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WO2025024288A1 - Inhibiteurs hétérocycliques de pad4 - Google Patents

Inhibiteurs hétérocycliques de pad4 Download PDF

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Publication number
WO2025024288A1
WO2025024288A1 PCT/US2024/038782 US2024038782W WO2025024288A1 WO 2025024288 A1 WO2025024288 A1 WO 2025024288A1 US 2024038782 W US2024038782 W US 2024038782W WO 2025024288 A1 WO2025024288 A1 WO 2025024288A1
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compound
disease
mmol
formulae described
alkyl
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Inventor
Makonen Belema
John A. Bender
Alyssa H. Antropow
Jason M. Guernon
Alan Xiandong WANG
Daniel L. Cheney
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the disclosure generally relates to substituted heterocyclic compounds, methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and use of these compounds in the treatment of diseases or disorders associated with PAD4 enzyme activity.
  • PAD4 (SEQ ID NO: 1) is a member of the peptidylarginine deiminase (PAD) family of enzymes capable of catalysing the citrullination of arginine into citrulline within peptide sequences. PAD4 is responsible for the deimination or citrullination of a variety of proteins in vitro and in vivo, with consequences of diverse functional responses in a variety of diseases (Jones J.E. et al, Curr. Opin. Drug Discov. DeveL, 12(5), (2009), 616-627).
  • Examples of exemplar diseases or disorders include rheumatoid arthritis, diseases with neutrophilic contributions to pathogenesis (for example vasculitis, systemic lupus erythematosus, ulcerative colitis) in addition to oncology indications.
  • PAD4 inhibitors also have wider applicability as tools and therapeutics for human diseases and disorders through epigenetic mechanisms.
  • RA Rheumatoid Arthritis
  • RA is an autoimmune disease affecting approximately 1% of the population (Wegner N. et al, Immunol. Rev., 233(1), (2010), 34-54). It is characterized by inflammation of articular joints leading to debilitating destruction of bone and cartilage.
  • a weak genetic association between PAD4 polymorphisms and susceptibility to RA has been suggested, albeit inconsistently, in a number of population studies (Kochi Y. et al, Ann. Rheum. Dis., 70, (2011), 512-515).
  • PAD4 (along with family member PAD2) has been detected in synovial tissue where it is responsible for the deimination of a variety of joint proteins. This process is presumed to lead to a break of tolerance to, and initiation of immune responses to, citrullinated substrates such as fibrinogen, vimentin and collagen in RA joints.
  • ACPA anti-citrullinated protein antibodies
  • citrullination may also offer additional direct contributions to disease pathogenesis through its ability to affect directly the function of several joint and inflammatory mediators (e.g., fibrinogen, anti-thrombin, and multiple chemokines).
  • inflammatory mediators e.g., fibrinogen, anti-thrombin, and multiple chemokines.
  • anti -PALM antibodies can be measured and may correlate with a more erosive form of the disease.
  • PAD4 inhibitors are also useful for the reduction of pathological neutrophil activity in a variety of diseases.
  • NET Neutrophil Extracellular Trap
  • PAD4 knockout mice Naelil. et al, J. Immunol., 180, (2008), 1895-1902, and Li P. et al, J. Exp. Med., 207(9), (2010), 1853-1862.
  • PALM inhibitors may therefore have applicability for diseases where NET formation in tissues contributes to local injury and disease pathology.
  • Such diseases include, but are not limited to, small vessel vasculitis (Kessenbrock K. et al, Nat. Med., 15(6), (2009), 623-625), systemic lupus erythematosus (Hakkim A. etal, 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.
  • NETs may contribute to pathology in diseases affecting the skin, e.g., in cutaneous lupus erythematosis (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), so a PAD4 inhibitor may show benefit to tackle NET skin diseases, when administered by a systemic or cutaneous route. PAD4 inhibitors may affect additional functions within neutrophils and have wider applicability to neutrophilic diseases.
  • PAD4 inhibitors are also useful in the treatment of cancers (Slack J.L. et al, Cell. Mol. Life Sci., 68(4), (2011), 709-720). Over-expression of PAD4 has been demonstrated in numerous cancers (Chang X. etal, BMC Cancer, 9, (2009), 40). An anti-proliferative role has been suggested for PAD4 inhibitors from the observation that PAD4 citrullinates arginine residues in histones at the promoters of p53 -target genes such as p21, which are involved in cell cycle arrest and induction of apoptosis (Li P. et al, Mol. Cell Biol., 28(15), (2008), 4745-4758).
  • PAD4 is the primary PAD family member observed to be resident in the nucleus as well as the cytoplasm. Early evidence that PAD4 may act as a histone demethyliminase as well as a deiminase is inconsistent and unproven. However, it may reduce histone arginine methylation (and hence epigenetic regulation associated with this mark) indirectly via depletion of available arginine residues by conversion to citrulline. PAD4 inhibitors are useful as epigenetic tools or therapeutics for affecting expression of varied target genes in additional disease settings.
  • PAD4 inhibitors may also be effective in controlling citrullination levels in stem cells and may therefore therapeutically affect the pluripotency status and differentiation potential of diverse stem cells including, but not limited to, embryonic stem cells, neural stem cells, haematopoietic stem cells and cancer stem cells. Accordingly, there remains an unmet need to identify and develop PAD4 inhibitors for the treatment of PAD4-mediated diseases or disorders.
  • the present disclosure relates to compounds of Formula I: I and pharmaceutically acceptable salts, isomers, enantiomers, or tautomers thereof, wherein X 1 and X 2 are each independently CR 8 or N; Y is selected from -(CR9R10)p–, –O–(CR9R10)p-, –(CR9R10)p–O–(CH2)m-, –(CR9R10)p–O–(CH2)m– O–CH2–, and –(CR9R10)p–O–(CH2)m–O–; R 1 is independently –CH(NHR 7 )-(C 1 -C 3 alkyl) or a 4- to 8-membered heterocyclyl containing at least one heteroatom selected from the group consisting of N, O, or S, wherein the alkyl or heterocyclyl is optionally substituted with one or more R11; R 2 is independently H, or C 1 -C 4 alkyl; R 3 are independently H,
  • the present disclosure provides a pharmaceutical composition comprising at least one compound of Formula I, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers, excipients, or vehicles
  • a provided pharmaceutical composition is suitable for oral, parenteral, mucosal, transdermal, or topical administration.
  • the present disclosure provides a method of treating a disease or a disorder associated with PAD4 enzyme activity, comprising administering to a subject in need of such treatment, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.
  • the present disclosure provides a method of treating diseases or disorders associated with PAD4 enzyme activity, comprising administering to a subject in need of such treatment, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, isomer, enantiomer, or tautomer thereof.
  • disorders or conditions include, among others, rheumatoid arthritis, vasculitis, systemic lupus erythematosus, and ulcerative colitis.
  • Another aspect of the present disclosure is directed to a method of treating or preventing a condition disclosed herein in a subject in need thereof. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the present disclosure relates to compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a condition disclosed herein.
  • Another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of a condition disclosed herein.
  • the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Examples 1-44).
  • the present disclosure provides a method of preparing a compound of the present disclosure.
  • the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “carbocyclic”, “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, zz-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
  • “carbocyclic” refers to a C3-C8 hydrocarbon, which may be monocyclic or multicyclic, that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • the rings of multi-ring carbocyclics may exist as fused, bridged and/or joined through one or more spiro union to 1 or 2 aromatic cycloalkyl or heterocyclic rings.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, and the like.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2Z/-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,”
  • aryloxy refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system and exemplary groups include phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 K electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • 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.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Examplary groups include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4/f-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
  • a heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3, 4-di hydro-27/ pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in /V substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the disclosure may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • Substituted applies to one or more hydrogens that are either explicit or implicit from the structure (e.g., refers to at least ; and refers to at least , , or ).
