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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • 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
  • A61P5/00—Drugs for disorders of the endocrine system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/20—Spiro-condensed systems
• • 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

• MC2R MODULATOR COMPOUNDS This application relates to novel compounds and their use as melanocortin subtype-2 receptor (MC2R) antagonists. Compounds described herein may be useful in the treatment or prevention of diseases in which MC2R is involved. This application is also directed to pharmaceutical compositions comprising these compounds and the manufacture and use of these compounds and compositions in the prevention or treatment of such diseases in which MC2R is involved.
• Adenocorticotropic hormone is a 39-amino acid peptide implicated in the regulation of adrenal glucocorticoid synthesis and secretion within the hypothalamic-pituitary-adrenal (HPA) axis, and as such, plays a primary role in regulation of stress responses.
• ACTH is synthesized by corticotropic cells in the anterior pituitary via proteolytic cleavage of proopiomelanocortin (POMC). Upon stressful stimuli, ACTH is secreted and acts at the melanocortin 2 receptor (MC2R) in adrenal glands to regulate synthesis and secretion of glucocorticoids and androgens.
• M2R melanocortin 2 receptor
• the secretion of glucocorticoids provides negative feedback to both hypothalamus and anterior pituitary to reduce production and secretion of corticotropic releasing hormone (CRH) and ACTH respectively – thereby providing a fine balance in regulating stress responses.
• CHL corticotropic releasing hormone
• ACTH corticotropic releasing hormone
• Diseases linked to ACTH dysfunction range from Cushing’s disease to congenital adrenal hyperplasia and polycystic ovarian syndrome (PCOS) (Microsc. Res. Tech.61, 275–287 (2003)).
• the MC2R belongs to the melanocortin family of G protein-coupled receptors (GPCRs), of which there are five subtypes - MC1R, MC2R, MC3R, MC4R and MC5R.
• GPCRs G protein-coupled receptors
• MC1R is associated with pigmentation regulation, MC2R with glucocorticoid synthesis, MC3R and MC4R with energy homeostasis and MC5R with exocrine gland physiology.
• MC2R is selectively activated by ACTH, while the remaining receptor subtypes also bind the melanocortin peptides ⁇ -, ⁇ -, and ⁇ - melanocyte-stimulating hormone ( ⁇ -MSH, ⁇ -MSH, and ⁇ -MSH) (Am. J. Physiol. Endocrinol. Metab.284, E468-74 (2003); Life Sci.59, 797–801 (1996)).
• MRAP melanocortin 2 receptor protein
• MRAP is a single transmembrane protein which forms an antiparallel homodimer with MC2R to allow trafficking of the receptor to the plasma membrane (Proc. Natl. Acad. Sci. 104, 20244 LP – 20249 (2007))
• Binding of ACTH to the MC2R/MRAP complex in adrenal cortical cells activates cAMP production via the G s signalling pathway. Increases in intracellular cAMP in turn stimulates cortisol synthesis and secretion (Microsc. Res.
• CAH Congenital adrenal hyperplasia
• CYP21A2 the most common form
• HSD3B2 3 ⁇ -hydroxysteroid dehydrogenase
• CYP11B1 11 ⁇ - hydroxylase
• PCOS polycystic ovary syndrome
• inhibitors with longer residence times offer the advantage of insurmountable antagonism, whereby receptor inhibition remains in the face of high ACTH concentrations.
• a means of achieving these favourable drug properties involves developing a compound with slow dissociation (k off ) kinetics (Neurochemistry international 2007, 51(5), 254–260). This has been demonstrated at various targets, ranging from fevipiprant at the DP2 receptor to NK 1 neurokinin receptor antagonists (Mol Pharmacol 2016, 89(5), 593-605; The Journal of pharmacology and experimental therapeutics 2007, 322(3), 1286–1293).
• the present invention provides compounds having activity as melanocortin subtype-2 receptor (MC2R) antagonists.
• a compound of Formula (1) or a salt thereof, wherein; J is N or CH; X is -CO-, -CH 2 - or -CH 2 CH 2 -; Z is a bond, -CH 2 - or -CO-; L 1 is -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or -CO(CH 2 ) n -, where n is 0-5; R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; R 2 is H, CO 2 H, OH
• Compounds of the present invention may be used as melanocortin subtype-2 receptor (MC2R) modulators.
• Compounds of the present invention may be used as MC2R inhibitors.
• Compounds of the present invention may be used as MC2R antagonists.
• Compounds of the present invention may be used as MC2R antagonists with a long residence time at the receptor.
• Compounds of the present invention may be used in the treatment of a disease or disorder associated with MC2R.
• Compounds of the present invention may be used in the treatment of a disease or disorder that would benefit from the modulation of MC2R activity.
• Compounds of the present invention may be used in the manufacture of medicaments.
• the compounds or medicaments may be for use in treating, preventing, ameliorating, controlling or reducing the risk of diseases or disorders in which MC2R is involved.
• Compounds of the present invention may be for use as a single agent or in combination with one or more additional pharmaceutical agents.
• Compounds of the present invention may be useful in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome (or ectopic Cushing’s syndrome), polycystic ovary syndrome (PCOS), depressive illness, septic shock, and disorders or symptoms related thereto.
• CAH congenital adrenal hyperplasia
• PCOS polycystic ovary syndrome
• depressive illness septic shock
• disorders or symptoms related thereto DETAILED DESCRIPTION OF THE INVENTION
• the invention relates to novel compounds.
• the invention also relates to the use of novel compounds as modulators of the melanocortin subtype-2 receptor (MC2R), in particular as MC2R antagonists.
• M2R melanocortin subtype-2 receptor
• the invention further relates to novel compounds as MC2R anatagonists which have a long residence time at the receptor.
• the invention further relates to the use of novel compounds in the manufacture of medicaments for use as MC2R antagonists.
• the invention further relates to compounds, compositions and medicaments that may be useful in the treatment of a disease or disorder characterised by activation of the MC2R receptor.
• a compound of formula (1) or a salt thereof, wherein; J is N or CH; X is -CO-, -CH 2 - or -CH 2 CH 2 -; Z is a bond, -CH 2 - or -CO-; L 1 is -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or -CO(CH 2 ) n -, where n is 0-5; R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH2C3-4cycloalkyl optionally substituted with 1-3 fluorine atoms; R 2 is H, CO 2 H, OH, NR 2a R 2b , CONR 2a R 2b , SO 2 NR 2a R 2b ,
• a compound of Formula (1) or a salt thereof, wherein; J is N or CH; X is -CO-, -CH 2 - or -CH 2 CH 2 -; Z is a bond, -CH 2 - or -CO-; L 1 is -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or -CO(CH 2 ) n -, where n is 0-5; R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; R 2 is H, CO 2 H, OH, NR 2a R 2b , CONR 2a R 2b , SO 2 NR 2a R 2b ,
• a compound of Formula (1) or a salt thereof, wherein; J is N or CH; X is -CO-, -CH 2 - or -CH 2 CH 2 -; Z is a bond, -CH2- or -CO-; L 1 is -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or -CO(CH 2 ) n -, where n is 0-5; R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; R 2 is H, CO 2 H, OH, NR 2a R 2b , CONR 2a R 2b , SO 2 NR 2a R 2b , a
• a compound of Formula (1) or a salt thereof, wherein; J is N or CH; X is -CO-, -CH 2 - or -CH 2 CH 2 -; Z is a bond, -CH 2 - or -CO-; L 1 is -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or -CO(CH 2 ) n -, where n is 0-5; R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; R 2 is H, CO 2 H, OH, NR 2a R 2b , CONR 2a R 2b , SO 2 NR 2a R 2b ,
• a compound of Formula (1) or a salt thereof, wherein; J is N or CH; X is -CO-, -CH 2 - or -CH 2 CH 2 -; Z is a bond, -CH2- or -CO-; L 1 is -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or -CO(CH 2 ) n -, where n is 0-5; R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; R 2 is H, CO 2 H, OH, NR 2a R 2b , CONR 2a R 2b , SO 2 NR 2a R 2b , a
• a compound of Formula (1) or a salt thereof, wherein; J is N or CH; X is -CO-, -CH 2 - or -CH 2 CH 2 -; Z is a bond, -CH 2 - or -CO-; L 1 is -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or -CO(CH 2 ) n -, where n is 0-5; R 1 is C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; R 2 is H, OH, NR 2a R 2b , CONR 2a R 2b , SO 2 NR 2a R 2b , a 3-6
• J can be N or CH. J can be N. J can be CH.
