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  • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
  • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
  • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
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  • 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
  • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
  • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to substituted heterocyclic compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions for the treatment, management, and/or lessening the severity of diseases, disorders, syndromes or conditions associated with the modulation of calcium sensing receptors (CaSR).
• the invention also relates to 10 methods of treating, managing and/or lessening the severity of diseases disorders, syndromes or conditions associated with the modulation of calcium sensing receptors (CaSR).
• the invention also relates to processes for the preparation of the compounds of the invention.
• Ca 2+ is known to be an intracellular second messenger, with the molecular identification of an extracellular calcium sensing receptor (CaSR), it has further opened the possibility that Ca 2+ might also function as a messenger outside the cells. Information about the local changes in extracellular concentration of Ca 2+ is conveyed to the interior of many types of cells through this unique receptor.
• CaSR extracellular calcium sensing receptor
• CaSR Calcium-sensing receptor
• GPCR G-protein-coupled receptor
• the CaSR belongs to the subfamily C of the GPCR superfamily. Structurally, CaSR has an exceptionally large amino-terminal extracellular (ECD) domain (about 600 aminoacids), a feature that is shared by all of the members of the family C
• PHPT primary hyperparathyroidism
• SHPT secondary hyperparathyroidism
• the invention provide compounds having the structure of Formula (I),
• R a is selected from
• R b is selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted haloalkyl;
• R a is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted cycloalkyl and substituted or unsubstituted haloalkyl; or
• R a and R b together attached on the same carbon atom form C(O) or C(S);
• R a is .
• L is selected from a bond, -(CR c R d )m, -C(O)-, -C(S)-, -C(0)NR 7 -, -S(0) 2 -, -S(0) 2 - NR 7 , -C(0)CH 2 -, -CH 2 C(0)- and -C(0)0-;
• ring A is aryl
• Rc and R ⁇ i which may be same or different at each occurrence, are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl and substituted or unsubstituted haloalkyl;
• X is selected from a bond, -(CR e R f ) m , -0-, -0(CR e R f ) m -, -(CR e R f ) m O-, - C(0)(CR e Rf) m -, -C(0)NR 7 -, -C(0)NR 7 (CR e Rf) m -, -cycloalkylene-, and -O-cycloalkylene- R e and Rf, which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or R e and Rf, together with the carbon atom to which they are attached, form a substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring;
• Ri is -OR 6 or -NR 7 R 8 ;
• R 2 is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl;
• R 3 and R4 which may be same or different at each occurrence, are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy and substituted or unsubstituted cycloalkyl;
• R5 is substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl
• R 7 and R 8 which may be same or different at each occurrence, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted heterocyclylalkyl; or R7 and R 8, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 3 to 12 membered cyclic ring, where the cyclic ring may be heteroaryl or heterocyclyl;
• R9 which may be same or different at each occurrence, is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, aryl, -OR 6 , -C(0)R 6 , -C(0)OR 6 , -(CH 2 ) r - C(0)OR 6 , -0(CH 2 ) r -C(0)OR 6 , -NR 7 R 8 , -C(0)NR 7 R 8 , -NR 7 C(0)R 6 , -S(O) 0 - 2 R 6 , - S(0) 2 NR 7 R 8 , and -NR 7 S(0) 2 R 6 ;
• Rio which may be same or different at each occurrence, is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, -OR 6 , -C(0)R6, -NR 7 R 8 , -
• 'm' is an integer ranging from 1 to 3, both inclusive;
• 'n' is an integer ranging from 1 to 3, both inclusive;
• 'p' is an integer ranging from 0 to 3, both inclusive;
• 'q' is an integer ranging from 0 to 4, both inclusive;
• 'r' is an integer ranging from 1 to 3, both inclusive;
• L is selected from a bond, -(CR c d )m, -C(O)-, -C(0)NR 7 -, -C(0)CH 2 -, and - CH 2 C(0)-;
• Aryl is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl
• Rc, d, X, Ri, R7, R 9 , Rio, 'm', 'p' and 'q' are as defined in Formula (I).
• L is selected from a bond, -(CR c R d ) m , -C(O)-, -C(0)NR 7 -, -C(0)CH 2 -, and - CH 2 C(0)-;
• Aryl is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl
• Rc, Rd, X, Ri, R7, R 9 , Rio, 'm', 'p' and 'q' are as defined in Formula (I).
