compound or its stereoisomer, enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt for use in the preparation of 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 stereoisomers, enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts 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 stereoisomers, enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts in the preparation of a medicament for treating rheumatoid arthritis. In another embodiment, the present disclosure provides the use of a compound or its stereoisomers, enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts 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 stereoisomers, enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts in the preparation of a medicament for treating vasculitis.In another embodiment, the present disclosure provides the use of a compound or its stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts 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 stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts 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 stereoisomers, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts. 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, comprising a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing vasculitis, comprising a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing cutaneous lupus erythematosus, comprising a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing psoriasis, comprising a provided compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.

[0157] All features of each aspect of the present invention are applicable to all other aspects as necessary. In order to more fully understand the invention described herein, the following examples are listed. It should be understood that these examples are for illustrative purposes only and should not be considered to limit the present invention in any way. 6. Examples

[0158] 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, CH3CN acetonitrile Alk alkyl AlMe3 trimethylaluminum BBr3 Boron tribromide BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BH3 Borane Bn benzyl Boc tert-butyloxycarbonyl Boc2O Di-tert-butyl dicarbonate Butyl i-Bu isobutyl t-Bu tert-butyl t-BuOH tert-Butanol Cbz benzyloxycarbonyl CDCl3 deuterated chloroform CD3OD, methanol-d4 deuterated methanol CH2Cl2 dichloromethane CH3CN acetonitrile CHCl3 chloroform DAST Diethylaminosulfur trifluoride D2O Deuterium oxide DCM dichloromethane DIEA,DIPEA or Diisopropylethylamine DTBAD Di-tert-butyl azodicarboxylate DMF dimethylformamide DMSO dimethyl sulfoxide DMSO-d6 deuterated dimethyl sulfoxide equiv,eq. equivalent Et ethyl Et3N or TEA triethylamine Et2O ether ESI electrospray ionization EtOAc EtOH HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate HCl HPLC high-performance liquid chromatography Prep-HPLC Ir(dF(CF3)ppy)2(dtbbpy)PF6(4,4'-bis-tert-butyl-2,2'-bipyridyl)bis[3,5-difluoro-2-(5-trifluoromethyl-2-pyridyl-kN)phenyl-kC]iridium(III) hexafluorophosphate K2CO3 potassium carbonate K2HPO4 Dipotassium hydrogen phosphate K3PO4 tripotassium phosphate KNO3 potassium nitrate LCMS liquid chromatography mass spectrometry LiAlH4,LAH Lithium aluminum hydride LiHMDS Lithium bis(trimethylsilyl)amide Me methyl MeOH, CH3OH methanol MeI,CH3I iodomethane MgSO4 magnesium sulfate min,min. minutes MS MsOH or MSA methanesulfonic acid MsCl methanesulfonyl chloride NaCl Sodium chloride Na2CO3 sodium carbonate NaHCO3 sodium bicarbonate NaIO4 sodium periodate NaOH sodium hydroxide Na2SO4 sodium sulfate Na2S2O4 sodium dithionite NBS N-bromosuccinimide NH3 ammonia NH4Cl ammonium chloride NH4OAc ammonium acetate TMEDA N,N,N,N-Tetramethylethylenediamine NMR Nuclear Magnetic Resonance Pd(OAc)2 Palladium(II) acetate Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0) PG protecting group Ph Phenyl Pr Propyl i-Pr isopropyl i-PrOH or IPA Isopropyl alcohol Rt retention time RuCl3 Ruthenium(III) chloride SiO2 silicon dioxide SOCl2 Thionyl chloride SFC Supercritical Fluid Chromatography TBAI Tetrabutylammonium iodide TBAF Tetrabutylammonium fluoride TBSCl,TBDMSCl tert-Butyldimethylsilyl chloride TBDPSCl tert-Butyldiphenylsilyl chloride TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF Tetrahydrofuran TiCl4 Titanium Tetrachloride T3P 1-Propylphosphonic acid cyclic anhydride TLC thin layer chromatography

[0159] Description of Preparative HPLC and Analytical LCMS Methods:

[0160] Method A: Column: XBridge Shield RP18 OBD, 19x250 mm, 10 μm; Mobile phase A: water + 10 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 25 mL / min.; Gradient: 57% B to 82% B in 7 min; Detection: UV (210 / 254 nm).

[0161] Method B: 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: 1.2000 mL / min.; Gradient: 5% B to 95% B in 2 min; Hold at 95% for 0.7 min., 95% B to 5% B in 0.05 min; Detection: MS and UV (254 nm).

[0162] Method C: Column: XBridge Prep C18 OBD, 19x150 mm, 5 μm; Mobile phase A: water + 10 mmol / L NH4HCO3, Mobile phase B: ACN; Flow rate: 25 mL / min.; Gradient: 21% B to 51% B in 7 min; Detection: UV (254 / 210 nm).

[0163] Method D: Column: HALO C18, 3x30 mm, 2.7 μm; Mobile phase A: water + 0.05% TFA, Mobile phase B: ACN + 0.05% TFA; Flow rate: 1.5000 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).

[0164] Method E: 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).

[0165] Method F: Column: X Bridge Prep Phenyl OBD, 19x150 mm; 5 μm; Mobile phase A: water + 0.05% HCl, Mobile phase B: ACN; Flow rate: 20 mL / min.; Gradient: 15% B to 45% B in 6 min; Detection: UV (254 nm).

[0166] Method G: Column: SunFire C18 OBD Prep 19x150 mm; 5 um; 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).

[0167] Method H: Column: Shim-pack Scepter C18, 3.0 mm x 50 mm; 3.0 μm; Mobile phase A: water + 0.04% NH3H2O, Mobile phase B: ACN; Gradient: 10% B to 95% B over 1 min, then hold at 95% B for 0.60 min.; Flow rate: 1.5 mL / min.; Detection: MS and UV (254 / 220 nm).

[0168] Method I: Column: XBridge BEH C18 column 3x50 mm, 2.5 mm; Mobile phase A: water + 0.05% TFA, Mobile phase B: ACN + 0.05% TFA; Flow rate: 1.2 mL / min.; Gradient: 10% B to 95% B in 2 min; Hold at 95% for 0.79 min., 95% B to 5% B in 0.06 min; Detection: UV (254 nm).

[0169] Method J: Column: Titank C18 column 3x50 mm, 3.0 mm; Mobile phase A: water + 5 mM NH4HCO3, Mobile phase B: ACN; Flow rate: 1.5 mL / min.; Gradient: 10% B to 60% B in 2.25 min, maintained at 95% for 0.5 min., 95% B to 10% B in 0.05 min; Detection: UV (254 nm).

[0170] Method K: Atlantis HILIC OBD column, 19x150 mm, 5 μm; mobile phase A: water + 0.05% TFA, mobile phase B: ACN; flow rate: 20 mL / min.; gradient: 20% B to 35% B, 35% B in 4.3 min; detection: UV (254 / 210 nm).

[0171] Method L: L-column 3C18, 3.0 mm x 30 mm, 2.0 μm; 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 0.60 min.; detection: UV (254 / 210 nm).

[0172] Method M: Column: Atlantis Prep T3 OBD column, 19x250 mm 10 μm; 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).

[0173] Method N: 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).

[0174] Method O: Column: Waters BEH C18 column 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).

[0175] Method P: Column: kinetex XB-C18 100A column 2.1x30 mm, 1.7 um; mobile phase A: water + 0.05% TFA, mobile phase B: acetonitrile + 0.05% TFA; flow rate: 1.2 mL / min.; gradient: 5% B to 100% B in 2.8 min; hold at 100% for 1 min., 100% B to 5% B in 0.03 min; detection: UV 210 nm. Synthesis Example General Procedure 1: Alkylation of Lactams with Cyclic Sulfamidates

[0176] To a stirred solution of lactam (1.0 equiv) in DMF was added NaH (60%, 2.0 equiv) and cyclic aminosulfonate (1.4 equiv) at 0°C. The reaction was heated to room temperature for 2 h. TLC showed that 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

[0177] A solution of N-Boc amine (1.0 equivalent) in DCM:TFA (3:1, 0.02 M) was stirred at room temperature for 30 min. TLC showed the reaction was complete, and the mixture was filtered. The product was purified by preparative HPLC or column chromatography. General Procedure 3: Alkylation of heterocyclic NH or phenolic OH groups with potassium carbonate base

[0178] To a stirred solution (0.2 M) of the substituted indole (1.0 equiv) in DMF was added KCO (3.0 equiv), TBAI (0.1 equiv) and an alkyl electrophile (1.5 equiv) at room temperature. The reaction solution was heated 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 organic layer was washed with brine (× 2), dried over sodium sulfate, concentrated and purified by column chromatography. General Procedure 4: Cyclization to form tricyclic benzimidazoles

[0179] To a stirred solution of aldehyde (1.0 equiv) in ethanol: water (2: 1, 0.08 M) was added aniline (1.0 equiv) and Na2S2O4 (3.0 equiv) at room temperature. The reaction solution was heated to 90 ° C for 2 h. TLC showed that the reaction was complete. The reactants were concentrated under vacuum, then diluted with water (20 mL), and then extracted with DCM / MeOH (10: 1) (× 3). The organic layer was dried over sodium sulfate, concentrated and purified by preparative HPLC or column chromatography. General Procedure 5: Reduction of Esters or Acids with Lithium Aluminum Hydride

[0180] To a stirred solution of acid or ester (1.0 equivalent) in DMF (0.3 M) was added LiAlH 4 (2.0 equivalents) at 0° C. The resulting solution was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction was then quenched with water (0.5 mL) / NaOH (15%) (1:4 ratio) and stirred at room temperature for 20 min. The solid was filtered off and the resulting solution was concentrated under vacuum. The crude product was purified by column chromatography. General Procedure 6: Oxidation of Alcohols with Manganese Dioxide

[0181] Under nitrogen atmosphere, MnO 2 (2.0 equiv) was added to a stirred solution of alcohol (1.0 equiv) in DCM (0.1 M) at room temperature. The resulting mixture was stirred at room temperature for 12 h. LCMS showed that the reaction was complete and the solid was filtered out. The resulting mixture was concentrated to give the crude product, which was used without further purification or purified by column chromatography. General Procedure 7: Alkylation of Indole NH with Sodium Hydride Base

[0182] Under a nitrogen atmosphere, NaH (1.5 equivalents) was added in batches to a stirred solution of the substituted indole (1.0 equivalent) in DMF (0.15M) at 0°C. The resulting mixture was stirred at room temperature for 0.5h. The reaction solution was cooled to 40°C, and an alkyl electrophilic reagent (1.5 equivalents) was added in batches. The resulting mixture was stirred at room temperature for 2h. The reaction was monitored by TLC or LCMS. The reaction was then quenched with water and extracted with ethyl acetate (× 2). 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: Alkylation of heterocyclic NH or phenolic OH groups with cesium carbonate base

[0183] To a stirred solution of the substituted indole (1.0 equiv) in DMF (0.2 M) was added CsCO (3.0 equiv), TBAI (0.1 equiv) and an alkyl electrophile (1.5 equiv) at room temperature. The reaction solution was heated 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 organic layer was washed with brine (× 2), dried over sodium sulfate, concentrated and purified by column chromatography. General Procedure 9: Deprotection of benzyloxyethers via hydrogenation

[0184] To a stirred solution of benzyloxyether (1.0 equiv) in a solvent mixture (0.02-0.1 M) was added 10% Pd / C (1.0 equiv) in portions at room temperature under nitrogen. The resulting solution was stirred at room temperature overnight under a hydrogen atmosphere. The reaction was monitored by TLC and LCMS. The solid was filtered off and the resulting mixture was concentrated. The crude product was used without further purification or purified by column chromatography. General Procedure 10: Deprotection of N-sulfonic Acids with HCl

[0185] 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. Intermediate 1. 6-(Methylamino)-7-nitro-3,4-dihydroisoquinolin-1(2H)-one Step 1: Synthesis of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one

[0186] To a solution of bis(trichloromethyl)carbonate (2.0g, 6.74mmol) in DCM (20mL) was added 2-(3-fluorophenyl)ethyl-1-amine (2.7g, 19.5mmol) and EtN (2.82mL, 20.2mmol) in DCM (10mL) at 0°C. The resulting mixture was stirred at room temperature for 2h. The reaction was monitored by LCMS. The solid was filtered out and the solvent was added dropwise to a solution of AlCl(7.8g, 58.6mmol) in DCM (20mL) at 0°C. The resulting mixture was then quenched by adding water (50mL) and acidified with hydrochloric acid (aq.) (4M) to dissolve all solids, extracted with DCM (2x50 mL). The combined organic extracts were washed with brine (20mL), 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 (1.0g, 90%) as a light yellow solid. LCMS (ESI, m / z): 200 [M+H]+. Step 2: Synthesis of 6-fluoro-7-nitro-3,4-dihydro-2H-isoquinolin-1-one

[0187] Under a nitrogen atmosphere, 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (2 g, 12.1 mmol) was added to a solution of KNO (1.8 g, 18.2 mmol) in HSO (15 mL) at 0°C. The resulting solution was stirred at 0°C for 2 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of ice water (45 mL). The solid was filtered off and washed with water to obtain the title compound (2.0 g, 79%) as a yellow solid. (ESI, m / z): 211 [M+H]. Step 3: Synthesis of 6-(methylamino)-7-nitro-3,4-dihydroisoquinolin-1(2H)-one

[0188] Under a nitrogen atmosphere, 6-fluoro-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (2.0 g, 12.1 mmol) was added to a solution of methylamine (1.3 g, 42.8 mmol) in ethanol (30 mL) at 0°C. The resulting solution was stirred at 70°C for 4 h. The reaction was monitored by LCMS. The mixture was concentrated under vacuum. The crude product was purified by column chromatography (DCM / MeOH=10:1) to obtain the title compound (2.5 g, 79%) as a yellow solid. (ESI, m / z): 222 [M+H]+. Intermediate 2. 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of 1-(cyclopropylmethyl)indole-2-carbaldehyde

[0189] 1H-Indole-2-carbaldehyde (2 g, 13.8 mmol) was reacted with (bromomethyl)cyclopropane (2.2 g, 16.5 mmol) according to General Procedure 8. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to afford the title compound (2 g, 74%) as a pale yellow oil. LCMS (ESI, m / z): 200 [M+H] +. Step 2: Synthesis of 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0190] Intermediate 1 (1 g, 4.52 mmol) was reacted with 1-(cyclopropylmethyl)indole-2-carbaldehyde (900 mg, 4.52 mmol) according to General Procedure 4. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to afford the title compound (1.2 g, 72%) as a yellow solid. LCMS (ESI, m / z): 371 [M+H] +. Intermediate 3. (R)-tert-Butyl (1-(6-(methylamino)-7-nitro-1-oxo-3,4-dihydroisoquinolin-2(1H)-ylpropan-2-yl)carbamate Step 1: Synthesis of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one

[0191] Under a nitrogen atmosphere, to a solution of bis(trichloromethyl)carbonate (5.3g, 17.9mmol) in DCM (100mL) was added a solution of 2-(3-fluorophenyl)ethylamine (5g, 35.9mmol) in DCM (30mL) at 0°C, followed by dropwise addition of TEA (18.7mL, 107.8mmol) at 0°C. The resulting solution was stirred for 2h, then filtered through a Celite pad and washed with DCM (50mL). The filtrate was added to a suspension of AlCl3 (95g, 720mmol) in DCM (150mL) at 0°C. The resulting filtrate was warmed to room temperature and stirred for 16h. The reaction was quenched by adding water (150mL) and 10% HCl (25mL) and extracted with DCM (150mL). The combined DCM layers were washed with saturated sodium bicarbonate solution (500 mL) and brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1:1) to afford the title compound as a light yellow solid. LCMS (ESI, m / z): 166 [M+H] +. Step 2: Synthesis of tert-butyl (R)-(1-(6-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate

[0192] A solution of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (1.6 g, 10 mmol) was reacted with (R)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (2.8 g, 12 mmol) according to General Procedure 1. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to afford the title compound (1 g, 31%) as a yellow solid. LCMS (ESI, m / z): 323 [M+H]+. Step 3: Synthesis of tert-butyl (R)-(1-(6-(methylamino)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate

[0193] To a solution of tert-butyl (R)-(1-(6-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate (1 g, 3.1 mmol) in MeCN (30 mL) was added methylamine (2 M) (1.5 eq) in THF at room temperature. The resulting solution was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The solution was concentrated under vacuum. The crude product was purified by column chromatography (DCM / MeOH=10:1) to give the title compound (1 g, 96%) as a light yellow solid. LCMS (ESI, m / z): 334 [M+H]. Step 4: Synthesis of tert-butyl (R)-(1-(6-(methylamino)-7-nitro-1-oxo-3,4-dihydroisoquinolin-2(1H)ylpropan-2-yl)carbamate

[0194] To a solution of (R)-(1-(6-(methylamino)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamic acid tert-butyl ester (1 g, 3.0 mmol) in HSO (10 mL) was added KNO (1.2 g, 12 mmol) in portions at 0°C. The mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS. The mixture was poured into ice water (50 mL) and extracted with ethyl acetate (2 x 30 mL), the aqueous phase was basified with NaCO to pH = 9-10, THF (50 mL) and BocO (785 mg, 3.6 mmol) were added and stirred at room temperature for 16 h. The mixture was extracted with ethyl acetate (2 x 150 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, 71% yield) as a yellow solid. LCMS (ESI, m / z): 379 [M+H] +. Intermediate 4. (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)propionate

[0195] To a solution of (2S)-2-(tert-butyloxycarbonylamino)-3-hydroxy-propionic acid methyl ester (90g, 410mmol) and imidazole (30.7g, 452mmol) in DCM was added TBSCl (80.4g, 534mmol) at 0°C. After addition, the reaction mixture was stirred at 20°C for 2h. TLC showed that the starting material was completely consumed. The reaction was quenched with water at 0°C and extracted with DCM (800mL x 3). The combined organic layers were washed with brine (1L x 2), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (140g, crude material) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ: 5.34 (d, J = 8.4Hz, 1H), 4.36 (d, J = 8.8Hz, 1H), 4.06 (d, J = 2.4Hz, 1 H), 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 tert-butyl N-[(1R)-1-[[tert-butyl(dimethyl)silyl]oxyalkyl]-2-hydroxy-ethyl]carbamate

[0196] To a suspension of LiAlH4 (27.9 g, 734 mmol) in THF (1.2 L) was added a solution of (S)-2-((tert-butyloxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)methyl propionate (144 g, 432 mmol) in THF (300 mL) at 0 ° C. After addition, the reaction mixture was then stirred at 0 ° C for 1 h. TLC showed that the starting material was completely consumed. The mixture was quenched with saturated NH4Cl aqueous solution (800 mL) and filtered. Ethyl acetate (800 mL x 2) was added to the filtrate and washed with brine (800 mL), dried over anhydrous Na2SO4. The mixture was filtered and concentrated to obtain the title compound (110 g, crude material) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ: 5.06 (s, 1H), 3.75-3.58 (m, 4H), 2.70-2.61 (m, 1H), 1.38 (s, 9H), 0.82 (s, 9H), 0.00 (s, 6H). Step 3. Synthesis of tert-butyl (3R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-oxo-oxathiazolidine-3-carboxylate

[0197] To a solution of imidazole (147 g, 2.16 mol) in DCM (700 mL) was added a solution of SOCl2 (77.1 g, 648 mmol) in DCM (400 mL) at 0 ° C. After addition, the reaction mixture was stirred at 18 ° C for 1 h. A solution of tert-butyl N-[(1R)-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-hydroxy-ethyl]carbamate (110 g, 360 mmol) in DCM (600 mL) was then added to the reaction at -10 ° C. After addition, the reaction mixture was stirred at 18 ° C for 1 hr. TLC showed that the starting material was completely consumed. The reaction was quenched with aqueous citric acid solution (10%, 800 mL) and extracted with DCM (1 L x 2). The combined organic layer was washed with water (1 L x 2), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (104 g, crude material) as a light yellow oil. 1 HNMR(400MHz, CDCl3)δ:5.00-4.98(m,1H),4.83-4.72(m,2H),4.07-4.03(m,1H),3.79-3.72(m,1H),1.53(s,9H),0.89(s,9H),0.07(s,6H). Step 4. Synthesis of tert-butyl (3R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-oxathiazolidine-3-carboxylate

[0198] 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 RuCl3 (30.7 mg, 148 umol) and NaIO4 (31.6 g, 148 mmol) in H2O (500 mL) at 18°C. After addition, the reaction mixture was stirred at 18°C ​​for 1 h. TLC (petroleum ether / ethyl acetate) =2:1, R f(#4A) =0.80, R f(#4) =0.75) showed that the starting material was completely consumed. The two batches of reaction were combined and diluted with water (1 L). The aqueous phase was extracted with DCM (1 L x 2). The combined organic layers were washed with water (500 mL x 2), dried over anhydrous Na2SO4 and concentrated to give the title compound (80 g, crude material) as a light yellow solid. 1 H NMR (400MHz, CDCl3) δ: 4.64-4.58 (m, 2H), 4.28-4.27 (m, 1H), 3.89-3.76 (m, 2H), 1.56 (s, 9H), 0.90 (s, 9H), 0.09 (s, 6H). Step 5. Synthesis of tert-butyl N-[(1S)-1-(fluoromethyl)-2-hydroxy-ethyl]carbamate