• X can be -CO-, -CH 2 - or -CH 2 CH 2 -. X can be -CO- or -CH 2 -. X can be - CO-. X can be -CH 2 -. X can be -CH 2 CH 2 -.
• Z can be a bond, -CH 2 - or -CO-. Z can be -CH 2 - or -CO-. Z can be - CH 2 -. Z can be -CO-. Z can be a bond.
• R 1 can be C 1-4 alkyl optionally substituted with 1-3 fluorine atoms, C 3- 4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms.
• R 1 can be C 1-4 alkyl optionally substituted with 1-3 fluorine atoms.
• R 1 can be C 1-4 alkyl.
• R 1 can be methyl or ethyl.
• R 1 can be methyl.
• R 1 can be ethyl.
• R 1 can be perdeuteroethyl.
• R 1 can be -CD 2 CD 3 .
• R 1 can be trideuteromethyl.
• R 1 can be -CD 3 .
• L 1 can be -(CH 2 ) n -, -(CH 2 ) n CONH-, -(CH 2 ) n COO-, -CO(CH 2 ) n NH- or - CO(CH 2 ) n -, where n is 0-5.
• L 1 can be a bond, -CH 2 CH 2 CONH-, -COO-, -CH 2 CH 2 COO-, - CH 2 CH 2 CO-, -COCH 2 NH-, -COCH 2 CH 2 NH-, -CO-, -COCH 2 -, -CH 2 CH 2 - or -CH 2 -.
• L 1 can be a bond.
• R 2 can be H, CO 2 H, OH, NR 2a R 2b , CONR 2a R 2b , SO 2 NR 2a R 2b , a 3-6 membered carbocyclic or heterocyclic ring which is optionally substituted with R 10 , R 11 and R 12 , or a 7-10 membered bicyclic or heterobicyclic ring system which is optionally substituted with R 10 , R 11 and R 12 .
• R 2 can be H, a 3-6 membered carbocyclic or heterocyclic ring which is optionally substituted with R 10 , R 11 and R 12 , or a 7-10 membered bicyclic or heterobicyclic ring system which is optionally substituted with R 10 , R 11 and R 12 .
• R 2 can be H, a piperidine ring which is optionally substituted with R 10 , R 11 and R 12 , a pyrrolidine ring which is optionally substituted with R 10 , R 11 and R 12 , an azetidine ring which is optionally substituted with R 10 , R 11 and R 12 , a hexahydro-1H- pyrrolizine ring system which is optionally substituted with R 10 , R 11 and R 12 , a 2-pyrrolidone ring which is optionally substituted with R 10 , R 11 and R 12 , a 1-azabicyclo[2.2.2]octane ring system which is optionally substituted with R 10 , R 11 and R 12 , a tetrahydrofuran ring which is optionally substituted with R 10 , R 11 and R 12 or a morpholine ring which is optionally substituted with R 10 , R 11 and R 12 .
• R 2a and R 2b can independently be H or C 1-3 alkyl optionally substituted with 1-3 fluorine atoms.
• R 2a and R 2b can independently be H or C 1-3 alkyl.
• R 2a and R 2b can independently be H or methyl.
• R 2a and R 2b can both be H.
• R 2a can be H or C 1-3 alkyl optionally substituted with 1-3 fluorine atoms.
• R 2a can be H or C 1-3 alkyl.
• R 2a can be H or methyl.
• R 2a can be H.
• R 2b can be H or C 1-3 alkyl optionally substituted with 1-3 fluorine atoms.
• R 2b can be H or C 1-3 alkyl.
• R 2b can be H or methyl.
• R 2b can be H.
• R 10 , R 11 and R 12 can be independently selected from H, OH, oxo, halo, C 1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO 2 NH 2 , OSO 2 OH, OSO 2 F, B(OH) 2 , Bpin, -(CH 2 ) g NR 13 R 14 , -CH 2 (CH 2 ) g (OCH 2 CH 2 O) y R 13 , -(CH 2 ) g CO 2 R 13 and -(CH 2 ) g CONR 13 R 14 , where g is 0-3 and y is 1-3.
• R 10 , R 11 and R 12 can be independently selected from H, OH, CH 2 CH 2 OH, CH 2 NH 2 and CH 2 CH 2 OCH 2 CH 2 OCH 3 .
• R 10 can be selected from H, OH, oxo, halo, C 1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO 2 NH 2 , OSO 2 OH, OSO 2 F, B(OH) 2 , Bpin, -(CH 2 ) g NR 13 R 14 , -CH 2 (CH 2 ) g (OCH 2 CH 2 O) y R 13 , -(CH2)gCO2R 13 and -(CH2)gCONR 13 R 14 , where g is 0-3 and y is 1-3.
• R 10 can be selected from H, OH, CH 2 CH 2 OH, CH 2 NH 2 and CH 2 CH 2 OCH 2 CH 2 OCH 3 .
• R 10 can be H.
• R 10 can be OH.
• R 10 can be CH 2 CH 2 OH.
• R 10 can be CH 2 NH 2 .
• R 10 can be CH 2 CH 2 OCH 2 CH 2 OCH 3 .
• R 11 can be selected from H, OH, oxo, halo, C 1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO 2 NH 2 , OSO 2 OH, OSO 2 F, B(OH) 2 , Bpin, -(CH 2 ) g NR 13 R 14 , -CH 2 (CH 2 ) g (OCH 2 CH 2 O) y R 13 , -(CH 2 ) g CO 2 R 13 and -(CH 2 ) g CONR 13 R 14 , where g is 0-3 and y is 1-3.
• R 11 can be selected from H, OH, CH 2 CH 2 OH, CH 2 NH 2 and CH 2 CH 2 OCH 2 CH 2 OCH 3 .
• R 11 can be H.
• R 11 can be OH.
• R 11 can be CH 2 CH 2 OH.
• R 11 can be CH 2 NH 2 .
• R 11 can be CH 2 CH 2 OCH 2 CH 2 OCH 3 .
• R 12 can be selected from H, OH, oxo, halo, C 1-3 alkyl optionally substituted with OH or 1-3 fluorine atoms, SO 2 NH 2 , OSO 2 OH, OSO 2 F, B(OH) 2 , Bpin, -(CH 2 ) g NR 13 R 14 , -CH 2 (CH 2 ) g (OCH 2 CH 2 O) y R 13 , -(CH 2 ) g CO 2 R 13 and -(CH 2 ) g CONR 13 R 14 , where g is 0-3 and y is 1-3.
