Heterocyclic PAD4 inhibitor

Abstract

The present disclosure generally relates to compounds of formula I which are inhibitors of PAD4, comprising a 1,6,7,8-tetrahydro-5H-imidazo[4,5-g][1,6]isoquinolin-5-one moiety directly attached to an azaindole or indole moiety, methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and their use in the treatment of diseases or disorders associated with PAD4 enzyme activity.

Description

Technical Field

[0001] (Cross-reference) This application claims priority to U.S. Provisional Application No. 63 / 346,111, filed May 26, 2022, the entire contents of which are hereby incorporated by reference herein.

[0002] (Incorporation by reference of Sequence Listing) The Sequence Listing portion contains a Sequence Listing submitted as an XML file via EFS-WEB, the entire contents of which are hereby incorporated by reference herein. The name of the copy of the XML file created on May 26, 2023 is "055920-607001WO_SeqList_ST26.xml" and the size is 3 KB.

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

Background Art

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

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

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

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

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

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

[0010] Formula I:

Chemical formula

[0011] In another aspect, Formula I':

Chemical formula

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

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

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

Mode for Carrying Out the Invention

[0015] 1. General description of the compounds of the present disclosure: In some embodiments, the present disclosure relates to Formula I:

Chemical formula

[0016] 2. Definitions: The compounds of the present disclosure generally include the above-described compounds and are further exemplified by the classes, subclasses, and species of the present disclosure. Unless otherwise specified, the following definitions used herein apply. For the purposes of the present disclosure, chemical elements are identified according to the CAS version of the Periodic Table of the Elements, Handbook of Chemistry and Physics, 75 th Ed. Further, general principles of organic chemistry as well as specific functional groups and reactivities are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

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

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

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

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

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

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

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

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

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

[0026] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to include rings having multiple unsaturated moieties, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0027] As described herein, the compounds of the present disclosure may contain moieties that are "optionally substituted." In general, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens on a particular moiety are replaced with an appropriate substituent. "Substituted" applies to one or more hydrogens that are directly or indirectly represented in the structure. For example,

Chem.

Chem.

Chem.

Chem.

[0028] Unless otherwise indicated, an "optionally substituted" group may have an appropriate substituent at each substitutable position of the group, and in any structure, if two or more positions are substituted with two or more substituents selected from a particular group, the substituents may be the same or different at each bond position. Combinations of substituents contemplated in the present disclosure form stable compounds or compounds that are chemically feasible. As used herein, the term "stable" refers to a compound that does not substantially change during its manufacture, detection, and in certain embodiments, its recovery, purification, and conditions for use for one or more purposes of the present disclosure.

[0029] Suitable monovalent substituents on replaceable carbon atoms of the "may be replaced as appropriate" group are, independently, halogen; -(CH 2 ) 0-4 R ○ ; -(CH 2 ) 0-4 OR ○ ; -O(CH 2 ) 0-4 R ○ , -O-(CH 2 ) 0-4 C(O)OR ○ ; -(CH 2 ) 0-4 CH(OR ○ ) 2 ; -(CH 2 ) 0-4 SR ○ ; R ○ -substituted -(CH 2 ) 0-4 Ph; R ○ -substituted -(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph; R ○ -substituted -CH=CHPh; R ○ -substituted -(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl; -NO 2 ; -CN; -N 3 ; -(CH 2 ) 0-4 N(R ○ ) 2 ; -(CH 2 ) 0-4 N(R ○ )C(O)R ○ ; -N(R ○ )C(S)R ○ ; -(CH 2 ) 0-4 N(R ○ )C(O)NR ○ 2 ; -N(R ○ )C(S)NR ○ 2 ; -(CH 2 )0-4 N(R ○ )C(O)OR ○ ; -N(R ○ )N(R ○ )C(O)R ○ ; -N(R ○ )N(R ○ )C(O)NR ○ 2 ; -N(R ○ )N(R ○ )C(O)OR ○ ; -(CH 2 ) 0-4 C(O)R ○ ; -C(S)R ○ ; -(CH 2 ) 0-4 C(O)OR ○ ; -(CH 2 ) 0-4 C(O)SR ○ ; -(CH 2 ) 0-4 C(O)OSiR ○ 3 ; -(CH 2 ) 0-4 OC(O)R ○ ; -OC(O)(CH 2 ) 0-4 SR ○ ; -(CH 2 ) 0-4 SC(O)R ○ ; -(CH 2 ) 0-4 C(O)NR ○ 2 ; -C(S)NR ○ 2 ; -C(S)SR ○ ; -SC(S)SR ○ 、-(CH 2 ) 0-4 OC(O)NR ○ 2 ; -C(O)N(OR ○ )R ○ ; -C(O)C(O)R ○ ; -C(O)CH 2 C(O)R ○ ; -C(NOR ○ )R ○ ; -(CH 2 )0-4 SSR ○ ; -(CH 2 ) 0-4 S(O) 2 R ○ ; -(CH 2 ) 0-4 S(O) 2 OR ○ ; -(CH 2 ) 0-4 OS(O) 2 R ○ ; -S(O) 2 NR ○ 2 ; -(CH 2 ) 0-4 S(O)R ○ ; -N(R ○ )S(O) 2 NR ○ 2 ; -N(R ○ )S(O) 2 R ○ ; -N(OR ○ )R ○ ; -C(NH)NR ○ 2 ; -P(O) 2 R ○ ; -P(O)R ○ 2 ; -OP(O)R ○ 2 ; -OP(O)(OR ○ ) 2 ; SiR ○ 3 ; -(C 1-4 linear or branched alkylene)O-N(R ○ ) 2 ; or -(C 1-4 linear or branched alkylene)C(O)O-N(R ○ ) 2 where each R ○ may be substituted as defined below and is independently hydrogen, C 1-6 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, -CH 2-(5-6 membered heteroaryl ring); or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, two independent R ○ together with the atoms therebetween form a 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0030] R ○ (Or two independent R ○ Suitable monovalent substituents on the ring formed by (and the atoms therebetween) are independently halogen, -(CH 2 ) 0-2 R ● , -(Halo R ● ), -(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR ● , -(CH 2 ) 0-2 CH(OR ● ) 2 , -O(HaloR ● ), -CN, -N 3 , -(CH 2 ) 0-2 C(O)R ● , -(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR ● , -(CH 2 ) 0-2 S.R. ● , -(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 , -(CH 2 ) 0-2 NHR ● , -(CH 2 ) 0-2 NR ● 2 , -NO 2 , -SiR● 3 ,-OSiR ● 3 ,-C(O)SR ● ,-(C 1-4 a linear or branched alkylene)C(O)OR ● , or -SSR ● and each R ● is unsubstituted or, if "halo" is present as a prefix, is substituted with only one or more halogens, and C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph; or is independently selected from a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atoms of R ○ include =O and =S.

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

[0032] R * Suitable substituents on the aliphatic of R ● include halogen, -R ● , -(haloR ● ), -OH, -OR ● , -O(haloR ● ), -CN, -C(O)OH, -C(O)OR 2 , -NH ● , -NHR ● 2 , or -NO 2 , where each R ● is unsubstituted or, if "halo" is pre-modifying, is substituted with only one or more halogens and is independently C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having from 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0033] Suitable substituents on the nitrogen of a "optionally substituted" group include -R + , -NR + 2 , -C(O)R + , -C(O)OR + , -C(O)C(O)R + , -C(O)CH 2 C(O)R + , -S(O) 2 R + , -S(O) 2 NR + 2 , -C(S)NR + 2 , -C(NH)NR + 2 , or -N(R+ )S(O) 2 R + is included, where each R + is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independent R + combine with the intervening atoms to form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] R + Suitable substituents on the aliphatic of R ● are independently halogen, -R ● , -(haloR ● ), -OH, -OR ● ), -O(haloR ● ), -CN, -C(O)OH, -C(O)OR 2 ), -NH ● ), -NHR ● 2 ), or -NO 2 ), where each R ● is unsubstituted or, if "halo" is pre-modified, is substituted only with one or more halogens and is independently C 1-4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0-1 Ph; or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] As used herein, the term "subject" refers to any human or non-human organism in which an effect can be obtained by treatment with a PAD4 inhibitor. Examples of subjects include humans and animals.

[0036] As used herein, the term "treatment" refers to, for example, treating a medical condition in a human or animal subject, and includes (a) suppressing the medical condition, i.e., impeding its progression; (b) alleviating the medical condition, i.e., reducing the symptoms of the medical condition; and / or (c) preventing the medical condition from occurring in the subject.

[0037] As used herein, the term "prevention" refers to prophylactic treatment (i.e., prevention and / or risk reduction) of an asymptomatic medical condition in a subject such as a human or an animal, aimed at reducing the probability of the occurrence of a clinical disease state. The subject may be selected for prophylactic treatment based on factors known to increase the risk of developing a clinical disease state compared to the general population. "Prevention" therapy can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in a subject who has not yet presented with a clinical disease state, while secondary prevention is defined as prevention of secondary occurrence of the same or a similar clinical disease state.

[0038] The term "therapeutically effective amount" refers to the amount of a compound or composition described in the present disclosure that is effective when administered alone or in combination to prevent or treat a disease or disorder associated with PAD4 enzyme activity. When used in combination, the term refers to the total amount of the active ingredients that provides a prophylactic or therapeutic effect, regardless of whether the combination is administered concomitantly, sequentially, or simultaneously.

[0039] "Pharmaceutically acceptable carrier" refers to a medium generally acceptable in the field of transporting biologically active agents to humans and / or animals. Pharmaceutically acceptable carriers are formulated according to many factors that are well within the expertise of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated, the patient to whom the composition containing the active agent is administered, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media. Such carriers can include, in addition to the active agent, many different components and additives, and such added components are included in the formulation for various reasons (e.g., stabilization of active agents, binders, etc., known to those skilled in the art). Typical examples of such carriers include, but are not limited to, diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, coating agents, and the like. Explanation of suitable pharmaceutically acceptable carriers and the factors involved in selecting them are described in various readily available literature, such as Allen, L. V., Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0040] This disclosure is intended to cover all isotopes of atoms contained in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. Common examples include, but are not limited to, isotopes of hydrogen such as deuterium (symbol D or 2 H) and tritium (symbol T or 3 H). For example, a methyl group may be represented by CH 3 or CD 3 . Isotopes of carbon include 13 C and 14C is included. The isotopically labeled compounds of the present disclosure can be prepared by conventional techniques generally known to those skilled in the art or by methods similar to those described herein, using appropriate isotopically labeled reagents in place of the unlabeled reagents otherwise employed.

[0041] The compounds of formula I form salts, and such salts are also within the scope of the present disclosure. Unless otherwise specified, references to the compounds of formula I herein are understood to include references to their salts. As used herein, the term "salt" refers to acid salts and / or base salts formed by inorganic and / or organic acids and bases. Further, when a compound of formula I has both a basic moiety and an acidic moiety, a zwitterion ("inner salt") may be formed and may be included within the term "salt" as used herein. Pharmaceutically acceptable salts include salts generally acceptable in the pharmaceutical art when administered to subjects such as humans and animals. Generally, a pharmaceutically acceptable salt is a non-toxic and physiologically acceptable salt. The salts of the compounds described in the present disclosure may be formed, for example, by reacting the compound with a certain amount of an acid or base (e.g., 1 equivalent) and precipitating the salt in a solvent, or by freeze-drying an aqueous solution.

[0042] Compounds of formula I containing a basic moiety can form salts with various organic and inorganic acids. Examples of acid addition salts include acetates (e.g., salts formed with acetic acid or trihaloacetic acids (e.g., trifluoroacetic acid)), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrobromic acid), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (e.g., formed with sulfuric acid), sulfonates (e.g., those described herein), tartrates, thiocyanates, toluenesulfonates (e.g., tosylates), undecanoates, and the like.

[0043] Compounds of formula I containing an acidic moiety can form salts with various organic and inorganic bases. Examples of base addition salts include ammonium salts, alkali metal salts (e.g., sodium, lithium, and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), organic bases (e.g., salts with organic amines (e.g., benzathine, dicyclohexylamine, hydrabamine (formed with N,N-bis(dehydroabietyl)-ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine), and salts with amino acids (e.g., arginine, lysine, etc.)). The basic nitrogen-containing group may be quaternized by reagents (e.g., lower alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, lauryl, myristyl, and stearyl), aralkyl halides (e.g., bromides of benzyl and phenethyl), and others).

[0044] This disclosure encompasses compounds of formula I, or pharmaceutically acceptable salts thereof, methods for producing these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds in the treatment of diseases or disorders associated with PAD4 enzyme activity.

[0045] 3. Description of Examples: In some embodiments, this disclosure relates to formula I:

Chemical formula

[0046] In some embodiments, the present disclosure provides a compound of formula I:

Chemical formula

[0047] In some embodiments, the present disclosure provides any compound selected from Formulae I-a, I-b, I-c, I-d, I-e, I-f, I-g, and I-h: [Chemical Formula] or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the present disclosure provides any compound selected from Formulae I-a-i, I-a-ii, I-b-i, I-b-ii, I-c-i, I-c-ii, I-d-i, I-d-ii, I-e-i, I-e-ii, I-f-i, I-f-ii, I-g-i, I-g-ii, I-h-i, and I-h-ii: [Chemical Formula] [Chemical Formula] or a pharmaceutically acceptable salt thereof.

[0049] As generally defined above, X is selected from C-R 6 and N. In some embodiments of Formula I, X is C-R 6 . In some embodiments of any Formula I, X is N.

[0050] As generally defined above, X' is selected from C-R 6' and N, where X and X' are not both N at the same time. In some embodiments of Formula I, X' is C-R 6' . In some embodiments of Formula I, X' is N.

[0051] In some embodiments of Formula I, X is C-R 6 and X' is C-R 6' . In some embodiments of Formula I, X is N and X' is C-R 6' . In some embodiments of Formula I, X is C-R 6 and X' is N.

[0052] As generally defined above, R 1 is C 1-4 aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-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 1 is -CH 3 -.

[0053] As generally defined above, R 2 is C 7 aliphatic substituted with 0 to 4 R 1-6 s. In some embodiments of any 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 to 4 R 1-4 s. In some embodiments of any 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 to 4 R 1-2 s.

[0054] In some embodiments of any of Formula 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 one or two R 1-6 In some embodiments of any of Formula 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 one or two R 1-4 In some embodiments of any of Formula 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 one or two R 1-2 In some embodiments of any of Formula 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 three or four R 1-6It is aliphatic. In some embodiments of any of Formula 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 substituted with 3 to 4 R 7 groups 1-4 It is aliphatic. In some embodiments of any of Formula 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 substituted with 3 to 4 R 7 groups 1-2 It is aliphatic.

[0055] In some embodiments of any of Formula 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

Chemical formula

[0056] As generally defined above, R 3 is C substituted with 0 to 3 R 8 groups 1-6It is aliphatic. In some embodiments of any of Formula 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 substituted with 0 to 3 R 8 groups. 1-4 It is aliphatic. In some embodiments of any of Formula 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 substituted with 0 to 3 R 8 groups. 1-2 It is aliphatic.

[0057] In some embodiments of any of Formula 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 substituted with 1 to 3 R 8 groups. 1-6 It is aliphatic. In some embodiments of any of Formula 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 substituted with 1 to 3 R 8 groups. 1-4It is aliphatic. In some embodiments of any of Formula 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 to 3 R 1-2 groups and is aliphatic.

[0058] In some embodiments of any of Formula 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

Chemical formula

[0059] As generally defined above, R 4 is halogen or C 1-4 and is aliphatic. In various embodiments, any substitutable site of the fused bicyclic moiety of any of Formula I, I', I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i may be substituted with R 4 groups. In some embodiments of any of Formula 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 of the above embodiments, R 4is fluoro or chloro. In some embodiments of any of Formula 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 C 1-4 aliphatic. In some embodiments of any of Formula 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 C 1-2 aliphatic. In some of the above embodiments, R 4 is -CH 3 thereof.

[0060] As generally defined above, R 5 is halogen. In some embodiments of any of Formula I, I-a, I-a-i, I-b, I-b-i, I-c, I-c-i, I-d, I-d-i, I-e, I-e-i, I-f, I-f-i, I-g, I-g-i, I-h, and I-h-i, R 5 is fluoro.

[0061] As generally defined above, each R 6 and R 6' is selected from hydrogen, C 1-6 aliphatic, -L 1 (R 9 ) q , and -O-L 2 -(R 9 ) p In some embodiments of Formula I, R 6 is hydrogen.

[0062] In some embodiments of any of Formula I, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, and I-d-ii, R 6 is halogen. In some embodiments of any of Formula I, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, and I-d-ii, R 6 is fluoro.

[0063] In some embodiments of any of Formula I, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, and I-d-ii, R 6 is -L 1 -(R 9 ) p wherein.

[0064] In some embodiments of any of Formula I, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, and I-d-ii, R 6 is -O-L 2 -(R 9 ) p wherein.

[0065] In some embodiments of any of Formula I, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, and I-d-ii, R 6 is C 1-6 aliphatic. In some embodiments of any of Formula I, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, and I-d-ii, R 6 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , or -C(CH 3 ) 3 wherein.

[0066] In some embodiments of any of Formulas I, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, and I-d-ii, R 6 is 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 selected from the group consisting of.

[0067] In some embodiments of any of Formulas I, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, and I-d-ii, R 6 is C 1-6 aliphatic, -R 9 ,

Chemical formula

[0068] In some embodiments of any of Formulas I, I-b, I-b-i, I-b-ii, I-c, I-c-i, I-c-ii, I-d, I-d-i, and I-d-ii, R 6 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 3 , -CN, halogen, -OCH 3 , -N(CH 3 ) 2 ,

Chemical formula

Chemical formula

Chem.

Chem.

[0069] In some embodiments of Formula I, R 6' is hydrogen.

[0070] In some embodiments of any of Formulas I, I-a, I-a-i, I-a-ii, I-c, I-c-i, I-c-ii, I-e, I-e-i, and I-e-ii, R 6 is halogen. In some embodiments of any of Formulas I, I-a, I-a-i, I-a-ii, I-c, I-c-i, I-c-ii, I-e, I-e-i, and I-e-ii, R 6' is fluoro or chloro.

[0071] In some embodiments of any of Formulas I, I-a, I-a-i, I-a-ii, I-c, I-c-i, I-c-ii, I-e, I-e-i, and I-e-ii, R 6' is -L 1 -(R 9 ) p is.

[0072] In some embodiments of any of Formulas I, I-a, I-a-i, I-a-ii, I-c, I-c-i, I-c-ii, I-e, I-e-i, and I-e-ii, R 6' is -O-L 2 -(R 9 ) p is.

[0073] In some embodiments of any of Formulas I, I-a, I-a-i, I-a-ii, I-c, I-c-i, I-c-ii, I-e, I-e-i, and I-e-ii, R 6' is C 1-6It is aliphatic. In some embodiments of any of Formulas I, I-a, I-a-i, I-a-ii, I-c, I-c-i, I-c-ii, I-e, I-e-i, and I-e-ii, R 6' is -CH 3 -, -CH 2 CH 3 -, -CH(CH 3 ) 2 -, or -C(CH 3 ) 3 .

[0074] In some embodiments of any of Formulas I, I-a, I-a-i, I-a-ii, I-c, I-c-i, I-c-ii, I-e, I-e-i, and I-e-ii, R 6' is selected from C 1-6 aliphatic, halogen, -CN, -OR, -Cy, -(C 1-4 aliphatic)-(halogen) 1-3 , -C(O)N(R) 2 , and -CO 2 R

[0075] In some embodiments of any of Formulas I, I-a, I-a-i, I-a-ii, I-c, I-c-i, I-c-ii, I-e, I-e-i, and I-e-ii, R 6' is selected from C 1-6 aliphatic, -R 9 ,

Chemical formula

Chemical formula

[0076] In some embodiments of any of Formulas I, I-a, I-a-i, I-a-ii, I-c, I-c-i, I-c-ii, I-e, I-e-i, and I-e-ii, R 6' is selected from C 1-6 aliphatic, -R 9 ,

Chemical formula

[0077] As generally defined above, R 7 is selected from halogen, -OR, -N(R) 2 , and -Cy. In some embodiments of any of Formulas I, I-a, I-a-i, I-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 halogen. In some embodiments of any 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 fluoro. In some embodiments of any 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 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) 2is. In some embodiments of any of Formula 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 of Formula 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 -NH 2 is. In some embodiments of any of Formula 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 of Formula 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 fluoro, -NH 2 and -Cy.

