Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• LN Lupus nephritis
• SLE systemic lupus erythematosus
• Treatment options for LN include powerful immunosuppressive drugs such as high-dose corticosteroids, e.g., glucocorticoids, alone or in combination with cytotoxic drugs.
• powerful immunosuppressive drugs such as high-dose corticosteroids, e.g., glucocorticoids, alone or in combination with cytotoxic drugs.
• a method for treating a lupus nephritis (LN) patient in need thereof comprises, in one embodiment, administering to the LN patient in need of treatment, a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof:
• R 2 is hydrogen, F, Cl, Br, OSC Cmalkyl, or Cmalkyl
• R 3 is hydrogen, F, Cl, Br, CN, CF3, SC Cmalkyl, CONH2 or S02NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or
• R 6 is Cmalkyl, optionally substituted by 1, 2 or 3 F and/or optionally by OH, OCmalkyl, N(Ci-3alkyl)2, cyclopropyl, or tetrahydropyran;
• R 7 is hydrogen, F, Cl or CH3;
• X is O, S or CF 2 ;
• Y is O or S
• Q is CH or N.
• the pharmaceutical composition comprises an effective amount of (2S)-N- ⁇ ( 1 S)- 1 -cyano-2-
• Administration routes include oral administration.
• Administration schedules can be determined by the user of the method, e.g., a prescribing physician. In one embodiment, administration is once daily. In another embodiment, administration is twice daily. In another embodiment, administration 1 c daily, once every other day, once every third day, once every fourth day, 2x weekly, 3x weekly or 4x weekly.
• Figure 1 is a schematic of the accelerated LN model and study design described in Example 2.
• Figure 2 is a graph of the albumin/creatinine ratio in urine at week 8 for the various treatment groups of NZB/WF1 mice subjected to the accelerated LN model. * P ⁇ 0.05 vs. vehicle as measured by ANOVA.
• Figure 3 is a graph of the urinary protein concentration at week 8 (mg/dL) for the various treatment groups of NZB/WF1 mice subjected to the accelerated LN model. * P ⁇ 0.05 vs. vehicle as measured by ANOVA.
• Figure 4 is a graph of blood urea nitrogen (BUN) levels at week 6 for the various treatment groups of NZB/WF1 mice subjected to the accelerated LN model. * P ⁇ 0.05 vs. vehicle as measured by ANOVA.
• Figure 5 is a pseudo survival curve for the various mouse treatment groups as a function of days post model initiation (IFNa5 adenovirus injection). Pseudo-survival is indicated by a urine protein level of ⁇ 750 mg/dL.
• Figure 6 is a graph of the renal pathology score sum (summed from individual scores for (i) glomerulonephritis, (ii) tubular protein and (iii) nephropathy) for the various treatment groups. * P ⁇ 0.05 vs. vehicle as measured by ANOVA.
• Figure 7 is a graph of the CD45+ cell percent of total kidney cells (as measured by FACS) for the various treatment groups. * P ⁇ 0.05 vs. vehicle as measured by ANOVA.
• Figure 8 is a graph of the myelocyte percent of total kidney cells (as measured by FACS, CD45+, CDl lb+) for the various treatment groups. * P ⁇ 0.05 vs. vehicle as measured by ANOVA.
• Figure 9 is a graph of the neutrophil percent of total kidney cells (as measured by FACS, CD45+, CD1 lb+, Ly6G+) for the various treatment groups.
• Figure 10 is a graph of the monocyte percent of total kidney cells (as measured by FACS, CD45+, CDl lb+, Ly6G-, Ly6C+) for the various treatment groups. * P ⁇ 0.05 vs. vehicle as measured by ANOVA.
• Figure 11 is a graph of the Ly6C+ macrophage percent of total kidney cells (as measured by FACS, CD45+, CDl lb+, F4/80+, Ly6C+, Ly6G-) for the various treatment groups. * P ⁇ 0.05 vs. vehicle as measured by ANOVA.
• Figure 12 is a graph of the Ly6C- macrophage percent of total kidney cells (as measured by FACS, CD45+, CD1 lb+, F4/80+, Ly6C-, Ly6G-) for the various treatment groups.
• Figure 13 is a graph of the T-lymphocyte percent of total kidney cells (as measured by FACS, CD45+, CD3+) for the various treatment groups. * P ⁇ 0.05 vs. vehicle as measured by ANOVA.