[0199] To a solution of (4S)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-oxathiazolidine-3-carboxylic acid tert-butyl ester in THF (850 mL) was added TBAF (1 M, 277 mL) and stirred at 20 ° C for 1 h. TLC showed that the starting material was completely consumed. The reaction was quenched with NH4Cl aqueous solution (100 mL) and extracted with ethyl acetate (800 mL x 2). The combined organic layer was washed with water (500 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by MPLC (petroleum ether / ethyl acetate=2 / 1) to obtain the title compound as a light yellow oil. 1 H NMR (400MHz, CDCl3) 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 tert-butyl (4S)-4-(fluoromethyl)-2-oxo-oxathiazolidine-3-carboxylate

[0200] To a solution of imidazole (42.3g, 621mmol) in DCM (200mL) was added dropwise SOCl2(22.2g, 186mmol) in DCM (200mL) at 0°C, and the reaction mixture was stirred at 20°C for 1h. Then, a solution of N-[(1S)-1-(fluoromethyl)-2-hydroxy-ethyl] tert-butyl carbamate (20g, 103mmol) dissolved in DCM (200mL) was added dropwise at -10°C, and the reaction mixture was finally stirred at 20°C for 1h. TLC showed that the starting material was completely consumed. The reactant was quenched with citric acid solution to pH=5 and extracted with DCM (300mL x 3). The combined organic layer was washed with brine (200mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (22g, crude material) as a yellow oil. 1 H NMR (400MHz, CDCl3) 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 tert-butyl (S)-4-(fluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

[0201] 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 (191 mg, 919 umol) under N2, followed by dropwise addition of a solution of NaIO4 (19.7 g, 91.9 mmol) in water. 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 layers were washed with water (300 mL x 2), brine (200 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (17.5 g, crude material) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ: 4.73-4.53 (m, 5H), 1.57 (s, 9H). Intermediate 5. tert-Butyl (S)-(1-fluoro-3-(6-(methylamino)-7-nitro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate Step 1: Synthesis of tert-butyl (S)-(1-fluoro-3-(6-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate

[0202] 6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one (1.6 g, 10 mmol) was reacted with intermediate 4 (3.1 g, 12 mmol) according to General Procedure 1. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (1 g, 29%) as a yellow solid. LCMS (ESI, m / z): 341 [M+H]+. Step 2: Synthesis of tert-butyl (S)-(1-fluoro-3-(6-(methylamino)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate

[0203] To a solution of tert-butyl (S)-(1-fluoro-3-(6-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate (1 g, 2.9 mmol) in MeCN (30 mL) was added methylamine (2 M) (1.5 eq.) in THF at room temperature. The resulting solution was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The solution was concentrated under vacuum. The crude product was purified by column chromatography (DCM / MeOH=10:1) to give the title compound (1 g, 98%) as a light yellow solid. LCMS (ESI, m / z): 352 [M+H]. Step 3: Synthesis of tert-butyl (S)-(1-fluoro-3-(6-(methylamino)-7-nitro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate

[0204] To a solution of tert-butyl (S)-(1-fluoro-3-(6-(methylamino)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate (1 g, 2.9 mmol) in H2SO4 (10 mL) was added KNO3 (1.17 g, 11.6 mmol) in portions at 0°C, and the mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS. The mixture was poured into ice water (50 mL) and extracted with ethyl acetate (2x30 mL). The aqueous phase was basified with Na2CO3 (aq.) to pH = 9-10, and then THF (50 mL) and Boc2O (759 mg, 3.5 mmol) were added. The resulting solution was stirred at room temperature for 16 h. The mixture was extracted with ethyl acetate (2x150 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 (800 mg, 70% yield) as a yellow oil.LCMS (ESI, m / z): 397 [M+H] + . Intermediate 6. (S)-tert-Butyl(1-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate Step 1: Synthesis of methyl 6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

[0205] Methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (3 g, 14.2 mmol) was reacted with bromomethylcyclopropane according to General Procedure 3. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title compound (3.4 g, 89%) as a white solid. LCMS (ESI, m / z): 265 [M+H]+. Step 2: Synthesis of (6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol

[0206] Methyl 6-chloro-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridine-2-carboxylate (1 g, 3.78 mmol) was reacted according to General Procedure 5. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound as a white solid (900 mg, 71%). LCMS (ESI, m / z): 237 [M+H]+. Step 3: Synthesis of 6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde

[0207] (6-Chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol (900 mg, 3.78 mmol) was reacted according to General Procedure 6. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title compound as a green solid (807 mg, 91%). LCMS (ESI, m / z): 235 [M+H]. Intermediate 7. tert-Butyl (S)-(1-(2-(1-(cyclopropylmethyl)-7-hydroxy-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate Step 1: Synthesis of (7-benzyloxy-1H-indol-2-yl) propionate

[0208] To a solution of 2-benzyloxyaniline (145g, 728mmol) and ethyl 2-oxopropionate (211g, 1819mmol) in DMSO (50mL) was added AcOH (41.7mL, 728mmol) and Pd(OAc) (16.3g, 72.8mmol) under N2. N2 was then replaced with O2 atmosphere. The resulting solution was stirred at 70°C for 16hr. LCMS showed that the starting material was consumed and the required Ms was detected. The reaction was then quenched by adding water (2L) and extracted with ethyl acetate (1L x 2). The organic layer was washed with water (1L x2) and brine (1L), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography (petroleum ether / ethyl acetate=10 / 1 to 5:1) to obtain the title compound (80g, yield: 37%) as a white solid. 1 H NMR(400MHzDMSO-d6)δ:11.97(s,1H),7.64(d,J=7.6Hz,2H),7.41(t,J=7.2Hz,2H),7.33(d,J=6.8Hz,1H),7.24(d,J=8.0Hz,1H), 7.15 (s, 1H), 6.98 (t, J = 8.0Hz, 1H), 6.88 (d, J = 7.6Hz, 1H), 5.29 (s, 2H), 4.35 (dd, J = 7.2Hz, J = 14.4Hz, 2H), 1.35 (d, J = 6.8Hz, 3H). Step 2: Synthesis of (7-benzyloxy-1H-indol-2-yl)methanol

[0209] Ethyl 7-benzyloxy-1H-indole-2-carboxylate (87 g, 295 mmol) was reacted according to General Procedure 5 to give the title compound as a white solid (80 g, yield: 54%). 1 H NMR(400MHz DMSO-d6)δ:10.96(s,1H),7.59(d,J=7.2Hz,2H),7.44-7.35(m,3H),7.07(d,J=7.6Hz,1H),6.86(t,J=8. 0Hz, 1H), 6.71 (d, J = 7.6Hz, 1H), 6.28 (s, 1H), 5.25 (s, 2H), 5.05 (t, J = 6.0Hz, 1H), 4.59 (d, J = 6.0Hz, 2H). Step 3: Synthesis of 7-benzyloxy-1H-indole-2-carbaldehyde

[0210] A solution of (7-benzyloxy-1H-indol-2-yl)methanol (30 g, 118 mmol) was reacted according to General Procedure 6. The reaction mixture was filtered and concentrated, then the residue was triturated with petroleum ether:MTBE (120 mL, v / v, 2 / 1) for 30 min to give 24.25 g of product, which was combined with the previous batch (3.5 g), diluted in DCM (150 mL), and concentrated under reduced pressure to give the title compound (24.3 g) as a yellow solid. 1 H NMR (400MHz DMSO-d6) δ: 12.19 (s, 1H), 9.87 (s, 1H), 7.63 (d, J = 7.2Hz, 2H), 7.41-7.30 (m, 5H), 7.02-6.96 (m, 2H), 5.29 (s, 2H). Step 4: Synthesis of 7-benzyloxy-1-(cyclopropylmethyl)indole-2-carbaldehyde

[0211] 7-Benzyloxy-1H-indole-2-carbaldehyde (5 g, 19.9 mmol) was reacted with bromomethylcyclopropane (4.03 g, 29.9 mmol) according to General Procedure 8. The crude material was purified by silica gel column (petroleum ether:ethyl acetate = 20:1 to 3:1) to give 4.85 g of product, which was combined with 1.8 g of product from the previous batch, diluted with DCM (30 mL), and concentrated under reduced pressure to give the title compound (4.85 g) as a yellow solid. 1H NMR(400MHz DMSO-d6)δ:9.85(s,1H),7.55(d,J=1.6Hz,2H),7.53-7.33(m,5H),7.06-7.04(m ,2H),5.25(s,2H),4.69(d,J=6.8Hz,2H),1.25-1.20(m,1H),0.27-0.18(m,4H). Step 5: Synthesis of tert-butyl (S)-(1-(2-(7-(benzyloxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0212] 7-Benzyloxy-1-(cyclopropylmethyl)indole-2-carbaldehyde (385 mg, 1.26 mmol) was reacted with Intermediate 3 (500 mg, 1.26 mmol) according to General Procedure 4. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give the title compound (53 mg, 96%) as a yellow solid. LCMS (ESI, m / z): 652 [M+H]+. Step 6: Synthesis of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-7-hydroxy-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0213] (S)-tert-Butyl(1-(2-(7-(benzyloxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (400 mg, 0.61 mmol) in methanol (5 mL) was reacted according to General Procedure 9. The crude product was purified by silica gel column chromatography (DCM / methanol=20:1) to give the title compound as a yellow solid (300 mg, 87%). LCMS (ESI, m / z): 562 [M+H]. Intermediate 8. (R)-Tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide Step 1: (3aR)-tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1-oxide

[0214] Under a nitrogen atmosphere, a solution of imidazole (17.4g, 256mmol) in DCM (40mL) was added dropwise at room temperature to a solution of SOCl2 (9.14g, 76.82mmol) in DCM (80mL). The resulting mixture was stirred at room temperature for 1h. Under a nitrogen atmosphere, a solution of (S)-morpholine-3-ylmethanol (5g, 42.68mmol) in DCM (80mL) was added dropwise to the above mixture. 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: (R)-Tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide

[0215] Under a nitrogen atmosphere, to a solution of (3aR)-tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1-oxide (6 g, 36.77 mmol) and RuCl (938 mg, 3.68 mmol) in MeCN (200 mL) was added a solution of NaIO (8.65 g, 40.44 mmol) in water (200 mL) at room temperature. 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 (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 (3.2 g, 48%) as a white solid. LCMS (ESI, m / z): 180 [M+H] +. Intermediate 9.5-Fluoro-6-(methylamino)-7-nitro-3,4-dihydroisoquinolin-1(2H)-one Step 1. Synthesis of 2-(3-chloro-2-fluoro-phenyl)acetonitrile

[0216] Under a nitrogen atmosphere, trimethylsilyl cyanide (10.2mL, 67mmol) and TBAF (81mL, 0.97mmol) are added to a solution of 1-(bromomethyl)-3-chloro-2-fluoro-benzene (15g, 67mmol) in MeCN. The resulting mixture is stirred at 85 ° C for 0.5h under a nitrogen atmosphere. The reaction is monitored by LCMS. The resulting solution is concentrated under vacuum. The reaction is then quenched by adding water (200mL) and extracted with ethyl acetate (200mL), washed with water (5x200 mL) and brine (5x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product is purified by column chromatography (petroleum ether / ethyl acetate=20: 1) to obtain the title compound (9g, 79%) as a yellow oil. Step 2: Synthesis of 2-(3-chloro-2-fluoro-phenyl)ethylamine

[0217] Under a nitrogen atmosphere, borane (1M in THF) (120 mL, 0.97 mmol) was added to a solution of 2-(3-chloro-2-fluoro-phenyl)acetonitrile (9 g, 53 mmol) in THF (120 mL). The resulting mixture was stirred at 70 ° C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding MeOH (120 mL). The resulting mixture was stirred at room temperature for 0.5 h. The resulting solution was concentrated under vacuum. The crude product was purified by column chromatography (DCM / MeOH=10: 1) to give the title compound (3 g, 32%) as a yellow oil. LCMS (ESI, m / z): 174 [M+H] +. Step 3: Synthesis of 6-chloro-5-fluoro-3,4-dihydro-2H-isoquinolin-1-one

[0218] Under a nitrogen atmosphere, 2- (3- chloro-2- fluoro-phenyl) ethylamine (9g, 52mmol) and TEA (18mL, 104mmol) in DCM (50mL) were added to a solution of triphosgene (81mL, 21mmol) in DCM (100mL) at 0°C. The resulting mixture was stirred for 2h at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The solid was filtered out and the solvent was added dropwise to a solution of AlCl (278g, 207mmol) in DCM (120mL) at 0°C under a nitrogen atmosphere. The resulting 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 (120mL) and acidified with HCl (aq.) (4M) until no solid appeared, extracted with DCM (2x200 mL). The combined organic extracts were washed with brine (2x200 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (ethyl acetate) to give the title compound as a pale yellow oil (450 mg, 4.3%). LCMS (ESI, m / z): 200 [M+H] + . Step 4: Synthesis of 6-chloro-5-fluoro-7-nitro-3,4-dihydroisoquinolin-1(2H)-one

[0219] To a solution of 6-chloro-5-fluoro-3,4-dihydro-2H-isoquinolin-1-one (500 mg, 2.5 mmol) in H2SO4 (5 mL) was added KNO3 (252 mg, 2.5 mmol) at 0 ° C. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The reaction was then quenched by adding it to crushed ice (10 mL) and basified to pH 8 with NaOH (aq.). The solid was filtered off and concentrated under vacuum. The crude product was purified by silica gel column chromatography (ethyl acetate) to give the title compound (500 mg, 80%) as a yellow solid. LCMS (ESI, m / z): 245 [M + H] +. Step 5: Synthesis of 5-fluoro-6-(methylamino)-7-nitro-3,4-dihydroisoquinolin-1(2H)-one

[0220] To a solution of 6-chloro-5-fluoro-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (500 mg, 2.04 mmol) in MeCN (15 mL) was added MeNH2 (2M in THF) (1.8 mL, 3.07 mmol) at room temperature. The resulting mixture was stirred at 50 ° C overnight. The reaction was monitored by LCMS. The reaction was concentrated under vacuum. The crude product was purified by column chromatography (ethyl acetate) to give the title compound (120 mg, 24.5%) as a yellow solid. LCMS (ESI, m / z): 240 [M + H] +. Example 1. (R)-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-6-(2-(methylamino)propyl)-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of tert-butyl (R)-(1-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate

[0221] Intermediate 2 (50 mg, 0.13 mmol) was reacted with (R)-tert-butyl 4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide according to General Procedure 1. TLC showed that the reaction was complete, and the mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The organic layer was washed with brine (2 x 40 mL), concentrated and purified by column chromatography (DCM / MeOH = 20: 1) to give the title compound (70 mg, 98%) as a light yellow oil. LCMS (ESI, m / z): 528 [M + H] +. Step 2: Synthesis of tert-butyl (R)-(1-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)(methyl)carbamate

[0222] To a stirred solution of tert-butyl (R)-(1-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate (70 mg, 0.13 mmol) in DMF (3 mL) was added 60% NaH (10 mg, 0.27 mmol) at 0° C. and stirred for 30 min. Then, MeI (0.01 mL, 0.16 mmol) was added at 0° C. and warmed to room temperature for 2 h. LCMS showed incomplete conversion of the starting material and it was difficult to separate from the reaction mixture. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was washed with brine (2 x 40 mL), concentrated and purified by column chromatography (DCM / MeOH = 10: 1) to give the title compound (60 mg) as a yellow oil including some starting material as an impurity. LCMS (ESI, m / z): 542 [M+H] +. Step 3: Synthesis of (R)-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-6-(2-(methylamino)propyl)-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0223] (R)-tert-Butyl(1-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)(methyl)carbamate (60 mg, 0.11 mmol) was reacted according to General Procedure 2. TLC showed the reaction was complete and the mixture was concentrated. The product was purified by preparative HPLC (Method A) to give the title compound as a white solid. 1 H NMR (400MHz, methanol-d4) δ8.41–8.33(m,1H),7.69(d,J=7.9Hz,1H),7.63–7.57(m,1H),7.55–7.50(m ,1H),7.37–7.28(m,1H),7.20–7.11(m,1H),7.00(d,J=0.9Hz,1H),4.39(d,J=6.8Hz,2H),3.99– 3.93 (m, 3H), 3.83–3.66 (m, 3H), 3.58–3.44 (m, 1H), 3.28–3.19 (m, 2H), 3.14–2.99 (m, 1H), 2.46 (d, J=4.8 Hz, 3H), 1.23–1.10 (m, 3H), 1.03–0.89 (m, 1H), 0.32–0.24 (m, 2H), -0.10–-0.17 (m, 2H). LCMS (ESI, m / z): 442 [M+H]. LCMS RT: 1.636 min. (Method B).

[0224] The compounds of Examples 2 to 4 in Table 1 were obtained by following a procedure similar to that for the compound of Example 1 using an appropriate alkylating agent in step 2. Table 1 Example 5. (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of tert-butyl N-[(1R)-1-[[2-[1-(cyclopropylmethyl)indol-2-yl]-1-methyl-5-oxo-7,8-dihydroimidazo[4,5-g]isoquinolin-6-yl]methyl]propyl]carbamate

[0225] Intermediate 2 (50 mg, 0.1300 mmol, 1.00 equiv) was reacted with (4R)-4-ethyl-2,2-dioxo-oxathiazolidine-3-carboxylic acid tert-butyl ester (67.84 mg, 0.2700 mmol, 2.00 equiv) according to General Procedure 1. The residue was purified by flash column chromatography on silica gel (eluting with a gradient of 0-100% ethyl acetate / n-heptane) to give the title compound (68 mg, 0.1255 mmol, 93% yield) as an off-white solid. LCMS (ESI, m / z): 542 [M+H]+. Step 2: Synthesis of (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0226] Tert-Butyl N-[(1R)-1-[[2-[1-(cyclopropylmethyl)indol-2-yl]-1-methyl-5-oxo-7,8-dihydroimidazo[4,5-g]isoquinolin-6-yl]methyl]propyl]carbamate (60.0 mg, 0.1100 mmol, 1.00 equiv) was reacted according to General Procedure 2. The crude material was triturated with n-heptane, DCM and diethyl ether to give the title compound (55.9 mg, 0.0981 mmol, 86% yield) as an amorphous white solid. 1 H NMR (DMSO-d6, 400MHz): δ = 8.26 (s, 1H), 7.85 (br s,3H),7.73(s,1H),7.70(d,J=2.6Hz,1H),7.63(s,1H),7.32(t,J=7.3Hz,1H),7.17(d,J=7.8Hz, 1H),7.15(s,1H),4.44-4.61(m,2H),3.98(s,3H),3.76-3.86(m,1H),3.46-3.76(m,4H),3.21(br t,J=6.2Hz,2H),1.26(d,J=6.4Hz,3H),1.02-1.14(m,1H),0.23-0.32(m,2H),-0.04-0.05ppm(m,2H). LCMS(ESI,m / z):428[M+H]+. LCMSRT: 1.12min. (Method N).