[0078] In some embodiments of any of Formula 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 [Chemical formula] is selected from.

[0079] As generally defined above, R 8 is halogen, -OR, -N(R) 2 , -C(O)N(R) 2 , and -Cy. In some embodiments of any 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 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 -OR. In some embodiments of any 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 embodiments of any 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 8is fluoro. In some embodiments of any of Formula 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 is.

[0080] In some embodiments of any of Formula 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 -CH 2 CH 3 is -CH(CH 3 ) 2 is

Chemical formula

Chemical formula

[0081] As generally defined above, R 9 is 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 of Formula 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 a halogen. In some embodiments of any 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 fluoro or chloro. In some embodiments of any 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 embodiments of any 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 -CH 3 Accordingly, in some embodiments of any 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 -OCH 3 In some embodiments of any 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) 2 In some embodiments of any 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 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 -NH 2 In some embodiments of any 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

[0082] In some embodiments of any of Formula 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.

[0083] In some embodiments of any of Formula 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 wherein.

[0084] In some embodiments of any of Formula 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.

[0085] In some embodiments of any of Formula 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.

[0086] In some embodiments of any of Formula 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 -CO 2 R.

[0087] In some embodiments of any of Formula 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 -OC(O)N(R) 2 is as follows.

[0088] In some embodiments of any 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.

[0089] As generally defined above, L 1 is a covalent bond or C 1-4 is aliphatic. In some embodiments of any 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 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 is aliphatic. In some embodiments of any 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 is aliphatic. In some embodiments of any 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 is aliphatic. In some embodiments of any 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 2-3 is aliphatic.

[0090] In some embodiments of any of Formula 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

Chemical formula

[0091] As generally defined above, L 2 is C 1-4 aliphatic. In some embodiments of any of Formula 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 of Formula 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 of Formula 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.

[0092] In some embodiments of any of Formula 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

Chemical formula

[0093] In some embodiments of any of Formula 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 fluoro, chloro, -CN, -OR, -N(R) 2 , -C(O)N(R) 2 , -CO 2 R, -OC(O)N(R) 2 , -N(R)C(O)OR,

Chemical formula

[0094] As generally defined above, Cy is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring; phenyl; a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 10-membered bicyclic aryl; a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8- to 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where Cy is substituted with 0 to 3 R 10 s. In some embodiments of any of Formula 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 1 to 2 R 10is replaced. In some embodiments of any of Formula 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 1 to 3 Rs 10 is replaced.

[0095] In some embodiments of any of Formula 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 carbocyclic ring. In some embodiments of any of Formula 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 carbocyclic ring. In some embodiments of any of Formula 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 carbocyclic ring. In some embodiments of any of Formula 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- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments of any of Formula 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 carbocyclic ring.In some embodiments of any of Formula 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 carbocyclic ring. In some embodiments of any of Formula 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 carbocyclic ring. In some embodiments of any of Formula 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 carbocyclic ring. In some embodiments of any of Formula 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 carbocyclic ring.

[0096] In some embodiments of any of Formula 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 heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-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, and sulfur. In some embodiments of any of Formula 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 heterocycle having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula 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 heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.In some embodiments of any of Formula I, I-a, I-a-i, I-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 heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-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 heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-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 heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-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 heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.In some embodiments of any of Formula I, I-a, I-a-i, I-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 heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0097] In some embodiments of any of Formula 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 phenyl.

[0098] In some embodiments of any of Formula 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- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-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 heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-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 heteroaryl having 2 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-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 heteroaryl having 2 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0099] In some embodiments of any of Formula 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 heteroaryl having 1 to 2 nitrogen atoms.

[0100] In some embodiments of any of Formula 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

Chemical formula

Chemical formula

[0101] As generally defined above, R 10 is selected from halogen, -OR, -N(R) 2 , -CN, -C(O)R, -C(O)OR, -C(O)N(R) 2 , oxo, and an optionally substituted group, and the optionally substituted group is selected from C 1-6 aliphatic; and a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula 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 10is a halogen. In some embodiments of any of Formula 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 fluoro or chloro.

[0102] In some embodiments of any of Formula 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.

[0103] In some embodiments of any of Formula 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 is.

[0104] In some embodiments of any of Formula 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.

[0105] In some embodiments of any of Formula 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 embodiments of any of Formula 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 of Formula 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 1-6 aliphatic. In some embodiments of any of Formula 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 of Formula 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.

[0106] In some embodiments of any of formula 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 optionally substituted 1-6 and is aliphatic. In some embodiments of any of formula 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 -OR ○ and is C optionally substituted 1-6 and is aliphatic. In some of the above embodiments of any of 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 and is aliphatic. In some embodiments of any of formula 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 -OR ○ and is C optionally substituted 1-4It is aliphatic. In some embodiments of any of Formula 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 -OR ○ optionally substituted with C 1-2 which is aliphatic.

[0107] In some embodiments of any of Formula 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.

[0108] In some embodiments of any of Formula 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 wherein.

[0109] In some embodiments of any of Formula 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.

[0110] In some embodiments of any of Formula 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 of Formula 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 of Formula 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 of Formula 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 -CH 3 or -CH 2 CH 3 is.

[0111] In some embodiments of any of Formula 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 an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-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 an optionally substituted 3-membered saturated or partially unsaturated heterocycle having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-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 an optionally substituted 4-membered saturated or partially unsaturated heterocycle having 1 heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula I, I-a, I-a-i, I-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 10is an optionally substituted 5-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of 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 an optionally substituted 5-membered saturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, I-a, I-a-i, I-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 an optionally substituted 6-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, I-a, I-a-i, I-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 an optionally substituted 6-membered saturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formulas I, I-a, I-a-i, I-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 10is an optionally substituted 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any of Formula 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 an optionally substituted 7-membered saturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0112] In some embodiments of any of Formula 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, fluoro, chloro, -CN, -CH 3 、-CH 2 CH 3 、-NH 2 、-OH, -OCH 3 、 [Chemical formula] selected from.

[0113] As generally defined above, R is hydrogen or an optionally substituted group, and the optionally substituted group is C 1-6Selected from aliphatic; 3- to 7-membered saturated or partially unsaturated carbocyclic rings; phenyl; 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any 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. In some embodiments of any 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 a group which may be optionally substituted, and the group which may be optionally substituted is C 1-6 Selected from aliphatic; 3- to 7-membered saturated or partially unsaturated carbocyclic rings; phenyl; 3- to 7-membered saturated or partially unsaturated heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of any 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 substituted C 1-6It is aliphatic. In some embodiments of any of Formula 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 halogen or -OR ○ optionally substituted C 1-6 It is aliphatic. In some embodiments of any of Formula 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 It is aliphatic. In some embodiments of any of Formula 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 halogen or -OR ○ optionally substituted C 1-6 is aliphatic, where R ○ is hydrogen or C 1-6 It is aliphatic.

[0114] As generally defined above, each m and n is 0 or 1. In some embodiments of any of the 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, m is 0. In some embodiments of any of the 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, m is 1. In some embodiments of any of the formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, and I-h, n is 0. In some embodiments of any of the formulas I, I-a, I-b, I-c, I-d, I-e, I-f, I-g, and I-h, n is 1. In some embodiments of formula I, m is 1 and n is 0. In some embodiments of formula I, m and n are each 0.

[0115] As generally defined above, p is from 1 to 4. In some embodiments of any of Formula 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, p is 1. In some embodiments of any of Formula 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, p is from 1 to 2. In some embodiments of any of Formula 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, p is 2. In some embodiments of any of Formula 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, p is 3.

[0116] In some embodiments, the compound of Formula I is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0117] 4. Pharmaceutical composition: In some embodiments, the present disclosure provides a composition comprising a compound provided by the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present disclosure is an amount effective to significantly inhibit PAD4 in a biological sample or a patient. In certain embodiments, the amount of the compound in the composition of the present disclosure is an amount effective to significantly inhibit PAD4 in a biological sample or a patient. In certain embodiments, the composition provided by the present disclosure is formulated for administration to a patient in need thereof. In some embodiments, the composition provided by the present disclosure is formulated for oral administration to a patient.

[0118] As used herein, the term "subject" is used synonymously with the term "patient" and means an animal or a mammal. In some embodiments, the subject or patient is a human. In other embodiments, the subject (or patient) is an animal subject (or patient). In some embodiments, the animal subject (or patient) is a dog, a cat, or a horse.

[0119] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound when formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions provided by the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0120] The compositions provided by the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, intravaginally, or by an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion. The compositions may be administered orally, intraperitoneally, or intravenously. The sterile injectable preparations of the compositions provided by the present disclosure may be aqueous solutions or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent (for example, a solution of 1,3-butanediol). Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending agent.

[0121] For this purpose, any sterile fixed oil containing synthetic monoglycerides or diglycerides may be used. Fatty acids (for example, oleic acid and its glyceride derivatives) are useful in the manufacture of injectables, and pharmaceutically acceptable natural oils (for example, olive oil or castor oil), especially those that have been polyoxyethylated, are also useful. These oils or suspensions also include diluents or dispersing agents of long-chain alcohols (for example, carboxymethylcellulose, or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions). Other commonly used surfactants (for example, Tweens, Spans, and other emulsifying agents or bioavailability enhancing substances commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms) may be used for formulation.

[0122] The pharmaceutically acceptable compositions provided by the present disclosure may be orally administered in any acceptable oral formulation including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of oral tablets, commonly used carriers include lactose and corn starch. Lubricants (such as magnesium stearate) are also generally added. In the case of capsules for oral administration, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifying agent and a suspending agent. Optionally, certain sweetening, flavoring or coloring agents may be added.

[0123] Alternatively, the pharmaceutically acceptable compositions provided by the present disclosure may be administered as suppositories for rectal administration. These can be manufactured by mixing with suitable non-irritating excipients such that they are solid at room temperature but liquid at rectal temperature and thus melt in the rectum to release the drug. Such substances include cocoa butter, beeswax and polyethylene glycol.

[0124] The pharmaceutically acceptable compositions provided by the present disclosure may be particularly topically administered in the case of treatments targeting sites or organs that are easily accessible for topical contact, such as diseases of the eye, skin, or lower gastrointestinal tract. Suitable topical formulations are readily manufactured for these sites or organs respectively. Topical administration to the lower gastrointestinal tract may be effective by rectal administration (see above) or suitable enema formulations. Topical transdermal patches may also be used. In topical administration, the pharmaceutically acceptable compositions of the present application may be formulated as suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. Carriers used for topical administration of the compounds provided by the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.

[0125] Alternatively, the pharmaceutically acceptable composition of the present application can be formulated as a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0126] When administered to the eye, the pharmaceutically acceptable composition of the present application may be formulated as a micronized suspension of sterile pH-adjusted isotonic saline or a solution of sterile pH-adjusted isotonic saline, with a preservative (e.g., benzalkonium chloride) appropriately added. Alternatively, when administered to the eye, the pharmaceutically acceptable composition may be formulated as an ointment (e.g., petrolatum).

[0127] The pharmaceutically acceptable composition provided by the present disclosure may be administered by nasal aerosol or nasal inhalation. The composition is manufactured according to techniques well known in the pharmaceutical formulation art and may be manufactured as a solution of saline with benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents added.

[0128] Furthermore, the pharmaceutically acceptable composition provided by the present disclosure may be formulated for oral administration. Such formulations may be administered with food or without food. In some embodiments, the pharmaceutically acceptable composition provided by the present disclosure is administered without food. In other embodiments, the pharmaceutically acceptable composition provided by the present disclosure is administered with food.

[0129] The pharmaceutically acceptable compositions provided by the present disclosure can be administered to humans and other animals, as necessary, by oral administration, rectal administration, parenteral administration, intra-tank administration, vaginal administration, intraperitoneal administration, topical administration (such as powders, ointments, or eye drops), buccal administration (such as oral or nasal sprays), etc. In certain embodiments, the compounds described in the present disclosure are administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg or about 1 mg / kg to about 25 mg / kg, once or more than once a day, depending on the weight of the subject, and a desired therapeutic effect may be obtained.

[0130] 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 forms may include inert diluents commonly used in the art (such as water or other solvents, solubilizers, and emulsifiers (such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof)). In addition to the inert diluent, the oral composition may also include adjuvants (such as wetting agents, emulsifiers, and suspending agents, sweetening agents, flavoring agents, and fragrances).

[0131] Injectable preparations (for example, sterile injectable aqueous or oily suspensions) may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent (for example, a solution of 1,3 - butanediol). Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, U.S.P. isotonic sodium chloride solution. Further, sterile fixed oils are conventionally used as solvents or suspending agents. For this purpose, any sterile, non-volatile oil including synthetic monoglycerides or diglycerides may be used. Further, fatty acids (for example, oleic acid) may also be used in the manufacture of injectable preparations.

[0132] Injectable preparations may be sterilized, for example, by filtration through a sterile filter, or by adding a sterilizing agent to the sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable solvents prior to use.

[0133] To prolong the effect of the compounds provided by the present disclosure, it is often desirable to delay the absorption of the compounds in subcutaneous or intramuscular injections, which can be achieved by using a suspension of crystalline or amorphous substances with low solubility in water. The absorption rate of the compound then depends on its dissolution rate, which can depend on the crystal size and crystal form. Alternatively, delaying the absorption of a parenterally administered compound is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot preparations are manufactured by forming a microencapsulation matrix of the compound in a biodegradable polymer such as a lactic / glycolic acid polymer. The release rate of the compound can be controlled according to the ratio of the compound to the polymer and the nature of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot preparations may be prepared by incorporating the compound into liposomes or microemulsions that are compatible with living tissues.

[0134] Compositions for rectal or vaginal administration may be suppositories produced by mixing the compounds described in the present disclosure with a suitable non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol, or suppository wax that is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity to release the active compound).

[0135] Solid preparations for oral administration include capsules, tablets, pills, powders, and granules. In such solid preparations, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate) and / or (a) fillers or extenders (such as starch, lactose, sucrose, glucose, mannitol, and silicic acid), (b) binders (such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), (c) wetting agents (such as glycerol), (d) disintegrants (such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate), (e) dissolution retardants (such as paraffin), (f) absorption promoters (such as quaternary ammonium compounds), (g) wetting agents (such as cetyl alcohol and glycerol monostearate), (h) absorbents (such as kaolin and bentonite clay), and (i) lubricants (such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof). In the case of capsules, tablets, and pills, the preparations may also contain buffering agents.

[0136] Similar types of solid compositions may use lactose or milk sugar and high molecular weight polyethylene glycol as excipients and may be used as fillers in soft and hard gelatin capsules. Solid preparations such as tablets, dragees, capsules, pills, and granule tablets can be manufactured by coating with coatings and shells (e.g., enteric coatings and other coatings well-known in the pharmaceutical field). These may optionally contain opacifiers and may be compositions that contain only the active ingredient or preferentially release the active ingredient and are slowly released as appropriate in a specific part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions may use lactose or milk sugar and high molecular weight polyethylene glycol as excipients and may be used as fillers in soft and hard gelatin capsules.

[0137] The active compound can be microencapsulated with one or more of the above excipients. Solid preparations such as tablets, dragees, capsules, pills, and granules can be manufactured by coating with coatings and shells (e.g., enteric coatings, sustained-release coatings, and other coatings well-known in the pharmaceutical field). In such solid preparations, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). Such preparations may conventionally contain additive substances other than inert diluents (e.g., lubricants for tableting such as magnesium stearate and microcrystalline cellulose and other tableting aids). In the case of capsules, tablets, and pills, the preparation may contain a buffering agent.

[0138] Formulations for topical or transdermal administration of the compounds provided by the present disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under aseptic conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffering agents. Ophthalmic formulations, ear drops, and eye drops are also considered to be within the scope of the present disclosure. Further, the present disclosure contemplates use in transdermal patches, which have the advantage of being able to provide controlled delivery of the compound into the body. Such formulations can be manufactured by dissolving or dispersing the compound in a suitable solvent. Absorption enhancers can also be used to increase the amount of compound passing through the skin. The rate can be controlled by providing a release control membrane or by dispersing the compound in a polymer matrix or gel.

[0139] The amount of the compounds of the present disclosure that can be combined with a carrier substance in producing a composition of a single dosage form varies depending on the subject to be treated and the specific method of administration. The compositions of the present application should be formulated such that the patients to whom these compositions are administered can be administered at a dosage of the inhibitor of 0.01 to 100 mg / kg (body weight) / day.

[0140] The compounds of the present disclosure can be administered alone or in combination with one or more other therapeutic compounds. In combination therapy, they can be administered in the form of an integrated combination, or the compounds of the present disclosure and one or more other therapeutic compounds can be administered alternately, or each independently, or in a combined administration of an integrated combination and one or more other therapeutic compounds. Examples of such other therapeutic agents include corticosteroids, loxapram, carmustine, cytokine-suppressive anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressive agents; nuclear import and export inhibitors (e.g., deoxyspergualin (DSG)); non-steroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen, celecoxib, and rofecoxib); steroids (e.g., prednisone or dexamethasone); antiviral drugs (e.g., abacavir); antiproliferative agents (e.g., methotrexate, leflunomide, FK506 (tacrolimus, Prograf)); cytotoxic drugs (e.g., azathioprine and cyclophosphamide); TNF-α inhibitors (e.g., tenidap, anti-TNF antibodies or soluble TNF receptors, and rapamycin (sirolimus or Rapamune), or derivatives thereof. The compounds of the present disclosure can be further administered in addition to chemotherapy, radiotherapy, immunotherapy, phototherapy, surgery, or combinations thereof, particularly for treating tumors. Similar to adjuvant therapy in the treatment strategies described above, long-term treatment is also possible. Other treatments include treatments for maintaining the patient's condition after tumor regression, or prophylactic chemotherapy, for example, in patients at risk.

[0141] The additional agents described above may be administered separately from the composition containing the compound of the present invention as part of a plurality of dosing regimens. Alternatively, the above agents may be part of a single dosage form and may be mixed with the compound of the present disclosure in a single composition. When administered as part of a plurality of dosing regimens, the two active agents may be administered simultaneously, sequentially, or alternately at intervals usually within 5 hours.

[0142] As used herein, the term "combination" and related terms refer to the co - administration or sequential administration of therapeutic agents in accordance with the present disclosure. For example, the compounds of the present disclosure may be co - administered or sequentially administered with another therapeutic agent in separate formulations or in a single integrated dosage form. Accordingly, the present disclosure provides a single dosage form comprising a compound of the present disclosure, another therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0143] (In the composition containing another therapeutic agent as described above), the amounts of the compound of the present application and another therapeutic agent that can be combined with a carrier substance to form a single dosage form vary depending on the subject to be treated and the specific method of administration. The compositions of the present disclosure should be formulated such that the dosage of the compound of the present application is administered at 0.01 - 100 mg / kg (body weight) / day.

[0144] In the above - described composition containing another therapeutic agent, the other therapeutic agent and the compound of the present disclosure may act synergistically. Accordingly, the amount of the other therapeutic agent in such a composition will be less than the amount required in a monotherapy using only that therapeutic agent.

[0145] The amount of the other therapeutic agent in the compositions of the present disclosure will be less than or equal to the amount normally contained in a composition containing that other therapeutic agent as the sole active ingredient. The amount of the other therapeutic agent in the compositions of the present disclosure will be in the range of about 50% - 100% of the amount normally contained in a composition containing that other drug as the sole therapeutic active ingredient.

[0146] It should also be understood that the specific dosage and treatment regimen in any particular patient will vary depending on a variety of factors, including the activity of the specific compound used, age, body weight, general health status, gender, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the specific disease or disorder being treated. The amount of the compound of the present disclosure in the composition also varies depending on the specific compound in the composition.

[0147] 5. Use of the Compound The compounds and compositions described herein are generally useful for the inhibition of PAD4.

[0148] In the present disclosure, the activity of a compound used as an inhibitor of PAD4 may be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine the inhibition of PAD4. The detailed conditions of the assay of a compound used as an inhibitor of PAD4 in the present disclosure are shown in the following examples. In some embodiments, the compounds of the present application selectively inhibit PAD4 over PAD2.