• the methods provided herein employ reversible inhibitors of DPP1 in methods for treating LN.
• C1-3 means a carbon group having 1, 2 or 3 carbon atoms.
• alkyl includes both straight and branched chain alkyl groups and may be substituted or non-substituted.
• Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl, pentyl.
• a pharmaceutically acceptable moiety e.g., a salt, dosage form, or excipient
• a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.
• a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof:
• R 2 is hydrogen, F, Cl, Br, OSC Cmalkyl, or Ci-3alkyl
• R 3 is hydrogen, F, Cl, Br, CN, CF3, SC Cmalkyl, CONH2 or S02NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring; or
• R 6 is Cmalkyl, optionally substituted by 1, 2 or 3 F and/or optionally by OH, OCmalkyl, N(Ci-3alkyl)2, cyclopropyl, or tetrahydropyran;
• R 7 is hydrogen, F, Cl or CH3;
• X is O, S or CF 2 ;
• Y is O or S; and Q is CH or N.
• R 3 is hydrogen, F, Cl, Br, OSC Cmalkyl, or Cmalkyl;
• R 3 is hydrogen, F, Cl, Br, CN, CF3, SC Cmalkyl, CONH2 or SC NR 4 R 5 , wherein R 4 and R 5 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine or piperidine ring.
• R 3 is hydrogen, F, Cl, CN or SC Cmalkyl.
• R 6 is Cmalkyl, optionally substituted by 1, 2 or 3 F and optionally substituted by OH, OCmalkyl, N(Ci-3alkyl)2, cyclopropyl, or tetrahydropyran; and R 7 is hydrogen, F, Cl or CH3.
• s Cmalkyl wherein the Cmalkyl is optionally substituted by 1, 2 or 3 F; and R 7 is hydrogen.
• R 2 is hydrogen, F, Cl, Br, OSC Cmalkyl or Cmalkyl.
• R 2 is hydrogen, F, Cl or Ci-3alkyl.
• R 2 is hydrogen, F or Cmalkyl.
• R 3 is hydrogen, F, Cl, Br, CN, CF3, SC Cmalkyl CONH2 or
• R 3 is selected from hydrogen, F, Cl, CN or SC Cmalkyl. [0038] In still a further embodiment, R 3 is selected from hydrogen, F or CN. [0039] In one embodiment, R 6 is Cmalkyl, wherein said Cmalkyl is optionally substituted by 1, 2 or 3 F and optionally by one substituent selected from OH, OCmalkyl, N(Ci-3alkyl)2, cyclopropyl, or tetrahydropyran.
• R 6 is Cmalkyl, wherein said Ci-3alkyl is optionally substituted by 1, 2 or 3 F.
• R 6 is methyl or ethyl.
• R 6 is methyl.
• R 7 is hydrogen, F, Cl or CH3. In a further embodiment, R 7 is hydrogen.
• the composition administered to the patient comprises an effective amount of (25)-/V- ⁇ (l5)-l-cyano-2-[4-(3-methyl-2-oxo-2,3- dihydro-l,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -l,4-oxazepane-2-carboxamide (INS 1007):
• the compound of formula (I) is:
• the LN treatment methods provided herein comprise the administration of a composition comprising an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need of LN treatment.
• the compounds of formula (I) and their pharmaceutically acceptable salts are inhibitors of dipeptidyl peptidase 1 (DPP1) activity.
• the compound is INS 1007, or a pharmaceutically acceptable salt thereof.
• Administration routes include oral administration.
• Administration schedules can be determined by the user of the method, e.g., a prescribing physician.
• administration is once daily.
• administration is twice daily.
• the patient is administered a compound of formula (I) 1 x daily at a dosage of 10 mg, 25 mg or 40 mg.
• the term“treating” in one embodiment includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in the patient that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g., arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); (3) relieving the condition (for example, by causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms).
• the methods provided herein comprise increasing the renal function of the patient being treated.
• Renal function in one embodiment, is assessed via the measurement of one or more of the following: (i) blood urea nitrogen (BUN); (ii) serum creatinine; (iii) creatinine clearance.
• BUN blood urea nitrogen
• serum creatinine serum creatinine
• creatinine clearance Factors that have been associated with worse renal outcomes include elevated titers of anti-double stranded DNA antibodies, low levels of C3 complement; increased levels of serum creatinine; decreased rates of creatinine clearance, increased proteinuria.