[0227] The compounds of Examples 6 to 13 in Table 2 were obtained by following procedures analogous to those used to prepare the compound of Example 5, using appropriate alkylating agents. Cyclic sulfamate alkylating agents can be prepared from appropriate amino alcohols via a reaction sequence analogous to that described for Intermediate 8. Table 2 Example 14. (S)-6-(2-amino-3,3-difluoropropyl)-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-6-(2,2-dimethoxyethyl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0228] To a solution of intermediate 2 (500 mg, 1.35 mmol) in anhydrous DMF (25 mL) was added NaH (60% in mineral oil, 162 mg, 4.05 mmol) at 0 ° C and stirred under a nitrogen atmosphere for 30 minutes. 2-Bromo-1,1-dimethoxy-ethane (1.14 g, 6.75 mmol) was added dropwise to the above mixture at 0 ° C. The resulting mixture was stirred at 50 ° C for 16 h. The reaction was monitored by LCMS. The reaction was quenched by adding water (100 mL) and extracted with ethyl acetate (100 mL). The combined organic extracts were washed with water (2x100 mL) and brine (2x100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (MeOH / DCM=1:50) to obtain the title compound (400 mg, 65%) as a light yellow oil. LCMS (ESI, m / z): 459[M+H]+. Step 2: Synthesis of 2-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)acetaldehyde

[0229] To a solution of 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-6-(2,2-dimethoxyethyl)-1-methyl-1,6,7,8-tetrahydrofuran-5H-imidazo[4,5-g]isoquinolin-5-one (400 mg, 2 mmol) in aqueous DCM (4 mL) was added TFA (4 mL) and stirred for 30 minutes at room temperature. The reaction was monitored by LCMS. The solution mixture was concentrated under vacuum and basified to pH 7 with NaHCO (aq.) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product of the title compound as a light yellow oil. LCMS (ESI, m / z): 413 [M+H]. Step 3: Synthesis of (E)-6-(2-((tert-butyl(11-oxoalkyl)-13-sulfanyl)imino)ethyl)-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0230] To a solution of 2-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)acetaldehyde obtained from the previous step in anhydrous THF (4 mL) was added tert-butyl(11-oxoalkyl)-13-thiamine (72 mg, 0.58 mmol) and Ti(Oi-Pr)4 (276 mg, 0.97 mmol) at room temperature. The resulting solution was stirred at room temperature for 16 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The solution was slowly added to a stirred solution of NH4Cl in crushed ice at 0°C and stirred for 10 minutes. The mixture solution was extracted with ethyl acetate (3x20 mL), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (DCM / MeOH=15:1) to give the title compound (150 mg, 60%) as a yellow oil. LCMS (ESI, m / z): 516 [M+H] + . Step 4: Synthesis of (R)-N-((S)-3-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-1,1-difluoro-1-(phenylsulfonyl)propan-2-yl)-2-methylpropane-2-sulfinamide

[0231] To a solution of (R,E)-N-(2-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)ethylidene)-2-methylpropane-2-sulfinamide (240 mg, 0.47 mmol) and difluoromethylsulfonylbenzene (116 mg, 0.61 mmol) in THF (4 mL) was added LDA (2M in THF) (0.94 mL, 1.88 mmol) at -78 °C under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 0.5 h. The reaction was monitored by LCMS. The reaction was then quenched by the addition of saturated aqueous NH4Cl solution (20 mL) at -78 °C and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (DCM / MeOH=20:1) to give the title compound (200 mg, 60.7%) as a yellow oil.LCMS (ESI, m / z): 708 [M+H] + . Step 5: Synthesis of (R)-N-((S)-3-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-1,1-difluoropropan-2-yl)-2-methylpropane-2-sulfenamide

[0232] To a solution of (R)-N-((S)-3-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-1,1-difluoro-1-(phenylsulfonyl)propan-2-yl)-2-methylpropane-2-sulfinamide (120 mg, 0.17 mmol) and Na2HPO4 (121 mg, 0.85 mmol) in methanol (5 mL) was added sodium amalgam (Na / Hg amalgam) (20 wt% Na in Hg) (98 mg, 0.85 mmol) at -20°C. The reaction mixture was stirred at -20°C to -10°C for 2 h. The reaction was monitored by LCMS. The reaction was then quenched by the addition of saturated aqueous NH4Cl solution (20 mL) at -10°C and extracted with ethyl acetate (2x20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by column chromatography (DCM / MeOH = 30:1) to give the title compound (35 mg, 36%) as a yellow oil. LCMS (ESI, m / z): 568 [M+H] +. Step 6: Synthesis of (S)-6-(2-amino-3,3-difluoropropyl)-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0233] To a solution of (R)-N-((S)-3-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-1,1-difluoropropan-2-yl)-2-methylpropane-2-sulfinamide (35 mg, 0.06 mmol) in methanol (1.5 mL) was added HCl (4 M in dioxane) (0.15 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The solvent was evaporated under vacuum. The crude product was purified by preparative HPLC (Method G) to give the title compound (24.7 mg, 86%) as a white solid. 1 H NMR (400MHz, methanol-d4) δ8.43(s,1H),7.72(d,J=8Hz,1H),7.64–7.62(m,2H),7.38–7.33(m,1H),7.18–7.16(m,1H),7.09(s,1H),6.35(t,J= 51.3Hz,1H),4.37(d,J=6.8Hz,2H),4.10–4.04(m,2H),4.00(s,3H),3.91–3.89(m,1H),3.81–3.77(m,2H),3.34–3.30(m,2H),0.97(s,br 1H),0.32–0.28(m,2H),-0.10–-0.14(m,2H). LCMS (ESI, m / z): 464 [M+H] +. LCMS RT: 1.468 min. (Method B). Examples 15a and 15b. 6-((2S,3S)-2-amino-3-fluorobutyl)-2-(1-(cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one and 6-((2S,3R)-2-amino-3-fluorobutyl)-2-(1-(cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of tert-butyl (4S)-4-(1-hydroxyethyl)-2,2-dimethyloxazolidine-3-carboxylate

[0234] Under a nitrogen atmosphere, MeMgBr (3M in Et2O) (8.7 mL, 26.17 mmol) was added to a stirred solution of rac-(4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2 g, 8.72 mmol) in THF at -10 ° C. The resulting mixture was stirred at -10 ° C for 2 h. TLC showed that the reaction was complete, and the mixture was quenched with saturated NH4Cl aqueous solution (40 mL) and extracted with ethyl acetate (3x50 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 = 5: 1) to give the title compound formate (1.78 g, 83.2%) as a colorless oil. LCMS (ESI, m / z): 246 [M + H] + . Step 2: Synthesis of tert-butyl (4S)-4-(1-fluoroethyl)-2,2-dimethyloxazolidine-3-carboxylate

[0235] Under a nitrogen atmosphere, DAST (2.33 g, 14.51 mmol) was added to a stirred solution of (4S)-4-(1-hydroxyethyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (1.78 g, 7.26 mmol) in DCM (50 mL) at -78 ° C. The resulting mixture was stirred at -78 ° C for 2 h. The mixture was then stirred at room temperature overnight. LCMS showed that the reaction was complete, and the resulting mixture was quenched with water (40 mL) and extracted with DCM (2x40 mL). The organic matter was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the title compound (570 mg, 32%) as a colorless oil. LCMS (ESI, m / z): 192 [M + H] + . Step 3: Synthesis of (2S)-2-amino-3-fluorobutan-1-ol

[0236] To a stirred solution of (4S)-tert-butyl 4-(1-fluoroethyl)-2,2-dimethyloxazolidine-3-carboxylate (570 mg, 2.3 mmol) in 1,4-dioxane was added HCl (4 M in dioxane) (5 mL). The resulting mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete, and the mixture was concentrated. The product was used directly in the next step without further purification. LCMS (ESI, m / z): 108 [M+H] + . Step 4: Synthesis of tert-butyl ((2S)-3-fluoro-1-hydroxybutan-2-yl)carbamate

[0237] A solution of (2S)-2-amino-3-fluorobutan-1-ol (240 mg, 2.24 mmol) in THF (10 mL) was added to a round-bottom flask, and the pH was adjusted to above 10 with a saturated sodium carbonate solution. (Boc)2O (976 mg, 4.48 mmol) in THF was then added dropwise with stirring. The resulting solution was stirred at room temperature overnight. LCMS showed that the reaction was complete, and the mixture was 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 = 5: 1) to give the title compound (450 mg, 97%) as a colorless oil. LCMS (ESI, m / z): 208 [M+H] + . Step 5: Synthesis of tert-butyl (4S)-4-(1-fluoroethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide

[0238] Under a nitrogen atmosphere, a solution of SOCl2 (0.29 mL, 3.91 mmol) in DCM (5 mL) was added dropwise to a stirred solution of imidazole (887 mg, 13.03 mmol) in DCM (10 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 1 h. A solution of tert-butyl ((2S)-3-fluoro-1-hydroxybutan-2-yl)carbamate (450 mg, 2.17 mmol) in DCM (5 mL) was then added dropwise to the above mixture. The resulting mixture was stirred at room temperature for 1 h. TLC showed that the reaction was complete, and the mixture was quenched with 10% citric acid (aq.) and adjusted to pH 5-6, and extracted with DCM (3x30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The product was used directly in the next step without further purification. LCMS (ESI, m / z): 254 [M+H] + . Step 6: Synthesis of tert-butyl (4S)-4-(1-fluoroethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

[0239] To a stirred solution of (4S)-4-(1-fluoroethyl)-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2-oxide (550 mg, 2.17 mmol) in MeCN (10 mL) was added RuCl3.HO (98 mg, 0.43 mmol). To the above mixture was then added a solution of NaIO4 (511 mg, 2.39 mmol) in water (10 mL). The resulting mixture was stirred at room temperature for 1 h. TLC showed that the reaction was complete, and the mixture was extracted with ethyl acetate (3x10 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 = 5: 1) to give the title compound (350 mg, 60%) as a white solid. LCMS (ESI, m / z): 270 [M+H] + . Step 7: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluorobutan-2-yl)carbamate

[0240] 2-[1-(Cyclopropylmethyl)-7-methoxy-indol-2-yl]-1-methyl-7,8-dihydro-6H-imidazo[4,5-g]isoquinolin-5-one (100 mg, 0.25 mmol) was reacted with (4S)-tert-butyl 4-(1-fluoroethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (134 mg, 0.5 mmol) according to General Procedure 7. The residue was purified by TLC (petroleum ether:ethyl acetate = 1:2) to give the title compound (100 mg, 68%) as a yellow solid. LCMS (ESI, m / z): 590 [M+H] + . Step 8: Synthesis of 6-((2S)-2-amino-3-fluorobutyl)-2-(1-(cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0241] Tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluorobutan-2-yl)carbamate (100 mg, 0.17 mmol) was reacted according to General Procedure 2. The residue was purified by chiral-HPLC (column: CHIRALPAK IF, 2×25 cm, 5 μm; mobile phase A: MTBE+0.2% IPA)—HPLC, mobile phase B: MeOH; flow rate: 15 mL / min.; gradient: 20B to 20B over 33 min.; detection: UV (220 / 254 nm).

[0242] Example 15a. Isomer 1: Chiral HPLC RT: 26.515 min. LCMS (ESI, m / z): 490 [M+H] + . LCMS RT: 1.118 min. (Method B).

[0243] Example 15b. Isomer 2: Chiral HPLC RT: 28.085 min. LCMS (ESI, m / z): 490 [M+H] + . LCMS RT: 1.118 min. (Method B). Example 16. (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-6,7-dimethyl-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of (6,7-dimethyl-1H-indol-2-yl)methanol

[0244] 6,7-Dimethyl-1H-indole-2-carboxylic acid (200 mg, 1.05 mmol) was reacted according to General Procedure 5. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound (160 mg, 75%) as a yellow solid. LCMS (ESI, m / z): 176 [M+H] +. Step 2: Synthesis of 6,7-dimethyl-1H-indole-2-carbaldehyde

[0245] (6,7-Dimethyl-1H-indol-2-yl)methanol (160 mg, 0.91 mmol) was reacted according to General Procedure 6. The reaction was concentrated to give the title compound as a yellow oil (115 mg, 73%). LCMS (ESI, m / z): 174 [M+H] +. Step 3: Synthesis of 1-(cyclopropylmethyl)-6,7-dimethyl-1H-indole-2-carbaldehyde

[0246] 6,7-Dimethyl-1H-indole-2-carbaldehyde (110 mg, 0.64 mmol) was reacted with bromomethylcyclopropane (128 mg, 0.95 mmol) according to General Procedure 7. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound (110 mg, 76%) as a yellow oil. LCMS (ESI, m / z): 228 [M+H]+. Step 4: Synthesis of tert-butyl (R)-(1-(2-(1-(cyclopropylmethyl)-6,7-dimethyl-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate

[0247] 1-(Cyclopropylmethyl)-6,7-dimethyl-indole-2-carbaldehyde (30 mg, 0.13 mmol) was reacted with Intermediate 3 (50 mg, 0.13 mmol) according to General Procedure 4. The crude product was purified by preparative HPLC (DCM / methanol = 30:1) to give the title compound as a yellow solid (60 mg, 81%). LCMS (ESI, m / z): 556 [M+H] +. Step 5: Synthesis of (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-6,7-dimethyl-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0248] (R)-tert-Butyl(1-(2-(1-(cyclopropylmethyl)-6,7-dimethyl-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate (60 mg, 0.11 mmol) was reacted according to General Procedure 2. The compound was purified by preparative HPLC (Method C) to give the title compound (22.6 mg, 44%) as a white solid. 1H NMR (400MHz, methanol-d4) δ8.39(s,1H),7.53(s,1H),7.42(d,J=8.0Hz,1H),7.03(d,J=8.0Hz,1H),6.94(s,1H),4.51(d,J=6.5Hz,2H),3.97(s,3H),3.7 5(t,J=6.5Hz,2H),3.65–3.50(m,2H),3.38(d,J=6.4Hz,1H),3.27(t,J=6 .5Hz,2H),2.76(s,3H),2.48(s,3H),1.22(d,J=6.4Hz,3H),0.93–0.83(m 1H), 0.28–0.19 (m, 2H), -0.32–-0.40 (m 2H). LCMS (ESI, m / z): 456 [M+H]+. LCMS RT: 1.144 min. (Method B). The compounds of Examples 17 to 34 in Table 3 were obtained following procedures similar to those used to prepare the compound of Example 16 using the appropriate 2-carboxyindole or indole-2-carboxaldehyde. Table 3 Example 35. (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of 1-(cyclopropylmethyl)-7-methoxy-1H-indole

[0249] 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 the title compound (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

[0250] Under a nitrogen atmosphere, n-BuLi (2.5M in n-hexane) (1.97mL, 4.97mmol) was added in batches to a solution of 1-(cyclopropylmethyl)-7-methoxy-indole (500mg, 2.48mmol) in THF (20mL) at -78°C. The mixture was stirred at room temperature for 1h. N,N-dimethylformamide (0.38mL, 4.97mmol) was added dropwise to the above mixture at -78°C under a nitrogen atmosphere. The mixture was stirred at room temperature for 1h. The reaction was monitored by LCMS. The reaction was then quenched by adding a saturated NH4Cl aqueous solution (20mL) at -58°C and extracted with ethyl acetate (2x20 mL). The combined organic extracts were washed with brine (40mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=15:1) to obtain the title compound (133mg, 23%) as a yellow oil. LCMS (ESI, m / z): 230 [M+H] +. Step 3: Synthesis of tert-butyl (R)-(1-(2-(1-(cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate

[0251] 1-(Cyclopropylmethyl)-7-methoxy-indole-2-carbaldehyde (212 mg, 0.92 mmol) was reacted with Intermediate 3 (350 mg, 0.92 mmol) according to General Procedure 4. The crude product was purified by column chromatography (DCM / MeOH=10:1) to give the title compound (405 mg, 79%) as a light yellow oil. LCMS (ESI, m / z): 558 [M+H]+. Step 4: Synthesis of (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0252] (R)-tert-Butyl(1-(2-(1-(cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate (345 mg, 0.62 mmol) was reacted according to General Procedure 2. The crude product was purified by preparative HPLC (Method F) to give the title compound (232.8 mg, 82%) as a light yellow solid. 1H NMR (300MHz, DMSO-d6) δ8.29(s,1H),8.18(s,3H),7.73(s,1H),7.32(d,J=8.1H z,1H),7.16(s,1H),7.11(t,J=7.8Hz,1H),6.89(d,J=7.5Hz,1H),4.62(d,J=6.6 Hz,2H),3.99(s,3H),3.97(s,3H),3.80–3.58(m,5H),3.25(t,J=6.6Hz,2H),1. 27(d,J=6.3Hz,3H),0.97–0.25(m,1H),0.25–0.18(m,2H),-0.10–-0.19(m,2H). LCMS (ESI, m / z): 458 [M+H] +. LCMS RT: 1.438 min. (Method B). Example 36. (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-7-(trifluoromethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0253] Example 36 was synthesized using a synthetic route similar to that of Example 35, starting from 7-(trifluoromethyl)-1H-indole in Step 1. 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H),8.07(d,J=8Hz,1H),7.87(s,3H),7.77(d,J=7.6Hz,1H),7.66(s,1H),7.41-7.33(m,2H),4.58(d,J=6.8H z,2H),4.05(s,3H),3.82–3.53(m,5H),3.23–3.20(m,2H),1.26(d,J=6 .4Hz,3H),0.82–0.69(m,1H),0.23(d,J=8Hz,2H),-0.45–-0.66(m,2H). LCMS(ESI,m / z):496[M+H]+. LCMS RT: 1.607 min. (Method B). Example 37. (R)-2-(1-(Cyclopropylmethyl)-7-methoxy-1H-indol-2-yl)-1-methyl-6-(2-(methylamino)propyl)-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0254] Example 37 was synthesized via a similar synthetic route to Example 1 starting from Intermediate 3. The final product was purified by preparative HPLC (Method G) to give the title compound (40.5 mg, 68%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ8.50(s,1H),8.37(s,1H),8.25(s,1H),7.61(s,1H),7.28(d,J =8Hz,1H),7.13–7.04(m,2H),6.86(d,J=7.6Hz,1H),4.71–4.63(m,2H),3.97(s,3H),3.9 1(s,3H),3.89–3.86(m,1H),3.74–3.53(m,4H),3.21(t,J=6.3Hz,2H),2.62(t,J=5.2Hz ,3H),1.27(d,J=6.4Hz,3H),1.01–0.96(m,1H),0.25–0.15(m,2H),-0.13–-0.21(m,2H). LCMS(ESI,m / z):472[M+H]+. LCMS RT: 1.482 min. (Method B). Example 38. (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-6-isopropyl-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of 6-bromo-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde

[0255] 6-Bromo-1H-indole-2-carbaldehyde (500 mg, 2.23 mmol) was reacted with bromomethylcyclopropane (451 mg, 3.35 mmol) according to General Procedure 3. The crude material was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give the title compound as a yellow oil (420 mg, 68%). LCMS (ESI, m / z): 278 [M+H] +. Step 2: Synthesis of 1-(cyclopropylmethyl)-6-(prop-1-en-2-yl)-1H-indole-2-carbaldehyde

[0256] Under nitrogen atmosphere, 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (241mg, 1.44mmol), K3PO4 (609mg, 2.88mmol) and Pd(PPh3)4 (58mg, 0.05mmol) were added in batches to a solution of 6-bromo-1-(cyclopropylmethyl)indole-2-carboxaldehyde (200mg, 0.72mmol) in 1,4-dioxanes (5mL) and water (1mL) at room temperature. The resulting solution was stirred at 80 DEG C for 2h. The reaction was monitored by LCMS. The reaction was then quenched by adding water (20mL) and extracted with ethyl acetate (2x20 mL). The combined organic extracts were washed with brine (20mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=4 / 1) to give 1-(cyclopropylmethyl)-6-isopropenyl-indole-2-carbaldehyde (165 mg, 96%) as a yellow oil. LCMS (ESI, m / z): 240 [M+H] + . Step 3: Synthesis of 1-(cyclopropylmethyl)-6-isopropyl-1H-indole-2-carbaldehyde

[0257] To a stirred solution of 1-(cyclopropylmethyl)-6-isopropenyl-indole-2-carboxaldehyde (165 mg, 0.69 mmol) in methanol (10 mL) was added PtO2 (156 mg, 0.69 mmol) under N2. The mixture was stirred at room temperature for 0.5 h under H2. TLC showed that the reaction of the starting material was complete and non-polar spots were formed. The solid was filtered off and the solvent was evaporated under vacuum. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=4 / 1) to give 1-(cyclopropylmethyl)-6-isopropyl-indole-2-carboxaldehyde (130 mg, 78%) as a yellow oil. LCMS (ESI, m / z): 242 [M+H]+. Step 4: Synthesis of tert-butyl (R)-(1-(2-(1-(cyclopropylmethyl)-6-isopropyl-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate

[0258] 1-(Cyclopropylmethyl)-6-isopropyl-indole-2-carbaldehyde (31 mg, 0.13 mmol) was reacted with Intermediate 3 (50 mg, 0.13 mmol) according to General Procedure 4. The crude material was purified by column chromatography (DCM / methanol=30 / 1) to give the title compound (51 mg, 58%) as a yellow oil. LCMS (ESI, m / z): 570 [M+H]+. Step 5: Synthesis of (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-6-isopropyl-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0259] (R)-tert-Butyl(1-(2-(1-(cyclopropylmethyl)-6-isopropyl-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate (51 mg, 0.09 mmol) was reacted according to General Procedure 2. The compound was purified by preparative HPLC (Method C) to give the title compound (23.1 mg, 55%) as a white solid. LCMS (ESI, m / z): 470 [M+H]. LCMS RT: 1.704 min. (Method B).