[0149] As used herein, the term "treatment" refers to the amelioration, reduction, delay in onset, or inhibition of progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be performed after one or more symptoms have progressed. In other embodiments, treatment may be performed before symptoms have developed. For example, treatment may be performed before symptoms develop in a subject who is predisposed to a disease (e.g., from the perspective of the history of symptoms and / or genetic factors or other factors that predispose to development). Treatment may be continued after symptoms have resolved, for example, to prevent or delay recurrence.

[0150] Since the compounds of the present application are inhibitors of PAD4, they are useful for treating one or more diseases or disorders associated with PAD4 enzyme activity. Thus, in one embodiment, the present disclosure provides a method for treating a disease or disorder associated with PAD4 enzyme activity, the method comprising administering to a patient in need thereof a compound of the present disclosure, or a pharmaceutically acceptable composition thereof.

[0151] In certain embodiments, a disease or disorder associated with PAD4 enzyme activity is a disease, condition, or disorder in which inappropriate PAD4 activity is involved. In some embodiments, the disease or disorder associated with PAD4 enzyme activity is selected from the group consisting of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, and psoriasis. In further embodiments, the disease or disorder associated with PAD4 enzyme activity is rheumatoid arthritis. In further embodiments, the disease or disorder associated with PAD4 enzyme activity is systemic lupus. In further embodiments, the disease or disorder associated with PAD4 enzyme activity is vasculitis. In further embodiments, the disease or disorder associated with PAD4 enzyme activity is cutaneous lupus erythematosus. In further embodiments, the disease or disorder associated with PAD4 enzyme activity is psoriasis.

[0152] In certain embodiments, the present application provides a method for treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, the method comprising administering to a human subject in need thereof a therapeutically effective amount of a compound of the present application or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.

[0153] In one embodiment, the present application provides a method for treating rheumatoid arthritis, which comprises administering to a human subject in need thereof a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof of the present application. In one embodiment, the present application provides a method for treating systemic lupus, which comprises administering to a human subject in need thereof a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof of the present application. In one embodiment, the present application provides a method for treating vasculitis, which comprises administering to a human subject in need thereof a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof of the present application. In one embodiment, the present application provides a method for treating cutaneous erythematosus, which comprises administering to a human subject in need thereof a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof of the present application. In one embodiment, the present application provides a method for treating psoriasis, which comprises administering to a human subject in need thereof a therapeutically effective amount of a compound, stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof of the present application.

[0154] In some embodiments, diseases or disorders associated with PAD4 enzyme activity include acid-induced lung injury, pyogenic arthritis, pyoderma gangrenosum, acne (PAPA), acute lymphoblastic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, aging, AIDS, alcoholic hepatitis, alcoholic liver disease, allergic asthma, allergic bronchopulmonary aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, weight loss, angina, angioedema, anhidrotic ectodermal dysplasia, ankylosing spondylitis, anterior uveitis, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, Behçet's disease, Bell's palsy, beryllium lung, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolism disorder, cataract, cerebral aneurysm, chemical irritation-induced inflammation, choroiditis, chronic heart failure, chronic lung disease of prematurity, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, Crohn's disease, cryopyrin-associated periodic syndrome, cryptococcus, cystic fibrosis, deficiency of interleukin-1 receptor antagonist (DIRA), dermatitis, dermal endotoxemia, dermatomyositis, diffuse panbronchiolitis, endometriosis, endotoxemia, epiglottitis, erythroleukemia, familial amyloid polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerulonephritis, gout, gouty arthritis, graft-versus-host disease, gastrointestinal diseases, head trauma, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Schönlein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster, herpes simplex, HIV-1, Hodgkin's disease, Huntington's disease, idiopathic pulmonary fibrosis, hyperammonemia, hypercalcemia, hypercholesterolemia, hyper IgD syndrome with periodic fever (HIDS), aplastic anemia, other anemias, idiopathic thrombocytopenic purpura, dyschromatosis, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect sting-induced inflammation, iritis, irritation-induced inflammation, ischemia / reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney damage due to parasitic infection, kidney transplant rejection, leptospirosis, leukemia, Reiter's syndrome, lung injury, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease,Selected from the group consisting of Macleod-Wells syndrome (urticaria, deafness, amyloidosis), multiple sclerosis, muscle weakness, muscular dystrophy, myasthenia gravis, myocarditis, juvenile polyposis, myelodysplastic syndrome, myositis, sinusitis, necrotizing enterocolitis, neonatal-onset multi-organ inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, non-allergic asthma, obesity, ophthalmic allergy, optic neuritis, organ transplantation, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), inflammation caused by plant irritation, pneumonia, lung infection, inflammation caused by poison ivy / oak, polyarteritis nodosa, polychondritis, polycystic kidney, polymyositis, psoriasis, psychosomatic disorders, lung diseases, pulmonary hypertension, pulmonary fibrosis, pyoderma gangrenosum, septic arthritis, kidney diseases, retinal diseases, rheumatic heart disease, rheumatic diseases, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell disease, sickle cell anemia, silica-induced diseases, Sjogren's syndrome, skin diseases, sleep apnea syndrome, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplantation, TNF receptor-associated periodic syndrome (TRAPS), toxoplasmosis, transplantation, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticaria, uveitis, granulomatosis with polyangiitis, interstitial pneumonia, psoriatic arthritis, juvenile idiopathic arthritis, Sjogren's syndrome, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, antiphospholipid syndrome, sepsis, deep vein thrombosis, fibrosis, Alzheimer's, scleroderma and CREST syndrome.,

[0155] 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 the treatment of a disease or disorder in which inappropriate PAD4 activity is involved. In another embodiment, the present disclosure provides a compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis. In another embodiment, the present disclosure provides a compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof for use in the treatment of rheumatoid arthritis. In another embodiment, the present disclosure provides a compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof for use in the treatment of systemic lupus. In another embodiment, the present disclosure provides a compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof for use in the treatment of vasculitis. In another embodiment, the present disclosure provides a compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof for use in the treatment of cutaneous lupus erythematosus. In another embodiment, the present disclosure provides a compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof for use in the treatment of psoriasis. In another embodiment, the present disclosure provides the use of a compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a disorder in which inappropriate PAD4 activity is involved. In another embodiment, the present disclosure provides the use of a compound or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis.In another embodiment, the present disclosure provides the use of a compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis. In another embodiment, the present disclosure provides the use of a compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of systemic lupus. In another embodiment, the present disclosure provides the use of a compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of vasculitis. In another embodiment, the present invention provides the use of a compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cutaneous erythematosus. In another embodiment, the present disclosure provides the use of a compound, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of psoriasis. In a further embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing a disease or disorder in which inappropriate PAD4 activity is involved, the pharmaceutical composition comprising a compound of the present application, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In a further embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, vasculitis, systemic erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous erythematosus, or psoriasis, the pharmaceutical composition comprising a compound of the present application, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In a further embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, the pharmaceutical composition comprising a compound of the present application, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.In a further embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing systemic lupus, the pharmaceutical composition comprising the compound of the present application, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In a further embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing vasculitis, the pharmaceutical composition comprising the compound of the present application, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In a further embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing cutaneous erythematosus, the pharmaceutical composition comprising the compound of the present application, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In a further embodiment, the present disclosure provides a pharmaceutical composition for treating or preventing psoriasis, the pharmaceutical composition comprising the compound of the present application, or a stereoisomer, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.

[0156] All features of each aspect of the present invention apply to all other aspects with necessary modifications. To better understand the invention described herein, the following examples are provided. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0157] 6. Examples: The following examples were prepared, isolated, and identified using the methods of the present disclosure. The following examples illustrate a part of the scope of the present disclosure and do not limit the scope of the present disclosure. [Table 1] [Table 2] [Table 3]

[0158] Description of Fractionation HPLC Method and Analytical LC-MS Method Method A: Column: XBridge Shield RP18 OBD, 19x250mm, 10μm; Mobile Phase A: Water + 10 mmol / L NH 4 HCO 3 , Mobile Phase B: ACN; Flow Rate: 25 mL / min; Gradient: Elute over 7 minutes from 57% B to 82% B; Detection: UV (210 / 254 nm) Method B: Column: Shim-pack XR-ODS, 3x50mm, 2.2μm; Mobile Phase A: Water + 0.05% TFA, Mobile Phase B: ACN + 0.05% TFA; Flow Rate: 1.2000 mL / min; Gradient: Elute over 2 minutes from 5% B to 95% B, then elute at 95% B for 0.7 minutes, and elute from 95% B to 5% B in 0.05 minutes; Detection: MS and UV (254 nm) Method C: Column: XBridge Prep C18 OBD, 19×150mm, 5μm; Mobile Phase A: Water + 10 mmol / L NH 4 HCO 3 , Mobile Phase B: ACN; Flow Rate: 25 mL / min; Gradient: Elute over 7 minutes from 21% B to 51% B; Detection: UV (254 / 210 nm) Method D: Column: HALO C18, 3x30mm, 2.7μm; Mobile Phase A: Water + 0.05% TFA, Mobile Phase B: ACN + 0.05% TFA; Flow Rate: 1.5000 mL / min; Gradient: Elute over 2.5 minutes from 5% B to 95% B, then elute at 95% for 1 minute, and elute from 95% B to 5% B in 0.05 minutes; Detection: MS and UV (254 nm) Method E: Column: XSelect CSH Prep C18 OBD, 19x250mm, 5μm; Mobile Phase A: Water + 0.05% TFA, Mobile Phase B: ACN; Flow Rate: 25 mL / min; Gradient: Elute over 5.5 minutes from 22% B to 50% B; Detection: UV (254 nm) Method F: Column: X Bridge Prep Phenyl OBD, 19×150mm, 5μm; Mobile phase A: water + 0.05% HCl, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: elution with 15% B - 45% B over 6 minutes; Detection: UV(254nm) Method G: Column: SunFire C18 OBD Prep 19x250mm, 5μm; Mobile phase A: water + 0.05% TFA, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: elution with 30% B - 55% B over 5.5 minutes; Detection: UV(254nm) Method H: Column: Shim - pack Scepter C18, 3.0mm x 50mm, 3.0μm; Mobile phase A: water + 0.04% aqueous ammonia; Mobile phase B: ACN; Gradient: elution with 10% B - 95% B over 1 minute, then elution with 95% B for 0.60 minutes; Flow rate: 1.5 mL / min; Detection: MS and UV(254 / 220nm) Method I: Column: XBridge BEH C18 Column, 3x50mm, 2.5mm; Mobile phase A: water + 0.05% TFA, Mobile phase B: CAN + 0.05% TFA; Flow rate: 1.2 mL / min; Gradient: elution with 10% B - 95% B over 2 minutes, elution with 95% B for 0.79 minutes, then elution with 95% B - 5% B for 0.06 minutes; Detection: UV(254nm) Method J: Column: Titank C18 Column, 3x50mm, 3.0mm; Mobile phase A: water + 5mM NH 4 HCO 3 3, Mobile phase B: ACN; Flow rate: 1.5 mL / min; Gradient: elution with 10% B - 60% B over 2.25 minutes, elution with 60% B - 95% B for 0.75 minutes, elution with 95% for 0.5 minutes, then elution with 95% B - 10% B for 0.05 minutes; Detection: UV(254nm) Method K: Atlantis HILIC OBD Column, 19x150mm, 5μm; Mobile phase A: water + 0.05% TFA, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: elution with 20% B - 35% B over 4.3 minutes, then 35% B; Detection: UV(254 / 210nm) Method L: Column: L-column3 C18, 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: elute with 10%B - 95%B over 1.2 minutes, then elute with 95%B for 0.60 minutes; Detection: UV(254 / 220 nm) Method M: Column: Atlantis Prep T3 OBD Column, 19 x 250 mm, 10 μm; Mobile phase A: water + 0.05% TFA, Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: elute with 20%B - 50%B for 6 minutes, then 50%B; Detection: UV(210 / 254 nm) Method N: Column: Waters BEH C18 Column, 2.1 x 50 mm, 1.7 μm; Mobile phase A: water + 0.1% formic acid (v / v), Mobile phase B: acetonitrile + 0.1% formic acid (v / v); Flow rate: 0.8 mL / min; Gradient: elute with 5%B - 95%B over 1.5 minutes, then elute with 95%B for 0.5 minutes, then elute with 95%B - 5%B for 0.1 minutes; Detection: PDA(210 - 400 nm) / MS (full ion detection positive / negative mode) Method O: Column: Waters BEH C18 Column, 2.1 x 50 mm, 1.7 μm; Mobile phase A: 95% / 5% water / ACN + 10 mmol ammonium acetate, Mobile phase B: 5% / 95% acetonitrile: water + 10 mM ammonium acetate; Flow rate: 0.8 mL / min; Gradient: elute with 5%B - 95%B over 1.5 minutes, then elute with 95%B for 0.5 minutes, then elute with 95%B - 5%B for 0.1 minutes; Detection: PDA(210 - 400 nm) / MS (full ion detection positive / negative mode) Method P: Column: kinetex XB-C18 100A Column, 2.1 x 30 mm, 1.7 μm; Mobile phase A: water + 0.05% TFA, Mobile phase B: acetonitrile + 0.05% TFA; Flow rate: 1.2 mL / min; Gradient: elute with 5%B - 100%B over 2.8 minutes, then hold at 100% for 1 minute, then elute with 100%B - 5%B for 0.03 minutes; Detection: UV 210 nm

[0159] (Synthesis Example) General Procedure 1: Alkylation of Lactam Using Cyclic Sulfamidate To a stirred solution of lactam (1.0 equiv) / DMF (0.05 M), NaH (60%, 2.0 equiv) and cyclic sulfamidate (1.4 equiv) were added at 0 °C, and the mixture was returned to room temperature over 2 h. When TLC indicated completion of the reaction, 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 afford the desired product.

[0160] General Procedure 2: Deprotection of N-Boc Using TFA A solution of N-Boc amine (1.0 equiv) / DCM:TFA (3:1, 0.02 M) was stirred at room temperature for 30 min. When TLC indicated completion of the reaction, the mixture was concentrated, and the product was purified by preparative HPLC or column chromatography.

[0161] General Procedure 3: Alkylation of Heterocyclic NH or Phenolic OH Using Potassium Carbonate Base To a stirred solution of substituted indole (1.0 equiv) / DMF (0.2 M), K 2 CO 3 (3.0 equiv), TBAI (0.1 equiv) and alkyl electrophile (1.5 equiv) were added at room temperature, and the solution was heated at 50 °C for 1.5 h. When TLC indicated completion of the reaction, 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.

[0162] General Procedure 4: Cyclization to Form Tricyclic Benzimidazole To a stirred solution of aldehyde (1.0 equiv) / ethanol:water (2:1, 0.08 M), aniline (1.0 equiv) and Na 2 S 2 O 4(3.0 equivalents) was added at room temperature. When the reaction solution was heated at 90 °C for 2 hours and the completion of the reaction was indicated by TLC, this reaction mixture was concentrated under reduced pressure, 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 TLC or column chromatography.

[0163] General procedure 5: Reduction of esters or acids using lithium aluminum hydride To a stirred solution of the acid or ester (1.0 equivalent) / THF (0.3 M), LiAlH 4 (2.0 equivalents) was added at 0 °C and the solution was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The reaction was then quenched with water (0.5 mL) / NaOH (15%) (ratio 1:4) and stirred at room temperature for 20 minutes. The solution obtained by filtering the solid was concentrated under reduced pressure. The crude product obtained was purified by column chromatography.

[0164] General procedure 6: Oxidation of alcohols using manganese dioxide To a stirred solution of the alcohol (1.0 equivalent) / DCM (0.1 M), under a nitrogen atmosphere, MnO 2 (10 equivalents) was added at room temperature and this mixture was stirred at room temperature for 12 hours. When the completion of the reaction was indicated by LCMS, the mixture obtained by filtering the solid was concentrated to give a crude product. This was used without further purification or purified by column chromatography.

[0165] General procedure 7: Alkylation of indole NH using sodium hydride base To a stirred solution of the substituted indole (1.0 equiv) / DMF (0.15 M), NaH (1.5 equiv) was added portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 0.5 h, the reaction solution was cooled, and the alkyl electrophile (1.5 equiv) was added portionwise. The resulting mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC or LCMS. Then water was added to quench the reaction, and the mixture was extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography.

[0166] General Procedure 8: Alkylation of Heterocyclic NH or Phenolic OH Using Cesium Carbonate Base To a stirred solution of the substituted indole (1.0 equiv) / DMF (0.2 M), Cs 2 CO 3 (3.0 equiv), TBAI (0.1 equiv) and the alkyl electrophile (1.5 equiv) were added at room temperature, and the solution was heated at 50 °C for 1.5 h. When TLC indicated completion of the reaction, 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.

[0167] General Procedure 9: Deprotection of Benzyloxy Ethers by Hydrogenation To a stirred solution of the benzyloxy ether (1.0 equiv) / solvent mixture (0.02 - 0.1 M), 10% Pd / C (1.0 equiv) was added portionwise at room temperature under a nitrogen atmosphere, and the solution was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was monitored by TLC and LCMS. The solid was filtered off, and the resulting mixture was concentrated. The resulting crude product was used without further purification or purified by column chromatography.

[0168] General Procedure 10: Deprotection of N - Sulfonic Acids Using HCl To a stirred solution of N-sulfonic acid (60 mg, 0.09 mmol) / THF (2 mL), 2M HCl (1 mL) was added and the mixture was stirred at 50 °C for 30 minutes. When the completion of the reaction was indicated by LCMS, the final compound was purified as described in the examples.

[0169] Intermediate 1: 6-(methylamino)-7-nitro-3,4-dihydroisoquinolin-1(2H)-one

Chemical formula

[0170] Step 1: Synthesis of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one To a solution of bis(trichloromethyl) carbonate (2.0 g, 6.74 mmol) / DCM (20 mL), 2-(3-fluorophenyl)ethan-1-amine (2.7 g, 19.5 mmol) / DCM (10 mL) and Et 3 N (2.82 mL, 20.2 mmol) was added at 0 °C and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. The solid was filtered and the solvent was added dropwise at 0 °C to a solution of AlCl 3 (7.8 g, 58.6 mmol) / DCM (20 mL). The resulting mixture was stirred at room temperature overnight and the reaction was monitored by LCMS. Then the reaction was quenched with water (50 mL), acidified with hydrochloric acid (4M) to dissolve all solids, and extracted with DCM (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (1.0 g, 90%, LCMS (ESI, m / z): 200 [M+H]+) as a pale yellow solid.

[0171] Step 2: Synthesis of 6-fluoro-7-nitro-3,4-dihydro-2H-isoquinolin-1-one KNO 3 (1.8 g, 18.2 mmol) / H 2 SO 4To a solution of (15 mL), 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (2 g, 12.1 mmol) was added at 0 °C under a nitrogen atmosphere, and the solution was stirred at 0 °C for 2 hours. The reaction was monitored by LCMS. Ice water (45 mL) was added to quench the reaction. The solid was filtered, washed with water, and the title compound (2.0 g, 79%, LCMS (ESI, m / z): 211 [M+H]+) was obtained as a yellow solid.

[0172] Step 3: Synthesis of 6-(methylamino)-7-nitro-3,4-dihydroisoquinolin-1(2H)-one To a solution of methylamine (1.3 g, 42.8 mmol) / ethanol (30 mL), 6-fluoro-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (2.0 g, 12.1 mmol) was added at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at 70 °C for 4 hours, and the reaction was monitored by LCMS. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 10:1) to obtain the title compound (2.5 g, 79%, LCMS (ESI, m / z): 222 [M+H]+) as a yellow solid.

[0173] Intermediate 2. 2-(1-(Cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one

Chemical formula

[0174] Step 1: Synthesis of 1-(cyclopropylmethyl)indole-2-carbaldehyde According to General Procedure 8, 1H-indole-2-carbaldehyde (2 g, 13.8 mmol) was reacted with (bromomethyl)cyclopropane (2.2 g, 16.5 mmol). The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the title compound (2 g, 74%, LCMS (ESI, m / z): 200 [M+H]+) as a pale yellow oil.

[0175] 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 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 obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (1.2 g, 72%, LCMS (ESI, m / z): 371 [M+H]+) as a yellow solid.