• treating a patient for LN comprises decreasing the serum creatinine levels in the patient, as compared to a baseline level measured prior to initiation of treatment.
• decreasing the serum creatinine comprises decreasing to the normal range for serum creatinine.
• the normal range for serum creatinine may be from about 0.6 to about 1.3 mg/dL, with some variation seen by age, between men and women, and from lab to lab.
• treating a patient for LN comprises decreasing the active urinary sediment and/or casts in the patient, or obtaining an inactive urinary sediment in the patient.
• the presence of urinary sediment and/or casts may be measured, e.g., by microscopic examination of urine. For example, the number of red blood cells in a urine sample may be assayed by microscopic examination.
• an inactive urinary sediment is defined as less than about 10 red blood cells (RBC) per high power field (HPF).
• Urinary casts may include without limitation red blood cell casts, white blood cell casts, renal tubular epithelial cell casts, waxy casts, hyaline casts, granular casts, and fatty casts.
• a urinary protein to creatinine ratio may be measured and assessed for treatment efficacy.
• treating in one embodiment comprises decreasing the UPCR in the patient, as compared to an initial value measured prior to treatment initiation.
• the presence of protein in the urine may also be assayed by tests including without limitation a urine albumin to creatinine ratio (UACR) and dipstick urinalysis.
• Treatment in one embodiment, comprises decreasing proteinuria in the patient, as compared to an initial value measured prior to treatment initiation.
• Other tests and/or measures that may be useful for examining renal function include without limitation a renal panel, creatinine clearance, sodium, potassium, chloride, bicarbonate, phosphorus, calcium, albumin, blood urea nitrogen (BUN), creatinine, glucose, estimated glomerular filtration rate (eGFR), BUN/creatinine ratio, and anion gap, and may include a measurement of the above parameters in the blood and/or urine, where appropriate.
• BUN blood urea nitrogen
• eGFR estimated glomerular filtration rate
• anion gap e.g., the American College of Rheumatology Guidelines for Screening, Case Definition, Treatment and Management of Lupus Nephritis (Hahn, B. et al. (2012) Arthritis Care Res. 64:797-808, incorporated by reference herein in its entirety for all purposes).
• treating a patient for LN comprises achieving a complete renal response (CRR) or a partial renal response (PRR) in the patient.
• CCR complete renal response
• PRR partial renal response
• complete renal response or“CRR” refers to a response to treatment that includes a normalization of serum creatinine, inactive urinary sediment, and a urinary protein to creatinine ratio of less than 0.5.
• Partial renal response refers to a response to treatment that is less than a CRR but still includes mitigation of one or more symptoms including without limitation a reduction in serum creatinine, reduced urinary sediment, and a reduction in proteinuria.
• CRR or PRR is measured, for example, about 3 months, about 6 months, about 9 months or about 12 months after the initiation of one of the methods of treatment provided herein.
• CRR is defined by the following characteristics:
• treating a patient for LN comprises decreasing the proteinuria in the patient, as compared to a baseline value.
• the baseline value is taken in one embodiment, immediately prior to initiation of one of the treatment methods provided herein.
• a composition comprising an effective amount of a compound of Formula (I) is administered orally.
• the compound of Formula (I) is INS 1007, or a pharmaceutically acceptable salt thereof.
• administration is 1 x daily, once every other day, once every third day, once every fourth day, 2x weekly, 3* weekly or 4* weekly. In even a further embodiment, administration of the compound is once daily.
• the dosage administered will vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
• the daily dosage of the compound of the disclosure may be in the range from 0.01 micrograms per kilogram body weight (pg/kg) to 100 milligrams per kilogram body weight (mg/kg).
• the compound of Formula (I) is administered in an oral dosage form.
• the compound of Formula (I) is administered as a 10 mg to 50 mg dosage form, for example, a 5 mg dosage form, a 10 mg dosage form, a 15 mg dosage form, a 20 mg dosage form, a 25 mg dosage form, a 30 mg dosage form, 35 mg dosage form, a 40 mg dosage form, a 45 mg dosage form or a 50 mg dosage form.
• the dosage form is a 25 mg or 40 mg dosage form.
• the dosage form is administered once daily.
• the compound is (2ri -/V- ⁇ (lri -l- cyano-2-[4-(3-methyl-2-oxo-2,3-dihydro-l,3-benzoxazol-5-yl)phenyl]ethyl ⁇ -l,4-oxazepane- 2-carboxamide, or a pharmaceutically acceptable salt thereof.