• R 12 can be selected from H, OH, CH2CH2OH, CH2NH2 and CH2CH2OCH2CH2OCH3.
• R 12 can be H.
• R 12 can be OH.
• R 12 can be CH 2 CH 2 OH.
• R 12 can be CH 2 NH 2 .
• R 12 can be CH 2 CH 2 OCH 2 CH 2 OCH 3 .
• R 13 and R 14 can independently be H or methyl.
• R 13 can be H or methyl.
• R 14 can be H or methyl.
• R 13 can be H.
• R 13 can be methyl.
• R 14 can be H. R 14 can be methyl.
• R 2 can be selected from:
• the moiety -L 1 -R 2 can be selected from:
• R 3 can be H, C 1-3 alkyl optionally substituted with 1-3 fluorine atoms, C 3- 4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; or R 3 can be joined to R 3a to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms.
• R 3 can be H or C 1-3 alkyl optionally substituted with 1-3 fluorine atoms.
• R 3 can be H or C 1-3 alkyl.
• R 3 can be H, methyl or ethyl.
• R 3a can be H or can be joined to R 3 to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms.
• R 3b can be H, C 1-3 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms; or R 3b can be joined to R 3c to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms.
• R 3b can be H or C 1-3 alkyl optionally substituted with 1-3 fluorine atoms.
• R 3b can be H or C 1-3 alkyl.
• R 3b can be H, methyl or ethyl.
• R 3c can be H or can be joined to R 3b to form a cyclopropyl or cyclobutyl ring either of which may be optionally substituted with 1-3 fluorine atoms.
• one or both of R 3 and R 3b is H.
• the structure of Formula (1) as defined herein can be effectively viewed as the scope of Formula (1’) and (1’’) taken together: All of R 3 , R 3a , R 3b and R 3c can be H.
• R 3 and R 3b can be C 1-3 alkyl optionally substituted with 1-3 fluorine atoms, C 3-4 cycloalkyl optionally substituted with 1-3 fluorine atoms or CH 2 C 3- 4cycloalkyl optionally substituted with 1-3 fluorine atoms and the other H.
• One of R 3 and R 3b can be methyl or ethyl and the other H.
• One of R 3 and R 3b can be methyl and the other H.
• One of R 3 and R 3b can be ethyl and the other H.
• L 2 can be a bond or -CO- and R 4 can be a group: Q 5 Q 9 ; wherein Q 5 is CR 5 or N; Q 6 is CR 6 or N; Q 7 is CR 7 or N; Q 8 is CR 8 or N; and Q 9 is CR 9 or N; where one, two or none of Q 5 , Q 6 , Q 7 , Q 8 and Q 9 is N; or L 2 can be -CO- and R 4 can be -(CH 2 ) q NH 2 , where q is 0-3.
• L 2 can be a bond or -CO- and R 4 can be a group selected from: or L 2 can be -CO- and R 4 can be -(CH 2 ) q NH 2 , where q is 0-3.
• L 2 can be a bond or -CO- and R 4 can be a group selected from: ; ; and ; or L 2 can be -CO- and R 4 can be -(CH 2 ) q NH 2 , where q is 0-3.
• L 2 can be a bond or -CO- and R 4 can be a group: ; wherein Q 5 is CR 5 or N; Q 6 is CR 6 or N; Q 7 is CR 7 or N; Q 8 is CR 8 or N; and Q 9 is CR 9 or N; where one, two or none of Q 5 , Q 6 , Q 7 , Q 8 and Q 9 is N.
• L 2 can be a bond or -CO- and R 4 can be a group: ; wherein Q 5 is CR 5 or N; Q 6 is CR 6 or N; Q 7 is CR 7 or N; Q 8 is CR 8 or N; and Q 9 is CR 9 or N; where one of Q 5 , Q 6 , Q 7 , Q 8 and Q 9 is N.
• L 2 can be a bond or -CO- and R 4 can be a group: ; wherein Q 5 is CR 5 or N; Q 6 is CR 6 or N; Q 7 is CR 7 or N; Q 8 is CR 8 or N; and Q 9 is CR 9 or N; where two of Q 5 , Q 6 , Q 7 , Q 8 and Q 9 are N.
• L 2 can be a bond or -CO- and R 4 can be a group: L 2 can be a bond or -CO- and R 4 can be a group selected from: L 2 can be a bond or -CO- and R 4 can be a group selected from: L 2 can be -CO- and R 4 can be -(CH 2 ) q NH 2 , where q is 0-3.
• R 5 , R 6 , R 7 , R 8 , and R 9 can be independently selected from H, halo, CN, NR 15 R 16 , C 1-3 alkyl optionally substituted with 1-3 fluorine atoms, OC 1-3 alkyl optionally substituted with 1-3 fluorine atoms, OCH 2 cyclopropyl optionally substituted with 1-3 fluorine atoms, OCH 2 CN and SO 2 Me.
• R 15 and R 16 can independently be H or C 1-3 alkyl.
• R 15 and R 16 can independently be H, methyl, ethyl, n-propyl or isopropyl.
• R 5 , R 6 , R 7 , R 8 , and R 9 can be independently selected from H, Cl, F, I, CN, CF3, CF2H, -OMe, - OEt, -O n Pr, -N(CH 3 )(CH 2 CH 2 CH 3 ), -N(CH 3 ) 2 , -OCH 2 CN, -OCH 2 cyclopropyl, -CO 2 H and -SO 2 Me.
• L 2 can be a bond or -CO- and R 4 can be a group selected from: .
• L 2 can be -CO- and R 4 can be -(CH 2 ) q NH 2 , where q is 0-3.
• L 2 can be -CO- and R 4 can be selected from: ; NH2 .
• R 4 can be a group selected from: C
• L 1 and L 2 are provided without limitation to a particular orientation with respect to the rest of the molecule. As such L 1 and L 2 definitions provided include all possible orientations unless stated otherwise.
• L 1 is defined as -CONH- both of the following may be included: .
• the compound can be a compound of Formula (1’) or (1’’): 1’); (1’’); or a salt thereof, wherein J, X, Z, L 1 , L 2 , R 1 , R 2 , R 3 , R 3a , R 3b , R 3c and R 4 are as defined herein.
• the compound can be a compound of Formula (1’’’), (1’’’’), (1’’’’’), (1’’’’’), (1’’’’’’), (1’’’’’’) or (1’’’’’’): or a salt thereof, wherein J, X, Z, L 1 , L 2 , R 1 , R 2 , R 3 and R 4 are as defined herein.
• the compound can be a compound of Formula (2a) or (2b): (2b); or a salt thereof, wherein X, Z, L 1 , R 2 , R 3 and R 4 are as defined herein.
• the compound can be a compound of Formula (2aD) or (2bD): 4 D (2bD); or a salt thereof, wherein X, Z, L 1 , R 2 , R 3 and R 4 are as defined herein.
• the compound can be a compound of Formula or a salt thereof, wherein X, Z, L 1 , R 2 and R 4 are as defined herein.
• the compound can be a compound of Formula (2aii), (2aiii), (2aiv), (2bii), (2biii) or (2biiv): or a salt thereof, wherein X, Z, L 1 , R 2 , R 3 and R 4 are as defined herein.
• the compound can be a compound of Formula (2av), (2avi), (2avii), (2bv), (2bvi) or (2bvii): or a salt thereof, wherein X, Z, L 1 , R 2 , R 3 and R 4 are as defined herein.