[0176] Intermediate 3. tert-Butyl (R)-(1-(6-(methylamino)-7-nitro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate

Chemical formula

[0177] Step 1: Synthesis of 6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one A solution of 2-(3-fluorophenyl)ethanamine (5 g, 35.9 mmol) / DCM (30 mL) was added to a solution of bis(trichloromethyl) carbonate (5.3 g, 17.9 mmol) / DCM (100 mL) at 0 °C. Subsequently, TEA (18.7 mL, 107.8 mmol) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting solution was stirred for 2 hours, then filtered through celite and washed with DCM (50 mL). The filtrate was treated with AlCl 3(95 g, 720 mmol) was added to a suspension of / DCM (150 mL) at 0 °C. The resulting solution was returned to room temperature and stirred for 16 h. Water (150 mL) and 10% HCl (25 mL) were added to quench the reaction, and the mixture was extracted with DCM (150 mL). 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 reduced pressure. The resulting crude product was purified by flash chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (1.6 g, 26.9%, LCMS (ESI, m / z): 166 [M+H]+) as a pale yellow solid.

[0178] Step 2: Synthesis of tert-butyl (R)-(1-(6-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate A solution of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (1.6 g, 10 mmol) was reacted with tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (2.8 g, 12 mmol) according to General Procedure 1. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (1 g, 31%, LCMS (ESI, m / z): 323 [M+H]+) as a yellow solid.

[0179] Step 3: Synthesis of tert-butyl (R)-(1-(6-(methylamino)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate 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 with methanamine / THF (2 M, 1.5 equiv) at room temperature, and the solution was stirred at room temperature for 2 h. The reaction was monitored by LCMS, and the solution was concentrated under reduced pressure. The obtained crude product was purified by column chromatography (DCM / MeOH = 10:1) to give the title compound (1 g, 96%, LCMS (ESI, m / z): 334 [M+H]+) as a pale yellow solid.

[0180] Step 4: Synthesis of tert-butyl (R)-(1-(6-(methylamino)-7-nitro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate tert-Butyl (R)-(1-(6-(methylamino)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate (1 g, 3.0 mmol) / H 2 SO 4 (10 mL) of the solution was added portionwise with KNO 3 (1.2 g, 12 mmol) at 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS. The obtained mixture was poured into ice water (50 mL), extracted with ethyl acetate (2 x 30 mL), and the aqueous layer was made basic (pH = 9 - 10) with Na 2 CO 3 and THF (50 mL) and Boc 2 O (785 mg, 3.6 mmol) were added, and the mixture was 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 reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (800 mg, yield 71%, LCMS (ESI, m / z): 379 [M+H]+) as a yellow solid.

[0181] Intermediate 4. tert-Butyl (S)-4-(fluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide [Chemical formula]

[0182] Step 1: Synthesis of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)propanoate (2S)-Methyl 2-(tert-butoxycarbonylamino)-3-hydroxy-propanoate (90 g, 410 mmol) and imidazole (30.7 g, 452 mmol) / DCM (900 mL) solution, TBSCl (80.4 g, 534 mmol) was added at 0 °C. After the addition, the reaction mixture was stirred at 20 °C for 2 h, and TLC showed that the starting material was completely consumed. The reaction was quenched with water (1 L) at 0 °C and extracted with DCM (800 mL x 3). The combined organic layers were washed with brine (1 L x 2) and dried over anhydrous Na 2 SO 4 and filtered, concentrated, and the title compound (140 g, crude) was obtained as a pale yellow oil. 1 1H NMR (400 MHz, CDCl 3 ) δ: 5.34 (d, J = 8.4 Hz, 1H), 4.36 (d, J = 8.8 Hz, 1H), 4.06 (d, J = 2.4 Hz, 1H), 4.03 (d, J = 2.4 Hz, 1H), 3.75 (s, 3H), 1.46 (s, 9H), 0.87 (s, 9H), 0.03 (d, J = 5.2 Hz, 6H)

[0183] Step 2: Synthesis of tert-butyl N-[(1R)-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-hydroxy-ethyl]carbamate LiAlH 4To a suspension of (27.9 g, 734 mmol) in THF (1.2 L) was added a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)propanoate (144 g, 432 mmol) in THF (300 mL) at 0 °C. After the addition, the reaction mixture was then stirred at 0 °C for 1 hour. TLC showed that the starting material was completely consumed. The reaction was quenched with saturated NH 4 Cl aqueous solution (800 mL) and filtered. The filtrate was added to ethyl acetate (800 mL x 2), washed with brine (800 mL), and dried over anhydrous Na 2 SO 4 . The resulting mixture was filtered and concentrated to give the title compound (110 g, crude) as a pale yellow oil. 1 1H NMR (400 MHz, CDCl 3 ) δ: 5.06 (s, 1H), 3.75 - 3.58 (m, 4H), 2.70 - 2.61 (m, 1H), 1.38 (s, 9H), 0.82 (s, 9H), 0.00 (s, 6H)

[0184] Step 3: Synthesis of tert-butyl (3R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-oxo-oxathiazolidine-3-carboxylate To a solution of imidazole (147 g, 2.16 mol) in DCM (700 mL) was added a solution of SOCl 2 (77.1 g, 648 mmol) in DCM (400 mL) at 0 °C. After the addition, the reaction mixture was stirred at 18 °C for 1 hour. Then 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 added to the reaction mixture at -10 °C. After the addition, the reaction mixture was stirred at 18 °C for 1 hour, and TLC showed that the starting material was completely consumed. The reaction was quenched with aqueous citric acid solution (10%, 800 mL) and extracted with DCM (1 L x 2). The combined organic layers were washed with water (1 L x 2) and dried over anhydrous Na 2 SO 4It was dried, filtered, concentrated, and the title compound (104 g, crude product) was obtained as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ: 5.00 - 4.98 (m, 1H), 4.83 - 4.72 (m, 2H), 4.07 - 4.03 (m, 1H), 3.79 - 3.72 (m, 1H), 1.53 (s, 9H), 0.89 (s, 9H), 0.07 (s, 6H)

[0185] Step 4: Synthesis of tert-butyl (3R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-oxathiazolidine-3-carboxylate To a solution of tert-butyl (3R)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-oxo-oxathiazolidine-3-carboxylate (52 g, 148 mmol) in MeCN (1000 mL) was added a solution of RuCl 3 (30.7 mg, 148 μmol), and a solution of NaIO 4 (31.6 g, 148 mmol) in H 2 O (500 mL) at 18 °C. After the addition, the reaction mixture was stirred at 18 °C for 1 h, and 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 reaction mixtures were combined and diluted with water (1 L), and the aqueous layer was extracted with DCM (1 L x 2). The organic layers were combined, washed with water (500 mL x 2), dried over anhydrous Na 2 SO 4 , filtered, and concentrated until the title compound (80 g, crude product) was obtained as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ: 4.64 - 4.58 (m, 2H), 4.28 - 4.27 (m, 1H), 3.89 - 3.76 (m, 2H), 1.56 (s, 9H), 0.90 (s, 9H), 0.09 (s, 6H)

[0186] Step 5: Synthesis of tert-butyl N-[(1S)-1-(fluoromethyl)-2-hydroxy-ethyl]carbamate To a solution of tert-butyl (4S)-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,2-dioxo-oxathiazolidine-3-carboxylate (85 g, 231 mmol) in THF (850 mL) was added TBAF (1 M, 277 mL), and the mixture was stirred at 20 °C for 1 h. TLC indicated that the starting material was completely consumed. The reaction was quenched with NH 4 Cl aqueous solution (100 mL) and extracted with ethyl acetate (800 mL x 2). The combined organic layers were washed with water (500 mL x 2), dried over anhydrous Na 2 SO 4 and filtered, and then concentrated. The obtained residue was purified by MPLC (petroleum ether / ethyl acetate = 2 / 1) to give the title compound (20 g, 44.7% yield) as a pale yellow oil. 1 1H NMR (400 MHz, CDCl 3 ) δ: 5.05 (d, J = 7.6 Hz, 2H), 4.57 - 4.44 (m, 2H), 3.81 - 3.73 (m, 3H), 1.45 (s, 9H)

[0187] Step 6: Synthesis of tert-butyl (4S)-4-(fluoromethyl)-2-oxo-oxathiazolidine-3-carboxylate To a solution of imidazole (42.3 g, 621 mmol) in DCM (200 mL) was added SOCl 2A solution of (22.2 g, 186 mmol) in DCM (200 mL) was added dropwise at 0 °C, then the reaction mixture was stirred at 20 °C for 1 hour. Next, tert-butyl N-[(1S)-1-(fluoromethyl)-2-hydroxy-ethyl]carbamate (20 g, 103 mmol) dissolved in DCM (200 mL) was added dropwise at -10 °C, and finally the reaction mixture was stirred at 20 °C for 1 hour. TLC showed that the starting material was completely consumed. The reaction was quenched by adjusting the pH to 5 with aqueous citric acid (10%) and extracted with DCM (300 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the title compound (22 g, crude) was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ: 5.29 - 4.97 (m, 2H), 4.86 - 4.57 (m, 2H), 4.42 - 4.10 (m, 3H), 1.52 (s, 9H)

[0188] Step 7: Synthesis of tert-butyl (S)-4-(fluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide RuCl 3 (191 mg, 919 μmol) was added to a solution of tert-butyl (4S)-4-(fluoromethyl)-2-oxo-oxathiazolidine-3-carboxylate (22 g, 91.9 mmol) in MeCN (440 mL), and then N 2 Under an atmosphere, a solution of NaIO 4 (19.7 g, 91.9 mmol) in water (220 mL) was added dropwise. Finally, the reaction mixture was stirred at 20 °C for 1 hour. TLC showed that the starting material was completely consumed and a new spot 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, then separated, and the combined organic layers were washed with water (300 mL x 2) and brine (200 mL x 2), dried over anhydrous Na 2 SO 4 and concentrated to obtain the title compound (17.5 g, crude) as a yellow solid. 11H NMR (400 MHz, CDCl 3 ) δ: 4.73 - 4.53 (m, 5H), 1.57 (s, 9H)

[0189] Intermediate 5. tert-Butyl (S)-(1-fluoro-3-(6-(methylamino)-7-nitro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate

Chem.

[0190] Step 1: Synthesis of tert-Butyl (S)-(1-fluoro-3-(6-fluoro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate According to General Procedure 1, 6-Fluoro-3,4-dihydro-2H-isoquinolin-1-one (1.6 g, 10 mmol) was reacted with Intermediate 4 (3.1 g, 12 mmol). The obtained 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]+

[0191] Step 2: Synthesis of tert-Butyl (S)-(1-fluoro-3-(6-(methylamino)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-yl)carbamate 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), methanamine / THF (2 M, 1.5 equiv) was added at room temperature and stirred at room temperature for 2 h. The reaction was monitored by LCMS. The solution was concentrated under reduced pressure and the obtained crude product was purified by column chromatography (DCM / MeOH = 10:1) to give the title compound (1 g, 98%) as a pale yellow solid. LCMS (ESI, m / z): 352 [M+H]+

[0192] 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 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) / H 2 SO 4 (10 mL) solution, KNO 3 (1.17 g, 11.6 mmol) was added portionwise at 0 °C. Then the mixture was stirred at room temperature for 3 h and 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 layer was made basic (pH = 9 - 10) with aqueous Na 2 CO 3 and then THF (50 mL) and Boc 2 O (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 (2 x 150 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (800 mg, 70% yield) as a yellow solid. LCMS (ESI, m / z): 397 [M+H]+

[0193] Intermediate 6. tert-butyl (S)-(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

Chemical formula

[0194] Step 1: Synthesis of methyl 6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate According to general procedure 3, methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (3 g, 14.2 mmol) was reacted with bromomethylcyclopropane. The resulting 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]+

[0195] Step 2: Synthesis of (6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol 6-Chloro-1-(cyclopropylmethyl)pyrrolo[2,3-b]pyridine-2-carboxylate (1 g, 3.78 mmol) was reacted according to general procedure 5. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound (900 mg, 71%) as a white solid. LCMS (ESI, m / z): 237 [M+H]+

[0196] Step 3: Synthesis of 6-chloro-1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (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 resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give the title compound (807 mg, 91%) as a green solid. LCMS (ESI, m / z): 235 [M+H]+

[0197] 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

Chemical Structure

[0198] Step 1: Synthesis of (7-benzyloxy-1H-indol-2-yl)propanoate To a solution of 2-benzyloxyaniline (145 g, 728 mmol) and ethyl 2-oxopropanoate (211 g, 1819 mmol) in DMSO (50 mL), N 2 Under an atmosphere, AcOH (41.7 mL, 728 mmol) and Pd(OAc) 2 (16.3 g, 72.8 mmol) were added, and then N 2 was replaced with O 2 This solution was stirred at 70 °C for 16 h. LCMS indicated that the starting material was consumed and the expected mass was detected. Then water (2 L) was added to quench the reaction, and the mixture was extracted with ethyl acetate (1 L x 2). The organic layer was washed with water (1 L x 2) and brine (1 L), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by flash silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 - 5 / 1) to give the title compound (80 g, yield: 37%) as a white solid. 1 H NMR (400 MHz DMSO-d 6 ) δ: 11.97 (s, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.33 (d, J = 6.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 5.29 (s, 2H), 4.35 (dd, J = 7.2 Hz, J = 14.4 Hz, 2H), 1.35 (d, J = 6.8 Hz, 3H)

[0199] Step 2: Synthesis of (7-benzyloxy-1H-indol-2-yl)methanol Ethyl 7-benzyloxy-1H-indole-2-carboxylate (87 g, 295 mmol) was reacted according to General Procedure 5 to give the title compound (80 g, yield: 54%) as a white solid. 11H NMR (400 MHz, DMSO-d 6 ) δ: 10.96 (s, 1H), 7.59 (d, J = 7.2 Hz, 2H), 7.44 - 7.35 (m, 3H), 7.07 (d, J = 7.6 Hz, 1H), 6.86 (t, J = 8.0 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.28 (s, 1H), 5.25 (s, 2H), 5.05 (t, J = 6.0 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H)

[0200] Step 3: Synthesis of 7 - Benzyloxy - 1H - indole - 2 - carbaldehyde (7 - Benzyloxy - 1H - indol - 2 - yl)methanol (30 g, 118 mmol) was reacted according to General Procedure 6. The reaction mixture was filtered, concentrated, and then the resulting residue was triturated with petroleum ether: MTBE (120 mL, v / v, 2 / 1) for 30 minutes to obtain the product (24.25 g). This was combined with the same product (3.5 g) synthesized previously, diluted in DCM (150 mL), and concentrated under reduced pressure to obtain the title compound (24.3 g) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d 6 ) δ: 12.19 (s, 1H), 9.87 (s, 1H), 7.63 (d, J = 7.2 Hz, 2H), 7.41 - 7.30 (m, 5H), 7.02 - 6.96 (m, 2H), 5.29 (s, 2H)

[0201] Step 4: Synthesis of 7 - Benzyloxy - 1 - (cyclopropylmethyl)indole - 2 - carbaldehyde 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 resulting crude product was purified by silica gel column (petroleum ether: ethyl acetate = 20:1 - 3:1) to obtain the product (4.85 g). This was combined with the same product (1.8 g) synthesized previously, diluted in DCM (30 mL), and concentrated under reduced pressure to obtain the title compound (4.85 g) as a yellow solid.1 1H NMR (400 MHz, DMSO-d 6 ) δ: 9.85 (s, 1H), 7.55 (d, J = 1.6 Hz, 2H), 7.53 - 7.33 (m, 5H), 7.06 - 7.04 (m, 2H), 5.25 (s, 2H), 4.69 (d, J = 6.8 Hz, 2H), 1.25 - 1.20 (m, 1H), 0.27 - 0.18 (m, 4H)

[0202] 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 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 obtained was purified by silica 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]+

[0203] 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 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 (400 mg, 0.61 mmol) / methanol (5 mL) was reacted according to General Procedure 9. The resulting crude product was purified by silica column chromatography (DCM / methanol = 20:1) to give the title compound (300 mg, 87%) as a yellow solid. LCMS (ESI, m / z): 562 [M+H]+

[0204] Intermediate 8. (R)-Tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide

Chemical formula

[0205] Step 1: (3aR)-Tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1-oxide A solution of imidazole (17.4 g, 256 mmol) / DCM (40 mL) was added dropwise with a solution of SOCl 2 (9.14 g, 76.82 mmol) / DCM (80 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. To the above mixture, a solution of (S)-morpholin-3-ylmethanol (5 g, 42.68 mmol) / DCM (80 mL) was added dropwise under a nitrogen atmosphere, and the mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The resulting mixture was diluted with water (200 mL) and acidified to pH 6 with citric acid. The reaction mixture was then extracted with DCM (3 x 200 mL), the organic extracts were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (6 g, 86%) as a yellow oil. LCMS (ESI, m / z): 164 [M+H]+

[0206] Step 2: (R)-Tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1,1-dioxide (3aR)-Tetrahydro-3H-[1,2,3]oxathiazolo[4,3-c][1,4]oxazine 1-oxide (6g, 36.77 mmol) and RuCl 3 (938 mg, 3.68 mmol) / MeCN (200 mL) solution was added with a solution of NaIO 4 (8.65 g, 40.44 mmol) / water (200 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 0.5 h under a nitrogen atmosphere, and the reaction was monitored by LCMS. The mixture was concentrated under reduced pressure, and the resulting crude product was extracted with ethyl acetate (2 x 300 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain the title compound (3.2 g, 48%) as a white solid. LCMS (ESI, m / z): 180 [M+H]+

[0207] Intermediate 9. 5-Fluoro-6-(methylamino)-7-nitro-3,4-dihydroisoquinolin-1(2H)-one

Chemical Structure

[0208] Step 1: Synthesis of 2-(3-chloro-2-fluoro-phenyl)acetonitrile To a solution of 1-(bromomethyl)-3-chloro-2-fluoro-benzene (15 g, 67 mmol) in MeCN (200 mL) were added trimethylsilyl cyanide (10.2 mL, 67 mmol) and TBAF (81 mL, 0.97 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 85 °C for 0.5 h under a nitrogen atmosphere, and the reaction was monitored by LCMS. The solution was concentrated under reduced pressure, then water (200 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL), washed with water (5 x 200 mL) and brine (5 x 200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give the title compound (9 g, 79%) as a yellow oil.

[0209] Step 2: Synthesis of 2-(3-chloro-2-fluoro-phenyl)ethanamine To a solution of 2-(3-chloro-2-fluoro-phenyl)acetonitrile (9 g, 53 mmol) in THF (120 mL) was added borane (1 M, THF solution, 120 mL, 0.97 mmol) under a nitrogen atmosphere. The mixture was stirred at 70 °C for 2 h under a nitrogen atmosphere, and the reaction was monitored by LCMS. Then MeOH (120 mL) was added to quench the reaction, and the mixture was stirred at room temperature for 0.5 h. The solution was concentrated under reduced pressure, and the obtained 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]+

[0210] Step 3: Synthesis of 6-chloro-5-fluoro-3,4-dihydro-2H-isoquinolin-1-one To a solution of triphosgene (81 mL, 21 mmol) in DCM (100 mL) were added 2-(3-chloro-2-fluoro-phenyl)ethanamine (9 g, 52 mmol) / DCM (50 mL) and TEA (18 mL, 104 mmol) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The solid was filtered off, and the solvent was evaporated at 0 °C under a nitrogen atmosphere using AlCl 3(278 g, 207 mmol) was added dropwise to a solution of DCM (120 mL). The mixture was stirred overnight at room temperature under a nitrogen atmosphere, and the reaction was monitored by LCMS. Then, water (120 mL) was added to quench the reaction, and the mixture was acidified with hydrochloric acid (4 M), resulting in the disappearance of the solid. The mixture was extracted with DCM (2 x 200 mL). The combined organic extracts were washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate) to obtain the title compound (450 mg, 4.3%) as a pale yellow solid. LCMS (ESI, m / z): 200 [M+H]+

[0211] Step 4: Synthesis of 6-chloro-5-fluoro-7-nitro-3,4-dihydroisoquinolin-1(2H)-one 6-chloro-5-fluoro-3,4-dihydro-2H-isoquinolin-1-one (500 mg, 2.5 mmol) / H 2 SO 4 (5 mL) solution, KNO 3 (252 mg, 2.5 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS and then quenched by adding crushed ice (10 mL). The mixture was basified to pH 8 with aqueous NaOH. The solid was filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate) to obtain the title compound (500 mg, 80%) as a yellow solid. LCMS (ESI, m / z): 245 [M+H]+

[0212] Step 5: Synthesis of 5-fluoro-6-(methylamino)-7-nitro-3,4-dihydroisoquinolin-1(2H)-one 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), MeNH 2(2M, THF solution, 1.8 mL, 3.07 mmol) was added at room temperature and stirred at 50 °C overnight. The reaction was monitored by LCMS and the mixture was concentrated under reduced pressure. The resulting 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]+

[0213] 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 [Chemical formula]

[0214] 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 According to General Procedure 1, Intermediate 2 (50 mg, 0.13 mmol) was reacted with tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide. When the completion of the reaction was indicated by TLC, 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 pale yellow oil. LCMS (ESI, m / z): 528 [M+H]+

[0215] 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 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 treated with 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 thereto at 0 °C and the mixture was stirred at room temperature for 2 h. LCMS indicated that the starting material was not completely converted and it was difficult to separate the starting material from the reaction mixture. 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 = 10:1) to afford the title compound (60 mg) as a yellow oil. This contained a small amount of the starting material as an impurity. LCMS (ESI, m / z): 542 [M+H]+

[0216] 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 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 (60 mg, 0.11 mmol) was reacted according to General Procedure 2. When TLC indicated completion of the reaction, the mixture was concentrated and the product was purified by preparative HPLC (Method A) to afford the title compound (18.2 mg, 96%) as a white solid. 1 H NMR (400 MHz, methanol-d 4) δ 8.41 - 8.33 (m, 1H), 7.69 (d, J = 7.9 Hz, 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 = 0.9 Hz, 1H), 4.39 (d, J = 6.8 Hz, 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)

[0217] The compounds of Examples 2 - 4 in Table 1 were obtained using an appropriate alkylating agent in Step 2 by the same procedure as for the preparation of the compound of Example 1.