• Treating, in one embodiment, is carried out over an administration period of about 3 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months or about 24 months.
• the compounds of formula (I), or pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in a composition comprising a pharmaceutically acceptable adjuvant(s), diluents(s) and/or carrier(s).
• a pharmaceutically acceptable adjuvant(s), diluents(s) and/or carrier(s) Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example,“Pharmaceuticals - The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 2°d Ed. 2002, incorporated by reference herein in its entirety for all purposes.
• the pharmaceutical composition will comprise from 0.05 to 99 %w (percent by weight), for example, from 0.05 to 80 %w, or from 0.10 to 70 %w, or from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
• the oral dosage form is a film-coated oral tablet.
• the dosage form is an immediate release dosage form with rapid dissolution characteristics under in vitro test conditions.
• the oral dosage form is administered once daily. In a further embodiment, the oral dosage form is administered at approximately the same time every day, e.g., prior to breakfast. In another embodiment, the composition comprising an effective amount of formula (I) is administered 2* day. In yet another embodiment, the composition comprising an effective amount of formula (I) is administered once-a-week, every other day, every third day, 2* week, 3* week, 4* week, or 5* week.
• the compound of the disclosure may be admixed with adjuvant(s), diluent(s) or carrier(s), for example, lactose, saccharose, sorbitol, mannitol; starch, for example, potato starch, com starch or amylopectin; cellulose derivative; binder, for example, gelatine or polyvinylpyrrolidone; disintegrant, for example cellulose derivative, and/or lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, and the like, and then compressed into tablets.
• adjuvant(s) for example, lactose, saccharose, sorbitol, mannitol
• starch for example, potato starch, com starch or amylopectin
• cellulose derivative for example, gelatine or polyvinylpyrrolidone
• disintegrant for example cellulose derivative
• lubricant for example, magnesium stearate,
• the cores may be coated with a suitable polymer dissolved or dispersed in water or readily volatile organic solvent(s).
• the tablet may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
• the compound of the disclosure may be admixed with, for example, a vegetable oil or polyethylene glycol.
• Hard gelatine capsules may contain granules of the compound using pharmaceutical excipients like the above-mentioned excipients for tablets.
• liquid or semisolid formulations of the compound of the disclosure may be filled into hard gelatine capsules.
• the composition is an oral disintegrating tablet (ODT).
• ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed whole
• the composition is an oral thin film or an oral disintegrating film (ODF).
• ODF oral disintegrating film
• the ODF contains a film-forming polymer such as hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), pullulan, carboxymethyl cellulose (CMC), pectin, starch, polyvinyl acetate (PVA) or sodium alginate.
• Liquid preparations for oral application may be in the form of syrups, solutions or suspensions. Solutions, for example, may contain the compound of the disclosure, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain coloring agents, flavoring agents, saccharine and/or carboxymethylcellulose as a thickening agent. Furthermore, other excipients known to those skilled in art may be used when making formulations for oral use.
• a compound of formula (I), or a pharmaceutically acceptable salt thereof, may also be administered in conjunction with a further compound used for the treatment of LN via one of the methods described herein.
• the further compound is administered concurrently, sequentially or in admixture with a compound of Formula (I), for the treatment of LN.
• the further compound is an immunosuppressant.
• the immunosuppressant is mycophenolate mofetil (MMF) or azathioprine.
• MMF mycophenolate mofetil
• the further compound is a steroid.
• the steroid is a corticosteroid.
• the further compound is a glucocorticoid.
• the further compound is cyclophosphamide (CYC), alone or in combination with one or more glucocorticoids.
• CYC cyclophosphamide
• the compound of the disclosure, or a pharmaceutically acceptable salt thereof is administered concurrently or sequentially with one or more further active ingredients selected from one or more of those provided above.
• the compound of Formula (I), or a pharmaceutically acceptable salt thereof may be administered concurrently or sequentially with a further pharmaceutical composition for use as a medicament for the treatment of LN.
• the further pharmaceutical composition may be a medicament which the patient may already be prescribed (e.g., an existing standard or care medication), and may itself be a composition comprising one or more active ingredients selected from those defined above.