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 ) 0 2 R*, -(haloR*), -(CH 2 ) 0 2 OH, -(CH 2 ) 0 2 OR’, -(CH 2 )o- 2 CH(OR*) 2 ; -O(haloR’), -CN, -N 3 , -(CH 2 )O- 2 C(0)R*, -(CH 2 ) O 2 C(O)OH, -(CH 2 )O 2 C(O)OR*, -(CH 2 )O 2 SR’, -(CH 2 )O 2 SH, -(CH 2 )O 2 NH 2 , -(CH 2 )O 2 NHR’, -(CH 2 )O 2 NR’ 2 , -NO 2 , -SiR%,
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR* 2 ) 2 -3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R* include halogen, -
  • each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH 2 Ph, 0(CH 2 )o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R ⁇ -NR f 2 , -C(O)R f , -C(O)OR t , -C(O)C(O)R + , -
  • each R 1 ' is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R : , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR*, -NR* 2 , or -NO 2 , wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH 2 Ph, -0(CH 2 )o iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • subject refers to and includes any human or non-human organism that could potentially benefit from treatment with a PAD4 inhibitor.
  • exemplary subjects include humans and animals.
  • treating refer to and include treatment of a disease-state in a subject, for example in a human or animal, and include: (a) inhibiting the disease-state, i.e., arresting it’s development; (b) relieving the disease-state, i.e., causing regression of the disease state; and/or (c) preventing the disease-state from occurring in a subject.
  • preventing or “prevention” as used herein refer to and include preventive treatment (i.e.
  • prophylaxis and/or risk reduction of a subclinical disease-state in a subject, for example in a human or animal, aimed at reducing the probability of the occurrence of a clinical disease-state.
  • Subjects may be selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population.
  • “Prophylaxis” therapies can be divided into (a) primary prevention, and (b) secondary prevention. Primary prevention is defined as treatment in a subject that has not yet presented with a clinical disease state, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.
  • a “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response.
  • a therapeutically effective amount of a substance is an amount that is sufficient, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition.
  • the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc.
  • the effective amount of a provided compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition.
  • a “therapeutically effective amount” is at least a minimal amount of a provided compound, or composition containing a provided compound, which is sufficient for treating one or more symptoms of an MK2-mediated disesase or disorder.
  • therapeutically effective amount refers to and includes an amount of a compound or a composition according to the disclosure that is effective when administered alone or in combination to prevent or treat the disease or disorder associated with PAD4 enzyme activity. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the preventive or therapeutic effect, whether administered in combination, serially, or simultaneously.
  • a “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to humans and/or animals.
  • Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation, the type and nature of the active agent being formulated, the subject to which the agent-containing composition is to be administered, the intended route of administration of the compound or composition, and, the therapeutic indication being targeted.
  • Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media.
  • Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art.
  • Typical, non-limiting examples of such carriers include diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, anti-bacterial agents, anti-fungal agents, lubricating agents, dispensing agents, coating agents, and the like.
  • the present disclosure is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium (symbol D or 2 H) and tritium (symbol T or 3 H).
  • a methyl group may be represented by CH3 or CD3.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • the compound of Formula I forms salts which are also within the scope of this disclosure.
  • Reference to a compound of the Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term “salt(s)”, as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
  • zwitterions inner salts
  • Pharmaceutically acceptable salts include those generally acceptable in the art of pharmaceutical sciences for administration in a subject, including humans and animals. In general, the pharmaceutically acceptable salts are non-toxic and physiologically acceptable salts. Salts of the compounds according to the disclosure may be formed, for example, by reacting the compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • the compounds of Formula I which contain a basic moiety may form salts with a variety of organic and inorganic acids.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, 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 hydrogen bromide), hydroiodides, 2-hydroxyethanesulfon
  • the compounds of Formula I which contain an acidic moiety may form salts with a variety of organic and inorganic bases.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehy droabietyl)- ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • organic bases for example, organic amines
  • organic bases for example, organic amines
  • benzathines such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(de
  • Basic nitrogen-containing groups may be quatemized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates
  • the disclosure encompasses compounds of Formula I, or pharmaceutically acceptable salts thereof, methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and use of these compounds in the treatment of diseases or disorders associated with PAD4 enzyme activity.
  • the present disclosure provides a compound of formula I:
  • the present disclosure provides a compound selected from a compound of any of Formulae la, la-1, la-2, la-3, la-4, and la-5: la,
  • X 3 is CH 2 , NH, O, or S; and r is an integer from 1 to 3.
  • the present disclosure provides a compound selected from a compound of any of Formulae lb, Ib-1, Ib-2, Ib-3, Ib-4, and Ib-5:
  • A is C3-C8 cycloalkyl, a 3- to 8-membered heterocyclyl, aryl, or heteroaryl.
  • the present disclosure provides a compound selected from a compound of any of Formulae Ic, Ic-1, Ic-2, Ic-3, Ic-4, and Ic-5:
  • A is Ca-Cs cycloalkyl, a 3- to 8-membered heterocyclyl, aryl, or heteroaryl.
  • the present disclosure provides a compound selected from a compound of any of Formulae Id, le, and If:
  • X1 is selected from CR8 or N. In some embodiments of any Formulae described herein, X1 is CR8. In some embodiments of any Formulae described herein, X 1 is N. [0055] In some embodiments, X2 is selected from CR8 or N.
  • X2 is CR8. In some embodiments of any Formulae described herein, X 2 is N. [0056] In some embodiments, Y is selected from -(CR9R10)p–, –O–(CR9R10)p-, – (CR9R10)p–O–(CH2)m-, –(CR9R10)p–O–(CH2)m–O–CH2–, and –(CR9R10)p–O–(CH2)m–O–. In some embodiments of any Formulae described herein, Y is -(CR9R10)p–. In some embodiments of any Formulae described herein, Y is –O–(CR 9 R 10 ) p -.
  • Y is –(CR 9 R 10 ) p –O–(CH 2 ) m -. In some embodiments of any Formulae described herein, Y is –(CR9R10)p–O–(CH2)m–O–CH2–. In some embodiments of any Formulae described herein, Y is –(CR9R10)p–O–(CH2)m–O–.
  • R 1 is –CH(NHR 7 )-(C 1 -C 3 alkyl) or a 4- to 8-membered heterocycle containing at least one heteroatom selected from the group consisting of N, O, or S, wherein the alkyl or heterocycle is optionally substituted with one or more R11.
  • R 1 is –CH(NHR 7 )-(C 1 -C 3 alkyl).
  • R1 is –CH(NHR7)-(C1-C3 alkyl)
  • the C1- C3 alkyl is substituted with one or more R11.
  • R 1 is a 4- to 8-membered heterocycle containing at least one heteroatom.
  • the heteroatom is selected from the group consisting of N, O, or S.
  • the heteroatom is N.
  • the heteroatom is O.
  • the heteroatom is S.
  • the 4- to 8-membered heterocycle containing at least one heteroatom is substituted with one or more R11.
  • R 2 is selected from H, and C 1 -C 4 alkyl.
  • R2 is H. In some embodiments of any Formulae described herein, R2 is C1-C4 alkyl. In some embodiments of any Formulae described herein, R2 is C 1 -C 3 alkyl. In some embodiments of any Formulae described herein, R 2 is C 1 -C 2 alkyl. In some embodiments of any Formulae described herein, R 2 is C 1 alkyl. [0059] As defined generally above, R3 is selected from H, halogen, and C1-C4 alkyl. In some embodiments of any Formulae described herein, R3 is H. In some embodiments of any Formulae described herein, R 3 is halogen.
  • R3 is C1-C4 alkyl. In some embodiments of any Formulae described herein, R3 is C1-C3 alkyl. In some embodiments of any Formulae described herein, R3 is C1-C2 alkyl. In some embodiments of any Formulae described herein, R 3 is C 1 alkyl. [0060] In some embodiments, R4 is selected from hydrogen, C1-C4 alkyl or C1-C4 haloalkyl. In some embodiments of any Formulae described herein, R4 is hydrogen. In some embodiments of any Formulae described herein, R4 is C1–C4 alkyl.
  • R 4 is C 1 –C 3 alkyl. In some embodiments of any Formulae described herein, R 4 is C 1 –C 2 alkyl. In some embodiments of any Formulae described herein, R 4 is C 1 alkyl. In some embodiments of any Formulae described herein, R4 is C2 alkyl. In some embodiments of any Formulae described herein, R4 is C3 alkyl. In some embodiments of any Formulae described herein, R 4 is C 4 alkyl. In some embodiments of any Formulae described herein, R 4 is C 1 –C 4 haloalkyl. In some embodiments of any Formulae described herein, R4 is C1–C3 haloalkyl.