• the compound can be a compound of Formula (3a), (3b), (3c), (3d), (3e) or (3f):
• the compound can be a compound of Formula (3ai), (3bi), (3ci), (3di), (3ei) or (3fi): or a salt thereof, wherein L 1 , R 2 , R 3 and R 4 are as defined herein.
• the compound can be a compound of Formula (3aii), (3bii), (3cii), (3dii), (3eii) or (3fii): or a salt thereof, wherein L 1 , R 2 , R 3 and R 4 are as defined herein.
• the compound can be a compound of Formula (3aiii), (3biii), (3ciii), (3diii), (3eiii) or (3fiii): or a salt thereof, wherein L 1 , R 2 , R 3 and R 4 are as defined herein.
• the compound can be a compound of Formula (3aiv), (3biv), (3civ), (3div), (3eiv) or (3fiv): or a salt thereof, wherein L 1 , R 2 , R 3 and R 4 are as defined herein.
• the compound can be a compound of Formula (3av), (3bv), (3cv), (3dv), (3ev) or (3fv):
• the compound can be a compound of Formula (5a) or (5b): or a salt thereof, wherein L 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined herein.
• the compound can be a compound of Formula (6a), (6b), (6c), (6d), (6e), (6f), (6g) or (6h):
• the compound can be a compound of Formula (9a), (9b), (9c), (9d), (9e) or (9f):
• the compound can be selected from any one of Examples 1 to 218 as shown in Table 1a or a salt thereof.
• the compound can be selected from the group consisting of: 1 '-[4-chloro-2-(trifluoromethyl)benzoyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7- n aphthyridine-5,4'-piperidine]-8-one; 1 '-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7- n aphthyridine-5,4'-piperidine]-8-one; 1 '-[3-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-
• the salt thereof can be a pharmaceutically acceptable salt.
• the salt thereof can be a formate salt, a trifluoroacetic acid (TFA) salt, a mesylate salt or a hydrochloride (HCl) salt.
• the salt thereof can be a formate salt or a trifluoroacetic acid (TFA) salt.
• the compound can be a salt selected from the group consisting of: 1 '-[4-chloro-3-(trifluoromethyl)pyridin-2-yl]-2-(2-ethoxypyridin-3-yl)-7-pyrrolidin-3-ylspiro[6H- 1 ,7-naphthyridine-5,4'-piperidine]-8-one formate salt; ( S)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidin-3-yl)-7',8'- d ihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-6'-one formate salt; ( R)-1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidin-3-
• Further embodiments of the invention include the use of a compound of Formula (1) or a salt thereof or a pharmaceutical composition comprising a compound of Formula (1) in medicine. Also included is the use of a compound of Formula (1) or a salt thereof or a pharmaceutical composition comprising a compound of Formula (1) as a melanocortin subtype-2 receptor (MC2R) modulator.
• M2R melanocortin subtype-2 receptor
• Compounds of the present invention may be used as MC2R receptor modulators.
• Compounds of the present invention may be used as MC2R receptor inhibitors or antagonists.
• Compounds of the present invention may be used in the treatment of a disease or disorder characterised by activation of MC2R.
• Compounds of the present invention may be used in the treatment of a disease or disorder associated with MC2R or in the treatment of a disease or disorder that would benefit from the modulation of MC2R activity.
• Compounds of the present invention may be used in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS) depressive illness, septic shock and disorders or symptoms related thereto.
• CAH congenital adrenal hyperplasia
• PCOS polycystic ovary syndrome
• compounds and compositions detailed herein are used as modulators of MC2R.
• Provided herein is a method of treating a disease in an individual comprising administering an effective amount of a compound of Formula (1) or any embodiment, variation or aspect thereof.
• MC2R modulators as disclosed herein can be useful as a prophylactic or therapeutic agent for MC2R associated diseases.
• a compound or salt thereof described herein or a composition described herein may be used in a method of treating Cushing’s disease in an individual.
• combinations comprising a compound of the present invention and a Corticotropin-releasing factor receptor-1 (CRF 1 ) antagonist.
• CRF 1 Corticotropin-releasing factor receptor-1
• the CRF 1 antagonist may be selected from the group consisting of tildacerfont, crinecerfont, NBI-27914, CP-316,311, NBI-462000, DMP696, pexacerfont, NBI-35965, ONO-2333Ms, antalarmin, NBI- 34041, DMP904, NBI-30775, SSR125543, NBI-77860, GSK876008, CRA5626/JNJ19567470/R317573, NBI-76169, verucerfont, and CP-154,526.
• the CRF 1 antagonist may be selected from: .
• combinations comprising a compound of the present invention and an ACTH antibody.
• the ACTH antibody may be ALD1613 (Feldhaus et al. Endocrinology, Jan 2017, 158(1): 1-8).
• the combinations may be used in the treatment of congenital adrenal hyperplasia (CAH), Cushing’s disease, ectopic ACTH syndrome, polycystic ovary syndrome (PCOS) depressive illness, septic shock and disorders or symptoms related thereto.
• CAH congenital adrenal hyperplasia
• PCOS polycystic ovary syndrome
• septic shock and disorders or symptoms related thereto are also provided herein are uses of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament.
• the manufacture of a medicament is for the treatment of a disorder or disease described herein.
• the manufacture of a medicament is for the prevention and/or treatment of a disorder or disease mediated by MC2R.
• a compound or salt thereof described herein or a composition described herein may be used in a method as either a stand-alone therapy, or as a conjunctive therapy with other agents that are either palliative (e.g., agents that relieve the symptoms of the disorder to be treated), and/or agents that target the etiology of the disorder.
• Compounds or compositions of the present invention may be used or administered in combination with a second therapeutic agent.
• a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent are sequentially administered, concurrently administered or simultaneously administered.
• a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent are administered with a time separation of about 15 minutes or less, such as about any of 10, 5, or 1 minutes or less.
• a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein and (b) an agent are administered with a time separation of about 15 minutes or more, such as about any of 20, 30, 40, 50, 60, or more minutes.
• M2R modulator refers to any compound which binds to and modulates the function of MC2 receptors.
• modulator should be interpreted to include modulation by modalities including, but not limited to antagonists.
• treatment in relation to the uses of any of the compounds described herein, including those of Formula (1) is used to describe any form of intervention where a compound is administered to a subject suffering from, or at risk of suffering from, or potentially at risk of suffering from the disease or disorder in question.
• treatment covers both preventative (prophylactic) treatment and treatment where measurable or detectable symptoms of the disease or disorder are being displayed.
• effective therapeutic amount refers to an amount of the compound which is effective to produce a desired therapeutic effect. For example, if the condition is pain, then the effective therapeutic amount is an amount sufficient to provide a desired level of pain relief.
• the desired level of pain relief may be, for example, complete removal of the pain or a reduction in the severity of the pain.
• Chemical terms are all used in their conventional sense (e.g. as defined in the IUPAC Gold Book), unless indicated otherwise.
• alkyl as used herein, means straight or branched chain, saturated alkyl groups.
• cycloalkyl as used herein, means a saturated carbocyclic group containing the indicated number of carbon atoms.
• carbocyclic ring as used herein, means a saturated or unsaturated carbocyclic group containing the indicated number of carbon atoms.
• heterocyclic ring refers to a saturated or unsaturated ring containing the indicated number of total ring member atoms in which one or more of the ring members is a heteroatom selected from O, S and N, and oxidised forms thereof and the remaining atoms are C.