• a compound of formula (I) or a pharmaceutically acceptable salt thereof can be synthesized by reacting a compound of formula (II),
• R 1 is as defined in formula (I), with a compound of formula (III),
• PG represents a protecting group (e.g. te/7-butoxy carbonyl), and optionally thereafter carrying out one or more of the following procedures: converting a compound of formula (I) into another compound of formula (I);
• the process is conveniently carried out in the presence of a base such as DiPEA or TEA and one or more activating agents such as EDCI, 2-pyridinol-l -oxide, or T3P.
• a base such as DiPEA or TEA
• activating agents such as EDCI, 2-pyridinol-l -oxide, or T3P.
• the reaction is conveniently carried out in an organic solvent such as DMF or DCM at a temperature, for example, in the range from 20 °C to 100 °C, in particular at ambient temperature (25 °C).
• PG represents a protecting group (e.g. fe/7-butoxy carbonyl), with a suitable reagent to remove the protecting group PG.
• a suitable reagent is formic acid.
• PG represents a protecting group (e.g., tert- butoxycarbonyl) and Hal represents a halogen (e.g. I or Br), with a compound of formula (VI) or an ester thereof,
• R 1 is as defined in formula (I)
• a catalyst such as Pd(dppf)Cl2 DCM or 1,1 te(di-/er/-butylphosphino)ferrocene palladium di chloride and a base such as potassium carbonate or sodium carbonate.
• the reaction is conveniently carried out in a solvent such as dioxane/water mixture or ACN/water mixture at a temperature, for example, in the range from 20 °C to 100 °C, particularly at 75 °C.
• PG represents a protecting group (e.g. tert-butoxy carbonyl) and Hal represents a halogen (e.g., I or Br), using standard literature procedures for the dehydration of an amide, for example with Burgess reagent, or with a reagent such as T3P with or without a base such as DiPEA, in a solvent such as DCM or DMF at a temperature in the range from -20 °C to 100 °C, for example at 0 °C.
• a protecting group e.g. tert-butoxy carbonyl
• Hal represents a halogen (e.g., I or Br)
• a halogen e.g., I or Br
• PG represents a protecting group (e.g. tert-butoxy carbonyl) and Hal represents ahalogen (e.g., I or Br), with an aqueous ammonia solution, using standard literature procedures for the formation of an amide, for example, in the presence of a base such as A-ethyl-morpholine or DiPEA and an activating agent such as TBTU or T3P.
• a base such as A-ethyl-morpholine or DiPEA
• an activating agent such as TBTU or T3P.
• the reaction is conveniently carried out in an organic solvent such as DMF, at a temperature in the range from -20 °C to 100 °C, for example at 0 °C.
• R 1 is as defined above and PG represents a protecting group (e.g. tert- butoxycarbonyl), using standard literature procedures for the dehydration of an amide, for example with Burgess reagent or with a reagent such as T3P with or without a base such as DiPEA, in a solvent such as DCM or DMF at a temperature in the range from -20 °C to 100 °C, for example at 25 °C, and thereafter reacting with a suitable reagent to remove the protecting group PG.
• a suitable reagent is formic acid.
• a compound of formula (IX) may be prepared by reacting a compound of formula (X), wherein PG represents a protecting group (e.g. tert-butoxy carbonyl),
• a catalyst such as bis[bis(l,2-diphenylphosphino)ethane]palladium(0), or Pd(dppf)Cl2 DCM
• a base such as potassium carbonate or sodium carbonate.
• the reaction is conveniently carried out in a solvent such as dioxane/water mixture or ACN/water mixture at a temperature, for example, in the range from 20 °C to 100 °C, particularly at 80 °C.
• a compound of formula (X) may be prepared by reacting a compound of formula (XII), wherein PG represents a protecting group (e.g. tert-butoxy carbonyl),
• a suitable catalyst such as Pd(dppf)Cl2 ⁇ DCM and with or without l, -bis(diphenylphosphino)ferrocene or l,l-Z>A(di-/e/7-butylphosphino)ferrocene palladium dichloride, with a suitable salt such as potassium acetate, in a solvent such as DMSO at a temperature in the range 60 °C to 100 °C, for example at 85 °C.
• a suitable catalyst such as Pd(dppf)Cl2 ⁇ DCM and with or without l, -bis(diphenylphosphino)ferrocene or l,l-Z>A(di-/e/7-butylphosphino)ferrocene palladium dichloride, with a suitable salt such as potassium acetate, in a solvent such as DMSO at a temperature in the range 60 °C to 100 °C, for example at 85 °C.