Table 4

[0218] 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

Chemical Structure

[0219] 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 Intermediate 2 (50 mg, 0.1300 mmol, 1.00 equiv) was reacted with tert-butyl (4R)-4-ethyl-2,2-dioxo-oxathiazolidine-3-carboxylate (67.84 mg, 0.2700 mmol, 2.00 equiv) according to General Procedure 1. The resulting residue was purified by flash column silica gel chromatography (elution: gradient of ethyl acetate / n-heptane 0 - 100%) to give the title compound (68 mg, 0.1255 mmol, 93% yield) as an off-white solid. LCMS (ESI, m / z): 542 [M+H]+

[0220] 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 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 resulting 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. 11H NMR (DMSO-d6, 400 MHz): δ ppm = 8.26 (s, 1H), 7.85 (br s, 3H), 7.73 (s, 1H), 7.70 (d, J = 2.6 Hz, 1H), 7.63 (s, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.17 (d, J = 7.8 Hz, 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 = 6.2 Hz, 2H), 1.26 (d, J = 6.4 Hz, 3H), 1.02 - 1.14 (m, 1H), 0.23 - 0.32 (m, 2H), -0.04 - 0.05 (m, 2H); LCMS (ESI, m / z): 428 [M + H]+; LCMS RT: 1.12 min (Method N)

[0221] The compounds of Examples 6 - 13 in Table 2 were obtained using an appropriate alkylating agent by the same procedure as for the preparation of the compound of Example 5. Similar to the reaction scheme described for Intermediate 8, the cyclic sulfamidate alkylating agent may be synthesized from a suitable amino alcohol. [Table 5] [Table 6] [Table 7]

[0222] 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 [Chemical Structure]

[0223] 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 To a solution of Intermediate 2 (500 mg, 1.35 mmol) in anhydrous DMF (25 mL) was added NaH (60% mineral oil, 162 mg, 4.05 mmol) at 0 °C, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. To the above mixture was added 2-bromo-1,1-dimethoxy-ethane (1.14 g, 6.75 mmol) dropwise at 0 °C, and the mixture was stirred at 50 °C for 16 hours. The reaction was monitored by LCMS. Water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with water (2 x 100 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (MeOH / DCM = 1:50) to give the title compound (400 mg, 65%) as a pale yellow oil. LCMS (ESI, m / z): 459 [M+H]+

[0224] 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 To a solution 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 (400 mg, 2 mmol) in DCM (4 mL) was added TFA (4 mL) at room temperature, and the mixture was stirred for 30 minutes. The reaction was monitored by LCMS. The solution mixture was concentrated under reduced pressure, basified to pH 7 with an aqueous NaHCO 3 solution, 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 reduced pressure to give the crude product of the title compound as a pale yellow oil. LCMS (ESI, m / z): 413 [M+H]+

[0225] Step 3: Synthesis of (E)-6-(2-((tert-butyl(sulfinylimino)ethyl)-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1,6,7,8-tetrahydro-5H-imidazo[4,5-g]isoquinolin-5-one To a solution of the crude product 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 / anhydrous THF (4 mL), tert-butylsulfinamide (72 mg, 0.58 mmol) and Ti(Oi-Pr) 4 (276 mg, 0.97 mmol) were added at room temperature, and the mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. The reaction was monitored by LCMS. This solution was slowly added to a stirred solution of NH 4 Cl / crushed ice at 0 °C and stirred for 10 min. The mixture was extracted with ethyl acetate (3 x 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained 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]+

[0226] 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 (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 a solution of difluoromethylsulfonylbenzene (116 mg, 0.61 mmol) / THF (4 mL) were added with LDA (2 M, THF solution, 0.94 mL, 1.88 mmol) at -78 °C under a nitrogen atmosphere and stirred at -78 °C for 0.5 h. The reaction was monitored by LCMS. Then saturated NH 4 Cl aqueous solution (20 mL) was added to quench the reaction, and the mixture was 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 reduced pressure. The obtained 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]+

[0227] 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-sulfinamide (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 Na 2 HPO 4To a solution of (121 mg, 0.85 mmol) in methanol (5 mL), Na / Hg amalgam (20 wt% Na / Hg, 98 mg, 0.85 mmol) was added at -20 °C, and the mixture was stirred at -20 °C to -10 °C for 2 h. The reaction was monitored by LCMS. Then, saturated NH 4 Cl aqueous solution (20 mL) was added at -10 °C to quench the reaction, and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (DCM / MeOH = 30:1) to give the title compound (35 mg, 36%) as a yellow solid. LCMS (ESI, m / z): 568 [M+H]+

[0228] 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 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), HCl (4 M, dioxane solution, 0.15 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by preparative HPLC (Method G) to give the title compound (24.7 mg, 86%) as a white solid. 11H NMR (400 MHz, methanol-d4) δ 8.43 (s, 1H), 7.72 (d, J = 8 Hz, 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 = 51.3 Hz, 1H), 4.37 (d, J = 6.8 Hz, 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)

[0229] 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

Chemical Structure

[0230] Step 1: Synthesis of tert - butyl (4S)-4-(1 - hydroxyethyl)-2,2 - dimethyloxazolidine - 3 - carboxylate To a stirred solution of tert - butyl rac - (4S)-4 - formyl - 2,2 - dimethyl - oxazolidine - 3 - carboxylate (2 g, 8.72 mmol) in THF (50 mL) under a nitrogen atmosphere, MeMgBr (3 M, Et 2Solution O (8.7 mL, 26.17 mmol) was added at -10 °C and the mixture was stirred at -10 °C for 2 hours. When TLC indicated completion of the reaction, the mixture was quenched with saturated aqueous NH 4 Cl (40 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford the carboxylate of the title compound (1.78 g, 83.2%) as a colorless oil. LCMS (ESI, m / z): 246 [M+H] +

[0231] Step 2: Synthesis of tert-butyl (4S)-4-(1-fluoroethyl)-2,2-dimethyloxazolidine-3-carboxylate To a stirred solution of tert-butyl (4S)-4-(1-hydroxyethyl)-2,2-dimethyloxazolidine-3-carboxylate (1.78 g, 7.26 mmol) in DCM (50 mL), DAST (2.33 g, 14.51 mmol) was added at -78 °C under a nitrogen atmosphere and the mixture was stirred at -78 °C for 2 hours. The mixture was then stirred at room temperature overnight. When LCMS indicated completion of the reaction, it was quenched with water (40 mL) and extracted with DCM (2 x 40 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to afford the title compound (570 mg, 32%) as a colorless oil. LCMS (ESI, m / z): 192 [M+H] +

[0232] Step 3: Synthesis of (2S)-2-amino-3-fluorobutan-1-ol To a stirred solution of tert-butyl (4S)-4-(1-fluoroethyl)-2,2-dimethyloxazolidine-3-carboxylate (570 mg, 2.3 mmol) in 1,4-dioxane (5 mL) was added HCl (4 M, dioxane solution, 5 mL), and the mixture was stirred at room temperature for 2 h. When LCMS indicated completion of the reaction, the mixture was concentrated and the product was used in the next step without further purification. LCMS (ESI, m / z): 108 [M+H] +

[0233] Step 4: Synthesis of tert-butyl ((2S)-3-fluoro-1-hydroxybutan-2-yl)carbamate A solution of (2S)-2-amino-3-fluorobutan-1-ol (240 mg, 2.24 mmol) in THF (10 mL) was placed in a round-bottom flask and then adjusted to a pH above 10 using saturated sodium carbonate solution. Subsequently, (Boc) 2 O (976 mg, 4.48 mmol) / THF was added dropwise with stirring, and the solution was stirred at room temperature overnight. When LCMS indicated completion of the reaction, the mixture was extracted with ethyl acetate (3 x 20 mL), the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to afford the title compound (450 mg, 97%) as a colorless oil. LCMS (ESI, m / z): 208 [M+H] +

[0234] Step 5: Synthesis of tert-butyl (4S)-4-(1-fluoroethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide To a stirred solution of imidazole (887 mg, 13.03 mmol) in DCM (10 mL) was added SOCl 2A solution of (0.29 mL, 3.91 mmol) in DCM (5 mL) was added dropwise and stirred at room temperature for 1 hour. Then, a solution of tert-butyl ((2S)-3-fluoro-1-hydroxybutan-2-yl)carbamate (450 mg, 2.17 mmol) in DCM (5 mL) was added dropwise to the above mixture, and the mixture was stirred at room temperature for 1 hour. When TLC indicated the completion of the reaction, the mixture was quenched with 10% aqueous citric acid to adjust the pH to 5 - 6 and extracted with DCM (3 x 30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was used in the next step without further purification. LCMS (ESI, m / z): 254 [M+H] +

[0235] Step 6: Synthesis of tert-butyl (4S)-4-(1-fluoroethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide RuCl 3 ·H 2 O (98 mg, 0.43 mmol) was added to a stirred solution of tert-butyl (4S)-4-(1-fluoroethyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (550 mg, 2.17 mmol) in MeCN (10 mL). Then, a solution of NaIO 4 (511 mg, 2.39 mmol) in water (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. When TLC indicated the completion of the reaction, the mixture was extracted with ethyl acetate (3 x 10 mL), the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the title compound (350 mg, 60%) as a white solid. LCMS (ESI, m / z): 270 [M+H] +

[0236] 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 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 tert-butyl (4S)-4-(1-fluoroethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (134 mg, 0.5 mmol) according to General Procedure 7. The resulting 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] +

[0237] 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 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 resulting residue was purified by chiral HPLC (column: Chiralpak IF, 2x25 cm, 5 μm; mobile phase A: MTBE + 0.2% IPA, mobile phase B: MeOH; flow rate: 15 mL / min; gradient: 20% B for 33 minutes; detection: UV (220 / 254 nm)). Example 15a. Isomer 1: Chiral HPLC retention time: 26.515 minutes; LCMS (ESI, m / z): 490 [M+H]+; LCMS RT: 1.118 minutes (Method B) Example 15b. Isomer 2: Chiral HPLC retention time: 28.085 minutes; LCMS (ESI, m / z): 490 [M+H]+; LCMS RT: 1.118 minutes (Method B)

[0238] 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

Chemical Structure

[0239] Step 1: Synthesis of (6,7-dimethyl-1H-indol-2-yl)methanol 6,7-Dimethyl-1H-indole-2-carboxylic acid (200 mg, 1.05 mmol) was reacted according to General Procedure 5. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give the title compound (160 mg, 75%) as a yellow solid. LCMS (ESI, m / z): 176 [M+H]+

[0240] Step 2: Synthesis of 6,7-dimethyl-1H-indole-2-carbaldehyde (6,7-Dimethyl-1H-indol-2-yl)methanol (160 mg, 0.91 mmol) was reacted according to General Procedure 6. The reaction mixture was concentrated to give the title compound (115 mg, 73%) as a yellow oil. LCMS (ESI, m / z): 174 [M+H]+

[0241] Step 3: Synthesis of 1-(cyclopropylmethyl)-6,7-dimethyl-1H-indole-2-carbaldehyde 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 resulting crude product was purified by silica 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]+

[0242] 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 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 resulting crude product was purified by preparative TLC (DCM / methanol = 30:1) to give the title compound (60 mg, 81%) as a yellow solid. LCMS (ESI, m / z): 556 [M+H]+

[0243] 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 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 (60 mg, 0.11 mmol) was reacted according to General Procedure 2. The resulting compound was purified by preparative HPLC (Method C) to give the title compound (22.6 mg, 44%) as a white solid. 1 H NMR (400 MHz, methanol-d 4) δ 8.39(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), 3.75(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)

[0244] The compounds of Examples 17 to 34 in Table 3 were obtained by the same procedure as the preparation of the compound of Example 16 using appropriate 2 - carboxyindole or indole - 2 - carbaldehyde.

Table 8

Table 9

Table 10

Table 11

Table 12

[0245] 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

Chemical Structure

[0246] Step 1: Synthesis of 1-(Cyclopropylmethyl)-7-methoxy-1H-indole 7-Methoxy-1H-indole (1 g, 6.79 mmol) was reacted with bromomethylcyclopropane (1.3 g, 10.19 mmol) according to General Procedure 7. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100:1) to give the title compound (1.35 g, 99%) as a yellow oil. LCMS (ESI, m / z): 202 [M+H]+

[0247] Step 2: Synthesis of 1-(Cyclopropylmethyl)-7-methoxy-1H-indole-2-carbaldehyde To a solution of 1-(cyclopropylmethyl)-7-methoxy-indole (500 mg, 2.48 mmol) in THF (20 mL) was added dropwise n-BuLi (2.5 M, n-hexane solution, 1.97 mL, 4.97 mmol) at -78 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. To the above mixture was added dropwise N,N-dimethylformamide (0.38 mL, 4.97 mmol) at -78 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. Then saturated NH 4 Cl aqueous solution (20 mL) was added at -58 °C to quench the reaction, and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 15:1) to give the title compound (133 mg, 23%) as a yellow oil. LCMS (ESI, m / z): 230 [M+H]+

[0248] Step 3: Synthesis of tert-butyl (R)-(1-(2-(1-(cyclopropylmethyl)-7-methoxy-1H-indole-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)propan-2-yl)carbamate According to general procedure 4, 1-(cyclopropylmethyl)-7-methoxy-indole-2-carbaldehyde (212 mg, 0.92 mmol) was reacted with intermediate 3 (350 mg, 0.92 mmol). The resulting crude product was purified by column chromatography (DCM / MeOH = 10:1) to give the title compound (405 mg, 79%) as a pale yellow solid. LCMS (ESI, m / z): 558 [M+H]+

[0249] 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 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 (345 mg, 0.62 mmol) was reacted according to general procedure 2. The resulting crude product was purified by preparative HPLC (method F) to give the title compound (232.8 mg, 82%) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.29(s, 1H), 8.18(s, 3H), 7.73(s, 1H), 7.32(d, J = 8.1Hz, 1H), 7.16(s, 1H), 7.11(t, J = 7.8Hz, 1H), 6.89(d, J = 7.5Hz, 1H), 4.62(d, J = 6.6Hz, 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)

[0250] 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

Chem.

[0251] 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

Chem.

[0252] 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

Chemical Structure

[0253] Step 1: Synthesis of 6-Bromo-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde 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 resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give the title compound (420 mg, 68%) as a yellow oil. LCMS (ESI, m / z): 278 [M + H]+

[0254] Step 2: Synthesis of 1-(Cyclopropylmethyl)-6-(prop-1-en-2-yl)-1H-indole-2-carbaldehyde To a stirred solution of 6-bromo-1-(cyclopropylmethyl)indole-2-carbaldehyde (200 mg, 0.72 mmol) in 1,4-dioxane (5 mL) and water (1 mL), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (241 mg, 1.44 mmol), K 3 PO 4 (609 mg, 2.88 mmol) and Pd(PPh 3 ) 4 (58 mg, 0.05 mmol) were added portionwise at room temperature under a nitrogen atmosphere, and the mixture was stirred at 80 °C for 2 h. The reaction was monitored by LCMS. Then water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting 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]+

[0255] Step 3: Synthesis of 1-(cyclopropylmethyl)-6-isopropyl-1H-indole-2-carbaldehyde To a stirred solution of 1-(cyclopropylmethyl)-6-isopropenyl-indole-2-carbaldehyde (165 mg, 0.69 mmol) in methanol (10 mL), N 2 atmosphere, PtO 2 (156 mg, 0.69 mmol) was added, and the mixture was stirred at room temperature under an H 2 atmosphere for 0.5 h. TLC indicated complete consumption of the starting material and the formation of a non-polar spot. The solid was filtered off, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative TLC (petroleum ether / ethyl acetate = 4 / 1) to give 1-(cyclopropylmethyl)-6-isopropyl-indole-2-carbaldehyde (130 mg, 78%) as a yellow oil. LCMS (ESI, m / z): 242 [M+H]+

[0256] 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 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 resulting crude product was purified by column chromatography (DCM / methanol = 30 / 1) to give the title compound (51 mg, 58%) as a yellow solid. LCMS (ESI, m / z): 570 [M+H]+

[0257] 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 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 (51 mg, 0.09 mmol) was reacted according to General Procedure 2. The resulting 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)

[0258] The compounds of Examples 39-41 in Table 4 were obtained by the same procedure as for the preparation of the compound of Example 38 using the appropriate boronate coupling partner for the Suzuki coupling in Step 2.

Table 13

[0259] 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

Chemical formula

[0260] Step 1: Synthesis of 1-(cyclopropylmethyl)-6-(oxetan-3-yl)-1H-indole-2-carbaldehyde To a stirred solution of 6-bromo-1-(cyclopropylmethyl)indole-2-carbaldehyde (40 mg, 0.14 mmol) in 1,2-dimethoxyethane (2 mL) under a nitrogen atmosphere, 3-bromooxetane (30 mg, 0.22 mmol), [Ir(dFCF 3 ppy) 2 (dtbpy)]PF 6 (2 mg), (TMS) 3 SiH (36 mg, 0.14 mmol), Na 2 CO 3 (31 mg, 0.29 mmol), NiCl(dme) (1 mg) and dtbpy (1 mg) were added. The mixture was stirred and irradiated with a blue LED light overnight (irradiated at a distance of 7 cm, and the reaction temperature was maintained at room temperature). When LCMS indicated the completion of the reaction, the reaction was quenched by exposure to air. The solid was filtered off and the resulting mixture was concentrated. The obtained residue was separated by 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] +

[0261] 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 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 resulting crude product 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] +

[0262] 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 A stirred solution 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 (30 mg, 0.05 mmol) / DCM (2 mL) was reacted according to General Procedure 2. The resulting residue was purified by preparative HPLC (Method G) to give the title compound (6.8 mg, 27%) as a white solid. 1 H NMR (400 MHz, CD 3 OD-d 4) δ 8.41(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] +

[0263] 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

Chem.

Chem.