• X is selected from a bond, -(CR e Rf) m , -0-, -0(CR e Rf) m -, - (CR e Rf) m O-, -C(0)(CR e Rf) m -, -C(0)NR 7 -, -C(0)NR 7 (CR e R f ) m -, -cycloalkylene-, and -O- cycloalkylene-; wherein R e and R f may be same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or R e and R f, together with the carbon atom to which they are attached, form a substituted or un
• R 9 is selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, -OR 6 , -C(0)R 6 , -C(0)OR 6 , -(CH 2 ) r - C(0)OR 6 , -0(CH 2 ) r -C(0)OR 6 , -NR 7 R 8 , -C(0)NR 7 R 8 , -NR 7 C(0)R 6 , -S(O) 0 - 2 R 6 , - S(0) 2 NR 7 R 8 , and -NR 7 S(0) 2 R 6 i R6 is selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted halo
• R 10 which may be same or different at each occurrence, is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, -OR 6 , -C(0)R 6 , -NR 7 R 8 , -NR 7 C(0)R 6 , -S(O) 0 - 2 R 6 , - S(0) 2 NR 7 R 8 , and - NR 7 S(0)2R6;
• R6 is selected from hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted haloalkyl;
• R 7 and R 8 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
• compounds of Formulae (II) and/or (III) in which Aryl is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl, wherein the substituents are one or more, same or different and independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy or substituted or unsubstituted haloalkoxy.
• L is selected from a bond, -(CR c R d ) m , -C(O)-, -C(0)NR 7 -, -C(0)CH 2 -, and - CH 2 C(0)-;
• ring A is aryl
• R c and R ⁇ i which may be same or different at each occurrence, are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl and substituted or unsubstituted haloalkyl;
• X is selected from a bond, -(CR e Rf) m , -0-, -0(CR e Rf) m -, -(CR e Rf) m O-, - C(0)(CR e Rf) m -, -C(0)NR 7 -, -C(0)NR 7 (CR e Rf) m -, -cycloalkylene-, and -O-cycloalkylene-
• R e and Rf which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or R e and Rf, together with the carbon atom to which they are attached, form a substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring;
• Ri is -OR 6 or -NR 7 R 8 ;
• R2 is substituted or unsubstituted aryl, wherein the aryl is substituted with one or more substitutents and independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy and substituted or unsubstituted haloalkoxy;
• R 3 and R4 are hydrogen
• R5 is substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl
• R6 is hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted haloalkyl
• R 7 and R 8 are hydrogen or substituted or unsubstituted alkyl
• R9 which may be same or different at each occurrence, is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, -OR 6 , -C(0)R 6 , -C(0)OR 6 , -(CH 2 ) r -C(0)OR 6 , -0(CH 2 ) r -C(0)OR 6 , -NR 7 R 8 , -C(0)NR 7 R 8 , - NR 7 C(0)R 6 , -S(0)o- 2 R 6 , -S(0) 2 NR 7 R 8 , and -NR 7 S(0) 2 R 6 ;
• Rio which may be same or different at each occurrence, is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, -OR 6 , -C(0)R6, - NR 7 R 8 , -NR 7 C(0)R 6 , -S(O) 0 - 2 R 6 , - S(0) 2 NR 7 R 8 , and -NR 7 S(0) 2 R 6 ;
• 'm' is 1 to 3; 'n' is 1 to 3; 'p' is 0 to 3; 'q' is 0 to 3; and 'r' is 1 to 2; or pharmaceutically acceptable salt thereof.
• R a is R 4 R2 .
• Q is hydrogen
• 3 ⁇ 4 is hydrogen or substituted or unsubstituted alkyl
• L is selected from a bond, -(CR c R d ) m , -C(O)-, -C(0)NR 7 -, -C(0)CH 2 -, and -
• ring A is aryl
• R c and R ⁇ i which may be same or different at each occurrence, are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl and substituted or unsubstituted haloalkyl;
• X is selected from a bond, -(CR e Rf) m , -0-, -0(CR e Rf) m -, -(CR e Rf) m O-, - C(0)(CR e R f ) m -, -C(0)NR 7 -, -C(0)NR 7 (CR e R f ) m -, -cycloalkylene-, and -O-cycloalkylene-
• R e and R f which may be same or different at each occurrence, are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or R e and R f, together with the carbon atom to which they are attached, form a substituted or unsubstituted 3 to 7 membered saturated carbocyclic ring;
• Ri is -OR 6 or -NR 7 R 8 ;
• R 2 is substituted or unsubstituted aryl, wherein the aryl is substituted with one or more substitutents and independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy and substituted or unsubstituted haloalkoxy;
• R 3 and R4 are hydrogen
• R5 is substituted or unsubstituted alkyl or substituted or unsubstituted haloalkyl
• R6 is hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted haloalkyl
• R 7 and R 8 are hydrogen or substituted or unsubstituted alkyl
• R9 which may be same or different at each occurrence, is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, -OR 6 , -C(0)R 6 , -C(0)OR 6 , -(CH 2 ) r -C(0)OR 6 , -0(CH 2 ) r -C(0)OR 6 , -NR 7 R 8 , -C(0)NR 7 R8, - NR 7 C(0)R 6 , -S(0)o- 2 R 6 , -S(0) 2 NR 7 R 8 , and -NR 7 S(0) 2 R 6 ;
• Rio which may be same or different at each occurrence, is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, -OR 6 , -C(0)R6, - NR 7 R 8 , -NR 7 C(0)R 6 , -S(O) 0 - 2 R 6 , - S(0) 2 NR 7 R 8 , and -NR 7 S(0) 2 R 6 ;
• 'm' is 1 to 3; 'n' is 1 to 3; 'p' is 0 to 3 ; 'q' is 0 to 3; and 'r' is 1 to 2; or pharmaceutically acceptable salt thereof.