• a compound of formula (XII) may be prepared by reacting a compound of formula
• PG represents a protecting group (e.g. tert-butoxy carbonyl) in the presence of a base such as DiPEA or TEA and an activating agent such as EDCI, 2-pyridinol-l -oxide, or T3P.
• a base such as DiPEA or TEA
• an activating agent such as EDCI, 2-pyridinol-l -oxide, or T3P.
• the reaction is conveniently carried out in an organic solvent such as DMF or DCM at a temperature, for example, in the range from 20 °C to 100 °C, in particular at ambient temperature (25 °C).
• PG is as defined in formula (VII)
• aqueous ammonia solution using standard literature procedures for the formation of an amide, for example, in the presence of a base such as V-e thy 1 -morpholine or DiPEA and an activating agent such as a“uronium” reagent (for example TBTU), or T3P.
• a base such as V-e thy 1 -morpholine or DiPEA
• an activating agent such as a“uronium” reagent (for example TBTU), or T3P.
• the reaction is conveniently carried out in an organic solvent such as DMF, at a temperature in the range from -20 °C to 100 °C, for example at 0 °C.
• a compound of formula (IX) may be prepared by reacting a compound of formula (XII) wherein PG represents a protecting group (e.g. tert- butoxycarbonyl), with a compound of formula (VI) or a boronate ester thereof, in the presence of a catalyst such as bis[bis( 1,2- diphenylphosphino)ethane]palladium(0) or Pd(dppf)Ch ⁇ DCM and a base such as potassium carbonate or sodium carbonate.
• a catalyst such as bis[bis( 1,2- diphenylphosphino)ethane]palladium(0) or Pd(dppf)Ch ⁇ DCM
• a base such as potassium carbonate or sodium carbonate.
• the reaction is conveniently carried out in a solvent such as dioxane/water or ACN/water mixture at a temperature, for example, in the range from 20 °C to 100 °C, particularly at 80 °C.
• PG represents a protecting group (e.g. tert-butoxy carbonyl), with a compound of formula (VI) or an ester thereof, wherein R 1 is as defined in formula (I), in the presence of a catalyst such as Pd(dppf)Cl2 DCM or 1,1 Z>A(di-/e/7-butylphosphino)ferrocene palladium dichloride and a base such as potassium carbonate or sodium carbonate.
• a catalyst such as Pd(dppf)Cl2 DCM or 1,1 Z>A(di-/e/7-butylphosphino)ferrocene palladium dichloride and a base such as potassium carbonate or sodium carbonate.
• the reaction is conveniently carried out in a solvent such as dioxane/water mixture or ACN/water mixture at a temperature, for example, in the range from 20 °C to 100 °C, particularly at 75 °C, and thereafter reacting with a suitable reagent to remove the protecting group PG.
• a suitable reagent is formic acid.
• Compounds of formula (XV) may be prepared from compounds of formula (XII) using standard procedures for the dehydration of an amide, for example with Burgess reagent or a reagent such as TBTU or T3P with or without a base such as DiPEA, in a solvent such as DCM or DMF at a temperature in the range from -20 °C to 100 °C, for example at 25 °C.
• R 1 is as defined in formula (I), with a compound of formula (III), conveniently carried out in the presence of a base such as DiPEA or TEA and one or more activating agents such as EDCI, 2-pyridinol-l -oxide, or T3P, followed by a dehydrating reagent such as T3P.
• a base such as DiPEA or TEA
• activating agents such as EDCI, 2-pyridinol-l -oxide, or T3P
• T3P dehydrating reagent
• the reaction is conveniently carried out in an organic solvent such as DMF or DCM at a temperature, for example, in the range from 20 °C to 100 °C, in particular at ambient temperature (25 °C).
• Compounds of formula (XVI) can be prepared from reacting compounds of formula (VII) with compounds of formula (VI) or an ester thereof, wherein R 1 is as defined in formula (I), in the presence of a catalyst such as Pd(dppf)Cl2 ⁇ DCM or 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride and a base such as potassium carbonate or sodium carbonate.
• a catalyst such as Pd(dppf)Cl2 ⁇ DCM or 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride and a base such as potassium carbonate or sodium carbonate.
• the reaction is conveniently carried out in a solvent such as dioxane/water mixture or ACN/water mixture at a temperature, for example, in the range from 20 °C to 100 °C, particularly at 75 °C, followed by deprotection of PG.