  • R4 is C1–C2 haloalkyl. In some embodiments of any Formulae described herein, R 4 is C 1 haloalkyl. In some embodiments of any Formulae described herein, R4 is C2 haloalkyl. In some embodiments of any Formulae described herein, R4 is C3 haloalkyl. In some embodiments of any Formulae described herein, R4 is C4 haloalkyl.
  • R 5 is selected from H, halogen, C 1 –C 4 alkyl, C 1 –C 4 alkoxy, C1–C4 haloalkyl, heteroaryl, or aryl; where the heteroaryl, or aryl is optionally substituted with one or more halogen, or C1–C6 alkoxy.
  • R 5 is H.
  • R 5 is halogen.
  • R5 is C1–C4 alkyl.
  • R5 is C1–C3 alkyl.
  • R 5 is C 1 –C 2 alkyl. In some embodiments of any Formulae described herein, R 5 is C 1 alkyl. In some embodiments of any Formulae described herein, R5 is C2 alkyl. In some embodiments of any Formulae described herein, R5 is C3 alkyl. In some embodiments of any Formulae described herein, R 5 is C 4 alkyl. In some embodiments of any Formulae described herein, R 5 is C 1 –C 4 alkoxy. In some embodiments of any Formulae described herein, R 5 is C 1 –C 3 alkoxy. In some embodiments of any Formulae described herein, R5 is C1–C2 alkoxy.
  • R5 is C1 alkoxy. In some embodiments of any Formulae described herein, R 5 is C 1 –C 4 haloalkyl. In some embodiments of any Formulae described herein, R5 is C1–C3 haloalkyl. In some embodiments of any Formulae described herein, R5 is C1–C2 haloalkyl. In some embodiments of any Formulae described herein, R5 is C1 haloalkyl. In some embodiments of any Formulae described herein, R 5 is C 2 haloalkyl. In some embodiments of any Formulae described herein, R5 is C3 haloalkyl.
  • R5 is C4 haloalkyl. In some embodiments of any Formulae described herein, R5 is heteroaryl. In some embodiments of any Formulae described herein, R5 is aryl. In some embodiments of any Formulae described herein, where R5 is heteroaryl or aryl, the heteroaryl, or aryl is substituted with one or more halogen. In some embodiments of any Formulae described herein, where Rs is heteroaryl or aryl, the heteroaryl, or aryl is substituted with one or more Ci- Ce alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more halogen.
  • Rs is heteroaryl, wherein the heteroaryl is substituted with one or more Ci-Ce alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C5 alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C4 alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C3 alkoxy.
  • Rs is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C2 alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more Ci alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more C2 alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more C3 alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more C4 alkoxy.
  • Rs is heteroaryl, wherein the heteroaryl is substituted with one or more Cs alkoxy. In some embodiments of any Formulae described herein, Rs is heteroaryl, wherein the heteroaryl is substituted with one or more Ce alkoxy. In some embodiments of any Formulae described herein, Rs is aryl, wherein the aryl is substituted with one or more halogen. In some embodiments of any Formulae described herein, Rs is aryl, wherein the aryl is substituted with one or more Ci-Ce alkoxy. In some embodiments of any Formulae described herein, Rs is aryl, wherein the aryl is substituted with one or more Ci- Cs alkoxy.
  • Rs is aryl, wherein the aryl is substituted with one or more C1-C4 alkoxy. In some embodiments of any Formulae described herein, Rs is aryl, wherein the aryl is substituted with one or more C1-C3 alkoxy. In some embodiments of any Formulae described herein, Rs is aryl, wherein the aryl is substituted with one or more C1-C2 alkoxy. In some embodiments of any Formulae described herein, Rs is aryl, wherein the aryl is substituted with one or more Ci alkoxy.
  • R5 is aryl, wherein the aryl is substituted with one or more C2 alkoxy. In some embodiments of any Formulae described herein, R5 is aryl, wherein the aryl is substituted with one or more C3 alkoxy. In some embodiments of any Formulae described herein, R5 is aryl, wherein the aryl is substituted with one or more C4 alkoxy. In some embodiments of any Formulae described herein, R5 is aryl, wherein the aryl is substituted with one or more C5 alkoxy. In some embodiments of any Formulae described herein, R5 is aryl, wherein the aryl is substituted with one or more Ce alkoxy.
  • Re is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, heteroaryl, or aryl; where the heteroaryl, or aryl is optionally substituted with one or more halogen, or Ci-Ce alkoxy.
  • Re is H.
  • Re is halogen.
  • Re is C1-C4 alkyl.
  • Re is C1-C3 alkyl.
  • Re is C1-C2 alkyl. In some embodiments of any Formulae described herein, Re is Ci alkyl. In some embodiments of any Formulae described herein, Re is C2 alkyl. In some embodiments of any Formulae described herein, Re is C3 alkyl. In some embodiments of any Formulae described herein, Re is C4 alkyl. In some embodiments of any Formulae described herein, Re is C1-C4 alkoxy. In some embodiments of any Formulae described herein, Re is C1-C3 alkoxy. In some embodiments of any Formulae described herein, Re is C1-C2 alkoxy. In some embodiments of any Formulae described herein, Re is Ci alkoxy.
  • Re is C1-C4 haloalkyl. In some embodiments of any Formulae described herein, Re is C1-C3 haloalkyl. In some embodiments of any Formulae described herein, Re is C1-C2 haloalkyl. In some embodiments of any Formulae described herein, Re is Ci haloalkyl. In some embodiments of any Formulae described herein, Re is C2 haloalkyl. In some embodiments of any Formulae described herein, Re is C3 haloalkyl. In some embodiments of any Formulae described herein, Re is C4 haloalkyl. In some embodiments of any Formulae described herein, Re is heteroaryl.
  • Re is aryl. In some embodiments of any Formulae described herein, where Re is heteroaryl or aryl, the heteroaryl, or aryl is substituted with one or more halogen. In some embodiments of any Formulae described herein, where Re is heteroaryl or aryl, the heteroaryl, or aryl is substituted with one or more Ci- Ce alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more halogen. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more Ci-Ce alkoxy.
  • Re is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C5 alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C4 alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C3 alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C1-C2 alkoxy.
  • Re is heteroaryl, wherein the heteroaryl is substituted with one or more Ci alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C2 alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C3 alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C4 alkoxy. In some embodiments of any Formulae described herein, Re is heteroaryl, wherein the heteroaryl is substituted with one or more C5 alkoxy.
  • Re is heteroaryl, wherein the heteroaryl is substituted with one or more Ce alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more halogen. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more Ci-Ce alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more Ci- C5 alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more C1-C4 alkoxy.
  • Re is aryl, wherein the aryl is substituted with one or more C1-C3 alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more C1-C2 alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more Ci alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more C2 alkoxy. In some embodiments of any Formulae described herein, Re is aryl, wherein the aryl is substituted with one or more C3 alkoxy.
  • Re is aryl, wherein the aryl is substituted with one or more C4 alkoxy.
  • R 6 is aryl, wherein the aryl is substituted with one or more C 5 alkoxy.
  • R 6 is aryl, wherein the aryl is substituted with one or more C6 alkoxy.
  • R5 and R6 together with the intervening atoms, form a C 3 -C 6 cycloalkyl or 4- to 8-membered heterocyclyl.
  • R5 and R6 together with the intervening atoms form a C3-C6 cycloalkyl. In some embodiments of any Formulae described herein, R5 and R6 together with the intervening atoms, form a C 3 -C 5 cycloalkyl. In some embodiments of any Formulae described herein, R5 and R6 together with the intervening atoms, form a C3-C4 cycloalkyl. In some embodiments of any Formulae described herein, R5 and R6 together with the intervening atoms, form a C 3 cycloalkyl.
  • R 5 and R 6 together with the intervening atoms form a 4- to 8-membered heterocyclyl. In some embodiments of any Formulae described herein, R5 and R6 together with the intervening atoms, form a 4- to 7-membered heterocyclyl. In some embodiments of any Formulae described herein, R 5 and R 6 together with the intervening atoms, form a 4- to 6-membered heterocyclyl. In some embodiments of any Formulae described herein, R5 and R6 together with the intervening atoms, form a 4- to 5-membered heterocyclyl.