[0264] 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 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 resulting 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]+

[0265] 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 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 was reacted according to General Procedure 2. The resulting 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 (400 MHz, DMSO-d 6 ) δ 8.28 - 8.20 (m, 2H), 7.89 (s, 3H), 7.64 (s, 1H), 7.31 - 7.24 (m, 2H), 4.55 (d, J = 15.6 Hz, 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: 1.535 min (Method B)

[0266] (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

Chemical formula

[0267] 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 To a solution of Intermediate 6 (50 mg, 0.09 mmol) and methanol (0.5 mL) / 1,4-dioxane (0.5 mL) under a nitrogen atmosphere, KOH (15 mg, 0.27 mmol), t-BuBrettPhos (8.6 mg, 0.02 mmol), and Pd 2 (dba) 3 (8.1 mg, 0.01 mmol) were added, and the mixture was irradiated with microwave at 90 °C for 2 hours. The reaction was monitored by LCMS, and then water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL), washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (48 mg, 97%) as a pale yellow solid. LCMS (ESI, m / z): 559 [M+H]+

[0268] Step 2: Synthesis of (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 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 (58 mg, 0.10 mmol) was reacted according to General Procedure 2. The crude product obtained 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)

[0269] 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

Chemical Structure

[0270] 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 [Chemical formula]

[0271] Step 1: Synthesis of 3-Fluoro-1H-indole-2-carbaldehyde To a solution of 1H-indole-2-carbaldehyde (300 mg, 2.07 mmol) in acetonitrile (10 mL) were added 1-(chloromethyl)-4-fluoropiperazine (315 mg, 2.07 mmol) and K 2 CO 3 (857 mg, 6.21 mmol), and the solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS, and the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (150 mg, 79%) as a pale yellow solid. LCMS (ESI, m / z): 163 [M+H]+

[0272] Step 2: Synthesis of 1-(Cyclopropylmethyl)-3-fluoro-1H-indole-2-carbaldehyde A solution of 3-fluoro-1H-indole-2-carbaldehyde (80 mg, 0.49 mmol) was reacted according to General Procedure 8. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain the title compound (75 mg, 41%) as a brown oil. LCMS (ESI, m / z): 217 [M+H]+

[0273] 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 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 obtained was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (50 mg, 66%) as a brown solid. LCMS (ESI, m / z): 546 [M+H]+

[0274] 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 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 (50 mg, 0.09 mmol) was reacted according to General Procedure 2. The crude product obtained was purified by preparative HPLC (Method E) to give the title compound (25.3 mg, 62%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (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 = 6.8 Hz, 2H), 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: 1.554 min (Method B)

[0275] The compounds of Examples 47 to 55 in Table 5 were obtained using the appropriate indole-2-carbaldehyde and Intermediate 4 in Step 4 by the same procedure as the preparation of the compound of Example 16.

Table 14

Table 15

Table 16

[0276] 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

Chemical Structure

[0277] Example 57. (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

Chemical Structure

[0278] 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 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), under a nitrogen atmosphere, Pd(dppf)Cl 2 (28 mg, 0.03 mmol) and Na 2 CO 3 (55 mg, 0.52 mmol) were added and the mixture was stirred at 70 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. Then water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL), washed with water (2 x 10 mL) and brine (2 x 10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:5) to give the title compound (100 mg, 77%) as a white solid. LCMS (ESI, m / z): 756 [M+H]+

[0279] 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 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 (80 mg, 0.11 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method G) to give the title compound (49.4 mg, 71%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.30 (s, 3H), 8.28 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.52 (t, J = 6.4 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.26 - 7.13 (m, 3H), 4.78 - 4.60 (m, 4H), 4.02 (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)

[0280] The compounds of Examples 58 - 60 in Table 6 were obtained using the appropriate boronate or boronic acid in Step 1 by the same procedure as for the preparation of the compound of Example 57.

Table 17

[0281] Synthesis of the major coupling partner of Example 58

Chem.

[0282] Step 1: Synthesis of 3-(4-bromo-3-methyl-phenyl)-5,5-dimethyl-oxazolidin-2-one To a solution of 1-bromo-4-iodo-2-methyl-benzene (520 mg, 1.75 mmol), 5,5-dimethyloxazolidin-2-one (403 mg, 3.5 mmol) and K 2 CO 3 (726 mg, 5.25 mmol) / MeCN (7 mL) was added CuI (66 mg, 0.35 mmol) and N,N,N',N'-tetramethyl-1,2-ethanediamine (81 mg, 0.70 mmol) under a nitrogen atmosphere, and the mixture was stirred at 70 °C for 16 h under a nitrogen atmosphere. The reaction was monitored by LCMS. Then water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 x 30 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by flash column chromatography (C18 silica) to give the title compound (490 mg, 98.5%) as a white solid. LCMS (ESI, m / z): 284 [M+H]+

[0283] 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 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) / 1,4-dioxane (5 mL) was added Pd(dppf)Cl 2 (77.2 mg, 0.11 mmol) under a nitrogen atmosphere, and the mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The obtained crude product was used in the next step. LCMS (ESI, m / z): 250 [M+H]+

[0284] Synthesis of the major coupling partner of Example 60

Chemical formula

[0285] Step 1: Synthesis of 4-Bromo-2-fluoro-5-methyl-benzamide 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) at room temperature and the mixture was stirred for 30 minutes. Then to this was added DIEA (2.24 mL, 12.87 mmol) and NH 4 Cl (278 mg, 5.15 mmol) at 0 °C and the mixture was warmed to room temperature and stirred for 2 hours. The reaction was monitored by TLC and LCMS. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with brine (2 x 30 mL), dried over sodium sulfate, concentrated and purified by preparative TLC (petroleum ether / ethyl acetate = 1:1) to give the title compound (830 mg, 83%) as a white solid. LCMS (ESI, m / z): 232 [M+H] +

[0286] Step 2: Synthesis of 2-Fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide To a stirred solution of 4-bromo-2-fluoro-5-methyl-benzamide (830 mg, 3.58 mmol) in MeCN (20 mL) were added bis(pinacolato)diboron (1817 mg, 7.15 mmol) and AcOK (1052 mg, 10.73 mmol). Then under a nitrogen atmosphere at room temperature, Pcy 3 ·HBF 4 (263 mg, 0.72 mmol) and Pd(OAc) 2 (80 mg, 0.36 mmol) were added and the mixture was heated to 80 °C and stirred overnight. The product was detected by LCMS. The mixture was filtered through celite and 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] +

[0287] 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

Chemical formula

[0288] Step 1: Synthesis of 5-bromo-6-ethyl-pyridin-2-amine To a solution of 6-ethylpyridin-2-amine (1.22 g, 9.99 mmol) in MeCN (100 mL) was added NBS (1.78 g, 9.99 mmol) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. Then water (300 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 x 300 mL), washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:3) to obtain the title compound (1.5 g, 74%) as a light brown solid. LCMS (ESI, m / z): 201 [M+H]+

[0289] Step 2: Synthesis of 3-(5-bromo-6-ethyl-2-pyridyl)oxazolidin-2-one 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) were added TMEDA (0.01 mL, 0.1 mmol), CuI (9 mg, 0.05 mmol), and K 2 CO 3(203 mg, 1.47 mmol) was added, and the mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. Then, water (20 mL) was added to quench the reaction, and the mixture was 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 reduced pressure. The resulting crude product was purified by silica 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]+

[0290] 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 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), under a nitrogen atmosphere, Pd(dppf)Cl 2 (13 mg, 0.02 mmol) and K 2 CO 3 (35 mg, 0.25 mmol) were added, and the mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. Then, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 x 10 mL), washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (C18 silica) to obtain the title compound (50 mg, 80%) as a pale yellow solid. LCMS (ESI, m / z): 737 [M+H]+

[0291] 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 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-fluoropropyl)carbamate (50 mg, 0.07 mmol) in DCM (3 mL) was added dropwise TFA (1 mL) at 0 °C under a nitrogen atmosphere. Under a nitrogen atmosphere, the solution was stirred at room temperature for 0.5 h and the reaction was monitored by LCMS. The resulting solution was concentrated under reduced pressure and 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)

[0292] 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

Chemical Structure

[0293] (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 [Chemical formula]

[0294] Step 1: Synthesis of methyl (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-carboxylate To a solution of Intermediate 6 (260 mg, 0.45 mmol) in methanol (20 mL) were added Et 3 N (0.19 mL, 1.34 mmol) and Pd(dppf)Cl 2 (33 mg, 0.04 mmol), and the mixture was stirred at 90 °C overnight under a carbon monoxide atmosphere (30 atm). The reaction was monitored by LCMS, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (DCM / MeOH = 20:1) to give the title compound (180 mg, 67%) as a pale yellow solid. LCMS (ESI, m / z): 605 [M+H]+

[0295] 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 A solution of methyl (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-carboxylate (110 mg, 0.18 mmol) in methanol (2 mL) and water (1 mL) was added with NaOH (73 mg, 1.82 mmol) under a nitrogen atmosphere. The mixture was stirred at 50 °C for 1 hour and the reaction was monitored by LCMS. The reaction mixture was concentrated and the resulting residue was adjusted to pH 5 - 6 with HCl (1 M). The mixture was extracted with ethyl acetate (3 x 20 mL), washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by flash column chromatography (C18 silica) to give the title compound (90 mg, 84%) as a yellow solid. LCMS (ESI, m / z): 591 [M+H]+

[0296] Step 3: Synthesis of tert-butyl (S)-(1-(2-(1-(cyclopropylmethyl)-6-(methylcarbamoyl)-1H-pyrrolo[2,3-b]pyridine-2-yl)-1-methyl-5-oxo-1,5,7,8-tetrahydro-6H-imidazo[4,5-g]isoquinolin-6-yl)-3-fluoropropyl)carbamate 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 with HATU (48 mg, 0.13 mmol), DIEA (0.04 mL, 0.25 mmol) and methanamine (4 mg, 0.11 mmol), and stirred at room temperature for 1 hour. The reaction was monitored by LCMS. Then water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were washed with water (2 x 20 mL) and brine (2 x 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (DCM / MeOH = 20:1) to give the title compound (40 mg, 78%) as a yellow solid. LCMS (ESI, m / z): 604 [M+H]+

[0297] 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 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-fluoropropyl)carbamate (40 mg, 0.07 mmol) was reacted according to General Procedure 2. The obtained crude product was purified by preparative HPLC (Method E) to give the title compound (29 mg, 87%) as a white solid. 1 1H NMR (400 MHz, DMSO-d 6+D2O): δ 8.29 - 8.26 (m, 2H), 7.91 (d, J = 8 Hz, 1H), 7.65 (s, 1H), 7.26 (s, 1H), 4.78 - 4.66 (m, 4H), 3.99 (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: 1.523 min (Method B)

[0298] 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

Chemical Structure

[0299] 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 [Chemical formula]

[0300] Step 1: Synthesis of ethyl 5-fluoro-7-methoxy-1H-indole-2-carboxylate To a stirred solution of 4-fluoro-2-methoxyaniline (500 mg, 3.54 mmol) in DMSO (30 mL) 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, and the mixture was stirred at 70 °C overnight under an O 2 atmosphere. When the completion of the reaction was indicated by LCMS, the mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with brine (2 x 60 mL), dried over sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give the title compound (370 mg, 44%) as a yellow oil. LCMS (ESI, m / z): 238 [M+H] +

[0301] Step 2: Synthesis of ethyl 1-(cyclopropylmethyl)-5-fluoro-7-methoxy-indole-2-carboxylate To a stirred solution of ethyl 5-fluoro-7-methoxy-1H-indole-2-carboxylate (370 mg, 1.56 mmol) in DMF (15 mL) under a nitrogen atmosphere, bromomethylcyclopropane (316 mg, 2.34 mmol), Cs 2 CO 3(1.5 g, 4.68 mmol) and TBAI (75 mg, 0.31 mmol) were added, and the mixture was stirred at 50 °C for 2 hours. The reaction was monitored by LCMS. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (2 x 40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by preparative TLC (petroleum ether:ethyl acetate = 20:1) to give the title compound (300 mg, 66%) as a yellow oil. LCMS (ESI, m / z): 292 [M+H] +

[0302] Step 3: Synthesis of 1-(cyclopropylmethyl)-5-fluoro-7-methoxy-indol-2-yl]methanol Ethyl 1-(cyclopropylmethyl)-5-fluoro-7-methoxy-indole-2-carboxylate (100 mg, 0.34 mmol) was reacted according to General Procedure 5. The obtained crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give the title compound (80 mg, 94%) as a yellow oil. LCMS (ESI, m / z): 250 [M+H] +

[0303] Step 4: Synthesis of 1-(cyclopropylmethyl)-5-fluoro-7-methoxy-indole-2-carbaldehyde (1-(Cyclopropylmethyl)-5-fluoro-7-methoxy-indol-2-yl)methanol (80 mg, 0.32 mmol) was reacted according to General Procedure 6. The obtained residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to give the title compound (70 mg, 88%) as a yellow oil. LCMS (ESI, m / z): 248 [M+H] +

[0304] 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 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 resulting 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] +

[0305] 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 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 (60 mg, 0.10 mmol) was reacted according to general procedure 2. The resulting crude product was purified by preparative HPLC (method G) to give the title compound (30.7 mg, 59%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6): δ 8.70 - 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 = 7.0 Hz, 2H), 4.00 (s, 3H), 3.94 (s, 3H), 3.87 - 3.76 (m, 3H), 3.75 - 3.68 (m, 2H), 3.24 (t, J = 6.4 Hz, 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)

[0306] 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 [Chemical Structure] Example 66 was synthesized in the same synthetic route as Example 65, starting from 4-fluoro-2-methoxy-aniline. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.30 (s, 3H), 8.25 (s, 1H), 7.62 (s, 1H), 7.42 (dd, J = 8.7, 4.6 Hz, 1H), 7.13 (s, 1H), 7.09 (dd, J = 12.2, 8.7 Hz, 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 = 6.4 Hz, 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)

[0307] 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

Chem.

[0308] 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 6-Bromo-1-(cyclopropylmethyl)indole-2-carbaldehyde (84 mg, 0.30 mmol) was reacted with intermediate 5 (100 mg, 0.25 mmol) according to General Procedure 4. The resulting crude product was purified by preparative TLC (DCM / MeOH (30:1)) to give the title compound (150 mg, 95%) as a yellow solid. LCMS (ESI, m / z): 624 [M+H]+

[0309] Step 2: Synthesis of methyl (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-carboxylate 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) under a nitrogen atmosphere were added AcONa (63 mg, 0.77 mmol) and Pd(dppf)Cl2 (28 mg, 0.04 mmol) was added. This mixed solution was stirred overnight at 80 °C under a carbon monoxide atmosphere, and the reaction mixture was monitored by LCMS and TLC respectively. The reaction mixture was cooled to ambient temperature, and the resulting mixture was partitioned between ethyl acetate (10 mL) and water (10 mL), and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The fractions of the organic layer were combined, washed with water (3 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was finally purified by preparative TLC (petroleum ether / ethyl acetate (1:1)) to give the title compound (102 mg, 88%) as a yellow solid. LCMS (ESI, m / z): 604 [M+H]+

[0310] 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 To a solution of methyl (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-carboxylate (60 mg, 0.10 mmol) in THF (2 mL) and water (1 mL), LiOH (39 mg, 0.99 mmol) was added and the mixture was stirred at ambient temperature for 6 h under a nitrogen atmosphere. The reaction was monitored by LCMS. Before purification, the resulting solution had to be adjusted to a pH value of less than 7 with 1 M HCl. Then water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the title compound (47 mg, 80%) was obtained as a yellow solid. LCMS (ESI, m / z): 590 [M+H]+

[0311] 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 (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 resulting crude product was purified by preparative HPLC (Method C) to give the title compound (23.8 mg, 64%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.83 (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 = 6.4 Hz, 2H), 1.14 - 1.02 (m, 1H), 0.29 (d, J = 9.2, 2.8 Hz, 2H), 0.02 (d, J = 6.0, 2.9 Hz, 2H); LCMS (ESI, m / z): 490 [M+H]+; LCMS RT: 1.293 min (Method B)

[0312] 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

Chem.

[0313] Step 1: Synthesis of Ethyl 6-bromo-1-(cyclopropylmethyl)-1H-indole-2-carboxylate 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 resulting 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]+

[0314] Step 2: Synthesis of Ethyl 1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indole-2-carboxylate 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) under a nitrogen atmosphere, K 2 CO 3 (445 mg, 3.23 mmol), DL-proline (37 mg, 0.32 mmol) and CuI (30 mg, 0.16 mmol) were added and the mixture was stirred at 110 °C for 22 h under a nitrogen atmosphere. The reaction was monitored by LCMS. Then water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL), washed with water (2 x 100 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (260 mg, 45%) as a yellow solid. LCMS (ESI, m / z): 357 [M+H]+

[0315] Step 3: Synthesis of (1-(Cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indol-2-yl)methanol Ethyl 1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)indole-2-carboxylate (250 mg, 0.7 mmol) was reacted according to General Procedure 5. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (200 mg, 90%) as a yellow solid. LCMS (ESI, m / z): 315 [M+H]+

[0316] Step 4: Synthesis of 1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)-1H-indole-2-carbaldehyde [1-(Cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)indol-2-yl]methanol (220 mg, 0.7 mmol) was reacted according to General Procedure 6. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (200 mg, 91%) as a yellow solid. LCMS (ESI, m / z): 313 [M+H]+

[0317] 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 1-(Cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)indole-2-carbaldehyde (39 mg, 0.13 mmol) was reacted with Intermediate 5 according to General Procedure 4. The resulting crude product was purified by preparative TLC (DCM / MeOH = 20:1) to give tert-butyl N-[(1S)-1-[[2-[1-(cyclopropylmethyl)-6-(4-methoxypiperidin-1-yl)indol-2-yl]-1-methyl-5-oxo-7,8-dihydroimidazo[4,5-g]isoquinolin-6-yl]methyl]-2-fluoroethyl]carbamate (50 mg, 60.2%) as a yellow solid. LCMS (ESI, m / z): 659 [M+H] +

[0318] 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 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-fluoropropyl)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 (22.7 mg, 53%) as a yellow solid. LCMS (ESI, m / z): 559 [M+H]+; LCMS RT: 1.173 min (Method D)

[0319] 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

Chemical Structure

[0320] Step 1: Synthesis of Ethyl 1-(cyclopropylmethyl)-7-(dimethylamino)indole-2-carboxylate To a solution of ethyl 7-bromo-1-(cyclopropylmethyl)indole-2-carboxylate (200 mg, 0.62 mmol) in toluene (5 mL) under a nitrogen atmosphere, N-methylmethanamine (36 mg, 0.81 mmol), Pd 2 (dba) 3(57 mg, 0.06 mmol), BINAP (77.3 mg, 0.12 mmol) and sodium tert-butoxide (179 mg, 1.86 mmol) were added and stirred at 50 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by column chromatography (DCM / MeOH = 10:1) to obtain the title compound (100 mg, 56%) as a yellow solid. LCMS (ESI, m / z): 287 [M+H]+

[0321] Step 2: Synthesis of (1-(cyclopropylmethyl)-7-(dimethylamino)-1H-indol-2-yl)methanol 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 reduced pressure to obtain the title compound (70 mg, 74%) as a light brown solid. LCMS (ESI, m / z): 245 [M+H]+

[0322] Synthesis of 1-(cyclopropylmethyl)-7-(dimethylamino)indole-2-carbaldehyde (1-(cyclopropylmethyl)-7-(dimethylamino)-1H-indol-2-yl)methanol (70 mg, 0.29 mmol) was reacted according to General Procedure 6. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the title compound (30 mg, 43%) as a light yellow solid. LCMS (ESI, m / z): 243 [M+H]+

[0323] Step 3: 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 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 resulting 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]+

[0324] Step 4: 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 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 (25 mg, 0.04 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method E) to give the title compound (10.2 mg, 48%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 +D 2 O): δ 8.26(s, 1H), 7.65(s, 1H), 7.41(d, J = 0.8 Hz, 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 = 6.4 Hz, 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)

[0325] 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

Chemical formula

[0326] The compounds of Examples 71 to 84 in Table 7 were obtained through the same procedure as in the production of the compound of Example 16, using an appropriate 2-carboxyindole as a starting material in Step 1 and / or using indole-2-carboxaldehyde and an alkylating agent in Step 3.