• bicyclic as used herein, means a saturated or unsaturated ring system comprising two joined rings and containing the indicated number of atoms in total. All possible modes of ring junction are included (including spirocyclic, fused and bridged).
• heterocyclic as used herein, means a saturated or unsaturated heterocyclic ring system comprising two joined rings and containing the indicated number of atoms in total.
• C n1-n2 The number of carbon atoms that are possible in the referenced groups herein may be indicated by subscript "C n1-n2 ”.
• C 1-3 alkyl represents an alkyl group having 1, 2 or 3 carbon atoms and includes methyl, ethyl, n-propyl and iso-propyl.
• optionally substituted as applied to any group means that the said group may if desired be substituted with one or more substituents, which may be the same or different.
• the term “optionally substituted with 1-6 fluorine atoms” as applied to a group means that the said group may if desired be substituted with 1, 2, 3, 4, 5 or 6 fluorine atoms.
• the present invention extends to all optical isomers of such compounds, whether in the form of racemates or resolved enantiomers.
• the invention described herein relates to all crystal forms, solvates and hydrates of any of the disclosed compounds however so prepared.
• any of the compounds disclosed herein have acid or basic centres such as carboxylates or amino groups, then all salt forms of said compounds are included herein. In the case of pharmaceutical uses, the salt should be seen as being a pharmaceutically acceptable salt.
• Salts or pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts.
• Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze- drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
• Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, potassium and calcium.
• Examples of acid addition salts include acid addition salts formed with acetic, 2,2-dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g. benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1,5- disulfonic and p-toluenesulfonic), ascorbic (e.g.
• D-glucuronic D-glucuronic
• glutamic e.g. L-glutamic
• ⁇ - oxoglutaric glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic
• lactic e.g. (+)-L- lactic and ( ⁇ )-DL-lactic
• lactobionic maleic, malic (e.g.
• Preferred solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent).
• a non-toxic pharmaceutically acceptable solvent referred to below as the solvating solvent.
• solvents include water, alcohols (such as ethanol, isopropanol and butanol) and DMSO.
• Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray crystallography.
• TGA thermogravimetric analysis
• DSC differential scanning calorimetry
• X-ray crystallography X-ray crystallography
• compositions may take the form, for example, of tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations.
• the compounds of the invention may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element.
• a reference to hydrogen includes within its scope 1 H, 2 H (D), and 3 H (T).
• references to carbon and oxygen include within their scope respectively 12 C, 13 C and 14 C and 16 O and 18 O.
• a reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise.
• a reference to an alkyl group such as an ethyl group or an alkoxy group such as a methoxy group also covers variations in which one or more of the hydrogen atoms in the group is in the form of a deuterium or tritium isotope, e.g. as in an ethyl group in which all five hydrogen atoms are in the deuterium isotopic form (a perdeuteroethyl group) or a methoxy group in which all three hydrogen atoms are in the deuterium isotopic form (a trideuteromethoxy group).
• the daily dose range may be from about 10 ⁇ g to about 30 mg per kg body weight of a human and non-human animal, preferably from about 50 ⁇ g to about 30 mg per kg of body weight of a human and non-human animal, for example from about 50 ⁇ g to about 10 mg per kg of body weight of a human and non-human animal, for example from about 100 ⁇ g to about 30 mg per kg of body weight of a human and non-human animal, for example from about 100 ⁇ g to about 10 mg per kg of body weight of a human and non-human animal and most preferably from about 100 ⁇ g to about 1 mg per kg of body weight of a human and non-human animal.
• PHARMACEUTICAL FORMULATIONS While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation). Accordingly, in some embodiments of the invention, there is provided a pharmaceutical composition comprising at least one compound of Formula (1) as defined above together with at least one pharmaceutically acceptable excipient.
• the pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g.
• a solid, liquid or semi-solid carrier e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents
• diluents e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents
• granulating agents binders, flow aids, coating agents, release-controlling agents (e.g. release retarding or delaying polymers or waxes), binding agents, disintegrants, buffering agents, lubricants, preservatives, anti-fungal and antibacterial agents, antioxidants, tonicity-adjusting agents, thickening agents, flavouring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions.
• diluents e.g solid diluents such as fillers or bulking agents; and liquid diluents
• pharmaceutically acceptable means compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
• Pharmaceutical compositions containing compounds of the Formula (1) can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
• compositions can be in any form suitable for oral, parenteral, intravenous, intramuscular, intrathecal, subcutaneous, topical, intranasal, intrabronchial, sublingual, buccal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration.
• Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.
• the composition may be a tablet composition or a capsule composition.
• Tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch.
• Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g.
• swellable crosslinked polymers such as crosslinked carboxymethylcellulose
• lubricating agents e.g. stearates
• preservatives e.g. parabens
• antioxidants e.g. BHT
• buffering agents for example phosphate or citrate buffers
• effervescent agents such as citrate/bicarbonate mixtures.
• excipients are well known and do not need to be discussed in detail here. Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the GI tract.
• the pharmaceutical compositions typically comprise from approximately 1% (w/w) to approximately 95%, preferably% (w/w) active ingredient and from 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient (for example as defined above) or combination of such excipients.
• a pharmaceutically acceptable excipient for example as defined above
• the compositions comprise from approximately 20% (w/w) to approximately 90% (w/w) active ingredient and from 80% (w/w) to 10% of a pharmaceutically acceptable excipient or combination of excipients.
• the pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient.
• compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre- filled syringes, dragées, powders, tablets or capsules.
• Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/ or bulking agents (depending on drug dose). They may also contain 0-10% (w/w) polymer binders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments.
• Slow release tablets would in addition typically contain 0-99% (w/w) release-controlling (e.g.
• the film coats of the tablet or capsule typically contain 0-10% (w/w) polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.
• the composition may be a parenteral composition.
• Parenteral formulations typically contain 0- 20% (w/w) buffers, 0-50% (w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI) (depending on dose and if freeze dried).
• WFI Water for Injection
• Formulations for intramuscular depots may also contain 0-99% (w/w) oils.
• the pharmaceutical formulations may be presented to a patient in “patient packs” containing an entire course of treatment in a single package, usually a blister pack.
• the compounds of the Formula (1) will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity.
• a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient.
• particular sub-ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g.0.1 milligrams to 2 milligrams of active ingredient).
• a unit dosage form may contain from 1 milligram to 2 grams, more typically 10 milligrams to 1 gram, for example 50 milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.
• the active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective amount).
• the precise amounts of compound administered may be determined by a supervising physician in accordance with standard procedures.
• compounds of formula [X3] may be prepared by the reaction of a compound of formula [X1] with a hetero-aromatic or substituted phenyl-compound of formula [X2] in a transition metal catalysed cross-coupling reaction such as a Buchwald– Hartwig amination with a catalyst such as Pd(dba)2, Pd(OAc)2 or Pd(o-Tolyl)3 with a phosphine ligand such as BINAP, DPPF, XantPhos or JohnPhos, with a base such as NaOtBu, K2CO3 or Cs2CO3 in a suitable solvent such as DMF, THF, dioxane or toluene.
• a transition metal catalysed cross-coupling reaction such as a Buchwald– Hartwig amination
• a catalyst such as Pd(dba)2, Pd(OAc)2 or Pd(o-Tolyl)3
• a phosphine ligand
• compounds of formula [X3] may also be prepared by the reaction of a compound of formula [X1] with a hetero-aromatic-compound of formula [X2] in a nucleophilic aromatic substitution (SNAr) related reaction with a base such as DIPEA, K2CO3, Cs2CO3 or KOH in a polar solvent such as DMF or THF.