  • each R7 is independently selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl. In some embodiments of any Formulae described herein, at least one R7 is H. In some embodiments of any Formulae described herein, at least one R 7 is C 1 -C 4 alkyl. In some embodiments of any Formulae described herein, at least one R 7 is C 1 -C 3 alkyl. In some embodiments of any Formulae described herein, at least one R7 is C1-C2 alkyl.
  • At least one R7 is C1 alkyl. In some embodiments of any Formulae described herein, at least one R 7 is C 2 alkyl. In some embodiments of any Formulae described herein, at least one R7 is C3 alkyl. In some embodiments of any Formulae described herein, at least one R7 is C3-C4 cycloalkyl. In some embodiments of any Formulae described herein, at least one R 7 is C 3 cycloalkyl. In some embodiments of any Formulae described herein, at least one R7 is C4 cycloalkyl. In some embodiments of any Formulae described herein, at least one R7 is cyclopropyl.
  • each Rs is independently selected from H, halogen, - C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy.
  • at least one Rs is independently selected from halogen, alkoxy and alkyl.
  • at least one Rs is H.
  • at least one Rs is halogen.
  • at least one Rs is C1-C4 alkyl.
  • at least one Rs is C1-C3 alkyl.
  • At least one Rs is C1-C2 alkyl. In some embodiments of any Formulae described herein, at least one Rs is Ci alkyl. In some embodiments of any Formulae described herein, at least one Rs is C2 alkyl. In some embodiments of any Formulae described herein, at least one Rs is C3 alkyl. In some embodiments of any Formulae described herein, at least one Rs is C4 alkyl. In some embodiments of any Formulae described herein, at least one Rs is C1-C4 haloalkyl. In some embodiments of any Formulae described herein, at least one Rs is C1-C3 haloalkyl.
  • At least one Rs is C1-C2 haloalkyl. In some embodiments of any Formulae described herein, at least one Rs is Ci haloalkyl. In some embodiments of any Formulae described herein, at least one Rs is C2 haloalkyl. In some embodiments of any Formulae described herein, at least one Rs is C3 haloalkyl. In some embodiments of any Formulae described herein, at least one Rs is C4 haloalkyl. In some embodiments of any Formulae described herein, at least one Rs is C1-C4 alkoxy. In some embodiments of any Formulae described herein, at least one Rs is C1-C3 alkoxy.
  • At least one Rs is C1-C2 alkoxy. In some embodiments of any Formulae described herein, at least one Rs is Ci alkoxy. In some embodiments of any Formulae described herein, at least one Rs is C2 alkoxy. In some embodiments of any Formulae described herein, at least one Rs is C3 alkoxy. In some embodiments of any Formulae described herein, at least one Rs is C4 alkoxy.
  • each R9 is independently selected from H, halogen, C1-C4 alkyl, and C3-C4 carbocyclyl.
  • R9 is H.
  • R9 is halogen.
  • R9 is C1-C4 alkyl.
  • R9 is C1-C3 alkyl.
  • R9 is C1-C2 alkyl.
  • R9 is Ci alkyl.
  • R9 is C2 alkyl. In some embodiments of any Formulae described herein, R 9 is C 3 alkyl. In some embodiments of any Formulae described herein, R 9 is C 4 alkyl. In some embodiments of any Formulae described herein, R9 is C3-C4 carbocyclyl. In some embodiments of any Formulae described herein, R9 is C3 carbocyclyl. In some embodiments of any Formulae described herein, R9 is C4 carbocyclyl. [0068] As defined generally above, each R 10 is independently selected from H, halogen, and C1-C4 alkyl. In some embodiments of any Formulae described herein, R10 is H.
  • R10 is halogen. In some embodiments of any Formulae described herein, R 10 is C 1 -C 4 alkyl. In some embodiments of any Formulae described herein, R10 is C1-C3 alkyl. In some embodiments of any Formulae described herein, R10 is C1-C2 alkyl. In some embodiments of any Formulae described herein, R10 is C1 alkyl. In some embodiments of any Formulae described herein, R 10 is C 2 alkyl. In some embodiments of any Formulae described herein, R 10 is C 3 alkyl. In some embodiments of any Formulae described herein, R10 is C4 alkyl.
  • R5, R6, and R9 together with the intervening and adjacent atoms form a C 3 -C 6 cycloalkyl, 4- to 8-membered heterocyclyl, a heteroaryl, or an aryl, where the cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more R12.
  • R5, R 6 , and R 9 together with the intervening and adjacent atoms form a C 3 -C 6 cycloalkyl.
  • R5, R6, and R9 together with the intervening and adjacent atoms form a C3 cycloalkyl.
  • R 5 , R 6 , and R 9 together with the intervening and adjacent atoms form a C 4 cycloalkyl.
  • R 5 , R 6 , and R 9 together with the intervening and adjacent atoms form a C5 cycloalkyl.
  • R5, R6, and R9 together with the intervening and adjacent atoms form a C6 cycloalkyl.
  • R 5 , R 6 , and R 9 together with the intervening and adjacent atoms form a 4- to 8-membered heterocyclyl.
  • R5, R6, and R9 together with the intervening and adjacent atoms form a 4- membered heterocyclyl.
  • R 5 , R 6 , and R 9 together with the intervening and adjacent atoms form a 5-membered heterocyclyl.
  • R5, R6, and R9 together with the intervening and adjacent atoms form a 6-membered heterocyclyl.
  • R 5 , R 6 , and R 9 together with the intervening and adjacent atoms form a 7- membered heterocyclyl. In some embodiments of any Formulae described herein, R 5 , R 6 , and R 9 together with the intervening and adjacent atoms, form an 8-membered heterocyclyl. In some embodiments of any Formulae described herein, R5, R6, and R9 together with the intervening and adjacent atoms, form a heteroaryl. In some embodiments of any Formulae described herein, R 5 , R6, and R9 together with the intervening and adjacent atoms, form an aryl.
  • R5, R6, and R9 together with the intervening and adjacent atoms form a C 3 -C 6 cycloalkyl, wherein the cycloalkyl, is substituted with one or more R 12 .
  • R5, R6, and R9 together with the intervening and adjacent atoms form a 4- to 8-membered heterocyclyl, wherein the heterocyclyl is substituted with one or more R 12 .
  • R 5 , R 6 , and R 9 together with the intervening and adjacent atoms form a heteroaryl, wherein the heteroaryl is substituted with one or more R12.
  • each R11 is independently selected from H, halogen, C1–C6 alkyl, and C1–C6 alkoxy.
  • R11 is H.
  • R 11 is halogen.
  • R11 is C1–C6 alkyl.
  • R11 is C1–C5 alkyl.
  • R 11 is C 1 –C 4 alkyl. In some embodiments of any Formulae described herein, R 11 is C 1 –C 3 alkyl. In some embodiments of any Formulae described herein, R 11 is C 1 –C 2 alkyl. In some embodiments of any Formulae described herein, R11 is C1 alkyl. In some embodiments of any Formulae described herein, R11 is C2 alkyl. In some embodiments of any Formulae described herein, R 11 is C 3 alkyl. In some embodiments of any Formulae described herein, R 11 is C 4 alkyl. In some embodiments of any Formulae described herein, R11 is C5 alkyl.
  • R11 is C6 alkyl. In some embodiments of any Formulae described herein, R 11 is C 1 –C 6 alkoxy. In some embodiments of any Formulae described herein, R 11 is C 1 – C5 alkoxy. In some embodiments of any Formulae described herein, R11 is C1–C4 alkoxy. In some embodiments of any Formulae described herein, R11 is C1–C3 alkoxy. In some embodiments of any Formulae described herein, R11 is C1–C2 alkoxy. In some embodiments of any Formulae described herein, R 11 is C 1 alkoxy. In some embodiments of any Formulae described herein, R 11 is C 2 alkoxy.
  • R 11 is C 3 alkoxy. In some embodiments of any Formulae described herein, R11 is C4 alkoxy. In some embodiments of any Formulae described herein, R11 is C5 alkoxy. In some embodiments of any Formulae described herein, R 11 is C 6 alkoxy.