• PG represents a protecting group (e.g. tert- butoxycarbonyl) is either commercially available, or may be prepared from a compound of formula (XVII),
• a compound of formula (XVII), wherein PG represents a protecting group (e.g. tert- butoxy carbonyl), may be prepared from a compound of formula (XVIII),
• a reducing agent for example BH3-DMS
• a solvent such as THF
• a compound of formula (XVIII), where PG represents a protecting group (e.g. tert- butoxycarbonyl), may be prepared from a compound of formula (XIX), using a biocatalytic transformation for chemoselective lactam formation, e.g., using a lipase such as Novozym 435, in a solvent such as an ether, e.g., dioxane, at a temperature in the range from 0 to 80 °C, for example at 55 °C, followed by conditions for introduction of the protecting group PG.
• a biocatalytic transformation for chemoselective lactam formation e.g., using a lipase such as Novozym 435
• a solvent such as an ether, e.g., dioxane
• a compound of formula (XIX) may be prepared from a compound of formula (XX),
• PG 1 and PG 2 are protecting groups (e.g., benzyl), using conditions for hydrogenation, for example using 3 ⁇ 4 (g), and a reagent such as palladium dihydroxide on carbon, in a solvent such as methanol or dioxane, under a pressure of for example 10 bar, at a temperature in the range from 25 to 80 °C, for example at 40 °C.
• protecting groups e.g., benzyl
• a reagent such as palladium dihydroxide on carbon
• a compound of formula (XX), wherein PG 1 and PG 2 are protecting groups (e.g., benzyl), may be prepared from a compound of formula (XXI),
• PG 1 and PG 2 are protecting groups (e.g. benzyl), using conditions for Oxa- Michael reaction, reacting with methyl propynoate, in presence of a base such as 4- methylmorpholine, in a solvent such as toluene, at a temperature in the range from 0 to 100 °C, for example at 25 °C.
• protecting groups e.g. benzyl
• a compound of formula (XXI), w wherein PG 1 and PG 2 are protecting groups (e.g. benzyl), may be prepared from reacting a diprotected benzyl amine (e.g., dibenzylamine) with fY)-methyl oxirane-2-carboxylate, in a solvent such as ethanol, at a temperature in the range from 0 to 78 °C, for example at 70 °C.
• PG represents a protecting group (e.g. tert- butoxycarbonyl) may be prepared from oxidation of a compound of formula (XXII),
• reagents such as TEMPO, and sodium hypochlorite, optionally in presence of a salt such as sodium bromide, in a solvent such as DCM/water, and in presence of a buffer such as NaHC03, and a phase transfer catalyst such as tetrabutylammonium bisulphate, at a temperature in the range from 0 to 100 °C, e.g., at 25 °C.
• a compound of formula (XXII), wherein PG represents a protecting group (e.g., tert- butoxy carbonyl) may be prepared from a compound of formula (XXIII),
• PG 1 and PG 2 are protecting groups (e.g. benzyl), reacting with a base such as sodium hydride, in a solvent such as THF, at a temperature in the range from 0 to 60 °C, e.g., 25 °C, followed by interconversion of protecting groups PG, PG 1 and PG 2 , as defined in formula (XXII) and (XXIII).
• a base such as sodium hydride
• a compound of formula (XXIII), wherein PG 1 and PG 2 are protecting groups (e.g., benzyl), may be prepared from reacting protected 3-aminopropanol (e.g. A-benzyl-3- aminopropanol) with (ri)-2-((benzyloxy)methyl)oxirane, in a solvent such as ethanol or propanol, at a temperature in the range from 0 to 70 °C, for example at 40 °C, followed by reacting the crude product with methanesulfonyl chloride, in prescence of a base such as DiPEA, in a solvent such as DCM, at a temperature in the range from -10 to 25 °C, e.g., -5 °C.
• protected 3-aminopropanol e.g. A-benzyl-3- aminopropanol
• (ri)-2-((benzyloxy)methyl)oxirane in a solvent such as ethanol or propanol
• a compound of formula (I) can be administered as a pharmaceutically acceptable salt.
• a pharmaceutically acceptable salt of a compound of formula (I) may be advantageous due to one or more of its chemical or physical properties, such as stability in differing temperatures and humidities, or a desirable solubility in 3 ⁇ 4(), oil, or other solvent.
• a salt may be used to aid in the isolation or purification of the compound of formula (I).