• SNAr nucleophilic aromatic substitution
• compounds of formula [X3] can be prepared via reaction with a carboxylic acid of formula [X2] in an amide coupling reaction with a coupling agent such as HATU, a solvent such as DCM or DMF and a base such as DIPEA.
• the reaction is usually conducted at RT.
• reaction product is purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation.
• Compounds of formula [X4] may be prepared by standard methods for the removal of the protecting group (PG) with compounds of formula [X3].
• PG protecting group
• a method such as hydrogenation under an atmosphere of hydrogen in the presence of palladium on activated carbon in a polar solvent such as ethanol or methanol.
• a method using strong base such as KOH in a solvent such as ethanol suitably conducted at elevated temperature.
• reaction product After reaction work up, typically filtration and/or liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC or re-crystallisation.
• Compounds of formula [X6] may be prepared by the reaction of a compound of formula [X4] with an aldehyde or ketone derivative of general formula [X5] by a reductive amination reaction with reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a polar solvent such as DCM, DCE or methanol.
• reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride
• a polar solvent such as DCM, DCE or methanol.
• alkyl halides [X5’] or alkyl methanesulfonates via substitution reaction using a strong base such as NaH and a solvent such as DMSO.
• they can be prepared with carboxylic acids of formula [X5’’] via an amide coupling reaction using a coupling agent such as HATU, a solvent such as DCM or DMF and a base such as DIPEA. The reaction is usually conducted at RT.
• the compounds of formula [X6] contain an amino group that is protected by nitrogen protecting group such as a tert-butyloxycarbonyl protecting group.
• compounds of formula [X7] are prepared through standard removal of a tert-butyloxycarbonyl protecting group by reaction of a compound of formula [X6] with an acid such as trifluoracetic acid or phosphoric acid in DCM, HCl in dioxane or formic acid. After reaction work up, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re- crystallisation.
• an acid such as trifluoracetic acid or phosphoric acid in DCM, HCl in dioxane or formic acid.
• compounds of formula [X3’] may be prepared by the reaction of compound of formula [X1’] with an aldehyde of formula [X2] by reductive amination reaction with a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a polar solvent such as DCM, DCE or methanol.
• a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride in a polar solvent such as DCM, DCE or methanol.
• alkyl halides [X2’] or alkyl methanesulfonates via substitution reaction using a strong base such as NaH and a solvent such as DMSO.
• they can be prepared with carboxylic acids of formula [X2’’] via an amide coupling reaction using a coupling agent such as HATU, a solvent such as DCM or DMF and a base such as DIPEA. The reaction is usually conducted at RT.
• Compounds of formula [X4’] may be prepared by standard methods for the removal of the protecting group (PG) with compounds of formula [X3’].
• Compounds of formula [X6] may be prepared with compounds of formula [X4’] by the reaction of a hetero-aromatic or substituted phenyl-compound of formula [X5] in a transition metal catalysed cross-coupling reaction such as a Buchwald–Hartwig amination with a catalyst such as Pd(dba)2, Pd(OAc)2 or Pd(o-Tolyl)3 with a phosphine ligand such as BINAP, DPPF, XantPhos or JohnPhos, with a base such as NaOtBu, K2CO3 or Cs2CO3 in a suitable solvent such as DMF, THF, dioxane or toluene.
• a transition metal catalysed cross-coupling reaction such as a Buchwald–Hartwig amination
• a catalyst such as Pd(dba)2, Pd(OAc)2 or Pd(o-Tolyl)3
• compounds of formula [X6] may also be prepared by the reaction of compounds of formula [X4’] with a hetero-aromatic- compound of formula [X5] in a nucleophilic aromatic substitution (SNAr) related reaction with a base such as DIPEA, K2CO3, Cs2CO3 or KOH in a polar solvent such as DMF or THF, the reaction is suitably conducted at elevated temperature.
• the compounds of formula [X6] contains an amino group that is protected by a nitrogen protecting group such as a tert-butyloxycarbonyl protecting group.
• compounds of formula [X7] are prepared through standard removal of a tert-butyloxycarbonyl protecting group by reaction of compound of formula [X6] with an acid such as trifluoracetic acid or phosphoric acid in DCM, HCl in dioxane or formic acid. After reaction work up, typically by liquid-liquid extraction, the reaction product is purified by flash column chromatography, reverse phase preparative HPLC, chiral preparative SFC or re-crystallisation.
• General Scheme 3 Compounds of formula [X1] and [X1’] can be obtained via different methodologies (General Scheme 3).
• compounds of formula [X1’] may be prepared by the reaction- cyclisation of a compound of formula [X1’_3] in one or two steps by reaction with a reducing agent such as Borane-THF complex, LiAlH 4 or RedAl in an anhydrous solvent such as THF or toluene at a suitable temperature.
• a reducing agent such as Borane-THF complex, LiAlH 4 or RedAl in an anhydrous solvent such as THF or toluene at a suitable temperature.
• they can be prepared using Raney-Ni in a hydrogen atmosphere with a suitable solvent such as ethanol and water.
• Compounds of formula [X1’_3] can be prepared via reaction of compounds of formula [X1’_1] with compounds of formula [X1’_2] using a strong base such as KHMDS in a suitable anhydrous solvent such as Toluene and THF and a suitable low temperature.
• compounds of formula [X1’] may be prepared by reduction of a compound of formula [X1’_5] using a suitable reducing agent/s such as PhSH, PhSiH3, Fe(acac)3 or NaBH4, NiCl2 or Pd/C, Ammonium formate or Mn(dpm)3, PhSiH3,TBHP in a suitable solvent, generally alcoholic, and at a suitable temperature.
• compounds of formula [X1’_5] may be prepared via the cyclisation reaction of compounds of formula [X1’_4] in one or two steps by reaction with a reducing agent such as Borane-THF complex, LiAlH 4 or RedAl in an anhydrous solvent like THF or toluene at a suitable temperature.
• a reducing agent such as Borane-THF complex, LiAlH 4 or RedAl in an anhydrous solvent like THF or toluene at a suitable temperature.
• they can be prepared using Raney-Ni in a hydrogen atmosphere with a suitable solvent such as ethanol and water.
• Compounds of formula [X1’_4] can be prepared via reaction of compounds of formula [X1’_1] with compounds of formula [X1’_2’] using a strong base such as KHMDS in a suitable anhydrous solvent such as Toluene and THF and a suitable low temperature.
• compounds of formula [X1’] can be prepared from compounds of formula [X1’_8] via standard deprotection conditions, depending on the nature of PG.
• Compounds of formula [X1] may be prepared with compounds of formula [X1_8] via typical benzyl deprotection conditions such as NaOH in solvents such as ethanol and water at high temperatures.
• they can also be prepared via a reduction reaction in a hydrogen atmosphere with a suitable catalyst such as Pd(OH)2 in a suitable solvent such as MeTHF, MeOH or IPA..
• Compounds of formula [X1_8] can be prepared by a reduction reaction of compounds of formula [X1_7] with suitable reducing agent/s such as PhSH, PhSiH3, Fe(acac)3 or NaBH4, NiCl2 or Pd/C, Ammonium formate or Mn(dpm)3, PhSiH3,TBHP in a suitable solvent, generally alcoholic, and at a suitable temperature.