  • each R12 is independently selected from H, halogen, -OH, - NH2, -CN, C1–C6 alkyl, C1–C4 alkoxy, C1–C4 haloalkoxy, C1–C4 haloalkyl, and C3–C4 cycloalkyl, 3- to 10-membered heterocyclyl, heteroaryl, and C 6 –C 10 aryl.
  • at least one R12 is selected from H, halogen, C1-C4 alkoxy, or C1-C6 alkyl.
  • R12 is H.
  • R 12 is halogen. In some embodiments of any Formulae described herein, R 12 is -OH. In some embodiments of any Formulae described herein, R12 is -NH2. In some embodiments of any Formulae described herein, R12 is -CN. In some embodiments of any Formulae described herein, R12 is C1–C6 alkyl. In some embodiments of any Formulae described herein, R 12 is C 1 –C 5 alkyl. In some embodiments of any Formulae described herein, R12 is C1–C4 alkyl. In some embodiments of any Formulae described herein, R12 is C1–C3 alkyl.
  • R12 is C1–C2 alkyl. In some embodiments of any Formulae described herein, R 12 is C 1 alkyl. In some embodiments of any Formulae described herein, R12 is C2 alkyl. In some embodiments of any Formulae described herein, R12 is C3 alkyl. In some embodiments of any Formulae described herein, R12 is C4 alkyl. In some embodiments of any Formulae described herein, R 12 is C 5 alkyl. In some embodiments of any Formulae described herein, R 12 is C 6 alkyl. In some embodiments of any Formulae described herein, R12 is C1–C4 alkoxy.
  • R12 is C1– C3 alkoxy. In some embodiments of any Formulae described herein, R12 is C1–C2 alkoxy. In some embodiments of any Formulae described herein, R 12 is C 1 alkoxy. In some embodiments of any Formulae described herein, R12 is C2 alkoxy. In some embodiments of any Formulae described herein, R12 is C3 alkoxy. In some embodiments of any Formulae described herein, R12 is C4 alkoxy. In some embodiments of any Formulae described herein, R 12 is C 1 –C 4 haloalkoxy. In some embodiments of any Formulae described herein, R12 is C1 haloalkoxy.
  • R12 is C2 haloalkoxy. In some embodiments of any Formulae described herein, Rn is C3 haloalkoxy. In some embodiments of any Formulae described herein, R12 is C4 haloalkoxy. In some embodiments of any Formulae described herein, R12 is C1-C4 haloalkyl. In some embodiments of any Formulae described herein, R12 is Ci haloalkyl. In some embodiments of any Formulae described herein, R12 is C2 haloalkyl. In some embodiments of any Formulae described herein, R12 is C3 haloalkyl.
  • R12 is C4 haloalkyl. In some embodiments of any Formulae described herein, R12 is C3-C4 cycloalkyl. In some embodiments of any Formulae described herein, R12 is C3 cycloalkyl. In some embodiments of any Formulae described herein, R12 is C4 cycloalkyl. In some embodiments of any Formulae described herein, R12 is C5 cycloalkyl. In some embodiments of any Formulae described herein, R12 is Ce cycloalkyl. In some embodiments of any Formulae described herein, R12 is C7 cycloalkyl.
  • R12 is Cs cycloalkyl. In some embodiments of any Formulae described herein, R12 is C9 cycloalkyl. In some embodiments of any Formulae described herein, R12 is C10 cycloalkyl. In some embodiments of any Formulae described herein, R12 is 3- to 10-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 3 -membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 4-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 5-membered heterocyclyl.
  • R12 is 6-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 7-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 8-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 9-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is 10-membered heterocyclyl. In some embodiments of any Formulae described herein, R12 is heteroaryl. In some embodiments of any Formulae described herein, R12 is Ce-Cio aryl. In some embodiments of any Formulae described herein, R12 is Ce aryl. In some embodiments of any Formulae described herein, R12 is Cs aryl. In some embodiments of any Formulae described herein, R12 is C9 aryl. In some embodiments of any Formulae described herein, R12 is C10 aryl.
  • L is selected from a covalent bond and -CH2-. In some embodiments of any Formulae described herein, L is a covalent bond. In some embodiments of any Formulae described herein, L is -CH2-. [0073] In some embodiments, m is an integer selected from 1, 2, and 3. In some embodiments of any Formulae described herein, m is 1. In some embodiments of any Formulae described herein, m is 2. In some embodiments of any Formulae described herein, m is 3.
  • p is an integer selected from 2, 3, 4, 5, and 6. In some embodiments of any Formulae described herein, p is 2. In some embodiments of any Formulae described herein, p is 3. In some embodiments of any Formulae described herein, p is 4. In some embodiments of any Formulae described herein, p is 5. In some embodiments of any Formulae described herein, p is and 6.
  • X3 is selected from CH2, NH, O, and S. In some embodiments of any Formulae described herein, X3 is CH2. In some embodiments of any Formulae described herein, X3 is NH. In some embodiments of any Formulae described herein, X3 is O. In some embodiments of any Formulae described herein, X3 is S.
  • A is selected from C3-C8 cycloalkyl, aryl, and heteroaryl.
  • A is C3-C8 cycloalkyl. In some embodiments of any Formulae described herein, A is C3 cycloalkyl. In some embodiments of any Formulae described herein, A is C4 cycloalkyl. In some embodiments of any Formulae described herein, A is C5 cycloalkyl. In some embodiments of any Formulae described herein, A is Ce cycloalkyl. In some embodiments of any Formulae described herein, A is C7 cycloalkyl. In some embodiments of any Formulae described herein, A is Cs cycloalkyl. In some embodiments of any Formulae described herein, A is aryl. In some embodiments of any Formulae described herein, A is heteroaryl.
  • r is an integer from 0 to 3. In some embodiments of any Formulae described herein, r is from 1 to 3. In some embodiments of any Formulae described herein, r is from 0 to 2. In some embodiments of any Formulae described herein, r is 0. In some embodiments of any Formulae described herein, r is 1. In some embodiments of any Formulae described herein, r is 2. In some embodiments of any Formulae described herein, r is 3.
  • a compound of Formula I is selected from:
  • the compounds of the present disclosure may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure.
  • the present disclosure embraces all geometric and positional isomers. For example, if a compound of the present disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the present disclosure, each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound.
  • the compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry.
  • the assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • converting e.g., hydrolyzing
  • some of the compounds of the present disclosure may be atropisomers (e.g., substituted biaryls) and are considered as part of this present disclosure.
  • Enantiomers
  • the compounds of the present disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the present disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure.
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this present disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • salt is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present disclosure provides a composition comprising a compound provided by this disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of a compound in the compositions of this disclosure is such that it is effective to measurably inhibit PAD4 in a biological sample or in a patient.
  • the amount of compound in compositions of this disclosure is such that it is effective to measurably inhibit PALM, in a biological sample or in a patient.
  • a composition provided by this disclosure is formulated for administration to a patient in need of such composition.
  • a composition provided by this disclosure is formulated for oral administration to a patient.
  • compositions provided by this disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions provided by this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3 -butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di -glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their poly oxy ethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions provided by this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions provided by this disclosure may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions provided by this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds provided by this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzyl al konium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions provided by this disclosure may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions provided by this disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions provided by this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions provided by this disclosure are administered with food.
  • compositions provided by this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, as required.
  • the compounds provided by this disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may also be used in the preparation of injectables.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot inj ectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds provided by this disclosure with suitable nonirritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature, and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature, and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • 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 starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents.
  • Dosage forms for topical or transdermal administration of a compound provided by this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure.
  • the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • injectables tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.
  • compositions in a single dosage form will vary depending upon the host treated, the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a compound of the current disclosure can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the disclosure and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.
  • Such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokinesuppressive anti-inflammatory drugs (CSALDs), Interleukin- 10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugs such as azathi prine and cyclophosphamide; TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof.
  • a compound of the current disclosure can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these.
  • Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above.
  • Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
  • Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this disclosure in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.
  • the term “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure.
  • a compound of the present disclosure may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a compound of the current disclosure, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • compositions of this disclosure should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a provided compound can be administered.
  • compositions which comprise an additional therapeutic agent that additional therapeutic agent and the compound of this disclosure may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent.