[0260] The compounds of Examples 39 to 41 in Table 4 were obtained following a procedure similar to that used to prepare the compound of Example 38, using the appropriate boronate Suzuki coupling partner in step 2. Table 4 Example 42. (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-6-(oxetan-3-yl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of 1-(cyclopropylmethyl)-6-(oxetan-3-yl)-1H-indole-2-carbaldehyde

[0261] To a stirred solution of 6-bromo-1-(cyclopropylmethyl)indole-2-carboxaldehyde (40 mg, 0.14 mmol) in ethylene glycol dimethyl ether (2 mL) was added 3-bromooxetane (30 mg, 0.22 mmol), [Ir(dFCF3ppy)2(dtbpy)]PF6(2 mg), (TMS)3SiH(36 mg, 0.14 mmol), Na2CO3(31 mg, 0.29 mmol), NiCl(dme)(1 mg) and dtbpy(1 mg) under a nitrogen atmosphere. The reaction was stirred and irradiated overnight with a blue LED lamp (7 cm outside, keeping the reaction temperature at room temperature). LCMS showed that the reaction was complete and quenched by exposure to air. The solid was filtered off. The resulting compound was concentrated. The residue was passed through preparative TLC (petroleum ether:ethyl acetate=4:1) to give the title compound (20 mg, 54%) as a yellow oil. LCMS (ESI, m / z): 256 [M+H] + . Step 2: Synthesis of tert-butyl (R)-(1-(2-(1-(cyclopropylmethyl)-6-(oxetan-3-yl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate

[0262] 1-(Cyclopropylmethyl)-6-(oxetan-3-yl)-1H-indole-2-carbaldehyde (20 mg, 0.08 mmol) was reacted with Intermediate 3 (30 mg, 0.08 mmol) according to General Procedure 4. The crude material was purified by preparative TLC (DCM:MeOH=20:1) to give the title compound (30 mg, 66%) as a yellow oil. LCMS (ESI, m / z): 584 [M+H] + . Step 3: Synthesis of (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-6-(oxetan-3-yl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0263] A stirred solution of (R)-tert-butyl(1-(2-(1-(cyclopropylmethyl)-6-(oxetan-3-yl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate (30 mg, 0.05 mmol) in DCM (2 mL) was reacted according to General Procedure 2. The residue was purified by preparative HPLC (Method G) to give the title compound (6.8 mg, 27%) as a white solid.1 H NMR(400MHz,CD3OD-d4)δ8.41(s,1H),7.74(d,J=8.2Hz,1H),7.64(s,1H),7.60(s,1H),7 .32(d,J=8.3Hz,1H),7.05(s,1H),5.21–5.15(m,2H),4.91–4.85(m,2H),4.52–4.43(m,1H ),4.40(d,J=6.8Hz,2H),3.99(s,3H),3.98–3.90(m,1H),3.84–3.60(m,5H),3.34–3.32( m,1H),1.41(d,J=6.6Hz,3H),1.02–0.93(m,1H),0.34–0.27(m,2H),-0.08–-0.16(m,2H). LCMS(ESI,m / z):484[M+H] + . Example 43. (R)-6-(2-aminopropyl)-2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of tert-butyl (R)-(1-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate

[0264] 6-Chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (186 mg, 0.79 mmol) was reacted with Intermediate 3 (300 mg, 0.79 mmol) according to General Procedure 4. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (161 mg, 36%) as a yellow solid. LCMS (ESI, m / z): 563 [M+H]+. Step 2: Synthesis of (R)-6-(2-aminopropyl)-2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0265] (R)-tert-Butyl(1-(2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate was reacted according to General Procedure 2. The crude product was purified by preparative HPLC (Method E) to give the title compound (36.4 mg, 84%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.28–8.20(m,2H),7.89(s,3H),7.64(s,1H),7.31–7.24(m,2H),4.55(d,J=15.6Hz,2H ),3.99(s,3H),3.81–3.54(m,5H),3.23–3.19(m,2H),1.27–1.08(m,4H),0.43–0.22(m,2H),0.11–0.08(m,2H). LCMS(ESI,m / z):463[M+H]+. LCMS RT: 1.535min. (Method B). Example 44. (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of tert-butyl (R)-(1-(2-(1-(cyclopropylmethyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate

[0266] To a solution of intermediate 6 (50 mg, 0.09 mmol) and methanol (0.5 mL) in 1,4-dioxane (0.5 mL) was added KOH (15 mg, 0.27 mmol) and t-Bu-BrettPhos (8.6 mg, 0.02 mmol) and Pd2(dba)3 (8.1 mg, 0.01 mmol) under a nitrogen atmosphere. The mixture was irradiated with microwave radiation at 90 ° C for 2 h. The reaction was monitored by LCMS. The reaction was then quenched by adding water (10 mL) and extracted with ethyl acetate (10 mL), washed with water (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 (48 mg, 97%) as a light yellow oil. LCMS (ESI, m / z): 559 [M+H]+. Step 2: Synthesis of (R)-6-(2-aminomethyl)-2-(1-(cyclopropylmethyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0267] (R)-tert-Butyl(1-(2-(1-(cyclopropylmethyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate (58 mg, 0.10 mmol) was reacted according to General Procedure 2. The crude product was purified by preparative HPLC (Method E) to give the title compound (47.1 mg, 99%) as a white solid. LCMS (ESI, m / z): 459 [M+H]. LCMS RT: 1.475 min. (Method B). Example 45. (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-6-oxo-6,7-dihydro-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0268] Example 45 was synthesized using a similar synthetic route to Example 44, using water as the nucleophile in Step 1. The crude product was purified by preparative HPLC (Method C) to give the title compound (22.5 mg, 88%). 1 H NMR (400MHz, DMSO-d6) δ8.23(d,J=1.6Hz,1H),7.94(d,J=8.0Hz,1H),7.85(s,3H),7.59(s,1H),6.52(d,J=8.0Hz,1H),4.51(d,J=36Hz,2H),3.97 (s,3H),3.81-3.51(m,5H),3.21-3.18(m,2H),3.23-3.20(m,2H),1.26(d ,J=4.0Hz,3H),1.15-1.08(m,1H),0.25–0.21(m,2H),0.09–0.04(m,2H). LCMS(ESI,m / z):445[M+H]+. LCMS RT: 1.142 min. (Method B). Example 46. (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-3-fluoro-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of 3-fluoro-1H-indole-2-carbaldehyde

[0269] To a solution of 1H-indole-2-carboxaldehyde (300 mg, 2.07 mmol) in acetonitrile (10 mL) was added 1-(chloromethyl)-4-fluoropiperazine (315 mg, 2.07 mmol) and K2CO3 (857 mg, 6.21 mmol). The resulting solution was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=5:1) to give the title compound (150 mg, 79%) as a light yellow solid. LCMS (ESI, m / z): 163 [M+H]+. Step 2: Synthesis of 1-(cyclopropylmethyl)-3-fluoro-1H-indole-2-carbaldehyde

[0270] A solution of 3-fluoro-1H-indole-2-carbaldehyde (80 mg, 0.49 mmol) was reacted according to General Procedure 8. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 8:1) to give the title compound as a brown oil (75 mg, 41%). LCMS (ESI, m / z): 217 [M+H] +. Step 3: Synthesis of tert-butyl (R)-(1-(2-(1-(cyclopropylmethyl)-3-fluoro-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate

[0271] 1-(Cyclopropylmethyl)-3-fluoro-indole-2-carbaldehyde (75 mg, 0.34 mmol) was reacted with Intermediate 3 (141 mg, 0.37 mmol) according to General Procedure 4. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound as a brown solid (50 mg, 66%). LCMS (ESI, m / z): 546 [M+H] +. Step 4: Synthesis of (R)-6-(2-aminopropyl)-2-(1-(cyclopropylmethyl)-3-fluoro-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0272] (R)-tert-Butyl(1-(2-(1-(cyclopropylmethyl)-3-fluoro-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate (50 mg, 0.09 mmol) was reacted according to General Procedure 2. The crude product was purified by preparative HPLC (Method E) to give the title compound (25.3 mg, 62%) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.28(s,1H),7.82–7.70(m,5H),7.64(s,1H),7.41–7.37(m,1H),7.35–7.21(m,1H),4.32(d,J=6.8Hz,2 H),3.88(s,3H),3.80–3.51(m,5H),3.26–3.21(m,2H),1.25(s,3H),0.97–0.95(m,1H),0.27–0.25(m,2H),-0.01–-0.12(m,2H). LCMS(ESI,m / z):446[M+H]+. LCMS RT: 1.554min. (Method B).

[0273] The compounds of Examples 47 to 55 in Table 5 were obtained by following a procedure similar to that used to prepare the compound of Example 16, using the appropriate indole-2-carboxaldehyde and Intermediate 4 in Step 4. Example 56. (S)-6-(2-amino-3-fluoropropyl)-2-(6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0274] Intermediate 6 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 (32.5 mg, 78%). LCMS (ESI, m / z): 481 [M+H] +; LCMS RT: 1.611 min. (Method B). Example 57. (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-6-(4-(1,1-dioxoisothiazolidin-2-yl)-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: tert-Butyl (S)-(1-(2-(1-(cyclopropylmethyl)-6-(4-(1,1-dioxidoisothiazolidin-2-yl)-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0275] To a solution of intermediate 6 (100 mg, 0.17 mmol) and 2-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-thiazolidine 1,1-dioxide (70 mg, 0.21 mmol) in DMF (1.5 mL) and water (0.3 mL) was added Pd(dppf)Cl2 (28 mg, 0.03 mmol) and Na2CO3 (55 mg, 0.52 mmol) under a nitrogen atmosphere. The mixture was stirred at 70 ° C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (10 mL) and extracted with ethyl acetate (10 mL), washed with water (2x10 mL) and brine (2x10 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1:5) to give the title compound (100 mg, 77%) as a white solid. LCMS (ESI, m / z): 756 [M+H] + . Step 2: Synthesis of (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-6-(4-(1,1-dioxidoisothiazolidin-2-yl)-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0276] (S)-tert-Butyl(1-(2-(1-(cyclopropylmethyl)-6-(4-(1,1-dioxidoisothiazolidin-2-yl)-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (80 mg, 0.11 mmol) was reacted according to General Procedure 2. The crude product was purified by preparative HPLC (Method G) to give the title compound as a yellow solid (49.4 mg, 71%). 1 H NMR (400MHz, DMSO-d6): δ8.30(s,3H),8.28(s,1H),8.20(d,J=8.0Hz,1H),7.65(s,1H) ,7.52(t,J=6.4Hz,1H),7.38(d,J=8.0Hz,1H),7.26–7.13(m,3H),4.78–4.60(m,4H),4 0.02 (s, 3H), 3.87–3.80 (m, 4H), 3.72–3.67 (m, 3H), 3.56 (t, J = 7.2 Hz, 2H), 3.22 (t, J = 6.0 Hz, 2H), 2.53–2.33 (m, 5H), 1.18–1.15 (m, 1H), 0.30–0.27 (m, 2H), 0.12–0.09 (m, 2H). LCMS (ESI, m / z): 656 [M+H]. LCMS RT: 1.325 min. (Method D).

[0277] The compounds of Examples 58 to 60 in Table 6 were obtained by following procedures similar to those used to prepare the compound of Example 57 using the appropriate boronic acid ester in Step 1. Table 6 Synthesis of key coupling partners used in Example 58 Step 1: Synthesis of 3-(4-bromo-3-methyl-phenyl)-5,5-dimethyl-oxazolidin-2-one

[0278] To a solution of 1- bromo- 4- indole -2- methyl - benzene (520mg, 1.75mmol), 5,5- dimethyloxazolidin-2-one (403mg, 3.5mmol) and K2CO3 (726mg, 5.25mmol) in MeCN (7mL) was added CuI (66mg, 0.35mmol) and N, N, N', N'-tetramethyl-1,2-ethylenediamine (81mg, 0.70mmol) under a nitrogen atmosphere. The resulting solution was stirred at 70 DEG C for 16h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (30mL) and extracted with ethyl acetate (2x30mL), washed with water (30mL) and brine (30mL), 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 (490mg, 98.5%) as a white solid. LCMS (ESI, m / z): 284 [M+H] +. Step 2: Synthesis of 5,5-dimethyl-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-2-one

[0279] To a solution of 3-(4-bromo-3-methyl-phenyl)-5,5-dimethyl-oxazolidin-2-one (150 mg, 0.53 mmol), bis(pinacolato)diboron (268 mg, 1.1 mmol) and potassium acetate (155 mg, 1.58 mmol) in 1,4-dioxane (5 mL) was added Pd(dppf)Cl2 (77.2 mg, 0.11 mmol) under a nitrogen atmosphere. The resulting solution was stirred at 80 ° C for 16 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The crude product was continued for the next step. LCMS (ESI, m / z): 250 [M + H] +. Synthesis of key coupling partners used in Example 60 Step 1: Synthesis of 4-bromo-2-fluoro-5-methyl-benzamide

[0280] To a stirred solution of 4-bromo-2-fluoro-5-methyl-benzoic acid (1000 mg, 4.29 mmol) in DMF (20 mL) was added HATU (2447 mg, 6.44 mmol) and stirred for 30 min at room temperature, DIEA (2.24 mL, 12.87 mmol) and NH4Cl (278 mg, 5.15 mmol) were then added thereto at 0 ° C. and warmed to room temperature for 2 h. The reaction was monitored by TLC and LCMS. The mixture was quenched with water (30 ml) and extracted with ethyl acetate (2x30 mL). The organic layer was washed with brine (2x30 mL) and dried over anhydrous sodium sulfate, concentrated and purified by preparative TLC (petroleum ether / ethyl acetate=1: 1) to obtain the title compound (830 mg, 83%) as a white solid. LCMS (ESI, m / z): 232 [M+H] + . Step 2: Synthesis of 2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

[0281] Under a nitrogen atmosphere, to a stirred solution of 4-bromo-2-fluoro-5-methyl-benzamide (830 mg, 3.58 mmol) in MeCN (20 mL) was added bis(pinacolato)diboron (1817 mg, 7.15 mmol) and AcOK (1052 mg, 10.73 mmol) at room temperature, followed by addition of Pcy3.HBF4 (263 mg, 0.72 mmol) and Pd(OAc)2 (80 mg, 0.36 mmol) and the mixture was warmed to 80 ° C and stirred overnight. The product was detected on LCMS. The mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and purified by column chromatography to give the title compound (80 mg, 8%) as a white solid. LCMS (ESI, m / z): 280 [M + H] + . Example 61. (S)-3-(5-(2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-6-ethylpyridin-2-yl)oxazolidin-2-one Step 1: Synthesis of 5-bromo-6-ethyl-pyridin-2-amine

[0282] Under a nitrogen atmosphere, NBS (1.78 g, 9.99 mmol) was added to a solution of 6-ethylpyridine-2-amine (1.22 g, 9.99 mmol) in MeCN (100 mL) at 0 ° C. 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 water (300 mL) and extracted with ethyl acetate (2x300 mL), washed with brine (500 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=1: 3) to obtain the title compound (1.5 g, 74%) as a light brown solid. LCMS (ESI, m / z): 201 [M+H] +. Step 2: Synthesis of 3-(5-bromo-6-ethyl-2-pyridyl)oxazolidin-2-one

[0283] Under a nitrogen atmosphere, TMEDA (0.01 mL, 0.1 mmol), CuI (9 mg, 0.05 mmol) and K2CO3 (203 mg, 1.47 mmol) were added to a stirred solution of 3,6-dibromo-2-ethyl-pyridine (130 mg, 0.49 mmol) and oxazolidin-2-one (42 mg, 0.49 mmol) in 1,4-dioxane (5 mL) at room temperature. The resulting mixture was stirred at 100 ° C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (20 mL) and extracted with ethyl acetate (2x20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10: 1) to obtain the title compound (50 mg, 37%) as a yellow solid. LCMS (ESI, m / z): 271 [M+H] +. Step 3: Synthesis of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-6-(2-ethyl-6-(2-oxooxazolidin-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0284] To a solution of (S)-(2-(6-(2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)boronic acid (45 mg, 0.17 mmol) in 1,4-dioxane (1 mL) was added Pd(dppf)Cl (13 mg, 0.02 mmol) and KCO (35 mg, 0.25 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 80 ° C. for 16 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by the addition of water (10 mL) and extracted with ethyl acetate (2×10 mL), washed with water (20 mL) and brine (20 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 as a light yellow solid (50 mg, 80%). LCMS (ESI, m / z): 737 [M+H] + . Step 4: Synthesis of (S)-3-(5-(2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-6-ethylpyridin-2-yl)oxazolidin-2-one

[0285] To a solution of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-6-(2-ethyl-6-(2-oxooxazolidin-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (50 mg, 0.07 mmol) in DCM (3 mL) was added TFA (1 mL) dropwise at 0° C. under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 0.5 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting solution was concentrated under vacuum. The crude product was purified by preparative HPLC (Method G) to give the title compound (38.1 mg, 87%) as a yellow solid. LCMS (ESI, m / z): 637 [M+H] + . LCMS RT: 1.088 min. (Method D). Example 62. (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-6-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0286] Example 62 was synthesized via a synthetic route similar to that of Example 44. LCMS (ESI, m / z): 477.5 [M+H] + ; LCMS RT: 1.20 min. (Method N). Example 63. (S)-2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-N-methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxamide Step 1: Synthesis of (S)-methyl 2-(6-(2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylate

[0287] To a solution of intermediate 6 (260 mg, 0.45 mmol) in methanol (20 mL) was added Et3N (0.19 mL, 1.34 mmol) and Pd (dppf) Cl2 (33 mg, 0.04 mmol). The resulting mixture was stirred at 90 ° C overnight under a carbon monoxide atmosphere (30 atm). The reaction was monitored by LCMS. The mixture was concentrated under vacuum. The crude product was purified by column chromatography (DCM / MeOH = 20: 1) to give the title compound (180 mg, 67%) as a light yellow solid. LCMS (ESI, m / z): 605 [M + H] +. Step 2: Synthesis of (S)-2-(6-(2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid

[0288] To a solution of (S)-2-(6-(2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid methyl ester (110 mg, 0.18 mmol) in methanol (2 mL) and water (1 mL) was added NaOH (73 mg, 1.82 mmol) under a nitrogen atmosphere. The resulting solution was stirred at 50 ° C for 1 h. The reaction was monitored by LCMS. The reaction mixture was concentrated. The residue was adjusted to pH 5-6 with HCl (1 M). The mixture was extracted with ethyl acetate (3×20 ml) and washed with brine (30 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 as a yellow solid (90 mg, 84%). LCMS (ESI, m / z): 591 [M+H] + . Step 3: Synthesis of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-6-(methylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0289] To a solution of (S)-2-(6-(2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (50 mg, 0.08 mmol) in DMF (1.5 mL) was added HATU (48 mg, 0.13 mmol), DIEA (0.04 mL, 0.25 mmol) and methylamine (4 mg, 0.11 mmol). The mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction was then quenched by the addition of water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with water (2×20 mL) and brine (2×20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (DCM / MeOH=20:1) to give the title compound (40 mg, 78%) as a yellow solid. LCMS (ESI, m / z): 604 [M+H] + . Step 4: Synthesis of (S)-2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-N-methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxamide

[0290] (S)-tert-Butyl(1-(2-(1-(cyclopropylmethyl)-6-(methylcarbamoyl)-1H-pyrrolo[2,3-b]pyridin-2yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2yl)carbamate (40 mg, 0.07 mmol) was reacted according to General Procedure 2. The crude product was purified by preparative HPLC (Method E) to give the title compound (29 mg, 87%) as a white solid. 1 H NMR (400MHz, DMSO-d6+D2O): δ8.29–8.26(m,2H),7.91(d,J=8Hz,1H),7.65(s,1H),7.26(s,1H),4.78–4.66(m,4H),3.9 9(s,3H),3.86–3.66(m,5H),3.24–3.21(m,2H),2.90(s,3H),1.12–1.01(m,1H),0.26–0.23(m,2H),0.09–0.02(m,2H). LCMS(ESI,m / z):504[M+H]+. LCMS RT: 1.523min. (Method B). Example 64. (S)-2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-N,N-dimethyl-1H-pyrrolo[2,3-b]pyridine-6-carboxamide

[0291] Example 64 was synthesized via a similar reaction sequence to Example 63 using dimethylamine in step 3. 1HNMR (400MHz, DMSO-d6+D2O): δ8.29–8.24(m,2H),7.65(s,1H),7.41(d,J=10.4Hz,1H),7.25(s,1H),4.86–4.58(m,4H),4.01( s,3H),3.89–3.68(m,5H),3.24–3.17(m,2H),3.08(d,J=2.4Hz,6H),1.12–1.01(m,1H),0.30–0.27(m,2H),0.07–0.05(m,2H). LCMS(ESI,m / z):518[M+H]+. RT: 2.183min. (Method B). Example 65. (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-5-fluoro-7-methoxy-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of ethyl 5-fluoro-7-methoxy-1H-indole-2-carboxylate

[0292] Under a nitrogen atmosphere, ethyl 2-oxopropanoate (617 mg, 5.31 mmol), Pd(OAc)2 (79 mg, 0.35 mmol) and AcOH (0.2 mL, 3.54 mmol) were added to a stirred solution of 4-fluoro-2-methoxy-aniline (500 mg, 3.54 mmol) in DMSO (30 mL). The reaction was stirred at 70 ° C overnight under an O2 atmosphere. LCMS showed that the reaction was complete, and the mixture was quenched with water (30 mL) and extracted with ethyl acetate (3x30 mL). The organic layer was washed with brine (2x60 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain the title compound (370 mg, 44%) as a yellow oil. LCMS (ESI, m / z): 238 [M + H] + . Step 2: Synthesis of 1-(cyclopropylmethyl)-5-fluoro-7-methoxy-indole-2-carboxylic acid ethyl ester