• suitable reducing agent/s such as PhSH, PhSiH3, Fe(acac)3 or NaBH4, NiCl2 or Pd/C, Ammonium formate or Mn(dpm)3, PhSiH3,TBHP
• suitable solvent generally alcoholic, and at a suitable temperature.
• Compounds of formula [X1_7] can be prepared via reaction of compounds of formula [X1_6] with NaNO2/CuCl/HCl in an alcoholic solvent such as methanol or water, typically at room temperature. This is followed by treatment with aqueous HCl in a suitable solvent such as
• the reaction mixture was heated to 100 °C and stirred at 100 °C for 16 hr. One additional vial was set up as described above. After cooling to RT, all two reaction mixtures were combined. The mixture was removed ethanol and acidified to pH 4 with hydrochloric acid (4 N). The suspension was filtered and the filtrate cake was dried under reduced pressure to get 1-benzyl-4-(6-chloropyridin-3-yl)piperidine-4-carboxylic acid (8 g) as a white solid, which was used to next step directly without further purification.
• reaction mixture was stirred at 25 °C for 12 hr.
• One additional vial was set up as described above. All of two reaction mixtures were combined, quenched by saturation sodium sulfite (200 mL) at 0 °C and extracted with DCM (3 ⁇ 100 mL). The combined organic phase was washed with saturation sodium carbonate (200 mL), brine (100 mL) and dried over sodium sulfate.
• reaction mixture After heating to 60 °C, the reaction mixture was stirred at 60 °C for 12 hr. After cooling to RT, the reaction mixture was quenched by water (20 mL) at 0 °C and extracted with EtOAc (20 mL ⁇ 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate and filtered.
• reaction mixture was filtered through celite and washed with 20% MeOH in DCM (2 x 20 mL). The filtrate was evaporated, and the crude product was purified by flash column chromatography using MeOH/DCM (0 to 10%) to afford 38 mg of the product.18 mg of the compound was further purified by prep-HPLC. The fractions were lyophilized.
• reaction mixture was filtered through celite, and the celite washed with 10% MeOH in DCM (50 mL). The combined filtrate was concentrated to get crude purified by prep-HPLC. The pure fractions were concentrated, and the residue was neutralized with 10% NaHCO 3 solution (20 mL) and extracted with (30 mL).
• reaction mixture was stirred at 25 °C for 2 h. Four additional vials were set up as described above. All five reaction mixtures were diluted with water (5 mL) and extracted with EtOAc (5 mL ⁇ 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate and filtered.
• reaction mixture was heated at 120 °C for 16 h.
• the reaction mixture filtered through celite bed, filtrate was evaporated, and crude product was purified by flash column chromatography using EtOAc in PET ether (0 to 20%) to afford (3S)- 3-ethyl-1-(2-(trifluoromethyl)phenyl)piperidine-4-carbonitrile (400 mg, 1.417 mmol, 65%) as a yellow liquid.
• reaction mixture was basified with 10% NaHCO 3 diluted with water (10 mL) and extracted with EtOAc (2 x10 mL). The combined organic layer was, dried over anhydrous sodium sulphate, evaporated and purified by flash column chromatography using EtOAc in PET ether (0 to 30%) to afford tert-butyl 6-(2- ethoxyphenyl)-3-fluoropicolinate (6 g, 17.96 mmol, 72%) (intermediate 101) as a pale-yellow solid.
• reaction mixture was stirred at 0 °C for 2 h. Five additional vials were set up as described above. After warming to RT, all six reaction mixtures were quenched with ice water (10 mL) and extracted with DCM (10 mL ⁇ 3). The combined organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate and purified by prep-HPLC method L to obtain (R)-2-(1-benzyl-7'-(pyrrolidin-2- ylmethyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-2'-yl)phenol (1 g, 42%) as a yellow solid.
• reaction mixture was stirred at 60 °C for 1 h under nitrogen atmosphere. Eight additional vials were set up as described above. After cooling to RT, all nine reaction mixtures were quenched by addition water (20 mL) and extracted with EtOAc (6 mL ⁇ 3).
• reaction mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. Four vials were set up as described above. Five reaction mixtures were quenched by addition of saturated NH 4 Cl solution (300 mL) at 0 °C and adjusted to pH 4 - 6 with formic acid, then extracted with EtOAc (200 mL ⁇ 3).
• reaction mixture was stirred at 60 °C for 30 min. Five additional vials were set up as described above. After cooling to 0 °C, the reaction mixture was quenched with MeOH (1 mL). All six mixtures were combined and stirred at 60 °C for 1 h.
• the structure was solved using SHELXT (Sheldrick, G. M.2015. Acta Cryst. A71, 3-8) and refined using SHELXL (against F2) (Sheldrick, G. M.2015. Acta Cryst. C71, 3-8).
• the total number of refined parameters was 389, compared with 5552 data. All reflections were included in the refinement.
• the largest differential peak and hole were 0.27 and -0.20 ⁇ -3.
• reaction mixture was stirred for 10 min and then added 4-chloro-2-(trifluoromethyl)benzoic acid (80 mg, 0.22 mmol).
• the reaction mixture was stirred at 25-30°C for 16h.
• the reaction was quenched with ice- cold water (10 mL) and extracted with DCM (2 x 20 mL). The organic layer was dried over Na 2 SO 4 and concentrated to get crude (100 mg) as brown sticky compound which shows 20% of desired product.
• Example 1 The crude product was further purified by prep HPLC, followed by lyophilization to afford 1'-[4-chloro-2-(trifluoromethyl)benzoyl]-2-(2-ethoxypyridin-3-yl)spiro[6,7-dihydro-1,7- naphthyridine-5,4'-piperidine]-8-one (10 mg, 8%) (Example 1) as light pink solid.
• Analytical data for Example 1 is in Table 2.
• Example 21 2-amino-1-(7'-(4-chloro-2- (trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-1-yl)ethan-1-one (4.25 mg, 7.51 ⁇ mol, 25%) (Example 21) as white solid. Analytical data for Example 21 is in Table 9.
• the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 2). combined organic extract was washed with brine (20 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude.
• the crude compound was purified by Biotage-Isolera using 25g silica gel cartridge and eluted with 0 to10% MeOH in DCM.
• Example 22 1-(4-chloro-3-iodopyridin-2- yl)-2'-(2-ethoxypyridin-3-yl)-6',7'-dihydro-8'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-8'-one) (4.2 mg) (Example 22) as off white solid.
• Analytical data for Example 22 is in Table 10.
• reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL x 2). Combined organic extract was washed with brine (30 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford crude.
• reaction mixture was precipitated using ACN (20 mL) and precipitate filtered off. Solid was washed with ACN (20 mL) and combined filtrate was collected and concentrated to get tert-butyl 3-(2'-(2-ethoxypyridin-3-yl)-1-(6-methoxy-2-(trifluoromethyl)nicotinoyl)-6'H-spiro[piperidine-4,5'- [1,7]naphthyridin]-7'(8'H)-yl)pyrrolidine-1-carboxylate (50 mg, 0.030 mmol, 32%) as brown gum.
• reaction mixture was quenched with water (5 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated.
• the crude product was purified by prep HPLC. The fractions were lyophilized. The residue was basified with 10% NaHCO 3 solution and extracted with DCM (3 x 5 mL).