Table 18

Table 19

Table 20

Table 21

[0327] 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

Chemical Structure

[0328] Step 1: Synthesis of (R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-ol 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 the mixture was stirred for 30 minutes. Then TBDPSCl (1.71 mL, 6.57 mmol) was added thereto at 0 °C, and the mixture was stirred at room temperature for 1 hour. When the completion of the reaction was indicated by LCMS, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with brine (2 x 60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained 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] +

[0329] Step 2: Synthesis of tert-butyldiphenyl((2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)silane To a stirred solution of (R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-ol (800 mg, 2.54 mmol) in DCM (25 mL) were added p-TSA (44 mg, 0.25 mmol) and 3,4-dihydro-2H-pyran (1.07 g, 12.72 mmol), and the mixture was stirred at room temperature for 2 hours. When the completion of the reaction was indicated by LCMS, the mixture was concentrated. The obtained residue was purified by silica gel (petroleum ether:ethyl acetate = 100:1) to obtain the title compound (340 mg, 33.5%) as a colorless oil. LCMS (ESI, m / z): 399 [M+H]+

[0330] Step 3: Synthesis of (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol 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, THF solution, 3 mL), and the mixture was stirred at room temperature for 3 hours. When LCMS indicated completion of the reaction, the mixture was concentrated and the resulting residue was purified by 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] +

[0331] Step 4: Synthesis of methanesulfonic acid (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl 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), and then MsCl (42 mg, 0.37 mmol) was added thereto at 0 °C, and the mixture was stirred at room temperature for 1 hour. When LCMS indicated completion of the reaction, the mixture was quenched with water (15 mL) and extracted with DCM (3 x 15 mL). The organic layer was washed with brine (2 x 40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by 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] +

[0332] 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 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 the mixture was stirred for 30 minutes. Then (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propyl methanesulfonate (106 mg, 0.45 mmol) and TBAI (14 mg, 0.06 mmol) were added thereto at 0 °C and the mixture was stirred at 50 °C overnight. Although LCMS indicated that the reaction was not complete, the mixture was quenched with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The organic layer was washed with brine (2 x 40 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was separated by 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] +

[0333] 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 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, 1,4-dioxane solution, 2 mL) and the mixture was stirred at room temperature for 0.5 hour. When LCMS indicated completion of the reaction, the mixture was concentrated. The resulting residue was purified by preparative HPLC (Method C) to give the title compound (52.1 mg, 61.9%) as a white solid. 1 H NMR (400 MHz, CD 3 OD-d 4) δ 8.37(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)

[0334] The compounds of Examples 86 to 91 in Table 8 were obtained in the same procedure as the preparation of the compound of Example 35, using appropriate substituted indoles and alkylating agents as starting materials in Step 1.

Table 22

Table 23

[0335] 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

Chemical Structure

[0336] Step 1: Synthesis of Ethyl 1-(2-hydroxy-2-methylpropyl)-1H-indole-2-carboxylate Ethyl 1H-indole-2-carboxylate (80 mg, 0.42 mmol) / DMF (2 mL), K 2 CO 3(175 mg, 1.27 mmol) and 2,2-dimethyloxirane (60 mg, 0.85 mmol) were added at room temperature and stirred at 70 °C for 4 h. When TLC indicated completion of the reaction, the reaction mixture was cooled to room temperature. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting orange sticky solid was purified by preparative TLC (petroleum ether / ethyl acetate = 2:1) to give the title compound (46 mg, 46.6%) as a yellow oil. LCMS (ESI, m / z): 262 [M+H]+

[0337] Step 2: Synthesis of 1-(2-(hydroxymethyl)-1H-indol-1-yl)-2-methylpropan-2-ol Ethyl 1-(2-hydroxy-2-methyl-propyl)indole-2-carboxylate (46 mg, 0.18 mmol) was reacted according to General Procedure 5. The resulting crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 1:1) to give the title compound (40 mg, 93.1%) as a yellow oil. LCMS (ESI, m / z): 220 [M+H]+

[0338] Step 3: Synthesis of 1-(2-hydroxy-2-methylpropyl)-1H-indole-2-carbaldehyde 1-(2-(Hydroxymethyl)-1H-indol-1-yl)-2-methylpropan-2-ol (40 mg, 0.18 mmol) was reacted according to General Procedure 6. The resulting crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 1:1) to give the title compound (27 mg, 68.1%) as a yellow oil. LCMS (ESI, m / z): 218 [M+H]+

[0339] 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 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 obtained 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]+

[0340] 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 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 (35 mg, 0.06 mmol) was reacted according to general procedure 2. The crude product obtained 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-d 4 ) δ 8.44(s, 1H), 7.80 - 7.65(m, 3H), 7.40(t, J = 8.4Hz, 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 = 6.5Hz, 3H), 1.08(s, 6H); LCMS (ESI, m / z): 446 [M+H]+; LCMS RT: 1.281 min (method D)

[0341] 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

Chemical Structure

[0342] Step 1: Synthesis of 1-(isoxazol-5-ylmethyl)indole-2-carbaldehyde 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 obtained crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 3:1) to give the title compound (30 mg, 64.1%) as a yellow oil. LCMS (ESI, m / z): 227 [M+H]+

[0343] 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 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 obtained 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]+

[0344] 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 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 was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method C) to give the title compound (27.5 mg, 83%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.34 (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 = 1.8 Hz, 1H), 4.88 - 4.53 (m, 2H), 3.99 (s, 3H), 3.92 - 3.69 (m, 2H), 3.67 (t, J = 6.5 Hz, 2H), 3.21 (t, J = 6.4 Hz, 2H); LCMS (ESI, m / z): 473 [M+H]+; LCMS RT: 1.50 min (Method B)

[0345] The compounds of Examples 94 - 101 in Table 9 were obtained in a similar procedure to the preparation of the compound of Example 93 using appropriate alkylating agents as starting materials.

Table 24

Table 25

[0346] 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

Chem.

[0347] 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 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 resulting 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]+

[0348] 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 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 (93 mg, 0.16 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method E) to give the title compound (69.3 mg, 89.8%) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6): δ 8.31 (s, 3H), 8.25 (s, 1H), 7.60 (s, 1H), 7.26 (d, J = 8 Hz, 1H), 7.08 - 7.01 (m, 2H), 6.84 (d, J = 7.6 Hz, 1H), 4.88 (t, J = 5.2 Hz, 2H), 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 = 5.6 Hz, 2H), 3.21 (t, J = 6.4 Hz, 2H), 2.86 (s, 3H); LCMS (ESI, m / z): 480 [M + H]+; LCMS RT: 1.314 min (Method B)

[0349] The compounds of Examples 103 to 146 in Table 10 were obtained in the same procedure as the production of the compound of Example 102, using an appropriate indole-2-carbaldehyde as a starting material. [Table 26] [Table 27] [Table 28] [Table 29] [Table 30] [Table 31] [Table 32] [Table 33] [Table 34] [Table 35]

Table 36

Table 37

Table 38

Table 39

[0350] 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

Chemical formula

[0351] Step 1: Synthesis of ethyl 2-indol-1-ylacetate 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 resulting 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 pale yellow oil. LCMS (ESI, m / z): 204 [M+H]+

[0352] Step 2: Synthesis of 1-(indol-1-ylmethyl)cyclopropanol Ethyl 2-indol-1-ylacetate (1.1 g, 5.41 mmol) and Ti(OPr-i) 4A solution of (2.31 g, 8.12 mmol) in THF (50 mL) was added dropwise with chloro(ethyl)magnesium (2 N, THF solution, 10.8 mL, 21.6 mmol) at 0 °C and stirred at room temperature for 0.5 h. The reaction was monitored by LCMS. Then HCl (1 N, 10 mL) was added to quench the reaction and the mixture was stirred at room temperature for 0.5 h. The pH value of the solution was adjusted to 8 with sodium hydrogen carbonate. Water (150 mL) was added to the obtained solution and extracted with ethyl acetate (2 x 100 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (650 mg, 65%) as a white solid. LCMS (ESI, m / z): 188 [M+H]+

[0353] Step 3: Synthesis of 1-((1-methoxycyclopropyl)methyl)-1H-indole To a solution of 1-(indol-1-ylmethyl)cyclopropanol (650 mg, 3.47 mmol) in DMF (34 mL), NaH (278 mg, 6.94 mmol) was added portionwise at 0 °C and stirred at room temperature for 0.5 h. Iodomethane (985 mg, 6.94 mmol) was added to this mixed solution at 0 °C and stirred at room temperature for 2 h. The reaction was monitored by LCMS. Then water (100 mL) was added to quench the reaction and extracted with ethyl acetate (100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the title compound (300 mg, 42.9%) as a pale yellow oil. LCMS (ESI, m / z): 202 [M+H]+

[0354] Step 4: Synthesis of 1-((1-methoxycyclopropyl)methyl)-1H-indole-2-carbaldehyde A solution of 1-((1-methoxycyclopropyl)methyl)-1H-indole (100 mg, 0.50 mmol) in THF (5 mL) was added dropwise with n-BuLi (2.5 N, n-hexane solution, 0.5 mL, 1.24 mmol) at -78 °C, and the mixture was stirred at room temperature for 1 hour. DMF (0.11 mL, 1.49 mmol) was added dropwise to the above mixture at -78 °C and stirred at room temperature for 1 hour. The reaction was monitored by LCMS. Then water (20 mL) was added to quench the reaction, and the mixture was 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 reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 50:1) to give the title compound (25 mg, 21.9%) as a pale yellow oil. LCMS (ESI, m / z): 230 [M+H]+

[0355] 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 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 the general procedure 4. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (31 mg, 34.2%) as a pale yellow solid. LCMS (ESI, m / z): 576 [M+H]+

[0356] 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 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 (31 mg, 0.05 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method C) to give the title compound (15.7 mg, 25.6%) as a white solid. 1 H NMR (400 MHz, methanol-d 4 ) 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)

[0357] 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

Chem.

[0358] Step 1: Synthesis of methyl 7-cyano-1H-indole-2-carboxylate To a solution of methyl 7-bromo-1H-indole-2-carboxylate (1.2 g, 4.7 mmol) in DMF (20 mL) was added CuCN (423 mg, 4.7 mmol), and the mixture was stirred at 155 °C for 6 h. The reaction was monitored by TLC. Then water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL), washed with water (2 x 100 mL) and brine (2 x 100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (460 mg, 48.6%) as a white solid.

[0359] Step 2: Synthesis of 2-(hydroxymethyl)-1H-indole-7-carbonitrile To a solution of methyl 7-cyano-1H-indole-2-carboxylate (460 mg, 2.3 mmol) in methanol (20 mL) was added NaBH 4 (17.5 mg, 46 mmol) at 0 °C, and the mixture was stirred at room temperature for 5 h. The reaction was monitored by LCMS. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with water (50 mL), extracted with DCM (3 x 50 mL), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (140 mg, 35.4%) as a white solid. LCMS (ESI, m / z): 173 [M+H]+

[0360] Step 3: Synthesis of 2-formyl-1H-indole-7-carbonitrile 2-(Hydroxymethyl)-1H-indole-7-carbonitrile (130 mg, 0.76 mmol) was reacted according to General Procedure 6. The resulting 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]+

[0361] Step 4: Synthesis of 2-formyl-1-(isoxazol-5-ylmethyl)indole-7-carbonitrile 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 resulting 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]+

[0362] 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 2-Formyl-1-(isoxazol-5-ylmethyl)indole-7-carbonitrile was reacted with Intermediate 5 according to General Procedure 4. The resulting 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]+

[0363] 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 (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 resulting crude product was purified by preparative HPLC (Method G) to give the title compound (28.3 mg, 66.1%) as a white solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.43 (s, 1H), 8.40 - 8.26 (m, 3H), 8.15 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.5 Hz, 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]+; LCMS RT: 1.546 min (Method B)

[0364] 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

Chem.

[0365] Step 1: Synthesis of (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 Intermediate 7 (50 mg, 0.09 mmol) / DMF (1.5 mL) was reacted with 3-(bromomethyl)oxetane (20 mg, 0.13 mmol) and Cs 2 CO 3 (87 mg, 0.27 mmol) at 50 °C according to General Procedure 8. The resulting 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] +

[0366] 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 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-fluoropropyl)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 reduced pressure. The resulting 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 (400 MHz, DMSO-d6+D 2O): δ 8.24 (s, 1H), 7.61 (s, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.88 (d, J = 8.1 Hz, 1H), 4.81 - 4.76 (m, 2H), 4.71 - 4.54 (m, 5H), 4.37 (d, J = 4.2 Hz, 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)

[0367] The compounds of Examples 150 to 186 in Table 11 were obtained in the same procedure as the production of the compound of Example 149 using an appropriate alkylating agent including alkyl iodide, alkyl bromide, alkyl chloride, and alkyl methanesulfonate. [Table 40] [Table 41] [Table 42] [Table 43] [Table 44] [Table 45] [Table 46] [Table 47] [Table 48]

Table 49

Table 50

Table 51

[0368] 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

Chem.

[0369] Step 1: Synthesis of tert-butyl (S)-3-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate To a stirred solution of tert-butyl (R)-3-(hydroxymethyl)morpholine-4-carboxylate (400 mg, 1.84 mmol) in DCM (10 mL) at 0 °C were added TEA (0.38 mL, 2.76 mmol) and MsCl (0.17 mL, 2.21 mmol), and the mixture was allowed to return to room temperature while stirring for 1 hour. 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 sodium sulfate and concentrated to give the title compound (550 mg, 101.2%) as a yellow solid. The crude product obtained was used directly in the next step. LCMS (ESI, m / z): 240 [M+H] +

[0370] 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 Intermediate 7 (50 mg, 0.09 mmol) / DMF (2 mL) was reacted with Cs 2 CO 3 (87 mg, 0.27 mmol), tert-butyl (S)-3-(((methylsulfonyl)oxy)methyl)morpholine-4-carboxylate (52 mg, 0.18 mmol) and TBAI (4 mg, 0.02 mmol) at 50 °C. The resulting 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] +

[0371] 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 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 (25 mg, 0.03 mmol) was reacted according to General Procedure 2. The reaction was monitored by TLC and LCMS. The solution was concentrated under reduced pressure and the resulting 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 (400 MHz, DMSO-d6 +D 2 O) δ 8.25 (s, 1H), 7.62 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 7.09 (s, 1H), 6.92 (d, J = 7.8 Hz, 1H), 4.83 - 4.68 (m, 2H), 4.67 - 4.54 (m, 2H), 4.47 - 4.35 (m, 2H), 4.21 (d, J = 10.0 Hz, 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, 4H), 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)

[0372] The compounds of Examples 188 to 193 in Table 12 were obtained using an appropriate alcohol in the same procedure as for the production of the compound of Example 187.

Table 52

Table 53

Table 54

[0373] 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

Chem.

[0374] Step 1: Synthesis of 2-(oxazol-5-yl)ethan-1-ol To a stirred solution of 2-oxazol-5-ylacetic acid (100 mg, 0.79 mmol) in THF (5 mL) was added BH 3 / THF (2.5 mL, 2.36 mmol) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 0 °C for 2 h under a nitrogen atmosphere. When LCMS indicated completion of the reaction, the mixture was quenched with MeOH. This was concentrated and the product was used in the next step without further purification. LCMS (ESI, m / z): 114 [M+H] +

[0375] 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 To a stirred solution of intermediate 7 (50 mg, 0.09 mmol) in toluene (2 mL) were added 2-(oxazol-5-yl)ethan-1-ol, DTBAD (31 mg, 0.13 mmol) and PPh 3 (35 mg, 0.13 mmol) at 80 °C under a nitrogen atmosphere, and the mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. Since no conversion from the starting material to the product was observed by LCMS, the mixture was concentrated. The resulting residue was purified by preparative TLC (DCM:MeOH = 20:1) to give the title compound (20 mg, 34.2%) as a yellow oil. LCMS (ESI, m / z): 657 [M+H] +

[0376] 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 (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. When LCMS indicated completion of the reaction, the mixture was concentrated. The resulting residue was purified by preparative HPLC (Method E) to afford the title compound (7.3 mg, 42.2%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.37 - 8.29 (m, 2H), 8.29 (s, 1H), 8.24 (s, 1H), 7.60 (s, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.08 - 7.02 (m, 3H), 6.88 (d, J = 7.8 Hz, 1H), 4.87 - 4.62 (m, 2H), 4.56 (d, J = 7.1 Hz, 2H), 4.45 (t, J = 6.0 Hz, 2H), 3.90 (s, 3H), 3.87 - 3.78 (m, 2H), 3.76 - 3.70 (m, 1H), 3.67 (t, J = 6.5 Hz, 2H), 3.28 (t, J = 6.0 Hz, 2H), 3.21 (t, J = 6.4 Hz, 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)

[0377] The compounds of Examples 195 - 204 in Table 13 were obtained using the appropriate carboxylic acid or alcohol reagent in a procedure similar to the preparation of the compound of Example 194.

Table 55

Table 56

Table 57

Table 58

[0378] 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

Chemical formula

[0379] Step 1: Synthesis of ethyl 7-benzyloxy-1-(cyclopropylmethyl)-1H-indole-2-carboxylate Ethyl 7-benzyloxy-1H-indole-2-carboxylate (1 g, 3.39 mmol) was alkylated with bromomethylcyclopropane according to General Procedure 8. The resulting 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]+

[0380] Step 2: Synthesis of ethyl 1-(cyclopropylmethyl)-7-hydroxy-1H-indole-2-carboxylate Ethyl 7-(benzyloxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate (500 mg, 1.42 mmol) / methanol (70 mL) and AcOH (70 mg, 1.16 mmol) were reacted according to General Procedure 9. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (350 mg, 45%) as a pale yellow solid. LCMS (ESI, m / z): 352 [M+H]+

[0381] Step 3: Synthesis of Ethyl 7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(cyclopropylmethyl)-1H-indole-2-carboxylate Ethyl 1-(cyclopropylmethyl)-7-hydroxy-1H-indole-2-carboxylate (100 mg, 0.39 mmol) / DMF (5 mL) was reacted with tert-butyl (2-iodoethoxy)dimethylsilane (331 mg, 1.15 mmol) and Cs 2 CO 3 (377 mg, 1.16 mmol) at 50 °C according to General Procedure 8. The resulting 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]+

[0382] Step 4: Synthesis of (7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(cyclopropylmethyl)-1H-indol-2-yl)methanol 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 resulting crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 1:1) to give the title compound (110 mg, 81.3%) as a yellow solid. LCMS (ESI, m / z): 376 [M+H]+

[0383] Step 5: Synthesis of 7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-1-(cyclopropylmethyl)-1H-indole-2-carbaldehyde (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 celite and concentrated. The resulting 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]+

[0384] 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 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 resulting 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]+

[0385] 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 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 (65 mg, 0.09 mmol) was reacted according to General Procedure 2. The resulting crude mixture was purified by preparative HPLC (Method G) to give the title compound (32.9 mg, 71.4%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 +D 2 O): δ 8.28 (s, 1H), 7.78 - 7.67 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 3.8 Hz, 1H), 7.08 (t, J = 7.9 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 4.95 - 4.54 (m, 4H), 4.20 (t, J = 4.9 Hz, 2H), 3.95 (d, J = 2.4 Hz, 3H), 3.92 - 3.74 (m, 5H), 3.74 - 3.66 (m, 2H), 3.24 (t, J = 6.2 Hz, 2H), 0.96 (d, J = 9.5 Hz, 1H), 0.31 - 0.12 (m, 2H), -0.03 - -0.15 (m, 2H); LCMS (ESI, m / z): 506 [M+H]+; LCMS RT: 1.636 min (Method B)

[0386] Compounds of Examples 206 - 210 in Table 14 were obtained in a similar procedure to the preparation of the compound of Example 205 using appropriate alkylating agents including alkyl iodides, alkyl bromides, alkyl chlorides, and alkyl methanesulfonates.