• pharmaceutically acceptable salts include, but are not limited to, an alkali metal salt, e.g., Na or K, an alkali earth metal salt, e.g., Ca or Mg, or an organic amine salt.
• pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts.
• the compounds of formula (I) may form mixtures of its salt and co-crystal forms. It is also to be understood that the methods provided herein can employ such salt/co-crystal mixtures of the compound of formula (I).
• Salts and co-crystals may be characterized using well known techniques, for example X-ray powder diffraction, single crystal X-ray diffraction (for example to evaluate proton position, bond lengths or bond angles), solid state NMR, (to evaluate for example, C, N or P chemical shifts) or spectroscopic techniques (to measure for example, O-H, N-H or COOH signals and IR peak shifts resulting from hydrogen bonding).
• X-ray powder diffraction for example to evaluate proton position, bond lengths or bond angles
• solid state NMR to evaluate for example, C, N or P chemical shifts
• spectroscopic techniques to measure for example, O-H, N-H or COOH signals and IR peak shifts resulting from hydrogen bonding.
• certain compounds of formula (I) may exist in solvated form, e.g., hydrates, including solvates of a pharmaceutically acceptable salt of a compound of formula (I).
• certain compounds of formula (I) may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. It is to be understood that the present disclosure encompasses all such isomeric forms.
• Certain compounds of formula (I) may also contain linkages (e.g., carbon-carbon bonds, carbon- nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring bond or double bond.
• Certain compound of formula (I) may also contain multiple tautomeric forms. It is to be understood that the present disclosure encompasses all such tautomeric forms. Stereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallization, or the stereoisomers may be made by stereoselective synthesis.
• the compounds of formula (I) encompasses any isotopically-labeled (or“radio-labelled”) derivatives of a compound of formula (I).
• a derivative is a derivative of a compound of formula (I) wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
• radionuclides examples include 2 H (also written as“D” for deuterium).
• a compound of formula (I) is provided where one or more hydrogen atoms are replaced by one or more deuterium atoms; and the deuterated compound is used in one of the methods provided herein for treating LN.
• the compounds of formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the formula (I).
• prodrugs include in vivo hydrolysable esters of a compound of the formula (I).
• An in vivo hydrolysable (or cleavable) ester of a compound of the formula (I) that contains a carboxy or a hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the parent acid or alcohol.
• ester prodrugs derivatives see: Curr. Drug. Metab. 2003, 4, 461, incorporated by reference herein in its entirety for all purposes.
• Various other forms of prodrugs are known in the art, and can be used in the methods provided herein. For examples of prodrug derivatives, see: Nature Reviews Drug Discovery 2008, 7, 255, the disclosure of which is incorporated by reference herein in its entirety for all purposes.
• INS1007 as a potential treatment for LN was assessed. 10-11 week old female New Zealand Black / New Zealand White Fl (NZB/WFl) mice (Jackson Laboratory) were subjected to a single injection of an adenovirus expressing IFNa5 (Ad-IFNa5, BioXcell, cat#BE0241. clone AR1-5A3) to accelerate the clinical manifestations of LN.
• Figure 1 provides a schematic overview of the study design.
• Treatment groups and dosing schedule are provided in Table 1. The duration of the study was 8 weeks from Ad-IFNa5 injection.
• Urine and blood collection was carried out at baseline (immediately after Ad-IFNa5 injection), and at weeks 2, 4, 6 and 8.
• Total protein (by chemstick), albumin (by ELISA) and creatinine (by a colorimetric assay kit) was measured in urine and blood urea nitrogen (BUN) was measured in plasma.
• BUN (mg/dL) levels 6 weeks after model induction are reported at Figure 4.
• the data demonstrate that BUN levels decreased in animals treated with INS 1007 in a dose dependent matter (Figure 4). Lower BUN levels are correlated with increased kidney function.
• the right kidneys of each animal were used for FACS analysis. Right kidneys were digested and subjected to Percoll centrifugation, fixable-viability-dye and surface staining for the following markers: CD45, CD3, CDl lb, F4/80, Ly6G and Ly6C. Results of FACS are provided at Figures 7-13.
• the figures shows INS 1007 significantly decreased a variety of immune cells, including myelocytes, Ly6C + monocyte, Ly6C + macrophages and T cells, which might possibly have played a pro-inflammatory role in nephritis pathogenesis.

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