• Route M Typical procedure for the preparation of lactams as exemplified by the preparation of (S)- 1-(4-chloro-2-(trifluoromethyl)phenyl)-2'-(2-ethoxypyridin-3-yl)-7'-(pyrrolidin-3-yl)-7',8'- dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-6'-one (Example 34).
• Example 36 Analytical data for Example 36 and Example 42 is in Table 15.
• Example 52 The DCM layer was dried over anhydrous sodium sulfate and concentrated to get white solid which was re-dissolved in ACN:water 1:3 and lyophilized to afford 2-amino-1-[1'-[4-chloro-2-(trifluoromethyl)phenyl]-2-(2-ethoxypyridin-3- yl)spiro[6,8-dihydro-1,7-naphthyridine-5,4'-piperidine]-7-yl]ethanone (3.94 mg, 0.076 mmol, 9%) (Example 52) as an off white solid. Analytical data for Example 52 is in Table 17.
• the reaction mixture was stirred at RT for 1 h.
• the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL).
• the combined organic extracts were washed with brine (10 mL), dried over sodium sulfate and evaporated.
• the crude product was purified by prep-HPLC.
• reaction mixture was heated to 100 °C and stirred at 100 °C for 2 hr. Seven additional vials were set up as described above. After cooling to RT, all eight reaction mixtures were combined, diluted with water (20 mL) and extracted with EtOAc (20 mL ⁇ 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and filtered.
• Example 59 Analytical data for Example 59 is in Table 20.
• the reaction mixture was stirred at 70 °C for 16 h.
• the reaction mixture was filtered and evaporated.
• the crude product was purified by flash column chromatography using MeOH in DCM (0 to 10%). The pure fractions were evaporated, and the product was further purified by prep-HPLC. The fractions were lyophilized.
• reaction mixture was concentrated, neutralized with 10% NaHCO 3 (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated afforded crude compound, which was purified by prep-HPLC.
• Example 97 Analytical data for Example 97 is in Table 23.
• reaction mixture was stirred at RT for 30 min.
• Tert-butyl (R)-3-((methylsulfonyl)oxy)pyrrolidine-1- carboxylate (128 mg, 0.484 mmol) was added at RT.
• the reaction mixture was stirred at 60 °C for 16 h.
• the reaction mixture was quenched cautiously with saturated ammonium chloride solution (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over sodium sulfate and evaporated.
• reaction mixture was stirred at 25 °C for 12 h.
• Example 117 3-(2'-(2-ethoxypyridin-3-yl)-1-(3- methoxy-2-(trifluoromethyl)phenyl)-6'H-spiro[piperidine-4,5'-[1,7]naphthyridin]-7'(8'H)-yl)-3- oxopropanoic acid (9.7 mg, 35%) (Example 117) as white solid.
• Analytical data for Example 117 is in Table 26.
• reaction mixture was basified to pH 9 by Et 3 N, then added 2'-(2-ethoxypyridin-3-yl)-1-(3-methoxy-2- (trifluoromethyl)phenyl)-7',8'-dihydro-6'H-spiro[piperidine-4,5'-[1,7]naphthyridine] (50 mg, 100.29 ⁇ mol) (intermediate 61) and NaCNBH 3 (31.51 mg, 501.47 ⁇ mol). The reaction mixture was heated to 60 °C and stirred at 60 °C for 12 h. Three additional vials were set up as described above.
• the reaction mixture was basified cautiously with 10% NaHCO 3 solution (10 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were dried over sodium sulphate. The resulting residue was purified by prep-HPLC (Method B). The pure prep fractions were lyophilized.
• the reaction was concentrated and the resulting residue neutralized with aqueous 10% NaHCO 3 solution (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 and purified by Prep. HPLC. The prep fractions were concentrated, and the residue was neutralized with 10% NaHCO 3 solution (10 mL) and extracted with DCM (10 mL).
• the reaction mixture was stirred at 100 o C for 42 h.
• the reaction mixture was cooled to RT and diluted with 10% MeOH in DCM (2 x 20 mL). pH of the reaction mixture was adjusted to ⁇ 8 by using 10% sodium hydroxide solution (50 mL) and separated the layers. The aq. layer was extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over Na 2 SO 4 and concentrated under vacuum to afford crude compound (100 mg; HPLC purity: 56.0%).
• Crystal growth Crystallization by slow evaporation of the solvent was adopted for growing crystals suitable for single-crystal X-ray diffraction studies. Crystals were obtained from Methyl tert-Butyl Ether (MTBE) solvent. About 20 mg of the compound (B.No. OMA-SYN-C37s-E1- R-004) was dissolved in Methyl tert-Butyl Ether (3ml) solvent under hot conditions and the solution was filtered into a clean beaker and kept for crystallization at room temperature. Crystals were obtained on the walls of the beaker after 10 days.
• MTBE Methyl tert-Butyl Ether
• the raw data frames were reduced and corrected for absorption effects using the Bruker Apex 3 software suite programs (Bruker (2016). APEX3, SAINT and SADABS. Bruker AXS, Inc., Madison, Wisconsin, USA).
• the structure was solved using intrinsic phasing method [2] and further refined with the SHELXL (Sheldrick G. M. (2015). Acta Crystallogr C71: 3-8) program and expanded using Fourier techniques. Anisotropic displacement parameters were included for all non-hydrogen atoms.
• Atom C1 of molecule A was disordered over two positions and its site occupational factors were refined to 0.6(5) and 0.4(5) respectively.
• the atoms C17/C18/C19/C20/C21/N3 of molecule B were disordered over two positions and their site occupational factors were refined to 0.755(6) and 0.245(6) respectively.
• the N-H and O-H atoms were located in the difference Fourier map and their positions and isotropic displacement parameters were refined. Hydrogen atoms could not be located on the partial occupy water O2W.
• BIOLOGICAL ACTIVITY Terbium labelling and preparation of SNAP-tagged MC2 membranes Cells were labelled with 100 nM of SNAP-Lumi4-Tb and incubated for 1 h at 37 °C under 5% CO 2 prior to harvesting, and pelleting by centrifugation at 3 min at 1200 rpm. Cell pellets were homogenized using an FastPrep-245G homogeniser (MP Biomedicals) and subsequently centrifuged and resuspended twice at 22,000 ⁇ g at 4 °C (Eppendorf Centrifuge) for 30 min.
• MP Biomedicals FastPrep-245G homogeniser
• TR-FRET Competitive Binding Kinetic Assay To determine the association (k on ) and dissociation (k off ) rates of unlabelled compounds, a competitive kinetic binding assay was performed which involved the simultaneous addition of 100nM fluorescent tracer and increasing concentrations of competing ligand to MC2 membranes (2 ⁇ g per well). The degree of bound fluorescent tracer at MC2 was determined at multiple timepoints by HTRF. In parallel, the association (k on ) and dissociation (k off ) rates for the fluorescent tracer were determined through incubation of increasing concentrations of fluorescent tracer with MC2 membranes in the absence and presence of 1 ⁇ M unlabelled MC2 antagonist. The degree of bound fluorescent tracer was calculated at multiple timepoints by HTRF detection and association kinetic curves were generated.
• EXAMPLE A pKi Group A >9, Group B 7.5 to 9, Group C 6 to 7.5 Koff: Group A ⁇ 0.02, Group B 0.02 to 0.07, Group C >0.07 cAMP accumulation assay
• Chinese hamster ovary (CHO) cells stably expressing human or rat MC2 with MRAP, were maintained in DMEM/F12 cell culture medium supplemented with 10% fetal bovine serum and 1% l-glutamine.

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