[0293] Under a nitrogen atmosphere, bromomethylcyclopropane (316 mg, 2.34 mmol), Cs2CO3 (1.5 g, 4.68 mmol) and TBAI (75 mg, 0.31 mmol) were added to a stirred solution of 5-fluoro-7-methoxy-1H-indole-2-carboxylic acid ethyl ester (370 mg, 1.56 mmol) in DMF (15 mL). The resulting mixture was stirred at 50 ° C for 2 h. The reaction was monitored by LCMS. The reaction was quenched by adding water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic extracts were washed with brine (2x40 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC (petroleum ether: ethyl acetate = 20: 1) to obtain the title compound (300 mg, 66%) as a yellow oil. LCMS (ESI, m / z): 292 [M + H] + . Step 3: Synthesis of 1-(cyclopropylmethyl)-5-fluoro-7-methoxy-indol-2-yl]methanol

[0294] 1-(Cyclopropylmethyl)-5-fluoro-7-methoxy-indole-2-carboxylic acid ethyl ester (100 mg, 0.34 mmol) was reacted according to General Procedure 5. The crude material was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound as a yellow oil (80 mg, 94%). LCMS (ESI, m / z): 250 [M+H] + . Step 4: Synthesis of 1-(cyclopropylmethyl)-5-fluoro-7-methoxy-indole-2-carbaldehyde

[0295] (1-(Cyclopropylmethyl)-5-fluoro-7-methoxy-indol-2-yl)methanol (80 mg, 0.32 mmol) was reacted according to General Procedure 6. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to give the title compound as a yellow oil (70 mg, 88%). LCMS (ESI, m / z): 248 [M+H] + . Step 5: Synthesis of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-5-fluoro-7-methoxy-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0296] 1-(Cyclopropylmethyl)-5-fluoro-7-methoxy-indole-2-carbaldehyde was reacted with Intermediate 3 (50 mg, 0.13 mmol) according to General Procedure 4. The residue was purified by preparative TLC (DCM / MeOH=20:1) to give the title compound (60 mg, 80%) as a yellow oil. LCMS (ESI, m / z): 594 [M+H] + . Step 6: Synthesis of (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-5-fluoro-7-methoxy-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0297] (S)-tert-Butyl(1-(2-(1-(cyclopropylmethyl)-5-fluoro-7-methoxy-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (60 mg, 0.10 mmol) was reacted according to General Procedure 2. The crude material was purified by preparative HPLC (Method G) to give the title compound (30.7 mg, 59%) as a yellow solid. 1 HNMR (400MHz, DMSO-d6): δ8.70–8.57(m,3H),8.27(s,1H),7.74(s,1H),7.14( s,1H),7.10–7.04(m,1H),6.86–6.80(m,1H),4.86-4.59(m,2H),4.56(d,J=7. 0Hz,2H),4.00(s,3H),3.94(s,3H),3.87–3.76(m,3H),3.75–3.68(m,2H),3.2 4(t,J=6.4Hz,2H),1.01–0.90(m,1H),0.26–0.17(m,2H),-0.12–-0.20(m,2H). LCMS (ESI, m / z): 494 [M+H] + . LCMS RT: 1.118 min. (Method D). Example 66. (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-6-fluoro-7-methoxy-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0298] Example 66 was synthesized via a synthetic route similar to that of Example 65, starting from 4-fluoro-2-methoxy-aniline.1 H NMR (400MHz, DMSO-d6) δ8.30(s,3H),8.25(s,1H),7.62(s,1H),7.42(dd,J=8.7, 4.6Hz,1H),7.13(s,1H),7.09(dd,J=12.2,8.7Hz,1H),4.82–4.65(m,2H),4.64– 4.59(m,2H),4.05(s,3H),3.92(s,3H),3.88–3.79(m,2H),3.76–3.65(m,3H),3. 22(t,J=6.4Hz,2H),1.04–0.93(m,1H),0.24–0.18(m,2H),-0.16–-0.25(m,2H). LCMS (ESI, m / z): 494 [M+H] + . LCMS RT: 1.520 min. (Method D). Example 67. (S)-2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indole-6-carboxylic acid Step 1: Synthesis of tert-butyl (S)-(1-(2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0299] 6-Bromo-1-(cyclopropylmethyl)indole-2-carbaldehyde (84 mg, 0.30 mmol) was reacted with Intermediate 5 according to General Procedure 4 (100 mg, 0.25 mmol). The crude material was purified by preparative TLC with DCM / MeOH (30:1) to give the title compound as a yellow solid (150 mg, 95%). LCMS (ESI, m / z): 624 [M+H]. Step 2: Synthesis of (S)-methyl 2-(6-(2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indole-6-carboxylate

[0300] To a solution of tert-butyl (S)-(1-(2-(6-bromo-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (120 mg, 0.19 mmol) in methanol (5 mL) was added AcONa (63 mg, 0.77 mmol) and Pd(dppf)Cl2 (28 mg, 0.04 mmol) under a nitrogen atmosphere. The mixture solution was stirred at 80 ° C. overnight under a carbon monoxide atmosphere. The reaction was monitored by LCMS and TLC, respectively. The reaction was cooled to ambient temperature. The resulting mixture was partitioned between ethyl acetate (10 mL) and water (10 mL), and the aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic fractions were washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was finally purified by preparative TLC using petroleum ether / ethyl acetate (1:1) to afford the title compound (102 mg, 88%) as a yellow solid. LCMS (ESI, m / z): 604 [M+H]. Step 3: Synthesis of (S)-2-(6-(2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indole-6-carboxylic acid

[0301] To a solution of (S)-methyl 2-(6-(2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indole-6-carboxylate (60 mg, 0.10 mmol) in THF (2 mL) and water (1 mL) was added LiOH (39 mg, 0.99 mmol). The resulting mixture was stirred at ambient temperature for 6 h under a nitrogen atmosphere. The reaction was monitored by LCMS. Prior to purification, the resulting solution should be adjusted to a pH below 7 with 1 M HCl. The reaction was then quenched by the addition of water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (47 mg, 80%) as a yellow solid. LCMS (ESI, m / z): 590 [M+H] +. Step 4: Synthesis of (S)-2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indole-6-carboxylic acid

[0302] (S)-2-(6-(2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indole-6-carboxylic acid was reacted according to General Procedure 2. The crude material was purified by preparative HPLC (Method C) to give the title compound (23.8 mg, 64%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ12.83(br,1H),8.30(s,2H),8.26(br,3H),7.83-7.71(m,2H),7.64(s,1H),7.24(s,1H),4.82–4.64(m,2H),4.61(s,2H),3 .98(s,3H),3.92-3.76(m,2H),3.76-3.61(m,3H),3.22(t,J=6.4Hz,2H), 1.14-1.02(m,1H),0.29(d,J=9.2,2.8Hz,2H),0.02(d,J=6.0,2.9Hz,2H). LCMS(ESI,m / z):490[M+H]+. LCMS RT: 1.293 min. (Method B). Example 68. (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of ethyl 6-bromo-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0303] Ethyl 6-bromo-1H-indole-2-carboxylate (500 mg, 1.86 mmol) was reacted with bromomethylcyclopropane (377 mg, 2.8 mmol) according to General Procedure 8. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (600 mg, 99%) as a yellow solid. LCMS (ESI, m / z): 322 [M+H]+. Step 2: Synthesis of ethyl 1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indole-2-carboxylate

[0304] Under a nitrogen atmosphere, to a solution of ethyl 6-bromo-1-(cyclopropylmethyl)indole-2-carboxylate (520 mg, 1.61 mmol) and 4-methoxypiperidine (278 mg, 2.42 mmol) in DMSO (16 mL) was added KCO (445 mg, 3.23 mmol), DL-proline (37 mg, 0.32 mmol) and CuI (30 mg, 0.16 mmol). The mixture was stirred at 110 ° C for 22 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (100 mL) and extracted with ethyl acetate (100 mL), washed with water (2x100 mL) and brine (2x100 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 obtain the title compound (260 mg, 45%) as a yellow solid. LCMS (ESI, m / z): 357 [M+H] +. Step 3: Synthesis of (1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indol-2-yl)methanol

[0305] Ethyl 1-(cyclopropylmethyl)-6-(4-methoxy-1-piperidinyl)indole-2-carboxylate (250 mg, 0.7 mmol) was reacted according to General Procedure 5. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound as a yellow solid (200 mg, 90%). LCMS (ESI, m / z): 315 [M+H] +. Step 4: Synthesis of 1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indole-2-carbaldehyde

[0306] [1-(Cyclopropylmethyl)-6-(4-methoxy-1-piperidinyl)indol-2-yl]methanol (220 mg, 0.7 mmol) was reacted according to General Procedure 6. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound as a yellow solid (200 mg, 91%). LCMS (ESI, m / z): 313 [M+H]+. Step 5: Synthesis of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0307] 1-(Cyclopropylmethyl)-6-(4-methoxy-1-piperidinyl)indole-2-carbaldehyde (39 mg, 0.13 mmol) was reacted with Intermediate 5 according to General Procedure 4. The crude product was purified by preparative TLC (DCM / MeOH=20:1) to give tert-butyl N-[(1S)-1-[[2-[1-(cyclopropylmethyl)-6-(4-methoxy-1-piperidinyl)indol-2-yl]-1-methyl-5-oxo-7,8-dihydroimidazo[4,5-g]isoquinolin-6-yl]methyl]-2-fluoro-ethyl]carbamate (50 mg, 60.2%) as a yellow solid. LCMS (ESI, m / z): 659 [M+H] + . Step 6: Synthesis of (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0308] (S)-tert-Butyl(1-(2-(1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (50 mg, 0.08 mmol) was reacted according to General Procedure 2. The mixture was concentrated and purified by preparative HPLC (Method A) to give the title compound as a yellow solid (22.7 mg, 53%). LCMS (ESI, m / z): 559 [M+H] + . LCMS RT: 1.173 min. (Method D). Example 69. (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(dimethylamino)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of ethyl 1-(cyclopropylmethyl)-7-(dimethylamino)indole-2-carboxylate

[0309] Under a nitrogen atmosphere, to a solution of ethyl 7-bromo-1-(cyclopropylmethyl)indole-2-carboxylate (200 mg, 0.62 mmol) in toluene (5 mL) was added N-methylmethylamine (36 mg, 0.81 mmol), Pd2(dba)3 (57 mg, 0.06 mmol), BINAP (77.3 mg, 0.12 mmol) and sodium tert-butoxide (179 mg, 1.86 mmol). The resulting mixture was stirred at 50 ° C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The solvent was evaporated under vacuum. The crude product was purified by column chromatography (DCM / MeOH=10:1) to give the title compound (100 mg, 56%) as a yellow solid. LCMS (ESI, m / z): 287 [M+H] +. Step 2: Synthesis of (1-(cyclopropylmethyl)-7-(dimethylamino)-1H-indol-2-yl)methanol

[0310] Ethyl 1-(cyclopropylmethyl)-7-(dimethylamino)indole-2-carboxylate (100 mg, 0.39 mmol) was reacted according to General Procedure 5. The solid was filtered off and the solvent was concentrated under vacuum to give the compound as a light brown solid (70 mg, 74%). LCMS (ESI, m / z): 245 [M+H]+. Step 3: Synthesis of 1-(cyclopropylmethyl)-7-(dimethylamino)indole-2-carbaldehyde

[0311] (1-(Cyclopropylmethyl)-7-(dimethylamino)-1H-indol-2-yl)methanol (70 mg, 0.29 mmol) was reacted according to General Procedure 6. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound as a light yellow solid (30 mg, 43%). LCMS (ESI, m / z): 243 [M+H]. Step 4: Synthesis of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-7-(dimethylamino)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0312] 1-(Cyclopropylmethyl)-7-(dimethylamino)indole-2-carbaldehyde (20 mg, 0.08 mmol) was reacted with Intermediate 5 (30 mg, 0.08 mmol) according to General Procedure 4. The crude product was purified by column chromatography (DCM / MeOH=15:1) to give the title compound (25 mg, 56%) as a yellow solid. LCMS (ESI, m / z): 589 [M+H]+. Step 5: Synthesis of (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(dimethylamino)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0313] (S)-tert-Butyl(1-(2-(1-(cyclopropylmethyl)-7-(dimethylamino)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-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 the title compound (10.2 mg, 48%) as a yellow solid. 1 HNMR (400MHz, DMSO-d6+D2O): δ8.26(s,1H),7.65(s,1H),7.41(d,J=0.8Hz,1H),7.18(s,1H),7.11–7.06(m,2H),4.77–4.59(m,4H) ),3.97(s,3H),3.90–3.64(m,5H),3.21(t,J=6.4Hz,2H),2.76(s,6H),0.61–0.58(m,1H),0.08–0.06(m,2H),-0.27–-0.37(m,2H). LCMS(ESI,m / z):489[M+H]+. LCMS RT: 1.547 min. (Method B). Example 70. (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-6-fluoro-7-methoxy-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0314] Example 70 was synthesized via a similar reaction sequence to Example 69 using morpholine as the nucleophile in step 1. 1H NMR (400MHz, DMSO-d6+D2O): δ8.25(s,1H),7.63(s,1H),7.49–7.46(m,1H),7.16–7.09(m,3H),4.79–4.62(m,4H),3.95(s, 3H),3.90–3.65(m,9H),3.23–3.19(m,2H),3.08–2.92(m,4H),0.78–0.63(m,1H),0.16–0.05(m,2H),-0.14–-0.24(m,2H). LCMS(ESI,m / z):531[M+H]+. LCMS RT: 1.502 min. (Method B).

[0315] The compounds of Examples 71 to 84 in Table 7 were obtained following procedures analogous to those for the preparation of the compound of Example 16, starting from the appropriate 2-carboxyindole in step 1 and / or indole 2-carboxaldehyde and an alkylating agent in step 3. Table 7 Example 85. (R)-2-(1-(Cyclopropylmethyl)-1H-indol-2-yl)-6-(2-hydroxypropyl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of (R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-ol

[0316] To a stirred solution of (R)-propane-1,2-diol (500 mg, 6.57 mmol) in DMF (30 mL) was added NaH (394 mg, 9.86 mmol) at 0 ° C and stirred for 30 min. TBDPSCl (1.71 mL, 6.57 mmol) was then added thereto at 0 ° C. The reaction mixture was stirred at room temperature for 1 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 washed with brine (2x60 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=30: 1) to obtain the title compound (1.6 g, 77.4%) as a yellow oil. LCMS (ESI, m / z): 315 [M+H] + . Step 2: Synthesis of tert-butyldiphenyl((2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)silane

[0317] To a stirred solution of (R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-ol (800 mg, 2.54 mmol) in DCM (25 mL) was added p-TSA (44 mg, 0.25 mmol) and 3,4-dihydro-2H-pyran (1.07 g, 12.72 mmol). The resulting mixture was stirred at room temperature for 2 h. LCMS showed that the reaction was complete, and the mixture was concentrated. The residue was passed through silica gel (petroleum ether:ethyl acetate=100:1) to give the title compound (340 mg, 33.5%) as a colorless oil. LCMS (ESI, m / z): 399 [M+H] + . Step 3: Synthesis of (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol

[0318] To a stirred solution of tert-butyldiphenyl((2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)silane (340 mg, 0.85 mmol) in THF (3 mL) was added TBAF (1 M in THF) (3 mL). The resulting mixture was stirred at room temperature for 3 h. LCMS showed that the reaction was complete, and the mixture was concentrated. The residue was passed through silica gel (petroleum ether:ethyl acetate = 10:1) to give the title compound (100 mg, 73.2%) as a colorless oil. LCMS (ESI, m / z): 161 [M+H] + . Step 4: Synthesis of (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl methanesulfonate

[0319] To a stirred solution of (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (50 mg, 0.31 mmol) in DCM (3 mL) was added TEA (0.13 mL, 0.94 mmol). MsCl (42 mg, 0.37 mmol) was then added thereto at 0 ° C. The resulting mixture was stirred at room temperature for 1 h. LCMS showed that the reaction was complete, and the mixture was quenched with water (15 mL) and extracted with DCM (3x15 mL). The organic layer was washed with brine (2x40 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was passed through silica gel (petroleum ether: ethyl acetate = 20: 1) to give the title compound (60 mg, 80.7%) as a yellow oil. LCMS (ESI, m / z): 239 [M + H] + . Step 5: Synthesis of 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-6-((2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0320] To a stirred solution of 2-[1-(cyclopropylmethyl)indol-2-yl]-1-methyl-7,8-dihydro-6H-imidazo[4,5-g]isoquinolin-5-one (110 mg, 0.3 mmol) in DMF (3 mL) was added NaH (36 mg, 0.89 mmol) at 0 ° C and stirred for 30 min. Then, methanesulfonic acid (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl ester (106 mg, 0.45 mmol) and TBAI (14 mg, 0.06 mmol) were added thereto at 0 ° C. The resulting mixture was stirred at 50 ° C overnight. LCMS showed that the reaction was not complete, and the mixture was quenched with water (15 mL) and extracted with ethyl acetate (3x15 mL). The organic layer was washed with brine (2x40 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was subjected to preparative TLC (DCM:MeOH=20:1) to give the title compound (100 mg, 65.7%) as a yellow oil. LCMS (ESI, m / z): 513 [M+H] + . Step 6: Synthesis of (R)-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-6-(2-hydroxypropyl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0321] To a stirred solution of 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-6-((2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one in THF (2 mL) was added HCl (4N in 1,4-dioxane) (2 mL). The resulting mixture was stirred at room temperature for 0.5 h. LCMS showed the reaction was complete, and the mixture was concentrated. The residue was purified by preparative HPLC (Method C) to give the title compound (52.1 mg, 61.9%) as a white solid. 1H NMR (400MHz, CD3OD-d4) δ8.37(s,1H),7.69(d,J=7.9Hz,1H),7.60(d,J=8.4Hz,1H),7. 51(s,1H),7.36–7.28(m,1H),7.20–7.11(m,1H),6.99(s,1H),4.39(d,J=6.8Hz,2H),4. 19–4.07(m,1H),3.95(s,3H),3.88–3.70(m,3H),3.46–3.36(m,1H),3.23(t,J=6.6Hz, 2H),1.24(d,J=6.3Hz,3H),1.04–0.90(m,1H),0.33–0.22(m,2H),-0.09–-0.17(m,2H). LCMS(ESI,m / z):429[M+H] + . LCMS RT: 1.118 min. (Method D).

[0322] The compounds of Examples 86 to 91 in Table 8 were obtained following a procedure analogous to the preparation of the compound of Example 35, starting in step 1 from the appropriately substituted indole and an alkylating agent. Table 8 Example 92. (R)-6-(2-aminopropyl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of ethyl 1-(2-hydroxy-2-methylpropyl)-1H-indole-2-carboxylate

[0323] To 1H-indole-2-carboxylic acid ethyl ester (80 mg, 0.42 mmol) in DMF (2 mL) was added K2CO3 (175 mg, 1.27 mmol) and 2,2-dimethyloxirane (60 mg, 0.85 mmol) at room temperature. The resulting mixture was stirred at 70 ° C for 4 h. TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (2x30 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The obtained orange sticky solid was purified by preparative TLC (petroleum ether / ethyl acetate=2: 1) to obtain the title compound (46 mg, 46.6%) as a yellow oil. LCMS (ESI, m / z): 262 [M+H] +. Step 2: Synthesis of 1-(2-(hydroxymethyl)-1H-indol-1-yl)-2-methylpropan-2-ol

[0324] Ethyl 1-(2-hydroxy-2-methyl-propyl)indole-2-carboxylate (46 mg, 0.18 mmol) was reacted according to General Procedure 5. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 1:1) to give the title compound as a yellow oil (40 mg, 93.1%). LCMS (ESI, m / z): 220 [M+H] +. Step 3: Synthesis of 1-(2-hydroxy-2-methylpropyl)-1H-indole-2-carbaldehyde

[0325] 1-(2-(Hydroxymethyl)-1H-indol-1-yl)-2-methylpropan-2-ol (40 mg, 0.18 mmol) was reacted according to General Procedure 6. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 1:1) to give the title compound as a yellow oil (27 mg, 68.1%). LCMS (ESI, m / z): 218 [M+H]+. Step 4: Synthesis of tert-butyl (R)-(1-(2-(1-(2-hydroxy-2-methylpropyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate

[0326] 1-(2-Hydroxy-2-methyl-propyl)indole-2-carbaldehyde (27 mg, 0.12 mmol) was reacted with Intermediate 3 (47 mg, 0.12 mmol) according to General Procedure 4. The crude product was purified by preparative TLC (DCM / MeOH=10:1) to give the title compound (35 mg, 51.6%) as a yellow oil. LCMS (ESI, m / z): 546 [M+H]+. Step 5: Synthesis of (R)-6-(2-aminopropyl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0327] (R)-tert-Butyl(1-(2-(1-(2-hydroxy-2-methylpropyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate (35 mg, 0.06 mmol) was reacted according to General Procedure 2. The crude material was purified by preparative HPLC (Method C) to give the title compound (17.7 mg, 61.6%) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ 8.44 (s, 1H), 7.80–7.65 (m, 3H), 7.40 (t, J = 8.4 Hz, 1H), 7.28–7.17 (m, 2H), 4.55 (s, 2H), 4.09 (s, 3H), 4.01–3.92 (m, 1H), 3.87–3.64 (m, 4H), 1.43 (d, J = 6.5 Hz, 3H), 1.08 (s, 6H). LCMS (ESI, m / z): 446 [M+H]. LCMS RT: 1.281 min. (Method D). Example 93. (S)-6-(2-amino-3-fluoropropyl)-2-(1-(isoxazol-5-ylmethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of 1-(isoxazol-5-ylmethyl)indole-2-carbaldehyde

[0328] 1H-Indole-2-carbaldehyde (30 mg, 0.21 mmol) was reacted with 5-(bromomethyl)isoxazole (100 mg, 0.62 mmol) according to General Procedure 3. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound as a yellow oil (30 mg, 64.1%). LCMS (ESI, m / z): 227 [M+H] +. Step 2: Synthesis of tert-butyl (S)-(1-fluoro-3-(2-(1-(isoxazol-5-ylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate

[0329] 1-(Isoxazol-5-ylmethyl)indole-2-carbaldehyde (30 mg, 0.14 mmol) was reacted with Intermediate 5 (45 mg, 0.11 mmol) according to General Procedure 4. The crude product was purified by column chromatography (DCM / MeOH=20:1) to give the title compound (40 mg, 61.5%) as a yellow solid. LCMS (ESI, m / z): 573 [M+H]+. Step 3: Synthesis of (S)-6-(2-amino-3-fluoropropyl)-2-(1-(isoxazol-5-ylmethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0330] (S)-tert-Butyl(1-fluoro-3-(2-(1-(isoxazol-5-ylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate was reacted according to General Procedure 2. The crude material was purified by preparative HPLC (Method C) to give the title compound (27.5 mg, 83%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ8.34(br,4H),8.26(s,1H),7.83 -7.68(m,2H),7.62(s,1H),7.42-7.25(m,2H),7.25-7.13(m,1H),6.19(s,2H),6.12(d,J=1.8Hz,1H ),4.88-4.53(m,2H),3.99(s,3H),3.92-3.69(m,2H),3.67(t,J=6.5Hz,2H),3.21(t,J=6.4Hz,2H). LCMS(ESI,m / z):473[M+H]+. LCMS RT: 1.50min. (Method B).