Table 59

Table 60

[0387] (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 [Chemical formula]

[0388] 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 To a stirred solution 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 (80 mg, 0.11 mmol) in THF (3 mL) was added TBAF (1 M, THF solution, 1 mL), and the mixture was stirred at room temperature for 1 hour. When LCMS indicated completion of the reaction, the mixture was concentrated. The resulting 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] +

[0389] 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 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) / DCM (5 mL) in a stirred solution, under a nitrogen atmosphere, at 0 °C, TEA (0.2 mL, 0.74 mmol) and N-methylcarbamoyl chloride (69 mg, 0.74 mmol) were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. When LCMS indicated the completion of the reaction, the mixture was quenched with water (15 mL) and extracted with DCM (3 × 15 mL). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by preparative TLC (DCM:MeOH = 10:1) to obtain the title compound (40 mg, 81.2%) as a yellow oil. LCMS (ESI, m / z): 663 [M+H] +

[0390] 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 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 (65 mg, 0.09 mmol) was reacted according to General Procedure 2. The resulting crude mixture was purified by preparative HPLC (Method E) to obtain the title compound (7.2 mg, 20.3%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6): δ 8.36 - 8.27 (m, 3H), 8.24 (s, 1H), 7.61 (s, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.07 - 7.02 (m, 3H), 6.84 (d, J = 7.7 Hz, 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 = 6.5 Hz, 2H), 3.21 (t, J = 6.3 Hz, 2H), 2.58 (d, J = 4.4 Hz, 3H), 1.08 - 0.97 (m, 1H), 0.24 - 0.13 (m, 2H), -0.14 (q, J = 4.7, 4.2 Hz, 2H); LCMS (ESI, m / z): 563 [M + H]+; LCMS RT: 1.118 min (Method D)

[0391] 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

Chemical Structure

[0392] 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 To a stirred solution of Intermediate 7 (200 mg, 0.36 mmol) in ethanol (2 mL) were added (R)-2-methyloxirane (207 mg, 3.56 mmol) and TEA (0.25 mL, 1.78 mmol), and the mixture was irradiated with microwave 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 afford the title compound (153 mg, 69.3%) as a yellow oil. LCMS (ESI, m / z): 620 [M+H] +

[0393] 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)propan-2-yl methanesulfonate To a stirred 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-fluoropropyl)carbamate (153 mg, 0.25 mmol) in DCM (2 mL) were added TEA (0.05 mL, 0.37 mmol) and MsCl (0.02 mL, 0.30 mmol) at 0 °C, and the mixture was stirred and allowed to warm to room temperature over 1 h. The reaction was monitored by TLC and LCMS. The reaction mixture was concentrated to afford the title compound (157 mg, 91.1%) as a yellow solid. The crude product obtained was used directly in the next step. LCMS (ESI, m / z): 698 [M+H] +

[0394] 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 Methanesulfonic acid (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-yl (157 mg, 0.22 mmol) / DMF (2 mL) was reacted according to General Procedure 8. The resulting 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] +

[0395] 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 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 resulting 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 (400 MHz, DMSO-d 6 +D 2O) δ 9.40 - 9.35 (m, 1H), 8.23 (s, 1H), 8.06 (s, 1H), 7.78 (s, 1H), 7.61 (s, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.09 (t, J = 7.9 Hz, 1H), 7.06 (s, 1H), 6.91 (d, J = 7.9 Hz, 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 = 6.4 Hz, 2H), 3.22 (t, J = 6.5 Hz, 2H), 1.68 (d, J = 6.8 Hz, 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)

[0396] The compounds of Examples 213 to 216 in Table 15 were obtained using an appropriate epoxide by the same procedure as for the preparation of the compound of Example 212. [Table 61] [Table 62]

[0397] 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 [Chemical formula]

[0398] Step 1: Synthesis of Ethyl (S)-1-(cyclopropylmethyl)-7-(2-hydroxypropoxy)-1H-indole-2-carboxylate To a solution of ethyl 1-(cyclopropylmethyl)-7-hydroxy-indole-2-carboxylate (1 g, 3.86 mmol) in ethanol (12.5 mL) were added (2S)-2-methyloxirane (672 mg, 11.5 mmol) and TEA (3.36 mL, 19.3 mmol) under a nitrogen atmosphere, and the mixture was irradiated with microwave at 100 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS, and the reaction mixture was concentrated under reduced pressure. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give the title compound (1 g, 81%) as a peach-colored solid. LCMS (ESI, m / z): 318 [M+H]+

[0399] Step 2: Synthesis of Ethyl (S)-1-(cyclopropylmethyl)-7-(2-((methylsulfonyl)oxy)propoxy)-1H-indole-2-carboxylate To a solution of ethyl (S)-1-(cyclopropylmethyl)-7-(2-hydroxypropoxy)-1H-indole-2-carboxylate (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 under a nitrogen atmosphere. Then MsCl (866 mg, 7.56 mmol) was added dropwise at 0 °C under a nitrogen atmosphere. The solution was stirred at room temperature for 1 h under a nitrogen atmosphere, and then saturated NH 4 Cl aqueous solution (50 mL) was added at 0 °C to quench the reaction, and the mixture was extracted with DCM (3 × 50 mL). The combined organic extracts were washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the title compound (2 g, 80%) was obtained as a yellow oil at 0 °C. LCMS (ESI, m / z): 396 [M+H]+

[0400] Step 3: Synthesis of Ethyl (R)-1-(cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indole-2-carboxylate (S)-Ethyl 1-(cyclopropylmethyl)-7-(2-((methylsulfonyl)oxy)propoxy)-1H-indole-2-carboxylate (2 g, 5.06 mmol) in DMF (50 mL) was added with 4-fluoro-1H-imidazole (522 mg, 6.07 mmol) and Cs 2 CO 3 (4.95 g, 15.2 mmol) under a nitrogen atmosphere. The solution was stirred at 50 °C overnight under a nitrogen atmosphere, and the reaction was monitored by LCMS. Then water (150 mL) was added to quench the reaction, and the mixture was 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 reduced pressure. The obtained 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]+

[0401] Step 4: Synthesis of (R)-(1-(cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)methanol (R)-Ethyl 1-(cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indole-2-carboxylate (2 g, 5.19 mmol) was reacted according to General Procedure 5. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (1.5 g, 84%) as a yellow oil. LCMS (ESI, m / z): 344 [M+H]+

[0402] Step 5: Synthesis of (R)-1-(cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indole-2-carbaldehyde (R)-(1-(Cyclopropylmethyl)-7-(2-(4-fluoro-1H-imidazol-1-yl)propoxy)-1H-indol-2-yl)methanol was reacted according to General Procedure 6. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (1.4 g, 70%) as a pale green solid. LCMS (ESI, m / z): 342 [M+H]+

[0403] 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 (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 resulting crude product was purified by column chromatography (DCM / MeOH = 20:1) to give the title compound (50 mg, 49%) as a pale yellow oil. LCMS (ESI, m / z): 688 [M+H]+

[0404] 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 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 resulting crude product was purified by preparative HPLC (Method G) to give the title compound (27.4 mg, 63%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.25 (s, 4H), 7.60 (s, 1H), 7.52 (s, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.13 (dd, J = 8.4, 2.0 Hz, 1H), 7.08 - 7.04 (m, 2H), 6.87 (d, J = 8.0 Hz, 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 = 6.4 Hz, 2H), 1.55 (d, J = 7.2 Hz, 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)

[0405] 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

Chemical Structure

[0406] 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 7-Benzyloxy-1H-indole-2-carbaldehyde (300 mg, 1.19 mmol) was reacted with Intermediate 5 according to General Procedure 4. The resulting 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]+

[0407] 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 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 (600 mg, 1 mmol) / ethyl acetate (10 mL), methanol (10 mL) and acetic acid (0.1 mL) were reacted according to General Procedure 9. The resulting crude product was purified by silica 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]+

[0408] 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 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 (190 mg, 0.42 mmol) was reacted according to General Procedure 3. The resulting crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 1:3) to give the title compound (70 mg, 26.5%) as a pale yellow solid. LCMS (ESI, m / z): 666 [M+H]+

[0409] 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 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 (70 mg, 0.11 mmol) / DMF (3 mL) was reacted with Cs 2 CO 3 (102 mg, 0.32 mmol) and 5-(bromomethyl)isoxazole (68 mg, 0.42 mmol) at room temperature. The resulting crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 2:5) to give the title compound (55 mg, 70.0%) as a pale yellow solid. LCMS (ESI, m / z): 747 [M+H]+

[0410] 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 A solution of tert-butyl (S)-(1-(2-(7-((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-fluoropropyl)carbamate (55 mg, 0.07 mmol) / HCl (1 M, ethyl acetate, 4.0 mL) was stirred at room temperature for 1 hour, and the reaction was monitored by TLC and LCMS. The mixture was concentrated under reduced pressure. The resulting orange sticky 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 (400 MHz, DMSO-d 6 +D 2 O) δ 8.28 (d, J = 7.9 Hz, 2H), 7.67 (s, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.23 (s, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.31 (s, 2H), 6.09 (s, 1H), 4.85 - 4.57 (m, 2H), 4.16 (t, J = 4.7 Hz, 2H), 3.93 (s, 3H), 3.87 - 3.73 (m, 5H), 3.68 (t, J = 6.4 Hz, 2H), 3.22 (t, J = 6.3 Hz, 2H); LCMS (ESI, m / z): 533 [M+H]+; LCMS RT: 1.406 min (Method D)

[0411] 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

Chem.

Chem.

[0412] Step 1: Synthesis of 3-((2-Nitrophenoxy)methyl)pyrrolidin-2-one To a stirred solution of 3-(Hydroxymethyl)pyrrolidin-2-one (500 mg, 4.34 mmol) / DMF (10 mL) under a nitrogen atmosphere at room temperature, NaH (156 mg, 6.51 mmol) and 1-Fluoro-2-nitro-benzene (612 mg, 4.34 mmol) were added portionwise. The 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 the mixture was 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 reduced pressure. The obtained crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (260 mg, 25%) as a yellow solid. LCMS (ESI, m / z): 237 [M+H]+

[0413] Step 2: Synthesis of 3-((2-Aminophenoxy)methyl)pyrrolidin-2-one To a stirred solution of 3-((2-Nitrophenoxy)methyl)pyrrolidin-2-one (260 mg, 1.1 mmol) / methanol (10 mL) under a nitrogen atmosphere, Pd / C (60 mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere. When the completion of the reaction was indicated by LCMS, the solid was filtered off. The obtained mixture was concentrated to give the title compound (150 mg, 66%) as a yellow solid. LCMS (ESI, m / z): 207 [M+H]+

[0414] Step 3: Synthesis of Ethyl 7-((2-Oxopyrrolidin-3-yl)methoxy)-1H-indole-2-carboxylate To a stirred solution of 3-((2-aminophenoxy)methyl)pyrrolidin-2-one (150 mg, 0.73 mmol) in DMSO (5 mL), under a nitrogen atmosphere, ethyl 2-oxopropanoate (84 mg, 0.73 mmol), Pd(OAc) 2 (32 mg, 0.15 mmol), and AcOH (44 mg, 0.73 mmol) were added, and the mixture was stirred at 70 °C for 16 h under an oxygen atmosphere. The reaction was monitored by LCMS. Then water (20 mL) was added to quench the reaction, and the mixture was 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 reduced pressure. The resulting crude product was purified by silica 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]+

[0415] Step 4: Synthesis of 3-(((2-(hydroxymethyl)-1H-indol-7-yl)oxy)methyl)pyrrolidin-2-one 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), under a nitrogen atmosphere, at room temperature, LiBH 4 (28 mg, 1.32 mmol) was added portionwise, and the mixture was stirred at room temperature for 12 h. The reaction was monitored by LCMS. Then water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with brine (2 × 40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica 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]+

[0416] Step 5: Synthesis of 7-((2-oxopyrrolidin-3-yl)methoxy)-1H-indole-2-carbaldehyde 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 resulting crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 1:2) to give the title compound (60 mg, 71%) as a yellow solid. LCMS (ESI, m / z): 259 [M+H]+

[0417] Step 6: Synthesis of 1-(cyclopropylmethyl)-7-((2-oxopyrrolidin-3-yl)methoxy)-1H-indole-2-carbaldehyde 7-((2-Oxopyrrolidin-3-yl)methoxy)-1H-indole-2-carbaldehyde (60 mg, 0.23 mmol) / DMF (2 mL) was reacted with bromomethylcyclopropane (47 mg, 0.35 mmol) according to General Procedure 8. The resulting crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (50 mg, 68%) as a yellow solid. LCMS (ESI, m / z): 313 [M+H]+

[0418] 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 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 resulting crude product was purified by silica column chromatography (DCM / methanol = 20:1) to give the title compound (80 mg, 96%) as a yellow solid. LCMS (ESI, m / z): 659 [M+H]+

[0419] 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 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-fluoropropyl)-2-yl)carbamate (80 mg, 0.12 mmol) was reacted according to General Procedure 2. The resulting crude mixture was concentrated and purified by preparative HPLC (Method E) to give the title compound (46.5 mg, 68%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.28 (s, 3H), 8.26 (s, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.09 - 7.03 (m, 2H), 6.87 (d, J = 7.8 Hz, 1H), 4.72 - 4.59 (m, 4H), 4.31 (d, J = 4.2 Hz, 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)

[0420] The compounds of Examples 220 - 221 in Table 16 were obtained using the appropriate alcohol in a procedure similar to the preparation of the compound of Example 219.

Table 63

[0421] 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

Chemical Structure

[0422] 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-fluoropropyl)carbamate Intermediate 7 (100 mg, 0.18 mmol) / DMF (3 mL) was reacted with (R)-1-((tert-butyldiphenylsilyl)oxy)propan-2-yl methanesulfonate (140 mg, 0.36 mmol) according to General Procedure 8. The resulting crude product 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] +

[0423] 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-fluoropropyl)carbamate 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) / THF (2 mL) in a stirred solution, TBAF (1 M, THF solution, 1 mL) was added and stirred at room temperature for 2 hours. When the completion of the reaction was indicated by LCMS, the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to give the title compound (75 mg, 86.5%) as a yellow oil. LCMS (ESI, m / z): 620 [M+H] +

[0424] 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)propane methanesulfonate 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) / DCM (3 mL) under a nitrogen atmosphere at 0 °C, TEA (61 mg, 0.61 mmol) and MsCl (21 mg, 0.18 mmol) were added and stirred at room temperature for 2 hours. When the completion of the reaction was indicated by LCMS, 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), dried over sodium sulfate, concentrated to give the title compound (80 mg, 94.7%) as a yellow oil. LCMS (ESI, m / z): 698 [M+H] +

[0425] 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 Methanesulfonic acid (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 (80 mg, 0.11 mmol) was reacted with 1H-imidazole (39 mg, 0.57 mmol) according to General Procedure 8. The resulting 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] +

[0426] 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 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 resulting residue was purified by preparative HPLC (Method E) to give the title compound (28.1 mg, 41.2%) as a white solid.1 1H NMR (400 MHz, methanol-d 4 ): δ 9.03 (s, 1H), 8.41 (s, 1H), 7.75 (t, J = 1.8 Hz, 1H), 7.61 (s, 1H), 7.57 (t, J = 1.8 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 7.03 (s, 1H), 6.86 (d, J = 7.8 Hz, 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), 1.51 (d, J = 6.2 Hz, 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)

[0427] Example 223 of Table 17 was obtained using an appropriate alcohol in the same procedure as the production of the compound of Example 222. [Table 64]

[0428] 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 [Chemistry]

[0429] Step 1: Synthesis of 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 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 tert-butyl (S)-(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 resulting crude product was purified by column chromatography (ethyl acetate) to give the title compound mixture (80 mg, 39.2%) as a pale yellow solid. LCMS (ESI, m / z): 682 [M+H]+

[0430] 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 A mixture of 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-fluoropropyl)carbamate and 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-fluoropropyl)carbamate (40 mg, 0.06 mmol) was reacted according to General Procedure 2. The resulting crude product was purified by preparative HPLC (Method E) to give the title compound as a white solid. (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 (300 MHz, DMSO-d 6) δ 9.02(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) (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%) 1 H NMR(300MHz, DMSO-d 6 ) δ 8.45(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, 4H), 4.46(d, J = 6.8Hz, 2H), 3.92(s, 2H), 3.90 - 3.82(m, 3H), 3.71 - 3.46(m, 3H), 3.21(t, J = 6Hz, 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)

[0431] Examples 226a and 226b. 6-((S)-2-Amino-3-fluoropropyl)-2-(1-(cyclopropylmethyl)-7-((S)-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 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 [Chemical formula]

[0432] 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 Intermediate 7 (200 mg, 0.36 mmol) / DMF (3.5 mL) was reacted with ethyl 2-bromo-2-fluoroacetate (130 mg, 0.70 mmol) according to General Procedure 8. The resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give a diastereomeric mixture of the title compound (210 mg, 70%) as a yellow oil. LCMS (ESI, m / z): 666 [M+H]+

[0433] 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-fluoropropyl)carbamate 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) / ethanol (5 mL) solution was added with NaBH 4 (120 mg, 3.00 mmol) at 0 °C and stirred at room temperature for 2 h. The reaction was monitored by LCMS. Then acetone (10 mL) was added to quench the reaction and the mixed solution was concentrated under reduced pressure. The obtained crude product was purified by flash column chromatography (C18 silica) to give a diastereomeric mixture of the title compound (150 mg, 80%) as a yellow oil. LCMS (ESI, m / z): 624 [M+H]+

[0434] 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 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-fluoropropyl)-2-yl)carbamate (150 mg, 0.24 mmol) / DCM (4 mL) were added TEA (0.75 mL, 5.38 mmol) and MsCl (33 mg, 0.29 mmol) at 0 °C and stirred at room temperature for 1 h. The reaction was monitored by LCMS. Then saturated NH 4An aqueous Cl solution (10 mL) was added at 0 °C to quench the reaction, and the mixture was extracted with DCM (3 × 10 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure at 0 °C, and a diastereomeric mixture of the title compound (168 mg, 98%) was obtained as a pale yellow oil. LCMS (ESI, m / z): 702 [M+H]+

[0435] 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 To a solution of methanesulfonic acid 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 (168 mg, 0.24 mmol) in DMF (2.5 mL) were added 1H-imidazole (33 mg, 0.48 mmol) and Cs 2 C...

Claims

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

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

3. The compound has the formula 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: 【Transformation 3】 【Chemistry 4】 A compound according to claim 2, selected from the above, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

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

5. In the formula, R 5 The compound according to claim 1, wherein is fluoro, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

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

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

8. In the formula, R 4 The compound according to claim 1, wherein the halogen is a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

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

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

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

12. In the formula, R 2 but, 【Transformation 5】 A compound according to claim 1, selected from the group consisting of the above, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.

13. In the formula, R 3 However, -CH 2 CH 3 , -CH(CH 3 ) 2 , 【Transformation 6】 【Transformation 7】 A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof, selected from the above.

14. In the formula, R 6 However, hydrogen, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 -CF 3 -CN, halogen, -OCH 3 , -N(CH 3 ) 2 , 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof, selected from the above.

15. In the formula, R 6' However, hydrogen, fluoro, chloro, -CN, -OH, -OCH 3 -CF 3 , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 -C(CH 3 ) 3 , 【Chemistry 12】 A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof, selected from the above.

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

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

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

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

20. Equation I': 【Chemistry 13】 [In the formula, X is CR 6 and selected from N; X' is CR 6' and are selected from N, where X and X' cannot be N at the same time; R 1 C 1-4 It is aliphatic; R 2 This includes 0 to 4 R 7 C replaced by 1-6 It is aliphatic; R 3 This includes 0 to 3 R 8 C replaced by 1-6 It is aliphatic; R 4 is halogen or C 1-4 is aliphatic; R 5 It is a halogen; Each R 6 and R 6' is independently selected from hydrogen, C 1-6 aliphatic, -L 1 (R 9 ) q , and -O-L 2 -(R 9 ) p ; and is selected from Each R 7 These are independently halogen, -OR, and -N(R) 2 Selected from , and -Cy; Each R 8 These are independently halogen, -OR, and -N(R) 2 , -C(O)N(R) 2 Selected from , and -Cy; Each R 9 These are independently halogen, -CN, -OR, and -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 Selected from , and -Cy; L 1 is a covalent bond or C 1-4 It is aliphatic; L 2 C 1-4 It is aliphatic; Each Cy is independently selected from 3-7 member saturated or partially unsaturated carbon rings; phenyl; 3-7 member saturated or partially unsaturated heterorings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 10 member bicyclic aryls; 5-6 member heteroaryls having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 8-10 member bicyclic heteroaryls having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where Cy has 0-3 R 10 Replaced by; Each R 10 These are independently halogen, -OR, and -N(R) 2 , -CN, -C(O)R, -C(O)OR, -C(O)N(R) 2 A group selected from , oxo, and optionally substituted groups, wherein the optionally substituted group is C 1-6 Aliphatic; as well as selected from 3- to 7-membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where R 10 It is replaced by 0 to 3 R's; Each R is independently a hydrogen or optionally substituted group, and the optionally substituted group is C 1-6 Aliphatic, oxo, -CH 2 OCH 3 , selected from 3-7 member saturated or partially unsaturated carbon rings; phenyl; 3-7 member saturated or partially unsaturated heterorings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 member heteroaryls having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where R is 0-3 halogens, C 1-6 Aliphatic or substituted with -OH; Each m and n is independently 0 or 1; and Each p and q is independently between 1 and 4. Compounds thereof or their pharmaceutically acceptable salts, isomers, enantiomers, or tautomers.

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