  • the amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or disorder being treated.
  • the amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition.
  • the compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (I).
  • the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley - Interscience, 1994).
  • the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
  • compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Illustrative methods include but are not limited to those methods described below.
  • Compounds of the present invention can be synthesized by following the steps outlined in General Schemes A, B, C, and D, which comprise different sequences of assembling intermediates. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.
  • a provided compound inhibits PAD4 selectively as compared to PAD2.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • the present disclosure provides a method for treating a disease or a disorder associated with PAD4 enzyme activity, comprising the step of administering to a patient in need thereof a compound of the present disclosure, or a pharmaceutically acceptable composition thereof.
  • a disease or a disorder associated with PAD4 enzyme activity is a disease, condition, or disorder mediated by inappropriate PAD4 activity.
  • a disease or a 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.
  • the disease or a disorder associated with PAD4 enzyme activity is rheumatoid arthritis.
  • the disease or a disorder associated with PAD4 enzyme activity is systemic lupus.
  • the disease or a disorder associated with PAD4 enzyme activity is vasculitis. In a further embodiment, the disease or a disorder associated with PAD4 enzyme activity cutaneous lupus erythematosus. In a further embodiment, the disease or a disorder associated with PAD4 enzyme activity is psoriasis.
  • a method of treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.
  • a method of treatment of rheumatoid arthritis comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.
  • a method of treatment of systemic lupus which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.
  • a method of treatment of vasculitis comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.
  • a method of treatment of cutaneous lupus erythematosus which method comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.
  • a method of treatment of psoriasis comprises administering to a human subject in need thereof, a therapeutically effective amount of a provided compound, a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.
  • a disease or a disorder associated with PAD4 enzyme activity is selected from the group consisting of acid-induced lung injury, acne (PAPA), acute lymphocytic leukemia, acute respiratory distress syndrome, Addison’s disease, adrenal hyperplasia, adrenocortical insufficiency, ageing, AIDS, alcoholic hepatitis, alcoholic liver disease, allergen induced asthma, allergic bronchopulmonary, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer’s disease, amyloidosis, amyotropic lateral sclerosis, weight loss, angina pectoris, angioedema, anhidrotic ecodermal dysplasia-ID, ankylosing spondylitis, anterior segment, inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee
  • the disclosure provides a compound, or a pharmaceutically acceptable salt thereof, for use in therapy. In another embodiment, the disclosure provides a compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or a disorder mediated by inappropriate PAD4 activity.
  • the disclosure provides a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a 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.
  • the disclosure provides a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis.
  • the disclosure provides a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of systemic lupus.
  • the disclosure provides a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of vasculitis.
  • the disclosure provides a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of cutaneous lupus erythematosus.
  • the disclosure provides a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis.
  • the disclosure provides the use of a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disorder mediated by inappropriate PAD4 activity.
  • the disclosure provides the use of a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a 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.
  • the disclosure provides the use of a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis.
  • the disclosure provides the use of a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of systemic lupus.
  • the disclosure provides the use of a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of vasculitis.
  • the in disclosure vention provides the use of a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cutaneous lupus erythematosus.
  • the disclosure provides the use of a compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of psoriasis.
  • the disclosure provides a pharmaceutical composition for the treatment or prophylaxis of a disease or a disorder mediated by inappropriate PAD4 activity comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a pharmaceutical composition for the treatment or prophylaxis of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus, or psoriasis, comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a pharmaceutical composition for the treatment or prophylaxis of rheumatoid arthritis comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a pharmaceutical composition for the treatment or prophylaxis of systemic lupus comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a pharmaceutical composition for the treatment or prophylaxis of vasculitis comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a pharmaceutical composition for the treatment or prophylaxis of cutaneous lupus erythematosus comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a pharmaceutical composition for the treatment or prophylaxis of psoriasis comprising a provided compound, or a stereoisomer, an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.
  • PEPPSi-IPr [l,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3- chloropy ri dy 1 )pal 1 adium(II) di chi ori de
  • Si-Pyridine functionalized silica gel Silicycle R43030B, 40-63 micron particle size
  • Method A Column: XBridge Prep Shield RP Cl 8, 30*150 mm, 5 pm; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 24% B to 37% B in 8 min; Wavelength: 254 nm/220 nm.
  • Method B Column: HALO 90A Cl 8, 3.0*30 mm, 2.0 pm; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: ACN + 0.05%TFA; Flow rate: 1.5 mL/min; [Gradient]; Wavelength: 254 nm.
  • Method C Column: SunFire C18 OBD Prep, 19*250 mm, 5 pm; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: ACN; Flow rate: 25 mL/min; 32% B to 36% B in 6.5 min, 36% B; Wavelength: 254/210 nm.
  • Method D Column: Shim-pack Scepter Cl 8, 3.0*33 mm, 3.0 pm; Mobile Phase A: 5 mM NH4HCO3 in water, Mobile Phase B: ACN; Flow rate: 1.5 mL/min; [Gradient];
  • Method D Variations: [0132] Method E: Column: Xselect CSH Prep Cl 8, 30*150 mm, 5 pm; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: ACN; [Flow Rate]; [Gradient]; Wavelength: 254 nm/220 nm.
  • Method F Column: XBridge Prep OBD Cl 8, 30*150 mm, 5 pm; Mobile Phase A:
  • Method G Column: XBridge Prep Phenyl OBD Cl 8, 19*250 mm, 5 pm; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 22% B to 52% B in 10 min; Wavelength: 254 nm/220 nm.
  • Method H Column: HALO C18, 4.6*100 mm, 2.7 pm; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: ACN + 0.05% TFA; Flow rate: 1.5 mL/min; Gradient: 10% B to 95% B in 6 min, hold at 95% for 2 min, 95% B to 5% B in 2 min; Wavelength: 254 nm.
  • Method I Column: XBridge Cl 8, 19*200 mm, 5 pm; Mobile Phase A: 0.05% TFA in water / ACN 95:5, Mobile Phase B: 0.05% TFA in water / ACN 5:95; Flow rate: 20 mL/min; [Gradient]; Wavelength: 220 nm.
  • Method J Column: XBridge C18, 2.1*50, 1.7 pm, Mobile Phase A: 0.05% TFA in water / ACN 95:5, Mobile Phase B: 0.05% TFA in water / ACN 5:95; Flow rate: l.O mL/min;
  • Method K Column: HALO C18, 3.0*30 mm, 3.0 pm; Mobile Phase A: 0.05% TFA in water, Mobile Phase B: 0.05% TFA in ACN; Flow rate: 1.5 mL/min; [Gradient];
  • the compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.
  • Illustrative methods include but are not limited to those methods described below.
  • Compounds of the present invention can be synthesized by following the steps outlined in General Schemes A, B, C, and D, which comprise different sequences of assembling intermediates. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.
  • Example 3 (88.6 mg) was prepared as a white solid from Intermediate 3L and Intermediate 1I by using a similar synthetic protocol as that of Example 1.
  • Example 4 was prepared as a white solid from Intermediate 4D and Intermediate 1I by using a similar synthetic protocol as that of Example 2.
  • Example 5 (69.1 mg) as a white solid.
  • Example 6 (37.8 mg) was prepared as a white solid from Intermediate 6G (75 mg, 0.18 mmol) and Intermediate 1I by using a similar synthetic protocol as that of Example 2.
  • Example 7 [0205] To a solution of Intermediate 7C (14 mg, 0.02 mmol) in DCM (2 mL) was added TFA (0.5 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Method E1, RT: 8.63 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 7 (6.2 mg) as a white solid.
  • Example 8 [0207] To a solution of Intermediate 8A (40 mg, 0.05 mmol) in DCM (2 mL) was added TFA (0.5 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Method F, RT: 8.7 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 8 (15.2 mg) as a white solid. LCMS (ESI, m/z): 626 [M+H] + . LCMS RT: 1.377 min (Method B2).
  • Example 9 35 mg as a yellow solid.
  • Example 10 (R)-2-methyl-1 2 -(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-6-oxa-3-aza-1(6,1)-pyrrolo[2,3- b]pyridina-5(1,2)-benzenacyclodecaphan-4-one Synthesis of Example 10 [0214] Example 10 was prepared as a white solid from Intermediate 9C and tert-butyl 2- (4-bromobutoxy)benzoate (WO2021222353) by using a similar synthetic protocol as that of Example 9.