[0331] The compounds of Examples 94 to 101 in Table 9 were obtained following procedures analogous to the preparation of the compound of Example 93, starting from the appropriate alkylating agent. Table 9 Example 102. (S)-6-(2-amino-3-fluoropropyl)-2-(7-methoxy-1-(2-methoxyethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of tert-butyl (S)-(1-fluoro-3-(2-(7-methoxy-1-(2-methoxyethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate

[0332] 7-Methoxy-1-(2-methoxyethyl)indole-2-carbaldehyde (53 mg, 0.23 mmol) was reacted with Intermediate 5 (92 mg, 0.23 mmol) according to General Procedure 4. The crude product was purified by column chromatography (DCM / MeOH=15:1) to give the title compound (93 mg, 69%) as a yellow oil. LCMS (ESI, m / z): 580 [M+H]+. Step 2: Synthesis of (S)-6-(2-amino-3-fluoropropyl)-2-(7-methoxy-1-(2-methoxyethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0333] (S)-tert-Butyl(1-fluoro-3-(2-(7-methoxy-1-(2-methoxyethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate (93 mg, 0.16 mmol) was reacted according to General Procedure 2. The crude material was purified by preparative HPLC (Method E) to give the title compound (69.3 mg, 89.8%) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6): δ8.31(s,3H),8.25(s,1H),7.60(s,1H),7.26(d,J=8Hz,1H),7.08–7.01(m,2H),6.84(d,J=7.6Hz,1H),4.88(t,J=5.2Hz,2 H),4.78–4.61(m,2H),3.95(s,3H),3.89(s,3H),3.86–3.81(m,2H),3.74 –3.65(m,3H),3.45(t,J=5.6Hz,2H),3.21(t,J=6.4Hz,2H),2.86(s,3H). LCMS(ESI,m / z):480[M+H]+. LCMS RT: 1.314 min. (Method B).

[0334] The compounds of Examples 103 to 146 in Table 10 were obtained following procedures analogous to the preparation of the compound of Example 102, starting from the appropriate indole-2-carboxaldehyde. Table 10 Example 147. (S)-6-(2-amino-3-fluoropropyl)-2-(1-((1-methoxycyclopropyl)methyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of ethyl 2-indol-1-yl acetate

[0335] Indole (1.17 g, 9.99 mmol) was reacted with ethyl 2-bromoacetate (2.5 g, 15.0 mmol) according to General Procedure 7. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (1.1 g, 54.1%) as a light yellow oil. LCMS (ESI, m / z): 204 [M+H] +. Step 2: Synthesis of 1-(indol-1-ylmethyl)cyclopropanol

[0336] To a solution of ethyl 2-indol-1-yl acetate (1.1 g, 5.41 mmol) and Ti(OPr-i)4 (2.31 g, 8.12 mmol) in THF (50 mL) was added ethyl magnesium chloride (2N in THF) (10.8 mL, 21.6 mmol) dropwise at 0 ° C. The mixture was stirred at room temperature for 0.5 h. The reaction was monitored by LCMS. The reaction was then quenched by adding 10 mL of HCl (1 N). The mixture was stirred at room temperature for 0.5 h. The pH value of the solution was adjusted to 8 with sodium bicarbonate. Water (150 mL) was added to the resulting solution, extracted with ethyl acetate (2x100 ml), 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=5: 1) to obtain the title compound (650 mg, 65%) as a white solid. LCMS (ESI, m / z): 188 [M+H]+. Step 3: Synthesis of 1-((1-methoxycyclopropyl)methyl)-1H-indole

[0337] To a solution of 1-(indol-1-ylmethyl)cyclopropanol (650mg, 3.47mmol) in DMF (34mL) was added NaH (278mg, 6.94mmol) in batches at 0°C. The mixture was stirred at room temperature for 0.5h. Iodomethane (985mg, 6.94mmol) was added to the above mixture solution at 0°C. The mixture was stirred at room temperature for 2h. The reaction was monitored by LCMS. The reaction was then quenched by adding water (100mL) and extracted with ethyl acetate (100mL). The combined organic extracts were washed with water (100mL) and brine (100mL), 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 (300mg, 42.9%) as a light yellow oil. LCMS (ESI, m / z): 202[M+H]+. Step 4: Synthesis of 1-((1-methoxycyclopropyl)methyl)-1H-indole

[0338] To a solution of 1-((1-methoxycyclopropyl)methyl)-1H-indole (100 mg, 0.50 mmol) in THF (5 mL) was added n-BuLi (2.5 N in n-hexane) (0.5 mL, 1.24 mmol) in batches at -78 ° C. The mixture was stirred at room temperature for 1 h. DMF (0.11 mL, 1.49 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 quenched by adding water (20 mL) and extracted with ethyl acetate (2x20 mL). The combined organic extracts were purified by column chromatography (petroleum ether / ethyl acetate=50: 1) to give the title compound (25 mg, 21.9%) as a light yellow oil. LCMS (ESI, m / z): 230 [M + H] +. Step 5: Synthesis of tert-butyl (S)-(1-fluoro-3-(2-(1-((1-methoxycyclopropyl)methyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate

[0339] 1-((1-methoxycyclopropyl)methyl)-1H-indole-2-carbaldehyde (36 mg, 0.16 mmol) was reacted with Intermediate 5 (62 mg, 0.16 mmol) according to General Procedure 4. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (31 mg, 34.2%) as a light yellow solid. LCMS (ESI, m / z): 576 [M+H] +. Step 6: Synthesis of (S)-6-(2-amino-3-fluoropropyl)-2-(1-((1-methoxycyclopropyl)methyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0340] (S)-tert-Butyl(1-fluoro-3-(2-(1-((1-methoxycyclopropyl)methyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate (31 mg, 0.05 mmol) was reacted according to General Procedure 2. The crude product was purified by preparative HPLC (Method C) to give the title compound (15.7 mg, 25.6%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 8.44 (s, 1H), 7.73 (d, J = 8 Hz, 1H), 7.67-7.64 (m, 2H), 7.39-7.34 (m, 1H), 7.22-7.18 (m, 1H), 7.13 (s, 1H), 4.91-4.66 (m, 4H), 4.08-3.92 (m, 5H), 3.84-3.77 (m, 3H), 3.36-3.33 (m, 2H), 2.56 (s, 3H), 0.61-0.58 (m, 2H), 0.46-0.43 (m, 2H). LCMS (ESI, m / z): 476 [M+H]. LCMS RT: 1.382 min. (Method B). Example 148. (S)-2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(isoxazol-5-ylmethyl)-1H-indole-7-carbonitrile Step 1: Synthesis of methyl 7-cyano-1H-indole-2-carboxylate

[0341] To a solution of 7-bromo-1H-indole-2-formic acid methyl ester (1.2g, 4.7mmol) in DMF (20mL) was added CuCN (423mg, 4.7mmol). The resulting solution was stirred at 155 ° C for 6h. The reaction was monitored by TLC. The reaction was then quenched by adding water (100mL) and extracted with ethyl acetate (100mL), washed with water (2x100 mL) and brine (2x100 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 (460mg, 48.6%) as a white solid. Step 2: Synthesis of 2-(hydroxymethyl)-1H-indole-7-carbonitrile

[0342] To a solution of 7-cyano-1H-indole-2-carboxylic acid methyl ester (460 mg, 2.3 mmol) in methanol (20 mL) was added NaBH4 (17.5 mg, 46 mmol) at 0 ° C. The resulting solution was stirred at room temperature for 5 h. The reaction was monitored by LCMS. The solvent was evaporated under vacuum. The residue was diluted with water (50 mL) and extracted with DCM (3x50 mL), 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 (140 mg, 35.4%) as a white solid. LCMS (ESI, m / z): 173 [M+H]+. Step 3: Synthesis of 2-formyl-1H-indole-7-carbonitrile

[0343] 2-(Hydroxymethyl)-1H-indole-7-carbonitrile (130 mg, 0.76 mmol) was reacted according to General Procedure 6. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (100 mg, 77.8%) as a white solid. LCMS (ESI, m / z): 171 [M+H] +. Step 4: Synthesis of 2-formyl-1-(isoxazol-5-ylmethyl)indole-7-carbonitrile

[0344] 2-Formyl-1H-indole-7-carbonitrile (100 mg, 0.59 mmol) was reacted with 5-(bromomethyl)isoxazole (95 mg, 0.59 mmol) according to General Procedure 8. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound (110 mg, 74.5%) as a yellow solid. LCMS (ESI, m / z): 252 [M+H] +. Step 5: Synthesis of tert-butyl (S)-(1-(2-(7-cyano-1-(isoxazol-5-ylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0345] 2-Formyl-1-(isoxazol-5-ylmethyl)indole-7-carbonitrile was reacted with Intermediate 5 according to General Procedure 4. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:5) to give the title compound (55 mg, 73.1%) as a white solid. LCMS (ESI, m / z): 552 [M+H]+. Step 6: Synthesis of (S)-2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(isoxazol-5-ylmethyl)-1H-indole-7-carbonitrile

[0346] (S)-tert-Butyl(1-(2-(7-cyano-1-(isoxazol-5-ylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (51 mg, 0.09 mmol) was reacted according to General Procedure 2. The crude product was purified by preparative HPLC (Method G) to give the title compound (28.3 mg, 66.1%) as a white solid. 1HNMR(300MHz,DMSO-d6)δ8.43(s,1H),8.40-8.26(m,3H),8.15(d,J=7.8Hz,1H),7.87(d,J=7.5Hz,1H),7.64(s,1H),7.51(s,1H),7. 41–7.36(m,1H),6.41(s,2H),6.04(s,1H),4.81-4.56(m,2H),3.96(s,3H),3.91–3.81(m,2H),3.68-3.64(m,3H),3.21-3.11(m,2H). LCMS(ESI,m / z):498[M+H]+. LCMSRT: 1.546min. (Method B). Example 149. (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(oxetan-3-ylmethoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-7-(oxetan-3-ylmethoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0347] Intermediate 7 (50 mg, 0.09 mmol) in DMF (1.5 mL) was reacted with 3-(bromomethyl)oxetane (20 mg, 0.13 mmol) and Cs2CO3 (87 mg, 0.27 mmol) at 50°C according to General Procedure 8. The crude product was purified by column chromatography (DCM / MeOH=15:1) to give the title compound (50 mg, 59.7%) as a yellow oil. LCMS (ESI, m / z): 632 [M+H] + . Step 2: Synthesis of (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(oxetan-3-ylmethoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0348] (S)-tert-Butyl(1-(2-(1-(cyclopropylmethyl)-7-(oxetan-3-ylmethoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (50 mg, 0.08 mmol) was reacted according to General Procedure 2. The reaction was monitored by LCMS. The resulting solution was concentrated under vacuum. The crude product was purified by preparative HPLC (Method E) to give the title compound (31.3 mg, 72.6%) as a white solid. 1 H NMR (400MHz, DMSO-d6+D2O): δ8.24(s,1H),7.61(s,1H),7.29(d,J=7.9Hz,1H), 7.09–7.04(m,2H),6.88(d,J=8.1Hz,1H),4.81–4.76(m,2H),4.71–4.54(m,5H), 4.37(d,J=4.2Hz,2H),3.95–3.79(m,5H),3.73–3.59(m,4H),3.55–3.49(m,1H) ,3.24–3.16(m,2H),1.05–0.86(m,1H),0.21–0.15(m,2H),-0.18–-0.26(m,2H). LCMS (ESI, m / z): 532 [M+H] + . LCMS RT: 2.213 min. (Method B).

[0349] The compounds of Examples 150 to 186 in Table 11 were obtained by following procedures similar to those used to prepare the compound of Example 149 using appropriate alkylating agents including alkyl iodides, alkyl bromides, alkyl chlorides, and mesylate. Table 11 Example 187. 6-((S)-2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(((S)-morpholin-3-yl)methoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of tert-butyl (S)-3-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate

[0350] To a stirred solution of (R)-tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (400 mg, 1.84 mmol) in DCM (10 mL) was added TEA (0.38 mL, 2.76 mmol) and MsCl (0.17 mL, 2.21 mmol) at 0 ° C. The mixture was stirred for 1 h and the reaction was allowed to reach room temperature. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound (550 mg, 101.2%) as a yellow solid. The crude product was used directly in the next step. LCMS (ESI, m / z): 240 [M + H] + . Step 2: Synthesis of tert-butyl (S)-3-(((2-(6-((S)-2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)morpholine-4-carboxylate

[0351] Intermediate 7 (50 mg, 0.09 mmol) in DMF (2 mL) at 50° C. was reacted with CsCO (87 mg, 0.27 mmol), (S)-tert-butyl 3-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate (52 mg, 0.18 mmol) and TBAI (4 mg, 0.02 mmol) according to General Procedure 8. The crude product was purified by preparative TLC (DCM / MeOH=20:1) to give the title compound (25 mg, 36.9%) as a brown oil. LCMS (ESI, m / z): 761 [M+H] + . Step 3: Synthesis of 6-((S)-2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(((S)-morpholin-3-yl)methoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0352] (S)-tert-Butyl 3-(((2-(6-((S)-2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)methyl)morpholine-4-carboxylate (25 mg, 0.03 mmol) was reacted according to General Procedure 2. The reaction was monitored by TLC and LCMS. The resulting solution was concentrated under vacuum. The crude product was purified by preparative HPLC (Method E) to give the title compound (7.7 mg, 40.9%) as a white solid. 1 H NMR(400MHz, DMSO-d6+D2O)δ8.25(s,1H),7.62(s,1H),7.37(d,J=7.8Hz,1H),7.11(t,J=7.9Hz,1H), 7.09(s,1H),6.92(d,J=7.8Hz,1H),4.83–4.68(m,2H),4.67–4.54(m,2H),4.47–4.35(m,2H),4.21(d, J=10.0Hz,1H),4.04–3.97(m,1H),3.92(s,3H),3.89–3.83(m,2H),3.83–3.77(m,2H),3.77–3.67(m,4 H),3.41–3.33(m,1H),3.31–3.18(m,3H),1.03–0.91(m,1H),0.27–0.14(m,2H),-0.19–-0.38(m,2H). LCMS(ESI,m / z):561[M+H] + . LCMS RT: 1.831 min. (Method D).

[0353] The compounds of Examples 188 to 193 in Table 12 were obtained following procedures similar to those used to prepare the compound of Example 187 using the appropriate alcohol. Table 12 Example 194. (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(2-(oxazol-5-yl)ethoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of 2-(oxazol-5-yl)ethan-1-ol

[0354] Under a nitrogen atmosphere, BH3-THF (2.5 mL, 2.36 mmol) was added to a stirred solution of 2-oxazol-5-yl acetic acid (100 mg, 0.79 mmol) in THF (5 mL) at 0 ° C. The mixture was stirred at 0 ° C. for 2 h under a nitrogen atmosphere. LCMS showed that the reaction was complete, and the mixture was quenched with MeOH. The mixture was concentrated. The product was used directly in the next step without further purification. LCMS (ESI, m / z): 114 [M + H] + . Step 2: Synthesis of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-7-(2-(oxazol-5-yl)ethoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0355] Under a nitrogen atmosphere, 2-(oxazol-5-yl)ethane-1-ol, DTBAD (31 mg, 0.13 mmol) and PPh3 (35 mg, 0.13 mmol) were added to a stirred solution of intermediate 7 (50 mg, 0.09 mmol) in toluene (2 mL). The mixture was stirred at 80 ° C for 2 h under a nitrogen atmosphere. LCMS showed that the starting material was no longer converted into product and the mixture was concentrated. The residue was purified by preparative TLC (DCM: MeOH = 20: 1) to give the title compound as a yellow oil. LCMS (ESI, m / z): 657 [M + H] + . Step 3: Synthesis of (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(2-(oxazol-5-yl)ethoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0356] (S)-tert-Butyl(1-(2-(1-(cyclopropylmethyl)-7-(2-(oxazol-5-yl)ethoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (20 mg, 0.03 mmol) was reacted according to General Procedure 2. LCMS showed the reaction was complete, and the mixture was concentrated. The residue was purified by preparative HPLC (Method E) to give the title compound (7.3 mg, 42.2%) as a white solid. 1HNMR (400MHz, DMSO-d6): δ8.37–8.29(m,2H),8.29(s,1H),8.24(s,1H),7.60(s,1H),7.27(d,J=7. 9Hz,1H),7.08–7.02(m,3H),6.88(d,J=7.8Hz,1H),4.87–4.62(m,2H),4.56(d,J=7.1Hz,2H),4.45 (t,J=6.0Hz,2H),3.90(s,3H),3.87–3.78(m,2H),3.76–3.70(m,1H),3.67(t,J=6.5Hz,2H),3.28( t,J=6.0Hz,2H),3.21(t,J=6.4Hz,2H),0.89–0.79(m,1H),0.07–0.09(m,2H),-0.24–-0.31(m,2H). LCMS(ESI,m / z):557[M+H] + . LCMS RT: 1.118 min. (Method D). The compounds of Examples 195 to 204 in Table 13 were obtained by following procedures similar to those used to prepare the compound of Example 194 using appropriate carboxylic acid or alcohol reagents. Table 13 Example 205. (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(2-hydroxyethoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of ethyl 7-benzyloxy-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0357] Ethyl 7-benzyloxy-1H-indole-2-carboxylate (1 g, 3.39 mmol) was alkylated with bromomethylcyclopropane according to General Procedure 8. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 6:1) to give the title compound (850 mg, 89%) as a pale yellow solid. LCMS (ESI, m / z): 350 [M+H]. Step 2: Synthesis of ethyl 1-(cyclopropylmethyl)-7-hydroxy-1H-indole-2-carboxylate

[0358] Ethyl 7-(benzyloxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (500 mg, 1.42 mmol) was reacted in methanol (70 mL) and AcOH (70 mg, 1.16 mmol) according to General Procedure 9. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (350 mg, 45%) as a light yellow solid. LCMS (ESI, m / z): 352 [M+H]+. Step 3: Synthesis of ethyl 7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0359] Ethyl 1-(cyclopropylmethyl)-7-hydroxy-1H-indole-2-carboxylate (100 mg, 0.39 mmol) in DMF (5 mL) was reacted with tert-butyl(2-iodoethoxy)dimethylsilane (331 mg, 1.15 mmol) and CsCO (377 mg, 1.16 mmol) at 50° C. according to General Procedure 8. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 9:1) to give the title compound (100 mg, 62.1%) as a yellow oil. LCMS (ESI, m / z): 418 [M+H]+. Step 4: Synthesis of (7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol

[0360] Ethyl 7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (150 mg, 0.36 mmol) was reacted according to General Procedure 5. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 1:1) to give the title compound as a yellow solid (110 mg, 81.3%). LCMS (ESI, m / z): 376 [M+H]. Step 5: Synthesis of 7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde

[0361] (7-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol (70 mg, 0.19 mmol) was reacted according to General Procedure 6. The reaction mixture was filtered through a pad of Celite and concentrated. The crude product was finally purified by preparative TLC (petroleum ether / ethyl acetate = 4:1) to give the title compound (60 mg, 86.1%) as a yellow solid. LCMS (ESI, m / z): 374 [M+H] +. Step 6: Synthesis of tert-butyl (S)-(1-(2-(7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0362] 7-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (67 mg, 0.18 mmol) was reacted with Intermediate 5 (60 mg, 0.15 mmol) according to General Procedure 4. The crude product was purified by column chromatography (DCM / MeOH=20:1) to give the title compound (65 mg, 59.6%) as a yellow solid. LCMS (ESI, m / z): 720 [M+H]+. Step 7: Synthesis of (S)-6-(2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(2-hydroxyethoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0363] (S)-tert-Butyl(1-(2-(7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (65 mg, 0.09 mmol) was reacted according to General Procedure 2. The crude mixture was purified by preparative HPLC (Method G) to give the title compound (32.9 mg, 71.4%) as a yellow solid. 1H NMR (400MHz, DMSO-d6+D2O): δ8.28(s,1H),7.78–7.67(m,1H),7.30(d,J=8.0Hz,1H), 7.15(d,J=3.8Hz,1H),7.08(t,J=7.9Hz,1H),6.87(d,J=7.8Hz,1H),4.95–4.54(m,4H) ,4.20(t,J=4.9Hz,2H),3.95(d,J=2.4Hz,3H),3.92–3.74(m,5H),3.74–3.66(m,2H), 3.24(t,J=6.2Hz,2H),0.96(d,J=9.5Hz,1H),0.31–0.12(m,2H),-0.03–-0.15(m,2H). LCMS(ESI,m / z):506[M+H]+. LCMS RT: 1.636min (Method B).

[0364] The compounds of Examples 206 to 210 in Table 14 were obtained by following procedures similar to those used to prepare the compound of Example 205 using appropriate alkylating agents including alkyl iodides, alkyl bromides, alkyl chlorides, and mesylate. Table 14 Example 211. (S)-2-((2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)ethyl methylcarbamate Step 1: Synthesis of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-7-(2-hydroxyethoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0365] To a stirred solution of (S)-tert-butyl(1-(2-(7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (80 mg, 0.11 mmol) in THF (3 mL) was added TBAF (1 M in THF, 1 mL). The mixture was stirred at room temperature for 1 h. LCMS showed that the reaction was complete, and the mixture was concentrated. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the title compound (60 mg, 89.1%) as a yellow oil. LCMS (ESI, m / z): 606 [M+H] + . Step 2: Synthesis of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-7-(2-((methylcarbamoyl)oxy)ethoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0366] To a solution of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-7-(2-hydroxyethoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (45 mg, 0.07 mmol) in DCM (5 mL) was added TEA (0.2 mL, 0.74 mmol) and N-methylcarbamoyl chloride (69 mg, 0.74 mmol) at 0° C. under a nitrogen atmosphere. The mixture was stirred at room temperature overnight under a nitrogen atmosphere. LCMS showed that the reaction was complete, and the mixture was quenched with water (15 mL) and extracted with DCM (3×15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the title compound (40 mg, 81.2%) as a yellow oil. LCMS (ESI, m / z): 663 [M+H] + . Step 3: Synthesis of (S)-2-((2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)ethyl methylcarbamate

[0367] (S)-tert-Butyl(1-(2-(1-(cyclopropylmethyl)-7-(2-((methylcarbamoyl)oxy)ethoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (65 mg, 0.09 mmol) was reacted according to General Procedure 2. The crude mixture was purified by preparative HPLC (Method E) to give the title compound (7.2 mg, 20.3%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ8.36–8.27(m,3H),8.24(s,1H),7.61(s,1H),7.28(d,J=7.9Hz,1 H),7.07–7.02(m,3H),6.84(d,J=7.7Hz,1H),4.82–4.58(m,4H),4.47–4.31(m,4H),3.91( s,3H),3.86–3.79(m,2H),3.76–3.71(m,1H),3.67(t,J=6.5Hz,2H),3.21(t,J=6.3Hz,2H) ,2.58(d,J=4.4Hz,3H),1.08–0.97(m,1H),0.24–0.13(m,2H),-0.14(q,J=4.7,4.2Hz,2H). LCMS(ESI,m / z):563[M+H] + . LCMS RT: 1.118 min. (Method D). Example 212. 2-(7-((S)-2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-6-((S)-2-amino-3-fluoropropyl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of tert-butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-((R)-2-hydroxypropoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0368] To a stirred solution of intermediate 7 (200 mg, 0.36 mmol) in ethanol (2 mL) was added (R) -2-methyloxirane (207 mg, 3.56 mmol) and TEA (0.25 mL, 1.78 mmol). The mixture was irradiated with microwave radiation at 100 ° C for 2 h. The reaction was monitored by TLC and LCMS. The mixture was concentrated and purified by preparative TLC (DCM / MeOH = 15: 1) to give the title compound (153 mg, 69.3%) as a yellow oil. LCMS (ESI, m / z): 620 [M + H] + . Step 2: Synthesis of (R)-1-((2-(6-((S)-2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)propane-2-yl methanesulfonate

[0369] To a solution of tert-butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-((R)-2-hydroxypropoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (153 mg, 0.25 mmol) in DCM (2 mL) was added TEA (0.05 mL, 0.37 mmol) and MsCl (0.02 mL, 0.30 mmol) at 0°C. The mixture was stirred for 1 h and the reaction was allowed to reach room temperature. The reaction was monitored by TLC and LCMS. The reaction mixture was concentrated to give the title compound (157 mg, 91.1%) as a yellow solid. The crude product was used directly in the next step. LCMS (ESI, m / z): 698 [M+H] + . Step 3: Synthesis of tert-butyl ((S)-1-(2-(7-((S)-2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0370] (R)-1-((2-(6-((S)-2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)propan-2-methanesulfonate (157 mg, 0.22 mmol) was reacted in DMF (2 mL) according to General Procedure 8. The crude product was purified by preparative TLC (DCM / MeOH=10:1) to give the title compound (55 mg, 36.5%) as a yellow oil. LCMS (ESI, m / z): 670 [M+H] + . Step 4: Synthesis of 2-(7-((S)-2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-6-((S)-2-amino-3-fluoropropyl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0371] Tert-butyl ((S)-1-(2-(7-((S)-2-(1H-imidazol-1-yl)propoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (55 mg, 0.08 mmol) was reacted according to General Procedure 2. The crude mixture was concentrated and purified by preparative HPLC (Method E) to give the title compound (32.6 mg, 68.9%) as a white solid. 1 H NMR(400MHz, DMSO-d6+D2O)δ9.40–9.35(m,1H),8.23(s,1H),8.06(s,1H),7.78(s,1H),7.61(s,1H),7.3 2(d,J=7.9Hz,1H),7.09(t,J=7.9Hz,1H),7.06(s,1H),6.91(d,J=7.9Hz,1H),5.22–5.12(m,1H),4.81–4. 57(m,4H),4.50–4.41(m,1H),4.32–4.20(m,1H),3.90(s,3H),3.86–3.72(m,3H),3.67(t,J=6.4Hz,2H), 3.22(t,J=6.5Hz,2H),1.68(d,J=6.8Hz,3H),0.68–0.56(m,1H),0.12–0.06(m,2H),-0.37–-0.52(m,2H). LCMS(ESI,m / z):570[M+H] +LCMS RT: 1.265 min (Method D).

[0372] The compounds of Examples 213 to 216 in Table 15 were obtained following procedures similar to those used to prepare the compound of Example 212 using the appropriate epoxides. Table 15 Example 217. 6-((S)-2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-((R)-2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of ethyl (S)-1-(cyclopropylmethyl)-7-(2-hydroxypropoxy)-1H-indole-2-carboxylate

[0373] Under a nitrogen atmosphere, to a solution of 1-(cyclopropylmethyl)-7-hydroxy-indole-2-carboxylic acid ethyl ester (1g, 3.86mmol) in ethanol (12.5mL) was added (2S)-2-methyloxirane (672mg, 11.5mmol) and TEA (3.36mL, 19.3mmol). The mixture was irradiated with microwave radiation at 100 ° C for 2h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=5:1) to obtain the title compound (1g, 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

[0374] Under a nitrogen atmosphere, to a solution of (S)-1-(cyclopropylmethyl)-7-(2-hydroxypropoxy)-1H-indole-2-carboxylic acid ethyl ester (2 g, 6.3 mmol) in DCM (50 mL) was added TEA (3.3 mL, 18.9 mmol) and the resulting mixture was cooled to 0 ° C. Then MsCl (866 mg, 7.56 mmol) was added dropwise at 0 ° C under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction was then quenched by adding saturated NH4Cl aqueous solution (50 mL) at 0 ° C and extracted with DCM (3 × 50 mL). The combined organic extracts were washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum at 0 ° C to give the title compound (2 g, 80%) as a yellow oil. LCMS (ESI, m / z): 396 [M + H] +. Step 3: Synthesis of ethyl (R)-1-(cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazo-1-yl)propoxy)-1H-indole-2-carboxylate

[0375] Under a nitrogen atmosphere, to a solution of (S)-1-(cyclopropylmethyl)-7-(2-((methylsulfonyl)oxy)propoxy)-1H-indole-2-carboxylic acid ethyl ester (2 g, 5.06 mmol) in DMF (50 mL) was added 4-fluoro-1H-imidazole (522 mg, 6.07 mmol) and CsCO (4.95 g, 15.2 mmol). The resulting solution was stirred at 50 ° C overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was then quenched by adding water (150 mL) and extracted with ethyl acetate (150 mL), washed with water (2×150 mL) and brine (2×150 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 (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

[0376] (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 5. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound as a yellow oil (1.5 g, 84%). 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

[0377] (R)-(1-(Cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)methanol was reacted according to General Procedure 6. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the compound as a light green solid (1.4 g, 70%). LCMS (ESI, m / z): 342 [M+H] +. Step 6: Synthesis of tert-butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-((R)-2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0378] (R)-1-(Cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indole-2-carbaldehyde (50 mg, 0.15 mmol) was reacted with Intermediate 5 (87 mg, 0.22 mmol) according to General Procedure 4. The crude product was purified by column chromatography (DCM / MeOH = 20:1) to give the title compound (50 mg, 49%) as a light yellow oil. LCMS (ESI, m / z): 688 [M+H]+. Step 7: Synthesis of 6-((S)-2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-((R)-2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0379] Tert-butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-((R)-2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (50 mg, 0.07 mmol) was reacted according to General Procedure 2. The crude product was purified by preparative HPLC (Method G) to give the title compound (27.4 mg, 63%) as a white solid. 1H NMR (400MHz, DMSO-d6): δ8.25(s,4H),7.60(s,1H),7.52(s,1H),7.28(d,J=7.6Hz,1H),7.13 (dd,J=8.4,2.0Hz,1H),7.08–7.04(m,2H),6.87(d,J=8.0Hz,1H),4.79–4.61(m,3H),4.50–4. 38(m,4H),3.91(s,3H),3.90–3.86(m,1H),3.86–3.83(m,1H),3.83–3.68(m,3H),3.21(t,J=6 .4Hz,2H),1.55(d,J=7.2Hz,3H),0.82–0.72(m,1H),0.15–0.11(m,2H),-0.34–-0.36(m,2H). LCMS(ESI,m / z):588[M+H]+. LCMS RT: 0.883 min. (Method D). Example 218. (S)-6-(2-amino-3-fluoropropyl)-2-(7-(2-hydroxyethoxy)-1-(isoxazol-5-ylmethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of tert-butyl (S)-(1-(2-(7-(benzyloxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0380] 7-Benzyloxy-1H-indole-2-carbaldehyde (300 mg, 1.19 mmol) was reacted with Intermediate 5 according to General Procedure 4. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 1:3) to give the title compound (600 mg, 84.1%) as a yellow solid. LCMS (ESI, m / z): 598 [M+H] +. Step 2: Synthesis of tert-butyl (S)-(1-fluoro-3-(2-(7-hydroxy-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate

[0381] (S)-tert-Butyl(1-(2-(7-(benzyloxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (600 mg, 1 mmol) was reacted in ethyl acetate (10 mL), methanol (10 mL) and acetic acid (0.1 mL) according to General Procedure 9. The crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the title compound (450 mg, 88.3%) as a yellow solid. LCMS (ESI, m / z): 508 [M+H]. Step 3: Synthesis of tert-butyl (S)-(1-(2-(7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0382] (S)-tert-Butyl(1-fluoro-3-(2-(7-hydroxy-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate (190 mg, 0.42 mmol) was reacted according to General Procedure 3. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 1:3) to give the title compound (70 mg, 26.5%) as a light yellow solid. LCMS (ESI, m / z): 666 [M+H]. Step 4: Synthesis of tert-butyl (S)-(1-(2-(7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(isoxazol-5-ylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0383] (S)-tert-Butyl(1-(2-(7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (70 mg, 0.11 mmol) in DMF (3 mL) was reacted with CsCO (102 mg, 0.32 mmol) and 5-(bromomethyl)isoxazole (68 mg, 0.42 mmol) at room temperature according to General Procedure 8. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 2:5) to give the title compound (55 mg, 70.0%) as a light yellow solid. LCMS (ESI, m / z): 747 [M+H]. Step 5: Synthesis of (S)-6-(2-amino-3-fluoropropyl)-2-(7-(2-hydroxyethoxy)-1-(isoxazol-5-ylmethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0384] A solution of (S)-tert-butyl(1-(2-(7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(isoxazol-5-ylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (55 mg, 0.07 mmol) in HCl (1 M in ethyl acetate, 4.0 mL) was stirred at room temperature for 1 h. The reaction was monitored by TLC and LCMS. The mixture was concentrated under vacuum. The resulting orange viscous oil was purified by preparative HPLC (Method G) to give the title compound (18.9 mg, 47.7%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6+D2O) δ8.28(d,J=7.9Hz,2H),7.67(s,1H),7.30(d,J=7.9Hz,1H),7.23(s,1H),7.09(t,J=7.8Hz,1H),6.88(d,J=7.8Hz,1H), 6.31(s,2H),6.09(s,1H),4.85–4.57(m,2H),4.16(t,J=4.7Hz,2H),3.93 (s,3H),3.87–3.73(m,5H),3.68(t,J=6.4Hz,2H),3.22(t,J=6.3Hz,2H). LCMS(ESI,m / z):533[M+H]+. LCMS RT: 1.406 min. (Method D). Example 219. 6-((S)-2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-((2-oxopyrrolidin-3-yl)methoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of 3-((2-nitrophenoxy)methyl)pyrrolidin-2-one

[0385] Under a nitrogen atmosphere, NaH (156 mg, 6.51 mmol) and 1-fluoro-2-nitro-benzene (612 mg, 4.34 mmol) were added to a stirred solution of 3-(hydroxymethyl)pyrrolidin-2-one (500 mg, 4.34 mmol) in DMF (10 mL) in batches at room temperature. The resulting mixture was stirred at 0 ° C for 0.5 h. The reaction was monitored by TLC and LCMS. The reaction was quenched by adding water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1: 1) to obtain the title compound (260 mg, 25%) as a yellow solid. LCMS (ESI, m / z): 237 [M + H] +. Step 2: Synthesis of 3-((2-aminophenoxy)methyl)pyrrolidin-2-one

[0386] To a stirred solution of 3-((2-nitrophenoxy)methyl)pyrrolidin-2-one (260 mg, 1.1 mmol) in methanol (10 mL) was added Pd / C (60 mg) under a nitrogen atmosphere. The resulting solution was stirred overnight under a hydrogen atmosphere. LCMS showed the reaction was complete. The solid was filtered off. The resulting mixture was concentrated to give the title compound (150 mg, 66%) as a yellow solid. LCMS (ESI, m / z): 207 [M+H]. Step 3: Synthesis of ethyl 7-((2-oxopyrrolidin-3-yl)methoxy)-1H-indole-2-carboxylate

[0387] To a stirred solution of 3-((2-aminophenoxy)methyl)pyrrolidin-2-one (150 mg, 0.73 mmol) in DMSO (5 mL) was added ethyl 2-oxopropanoate (84 mg, 0.73 mmol), Pd(OAc)2(32 mg, 0.15 mmol) and AcOH (44 mg, 0.73 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 70 ° C for 16 h under an oxygen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine (2×40 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:1) to give the title compound (100 mg, 45%) as a yellow solid. LCMS (ESI, m / z): 303[M+H]+. Step 4: Synthesis of 3-(((2-(hydroxymethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one

[0388] Under a nitrogen atmosphere, LiBH4 (28 mg, 1.32 mmol) was added in batches to a stirred solution of ethyl 7-((2-oxopyrrolidin-3-yl)methoxy)-1H-indole-2-carboxylate (100 mg, 0.33 mmol) in THF (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The reaction was monitored by LCMS. The reaction was then quenched by adding water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with brine (2 × 40 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:3) to give the title compound (85 mg, 98%) as a yellow solid. LCMS (ESI, m / z): 261 [M+H]+. Step 5: Synthesis of 7-((2-oxopyrrolidin-3-yl)methoxy)-1H-indole-2-carbaldehyde

[0389] 3-(((2-(Hydroxymethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one (85 mg, 0.33 mmol) was reacted according to General Procedure 6. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound as a yellow solid (60 mg, 71%). LCMS (ESI, m / z): 259 [M+H]. Step 6: Synthesis of 1-(cyclopropylmethyl)-7-((2-oxopyrrolidin-3-yl)methoxy)-1H-indole-2-carbaldehyde

[0390] 7-((2-Oxopyrrolidin-3-yl)methoxy)-1H-indole-2-carbaldehyde (60 mg, 0.23 mmol) in DMF (2 mL) was reacted with bromomethylcyclopropane (47 mg, 0.35 mmol) according to General Procedure 8. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound as a yellow solid (50 mg, 68%). LCMS (ESI, m / z): 313 [M+H] +. Step 7: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-((2-oxopyrrolidin-3-yl)methoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0391] 1-(Cyclopropylmethyl)-7-((2-oxopyrrolidin-3-yl)methoxy)-1H-indole-2-carbaldehyde (39 mg, 0.13 mmol) was reacted with Intermediate 5 according to General Procedure 4. The crude product was purified by silica gel column chromatography (DCM / methanol = 20:1) to give the title compound as a yellow solid (80 mg, 96%). LCMS (ESI, m / z): 659 [M+H] +. Step 8: Synthesis of 6-((S)-2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-((2-oxopyrrolidin-3-yl)methoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0392] Tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-((2-oxopyrrolidin-3-yl)methoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (80 mg, 0.12 mmol) was reacted according to General Procedure 2. The crude mixture was concentrated and purified by preparative HPLC (Method E) to give the title compound (46.5 mg, 68%) as a white solid. 1H NMR (400MHz, DMSO-d6): δ8.28(s,3H),8.26(s,1H),7.82(s,1H),7.62(s,1H),7.28(d,J=7.9Hz,1 H),7.09–7.03(m,2H),6.87(d,J=7.8Hz,1H),4.72–4.59(m,4H),4.31(d,J=4.2Hz,2H),3.84(d,J= 15.6 Hz, 2H), 3.68 (t, J = 6.4 Hz, 3H), 3.33–3.26 (m, 2H), 3.22 (t, J = 6.4 Hz, 2H), 2.89–2.81 (m, 1H), 2.38–2.31 (m, 1H), 2.26–2.17 (m, 1H), 1.02–0.92 (m, 1H), 0.22–0.13 (m, 2H), -0.18–-0.31 (m, 2H). LCMS (ESI, m / z): 559 [M+H]. LCMS RT: 1.520 min. (Method B).