  • Example 11 was prepared as a white solid from Intermediate 9C and Intermediate 11A by using a similar synthetic protocol as that of Example 9.
  • Example 12 The resulting mixture was stirred at rt for 1 h, then concentrated to ⁇ 2 mL total volume under a stream of nitrogen. The remaining mixture was filtered and the filtrate was purified via Prep-HPLC (Method I1). Fractions containing the desired product were dried under vacuum. The purified material was then diluted with 3 mL of a 1:1 mixture of ethylene dichloride and methanol, treated with Si-Pyridine, and shaken for a minimum of 2 h. The resulting mixture was filtered and dried under vacuum to afford Example 12 (18.9 mg). LCMS (ESI, m/z): 634.1 [M+H] + . LCMS RT: 1.27 min (Method J). Example 13.
  • Example 14 was prepared as a white solid from Intermediate 14E and Intermediate 3L by using a similar synthetic protocol as that of Example 1.
  • Example 16 (R)-1 2 -(1-cyclopropyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8-tetrahydro- 1H-imidazo[4,5-g]isoquinolin-2-yl)-5 5 -fluoro-2-methyl-1 1 H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridina-5(4,3)-pyridinacyclodecaphan-4-one Synthes [0230]
  • Example 16 was prepared as a white solid from Intermediate 14D and Intermediate 5D by using a similar synthetic protocol as that of Example 5.
  • Example 17 (R)-5 5 -fluoro-2-methyl-1 2 -(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo- 5,6,7,8-tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridina-5(4,3)-pyridinacyclodecaphan-4-one Synthesi [0231 ]
  • Example 17 was prepared as a white solid from Intermediate 14E and Intermediate 2F by using a similar synthetic protocol as that of Example 2.
  • Example 18 (41.1 mg) as a white solid.
  • Example 19 (R)-2'-methyl-2'-(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)spiro[cyclopropane-1,5'-3-aza-1(6,1)- pyrrolo[2,3-b]pyridinacycloundecaphan]-4'-one [0235]
  • Example 19 was prepared as a white solid from Intermediate 1E, tert-butyl 1-(6- bromohexyl)cyclopropane-1-carboxylate (WO2021222353), and Intermediate 2F by using a similar synthetic protocol as that of Example 14.
  • Example 20 (R)-2,5,5-trimethyl-1 2 -(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacyclodecaphan-4-one Synt [0236]
  • Example 20 was prepared as a white solid from Intermediate 1E, tert-butyl 7- bromo-2,2-dimethylheptanoate (WO2021222353), and Intermediate 2F by using a similar synthetic protocol as that of Example 14.
  • Example 21 was prepared as a white solid from Intermediate 1E, Intermediate 21A, and Intermediate 2F by using a similar synthetic protocol as that of Example 14.
  • Example 23 was prepared from Intermediate 9C and Intermediate 23B by using a similar synthetic protocol as that of Example 12. LCMS ESI 616 [M+H] + . LCMS RT: 1.22 min (Method J).
  • Example 24 was prepared as a light yellow oil from Intermediate 24E and Intermediate 2F by using a similar synthetic protocol as that of Example 14.
  • Example 25 (R)-2,5,5-trimethyl-1 2 -(1-methyl-6-(((S)-morpholin-3-yl)methyl)-5-oxo-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-6-oxa-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one Synthe [025 3]
  • Example 25 was prepared from Intermediate 9C and tert-butyl 2-methyl-2-((5- (tosyloxy)pentyl)oxy)propanoate* by using a similar synthetic protocol as that of Example 12.
  • Example 26 & Example 27 [0255] A mixture of Example 26 and Example 27 was prepared from Intermediate 9C and Intermediate 26A by using a similar synthetic protocol as that of Example 12. The mixture was separated by Prep-HPLC (Method I2) to afford two homochiral, diastereomeric products.
  • Example 26 (diastereomer 1, first eluting): 1 H NMR (500 MHz, DMSO-d6) ⁇ 8.76 - 8.68 (m, 1H), 8.65 - 8.55 (m, 1H), 8.28 (s, 1H), 8.13 - 8.05 (m, 1H), 7.99 - 7.94 (m, 1H), 7.93 - 7.86 (m, 1H), 7.65 - 7.57 (m, 2H), 7.47 - 7.39 (m, 1H), 7.27 - 7.22 (m, 1H), 7.19 - 7.13 (m, 1H), 5.35 - 5.22 (m, 1H), 5.01 - 4.88 (m, 1H), 4.80 - 4.67 (m, 1H), 3.98 (s, 3H), 3.96 - 3.78 (m, 2H), 3.74 - 3.61 (m, 2H), 3.57 - 3.48 (m, 1H), 3.29 - 3.12 (m, 2H), 3.07 - 2.96 (m, 1H),
  • Example 28 (R)-2,5,5-trimethyl-1 2 -(1-methyl-5-oxo-6-(((S)-pyrrolidin-2-yl)methyl)-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-1 1 H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one y [0257] To solid 6-fluoro-3,4-dihydroisoquinolin-1(2H)-one (15.0 g, 90.8 mmol) was added H2SO4 (200 mL) dropwise at 0 °C, followed by portionwise addition of KNO3 (36.7 g, 364 mmol).
  • Example 28 (15.6 mg) as a white solid.
  • Example 29 (R)-2,5,5-trimethyl-12-(1-methyl-5-oxo-6-(((R)-pyrrolidin-2-yl)methyl)-5,6,7,8- tetrahydro-1H-imidazo[4,5-g]isoquinolin-2-yl)-11H-3-aza-1(6,1)-pyrrolo[2,3- b]pyridinacycloundecaphan-4-one Synthesis of Example 29 [0264] Example 29 was prepared as a white solid from Intermediate 28E and (R)- tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide by using a similar synthetic protocol as that of Example 28.
  • Example 30 53.4 mg as a white solid.
  • Examples 31-38 were prepared from Intermediate 28E and appropriate commercially available precursors by using a similar synthetic protocol as that of Example 30. Table 1. Characterization of Examples 31-38.
  • Example LCMS m/z [M+H] + ; LCMS RT (LCMS method); 1 H Structure - n , , 4 , 6 (m 4H) 215 190 (m 4H) 170 157 (m 2H) 145
  • Example 39 (15.6 mg) as a white solid.
  • Example 40 was prepared as a white solid from Intermediate 28E and Intermediate 40A by using a similar synthetic protocol as that of Example 39.
  • Example 41 [0281] To a solution of Intermediate 41D (35 mg, 0.05 mmol) in DCM (2 mL) was added TFA (0.5 mL). The resulting mixture was stirred at rt for 1 h, then concentrated under vacuum. The crude product was purified by Prep-HPLC (Method E5, RT: 8.5 min). The pure fractions were concentrated under vacuum to remove organic solvents and the residual aqueous solution was lyophilized to afford Example 41 (13.5 mg) as a white solid.
  • Example 43 was prepared from Intermediate 28E and Intermediate 43A by using a similar synthetic protocol as that of Example 39. LCMS (ESI, m/z): 632 [M+H] + .
  • Final assay conditions were as follows: Reaction volume: 26 ⁇ L; Assay buffer: 25 mM HEPES pH 7.5, 5 mM NaCl, 1 mM DTT, 0.2 mg/mL BSA, 0.01% CHAPS, 5 ⁇ M TPEN, and 50 ⁇ M Calcium (Condition 1) or 1 mM Calcium (Condition 2); Final concentrations: 5 nM hPAD4 enzyme, 250 ⁇ M BAEE, and 0.5% DMSO; Total incubation time: 30 min compound and enzyme preincubation at 37 °C, 90 min enzyme/substrate reaction, 30 min reaction with phenyl glyoxal at 37 °C; Stop solution: 40 ⁇ L of 5% trichloroacetic acid solution in ACN.
  • Assay protocol Compound solution (0.13 ⁇ L) was added to a solution of 10 nM PAD4 in assay buffer (13 ⁇ L). After 30 min, a solution of 500 ⁇ M of BAEE in assay buffer (13 ⁇ L) was added and the reaction was incubated for 90 min at 37 °C. The enzymatic reaction was quenched by addition of 6.1 N trichloroacetic acid (15 ⁇ L, 100% w/v). Final Concentration: 20%. A solution of 8.5 mM phenyl glyoxal (35 ⁇ L) was then added to a final concentration of 4 mM and the reaction was incubated for 30 min at 37 °C.