[0393] The compounds of Examples 220 to 221 in Table 16 were obtained following procedures similar to those used to prepare the compound of Example 219 using the appropriate alcohols. Table 16 Example 222. 2-(7-(((S)-1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-6-((S)-2-amino-3-fluoropropyl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of tert-butyl ((S)-1-(2-(7-(((S)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0394] Intermediate 7 (100 mg, 0.18 mmol) in DMF (3 mL) was reacted with (R)-1-((tert-butyldiphenylsilyl)oxy)propane-2-yl methanesulfonate (140 mg, 0.36 mmol) according to General Procedure 8. The crude material was purified by preparative TLC (petroleum ether:ethyl acetate=1:1) to give the title compound (120 mg, 78.5%) as a yellow oil. LCMS (ESI, m / z): 858 [M+H] + . Step 2: Synthesis of tert-butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-(((S)-1-hydroxypropan-2-yl)oxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0395] To a stirred solution of tert-butyl ((S)-1-(2-(7-(((S)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (120 mg, 0.14 mmol) in THF (2 mL) was added TBAF (1 M in THF, 1 mL). The mixture was stirred at room temperature for 2 h. LCMS showed that the reaction was complete, and the mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1) ​​to give the title compound (75 mg, 86.5%) as a yellow oil. LCMS (ESI, m / z): 620 [M+H] + . Step 3: Synthesis of (S)-2-((2-(6-((S)-2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)propyl methanesulfonate

[0396] To a stirred solution of tert-butyl ((S)-1-(2-(1-(cyclopropylmethyl)-7-(((S)-1-hydroxypropan-2-yl)oxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (75 mg, 0.12 mmol) in DCM (3 mL) at 0° C. under a nitrogen atmosphere were added TEA (61 mg, 0.61 mmol) and MsCl (21 mg, 0.18 mmol). The mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete, and the mixture was quenched with water (15 mL) and extracted with DCM (3×20 mL). The organic layer was washed with brine (2×50 mL) and dried over anhydrous sodium sulfate to give the title compound as a yellow oil (80 mg, 94.7%). LCMS (ESI, m / z): 698 [M+H] + . Step 4: Synthesis of tert-butyl ((S)-1-(2-(7-(((S)-1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0397] (S)-2-((2-(6-((S)-2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)propyl methanesulfonate (80 mg, 0.11 mmol) was reacted with 1H-imidazole (39 mg, 0.57 mmol) according to General Procedure 8. The residue was purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (70 mg, 91.1%) as a white solid. LCMS (ESI, m / z): 670 [M+H] + . Step 5: Synthesis of 2-(7-(((S)-1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-6-((S)-2-amino-3-fluoropropyl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0398] Tert-butyl ((S)-1-(2-(7-(((S)-1-(1H-imidazol-1-yl)propan-2-yl)oxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (80 mg, 0.12 mmol) was reacted according to General Procedure 2. The residue was purified by preparative HPLC (Method E) to give the title compound (28.1 mg, 41.2%) as a white solid. 1 H NMR (400MHz, methanol-d4): δ9.03(s,1H),8.41(s,1H),7.75(t,J=1.8Hz,1H),7.61(s,1H),7.57(t,J=1.8H z,1H),7.32(d,J=7.7Hz,1H),7.06(t,J=7.9Hz,1H),7.03(s,1H),6.86(d,J=7.8Hz,1H),5.30–5.22( m,1H),4.82–4.45(m,6H),4.07–3.87(m,2H),3.99(s,3H),3.85–3.74(m,3H),3.35–3.30(m,2H),1.5 1(d,J=6.2Hz,3H),0.86–0.76(m,1H),0.28–0.14(m,2H),-0.20–-0.29(m,1H),-0.32–-0.41(m,1H). LCMS(ESI,m / z):570[M+H] + . LCMS RT: 1.118 min. (Method D).

[0399] Example 223 in Table 17 was obtained following procedures similar to those used to prepare the compound in Example 222 using the appropriate alcohol. Table 17 Examples 224 and 225. (S)-1-(2-((2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)ethyl)-1H-1,2,4-triazole-3-carbonitrile and (S)-1-(2-((2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)ethyl)-1H-1,2,4-triazole-5-carbonitrile Step 1: (S)-tert-Butyl(1-(2-(7-(2-(3-cyano-1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate and synthesis of tert-butyl (S)-(1-(2-(7-(2-(5-cyano-1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0400] (S)-tert-Butyl(1-(2-(7-(2-bromoethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (200 mg, 0.3 mmol) was reacted with 1H-1,2,4-triazole-3-carbonitrile (42.2 mg, 0.45 mmol) according to General Procedure 8. The crude product was purified by column chromatography (ethyl acetate) to give the title compound (80 mg, 39.2%) as a light yellow solid. LCMS (ESI, m / z): 682 [M+H]. Step 2: Synthesis of (S)-1-(2-((2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)ethyl)-1H-1,2,4-triazole-3-carbonitrile and (S)-1-(2-((2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)ethyl)-1H-1,2,4-triazole-5-carbonitrile

[0401] tert-Butyl (S)-(1-(2-(7-(2-(3-cyano-1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate and (S)-(1-(2-(7- Tert-butyl (2-(5-cyano-1H-1,2,4-triazol-1-yl)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (40 mg, 0.06 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.

[0402] (S)-1-(2-((2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)ethyl)-1H-1,2,4-triazole-3-carbonitrile (14.9 mg, 43.3%). 1 H NMR(300MHz,DMSO-d6)δ9.02(s,1H),8.20–8.17(m,4H),7.54(s,1H),7.23(d, J=7.8Hz,1H),7.02–6.97(m,2H),6.83(d,J=8.1Hz,1H),4.82–4.72(m,3H),4. 69–4.53(m,3H),4.36(d,J=6.9Hz,2H),3.83–3.75(m,5H),3.64–3.45(m,3H), 3.14(t,J=5.7Hz,2H),0.57(s,1H),0.07–-0.09(m,2H),-0.37–-0.62(m,2H). LCMS (ESI, m / z): 582 [M+H] + . LCMS RT: 1.480 min. (Method B).

[0403] (S)-1-(2-((2-(6-(2-amino-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)ethyl)-1H-1,2,4-triazole-5-carbonitrile (2.8 mg, 8.3%). 1H NMR (300MHz, DMSO-d6) δ8.45(s,1H),8.28(s,3H),8.25(s,1H),7.60(s,1H),7.30(d,J=7. 6Hz,1H),7.08–7.04(m,2H),6.91(d,J=7.6Hz,1H),4.93(t,J=4.8Hz,2H),4.80–4.59(m,4 H), 4.46 (d, J = 6.8 Hz, 2H), 3.92 (s, 2H), 3.90–3.82 (m, 3H), 3.71–3.46 (m, 3H), 3.21 (t, J = 6 Hz, 2H), 0.57 (s, 1H), 0.09–0.05 (m, 2H), -0.36–-0.40 (m, 2H). LCMS (ESI, m / z): 582 [M+H]. LCMS RT: 1.469 min. (Method B). Examples 226a and 226b. 6-((S)-2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-((S)-1-fluoro-2-(1H-imidazo-1-yl)ethoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one and 6-((S)-2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-((R)-1-fluoro-2-(1H-imidazol-1-yl)ethoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of ethyl 2-((2-(6-((S)-2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-2-fluoroacetate

[0404] Intermediate 7 (200 mg, 0.36 mmol) in DMF (3.5 mL) was reacted with ethyl 2-bromo-2-fluoro-acetate (130 mg, 0.70 mmol) according to General Procedure 8. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (210 mg, 70%) as a yellow oil, which was a mixture of diastereomers. LCMS (ESI, m / z): 666 [M+H] +. Step 2: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-hydroxyethoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0405] To a solution of ethyl 2-((2-(6-((S)-2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-2-fluoroacetate (200 mg, 0.30 mmol) in ethanol (5 mL) was added NaBH4 (120 mg, 3.00 mmol) at 0°C. The mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The reaction was then quenched by the addition of acetone (10 mL). The mixture solution was concentrated under vacuum. The crude product was purified by flash column chromatography on C18 silica gel to give the title compound (150 mg, 80%) as a yellow oil as a mixture of diastereomers. LCMS (ESI, m / z): 624[M+H]. Step 3: Synthesis of 2-((2-(6-((S)-2-((tert-Butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-2-fluoroethyl methanesulfonate

[0406] To a solution of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-hydroxyethoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (150 mg, 0.24 mmol) in DCM (4 mL) was added TEA (0.75 mL, 5.38 mmol) and MsCl (33 mg, 0.29 mmol) at 0°C. The resulting solution was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The reaction was then quenched by the addition of saturated aqueous NH4Cl solution (10 mL) at 0°C and extracted with DCM (3×10 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum at 0° C. to give the title compound (168 mg, 98%) as a pale yellow oil as a mixture of diastereomers. LCMS (ESI, m / z): 702 [M+H] +. Step 4: Synthesis of tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-(1H-imidazol-1-yl)ethoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0407] To a solution of 2-((2-(6-((S)-2-((tert-butoxycarbonyl)amino)-3-fluoropropyl)-1-methyl-5-oxo-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1-(cyclopropylmethyl)-1H-indol-7-yl)oxy)-2-fluoroethyl methanesulfonate (168 mg, 0.24 mmol) in DMF (2.5 mL) was added 1H-imidazole (33 mg, 0.48 mmol) and CsCO (235 mg, 0.72 mmol). The resulting mixture was stirred at 50 ° C for 1 h. The reaction was monitored by LCMS. The reaction was then quenched by the addition of water (10 mL) and extracted with ethyl acetate (10 mL), washed with water (2×10 mL) and brine (2×10 mL), 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 (110 mg, 60%) as a yellow oil as a mixture of diastereomers. LCMS (ESI, m / z): 674 [M+H] + . Step 5: Synthesis of 6-((S)-2-amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-(1H-imidazol-1-yl)ethoxy)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0408] Tert-butyl ((2S)-1-(2-(1-(cyclopropylmethyl)-7-(1-fluoro-2-(1H-imidazol-1-yl)ethoxy)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (100 mg, 0.15 mmol) was reacted according to General Procedure 2. The crude product was purified by preparative HPLC (Method G) to give the title compound as a mixture of diastereomers.

[0409] The diastereomers were separated by chiral preparative HPLC (column: CHIRAL ART Cellulose-SB, 2×25 cm, 5 um; mobile phase A: MTBE+0.5% 2M NH 3 / MeOH, mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 30B to 30B in 31 min; detection: UV (220 / 254 nm).

[0410] Example 226a. Isomer 1: Chiral HPLC RT: 10.222 min. 1 H NMR (400MHz, DMSO-d6): δ8.23(s,1H),7.79(s,1H),7.60(s,1H),7.47(d,J=7.2Hz,1H ),7.34(s,1H),7.16–7.06(m,3H),6.98(s,1H),6.67–6.52(m,1H),4.74–4.65(m,2H), 4.63–4.50 (m, 2H), 4.50–4.38 (m, 2H), 3.92 (s, 3H), 3.70–3.66 (m, 2H), 3.65–3.59 (m, 3H), 3.19 (t, J=6.5 Hz, 2H), 0.94–0.87 (m, 1H), 0.25–0.13 (m, 2H), -0.20–-0.30 (m, 2H). LCMS (ESI, m / z): 574 [M+H]. LCMS RT: 1.263 min. (Method B).

[0411] Example 226b. Isomer 2: Chiral HPLC RT: 22.57 min. 1 H NMR (400MHz, DMSO-d6): δ8.22(s,1H),7.79(s,1H),7.60(s,1H),7.47(d,J=7.2Hz,1H ),7.34(s,1H),7.16–7.06(m,3H),6.98(s,1H),6.67–6.52(m,1H),4.74–4.65(m,2H), 4.60–4.37 (m, 3H), 4.36–4.25 (m, 1H), 3.92 (s, 3H), 3.74–3.55 (m, 3H), 3.54–3.41 (m, 2H), 3.17 (t, J=6.4 Hz, 2H), 0.97–0.86 (m, 1H), 0.25–0.13 (m, 2H), -0.17–-0.28 (m, 2H). LCMS (ESI, m / z): 574 [M+H]. LCMS RT: 1.266 min. (Method B). Example 227. (S,E)-2-(7-(3-(1H-imidazol-1-yl)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-6-(2-amino-3-fluoropropyl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of methyl 7-bromo-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0412] Methyl 7-bromo-1H-indole-2-carboxylate (1.25 g, 4.92 mmol) was reacted in DMF (30 mL) according to General Procedure 8. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (1.2 g, 80%) as a light yellow solid. LCMS (ESI, m / z): 308 [M+H]+. Step 2: Synthesis of methyl (E)-7-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0413] To a solution of methyl 7-bromo-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (1.2 g, 3.89 mmol) in dioxane (9 mL) and water (3 mL) was added (E)-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)boronic acid (1.68 g, 5.32 mmol), AmPhos-PdCl2 (120 mg, 0.4 mmol) and K3PO4 (1.61 g, 11.6 mmol). The resulting solution was stirred at 80 ° C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=5:1) to give the title compound (1.4 g, 89%) as a yellow oil. LCMS (ESI, m / z): 400 [M+H]+. Step 3: Synthesis of methyl (E)-1-(cyclopropylmethyl)-7-(3-hydroxyprop-1-en-1-yl)-1H-indole-2-carboxylate

[0414] To a solution of (E)-7-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxylic acid methyl ester (800 mg, 2.0 mmol) in THF (20 mL) was added TBAF (10 mL). The resulting solution was stirred at room temperature for 0.5 h. The reaction was monitored by LCMS. The reaction was then quenched by adding water (60 mL) and extracted with ethyl acetate (60 mL), washed with water (3 × 60 mL) and brine (3 × 60 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=8:1) to give the title compound (500 mg, 87%) as a yellow oil. LCMS (ESI, m / z): 286[M+H]+. Step 4: Synthesis of methyl (E)-1-(cyclopropylmethyl)-7-(3-((methylsulfonyl)oxy)prop-1-en-1-yl)-1H-indole-2-carboxylate

[0415] Under a nitrogen atmosphere, to a solution of (E)-1-(cyclopropylmethyl)-7-(3-hydroxyprop-1-en-1-yl)-1H-indole-2-carboxylic acid methyl ester (500 mg, 1.75 mmol) in DCM (9 mL) was added TEA (529 mg, 5.23 mmol) and MsCl (241 mg, 2.09 mmol) at 0 ° C. The resulting mixture was stirred at room temperature for 0.5 h. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NH4Cl aqueous solution (24 mL) at 0 ° C and extracted with DCM (3 × 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, and the mixture was concentrated under vacuum at 0 ° C to give the title compound (600 mg, 94%) as a brown oil. LCMS (ESI, m / z): 364 [M + H] +. Step 5: Synthesis of methyl (E)-7-(3-(1H-imidazol-1-yl)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate

[0416] (E)-1-(cyclopropylmethyl)-7-(3-((methylsulfonyl)oxy)prop-1-en-1-yl)-1H-indole-2-carboxylic acid methyl ester (600 mg, 1.65 mmol) was reacted with 1H-imidazole (224 mg, 3.31 mmol) at 50° C. according to General Procedure 8. The crude product was purified by column chromatography (petroleum ether / ethyl acetate=4:1) to give the title compound (450 mg, 82%) as a white solid. LCMS (ESI, m / z): 336 [M+H]+. Step 6: Synthesis of (E)-(7-(3-(1H-imidazol-1-yl)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol

[0417] (E)-methyl 7-(3-(1H-imidazol-1-yl)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (450 mg, 1.34 mmol) was reacted according to General Procedure 5. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give the title compound as a yellow solid (270 mg, 65%). LCMS (ESI, m / z): 308 [M+H]. Step 7: Synthesis of (E)-7-(3-(1H-imidazol-1-yl)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde

[0418] (E)-(7-(3-(1H-imidazol-1-yl)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol (270 mg, 0.87 mmol) was reacted according to General Procedure 6. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 6:1) to give the title compound as a yellow solid (200 mg, 43%). LCMS (ESI, m / z): 306 [M+H]. Step 8: Synthesis of tert-butyl (S,E)-(1-(2-(7-(3-(1H-imidazol-1-yl)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0419] (E)-7-(3-(1H-imidazol-1-yl)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (90 mg, 0.29 mmol) was reacted with Intermediate 8 according to General Procedure 4. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound as a brown solid (80 mg, 35%). LCMS (ESI, m / z): 652 [M+H]. Step 9: Synthesis of (S,E)-2-(7-(3-(1H-imidazol-1-yl)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-6-(2-amino-3-fluoropropyl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0420] Tert-butyl (S,E)-(1-(2-(7-(3-(1H-imidazol-1-yl)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (80 mg, 0.12 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 yellow solid (17.4 mg, 26%). 1 H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.39(s,3H),8.24(s,1H),7.86(s,1H),7.77(s,1H),7.7 2(d,J=32Hz,1H),7.62(s,1H),7.45(d,J=16Hz,1H),7.29(d,J=8.0Hz,1H),7.18(d,J=8.0Hz, 1H), 7.15 (s, 1H), 6.42–6.35 (m, 1H), 5.16–5.15 (m, 2H), 4.79–4.56 (m, 4H), 3.96 (s, 3H), 3.93–3.67 (m, 5H), 3.23–3.20 (m, 2H), 0.80–0.79 (m, 1H), 0.17–0.13 (m, 2H), -0.34–-0.37 (m, 2H). LCMS RT: 1.366 min. (Method B). Example 228. (S)-2-(7-(3-(1H-imidazol-1-yl)propyl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-6-(2-amino-3-fluoropropyl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of tert-butyl (S)-(1-(2-(7-(3-(1H-imidazol-1-yl)propyl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate

[0421] To a solution of tert-butyl (S,E)-(1-(2-(7-(3-(1H-imidazol-1-yl)prop-1-en-1-yl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (80 mg, 0.12 mmol) in ethanol (20 mL) was added Pd / C (8 mg, 0.04 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The solid was filtered off and the solvent was evaporated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (45 mg, 57%) as a light yellow solid. LCMS (ESI, m / z): 654 [M+H]. Step 2: Synthesis of (S)-2-(7-(3-(1H-imidazol-1-yl)propyl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-6-(2-amino-3-fluoropropyl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

[0422] (S)-tert-Butyl(1-(2-(7-(3-(1H-imidazol-1-yl)propyl)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropan-2-yl)carbamate (45 mg, 0.06 mmol) was reacted according to General Procedure 2. The crude product was purified by preparative HPLC (Method E) to give the title compound (34.1 mg, 89%) as a light yellow semisolid. 1 H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.35(s,3H),8.17(s,1H),7.92(s,1H),7.75(s,1 H),7.57(s,1H),7.56(d,J=8.0Hz,1H),7.18–7.08(m,3H),4.88–4.65(m,2H),4.57–4. 3.2 (m, 4H), 3.98 (s, 3H), 3.88 (s, 3H), 3.77–3.59 (m, 2H), 3.66–3.48 (m, 2H), 3.32–3.14 (m, 2H), 2.35–2.34 (m, 2H), 0.81–0.77 (m, 1H), 0.21–0.17 (m, 2H), -0.61–-0.65 (m, 2H). LCMS (ESI, m / z): 554 [M+H]. LCMS RT: 0.565 min. (Method D). Example 229. 2-(1-(Cyclopropylmethyl)-7-((5-oxopyrrolidin-3-yl)methoxy)-1H-indol-2-yl)-1-methyl-6-((R)-2-(methylamino)propyl)-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one Step 1: Synthesis of tert-butyl (R)-(1-(2-(7-(benzyloxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)(methyl)carbamate

[0423] To...

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 Halogen or C 1-4 Fat; R 5 is a halogen; Each R 6 and R 6′ are independently selected from hydrogen, C 1-6 Aliphatic, -L 1 (R 9 ) q and-OL 2 -(R 9 ) p ; Each R 7 independently selected from halogen, -OR, -N(R)2 and -Cy; Each R 8 independently selected from halogen, -OR, -N(R)2, -C(O)N(R)2 and -Cy; Each R 9 independently selected from halogen, -CN, -OR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, -OC(O)N(R)2, and -Cy; L 1 For covalent bonds or C 1-4 Fat; L 2 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, a 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy is replaced 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 of p and q 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, Ia-ii, Ibi, Ib-ii, Ici, Ic-ii, Idi, Id-ii, Iei, Ie-ii, Ifi, If-ii, Igi, Ig-ii, Ihi and Ih-ii: or a pharmaceutically acceptable salt thereof.

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

5. The compound according to any one of claims 1 to 4, wherein R 5 For fluorine.

6. The compound according to any one of claims 1 to 5, wherein m is 0.

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

8. A compound according to any one of claims 1 to 5 and 7, wherein R 4 It is a halogen.

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

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

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

12. A compound according to any one of claims 1 to 11, wherein R 2 Selected from the group consisting of:

13. A compound according to any one of claims 1 to 12, wherein R 3 Selected from – CH2CH3, -CH(CH3)2, 14. A compound according to any one of claims 1 to 13, wherein R 6 Selected from hydrogen, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CN, halogen, -OCH3, -N(CH3)2, 15. A compound according to any one of claims 1 to 14, wherein R 6′ Selected from hydrogen, fluorine, chlorine, -CN, -OH, -OCH3, -CF3, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, 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 for inhibiting PAD4 in a subject or in a biological sample, the method 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 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, 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 disease 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 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 Halogen or C 1-4 Fat; R 5 is a halogen; Each R 6 and R 6′ are independently selected from hydrogen, C 1-6 Aliphatic, -L 1 (R 9 ) q and-OL 2 -(R 9 ) p ; Each R 7 independently selected from halogen, -OR, -N(R)2 and -Cy; Each R 8 independently selected from halogen, -OR, -N(R)2, -C(O)N(R)2 and -Cy; Each R 9 independently selected from halogen, -CN, -OR, -N(R)2, -C(O)R, -C(O)OR, -OC(O)R, -C(O)N(R)2, -N(R)C(O)R, -N(R)C(O)OR, -OC(O)N(R)2, and -Cy; L 1 For covalent bonds or C 1-4 Fat; L 2 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, a 10-membered bicyclic aryl ring, a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy is replaced 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, wherein R 10 replaced by 0-3 Rs; Each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, oxo, -CH2OCH3, 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 R is replaced by 0-3 halogen, C 1-6 Aliphatic or -OH substituted; Each m and n is independently 0 or 1; and Each of p and q is independently 1-4.

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