  • Sciex API5500 triple quadrupole mass spectrometer (Applied Biosystems) equipped with ESI was used to analyze the peptidyl citrulline and internal standard ions.
  • Multiple reaction monitoring transition of product and internal standard were monitored at m/z 424.5 to 350.4 and m/z 293 to 247 respectively.
  • the dwell time for each transition was set at 200 ms, and the ESI voltage was used at 5500 with a source temperature of 400 °C.
  • Extracted ion peaks for each transition were integrated using the Rapid Fire Integrator software. Peak area of analyte was normalized with internal standard.
  • Table 2 shows the human PAD4 (hPAD4) IC 50 in the RapidFire mass spectrometry (RFMS) assay.
  • Table 2 shows the activity of selected compounds of this invention in the PAD4 assays described above.
  • Compounds having an activity designated as “A” provided an IC 50 ⁇ 10nM; compounds having an activity designated as “B” provided an IC5011-100nM; compounds having an activity designated as “C” provided an IC50101-500nM; compounds having an activity designated as “D” provided an IC 50 501-1000nM; compounds having an activity designated as “E” provided an IC 50 > 1000nM.
  • Table 2 shows Biological Activity Data RFMS Condition 1 (50 ⁇ M Ca 2+ )
  • RFMS Condition 2 (1 mM Ca 2+ )
  • a compound of Formula I drug, or tautomer thereof, wherein: X 1 and X 2 are each independently CR 8 or N; Y is selected from -(CR9R10)p–, –O–(CR9R10)p-, –(CR9R10)p–O–(CH2)m-, –(CR9R10)p–O–(CH2)m– O–CH 2 –, and –(CR 9 R 10 ) p –O–(CH 2 ) m –O–; R 1 is independently –CH(NHR 7 )-(C 1 -C 3 alkyl) or a 4- to 8-membered heterocycle containing at least one heteroatom selected from the group consisting of N, O, or S, wherein the alkyl or heterocycle is optionally substituted with one or more R11; R 2 is independently H, or C 1 -C 4 alkyl; R3 is independently H, halogen, or
  • Enumerated Embodiment 2 The compound of Enumerated Embodiment 1, wherein the compound is of Formula (Ia): w o 3. Enumerated Embodiment 3. The compound of any one of the previous Enumerated Embodiments, wherein the compound is of Formula (Ia-1):
  • Enumerated Embodiment 4 The compound of Enumerated Embodiment 1 or 2, wherein the compound is of Formula (Ia-2): wherei n A y y, y, y; wherein X3 is NH, O, or S.
  • Enumerated Embodiment 5. The compound of Enumerated Embodiments 1-3, wherein the compound is of Formula (Ia-3)
  • Enumerated Embodiment 6 The compound of Enumerated Embodiments 1, 2, or 4, wherein the compound is of Formula (Ia-4) wherein X 3 is CH 2 , NH, O, or S.
  • Enumerated Embodiment 7 The compound of Enumerated Embodiment 1 or 2, wherein the compound is of Formula (Ia-5)
  • Enumerated Embodiment 8 The compound of Enumerated Embodiment 1, wherein the compound is of Formula (Ib): f Enumerated Embodiment 1 or 8, wherein the compound is of Formula (Ib-1):
  • Embodiment 36 A pharmaceutically acceptable composition comprising the compound according to any one of Enumerated Embodiments 1-35, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • Enumerated Embodiment 37 A method of inhibiting PAD4 in a subject or in a biological sample comprising the step of contacting the PAD4 with a compound according to any one of Enumerated Embodiments 1-35.
  • a method of treating a PAD4-mediated disease, disorder, or condition in a subject in need thereof comprising the step of administering to said subject the composition according to Enumerated Embodiment 36.
  • Enumerated Embodiment 39 The method according to Enumerated Embodiment 38, wherein the PAD4-mediated disease, disorder, or condition is selected from the group consisting of acid-induced lung injury, acne (PAPA), acute lymphocytic leukemia, acute, respiratory distress syndrome, Addison’s disease, adrenal hyperplasia, adrenocortical insufficiency, ageing, AIDS, alcoholic hepatitis, alcoholic hepatitis, alcoholic liver disease, allergen induced asthma, allergic bronchopulmonary, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer’s disease, amyloidosis, amyotropic lateral sclerosis, and weight loss, angina pectoris, angioedema, anhidrotic ecodermal dysp
  • Enumerated Embodiment 40 The method according to Enumerated Embodiment 38, wherein the PAD4-mediated disease, disorder, or condition is selected from rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis.
  • the PAD4-mediated disease, disorder, or condition is selected from rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis.

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Abstract

L'invention concerne de manière générale des composés de formule I, qui sont des inhibiteurs de PAD4, des procédés de préparation de ces composés, des compositions pharmaceutiques comprenant ces composés et des utilisations de ces composés pour le traitement de maladies ou de troubles associés à l'activité enzymatique de PAD4.
PCT/US2024/038782 2023-07-21 2024-07-19 Inhibiteurs hétérocycliques de pad4 Pending WO2025024288A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021222353A1 (fr) 2020-04-30 2021-11-04 Gilead Sciences, Inc. Inhibiteurs macrocycliques de peptidylarginine déiminases

Non-Patent Citations (23)

* Cited by examiner, † Cited by third party
Title
"March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS
ALLEN, L. V., JR. ET AL.: "Remington: The Science and Practice of Pharmacy", vol. 2, 2012, PHARMACEUTICAL PRESS
BRINKMANN V. ET AL., SCIENCE, vol. 303, 2004, pages 1532 - 5
CHANG X. ET AL., BMC CANCER, vol. 9, 2009, pages 40
CHUMANEVICH A.A. ET AL., AM. J. PHYSIOL. GASTROINTEST. LIVER PHYSIOL., vol. 300, no. 6, 2011, pages G929 - G938
CLARK S.R. ET AL., NAT. MED., vol. 13, no. 4, 2007, pages 463 - 9
DWORSKI R. ET AL., J. ALLERGY CLIN. IMMUNOL., vol. 127, no. 5, 2011, pages 1260 - 6
E. L. ELIELS. H. WILENL. N. MANDER: "Stereochemistry of Organic Compounds", 1994, WILEY-INTERSCIENCE
HAKKIM A. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 107, no. 36, 2010, pages 15880 - 9818
J. MED. CHEM., vol. 62, no. 18, 2019, pages 8609
JONES J.E. ET AL., CURR. OPIN. DRUG DISCOV. DEVEL., vol. 12, no. 5, 2009, pages 616 - 627
KESSENBROCK K. ET AL., NAT. MED., vol. 15, no. 6, 2009, pages 623 - 625
KOCHI Y. ET AL., ANN. RHEUM. DIS., vol. 70, 2011, pages 512 - 515
LANGE S. ET AL., DEV. BIOL., vol. 355, no. 2, 2011, pages 205 - 14
LI P. ET AL., J. EXP. MED., vol. 207, no. 9, 2010, pages 1853 - 1862
LI P. ET AL., MOL. CELL BIOL., vol. 28, no. 15, 2008, pages 4745 - 4758
NEELI 1. ET AL., J. IMMUNOL., vol. 180, 2008, pages 1895 - 1902
SAVCHEFIKO A. ET AL., PATHOL. INT., vol. 61, no. 5, 2011, pages 290 - 7
SLACK J.L. ET AL., CELL. MOL. LIFE SCI., vol. 68, no. 4, 2011, pages 709 - 720
T. W. GREENEP. G. M. WUTS: "Protective Groups in Organic Synthesis", 1999, UNIVERSITY SCIENCE BOOKS
TETRAHEDRON, vol. 59, 2003, pages 149 - 153
VILLANUEVA E. ET AL., J. IMMUNOL., vol. 186, no. 7, 2011, pages 4396 - 4404
VITKOV L. ET AL., ULTRASTRUCTURAL PATHOL., vol. 34, no. 1, 2010, pages 25 - 30

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