• the provided compounds of Formula (I) structurally encompasses stereoisomers including enantiomers and diastereomers.
• a compound of Formula (I) useful in treating, managing or lessening the severity of diseases, disorders, syndromes or conditions associated with calcium sensing receptor (CaSR) modulators.
• CaSR calcium sensing receptor
• the invention provides a pharmaceutical composition comprising at least one compound of Formula (I) and at least one pharmaceutically acceptable excipient.
• the invention provides a pharmaceutical composition of compound of Formula (I) useful in treating, managing or lessening the severity of the diseases disorders, syndromes or conditions associated with calcium sensing receptor (CaSR) modulators in a subject, in need thereof, by administering to the subject, one or more compounds described herein in a therapeutically effective amount to cause modulation of such receptor.
• CaSR calcium sensing receptor
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable stereoisomer, salt, or in vivo hydrolysable ester thereof together with a pharmaceutically acceptable excipient.
• halogen or halo means fluorine, chlorine, bromine, or iodine.
• alkyl refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1- dimethylethyl (t-butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
• alkenyl refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond.
• alkenyl groups include ethenyl, 1 -propenyl, 2-propenyl (allyl), /so-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
• alkynyl refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon- carbon triple bond.
• Non- limiting examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
• alkoxy refers to an alkyl group attached via an oxygen linkage. Non- limiting examples of such groups are methoxy, ethoxy and propoxy and the like. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
• haloalkyl refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above.
• the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl.
• a monohaloalkyl can have one iodine, bromine, chlorine or fluorine atom.
• Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms.
• a polyhaloalkyl is substituted with up to 12 halogen atoms.
• Non-limiting examples of a haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like.
• a perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms. Unless set forth or recited to the contrary, all haloalkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
• haloalkoxy refers to a haloalkyl, defined herein, group attached via an oxygen linkage.
• Non-limiting examples of such groups are monohaloalkoxy, dihaloalkoxy or polyhaloalkoxy including perhaloalkoxy. Unless set forth or recited to the contrary, all haloalkoxy group described or claimed herein may be straight chain or branched, substituted or unsubstituted.
• hydroxyalkyl refers to an alkyl group, as defined above that is substituted by one or more hydroxy groups.
• the hydroxyalkyl is monohydroxyalkyl or dihydroxyalkyl.
• Non-limiting examples of a hydroxyalkyl include 2- hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and the like. Unless set forth or recited to the contrary, all hydroxyalkyl group described or claimed herein may be straight chain or branched, substituted or unsubstituted.
• cycloalkyl refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
• multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl and the like. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
• cycloalkylene refers to a saturated divalent cyclic hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone.
• C3-C7 cycloalkylene means a saturated divalent cyclic hydrocarbon radical with 3 to 7 carbon atoms e.g. cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and the like. Unless set forth or recited to the contrary, all cycloalkylene groups described or claimed herein may be substituted or unsubstituted.
• cycloalkenyl refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms and including at least one carbon-carbon double bond, such as cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
• cycloalkylalkyl refers to a cycloalkyl group as defined above, directly bonded to an alkyl group as defined above, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, etc. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
• aryl refers to an aromatic radical having 6- to 14- carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl and the like. Unless set forth or recited to the contrary, all aryl groups described or claimed herein may be substituted or unsubstituted.
• arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H5 and -C 2 H 4 C 6 H5. Unless set forth or recited to the contrary, all arylalkyl groups described or claimed herein may be substituted or unsubstituted.
• a “carbocyclic ring” or “carbocycle” as used herein refers to a 3- to 10- membered saturated or unsaturated, monocyclic, fused bicyclic, spirocyclic or bridged polycyclic ring containing carbon atoms, which may optionally be substituted, for example, carbocyclic rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, aryl, naphthyl, adamentyl etc. Unless set forth or recited to the contrary, all carbocyclic groups or rings described or claimed herein may be aromatic or non aromatic.
• heterocyclic ring or “heterocyclyl ring” or “heterocyclyl”, unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consists of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S.
• the heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states.
• heterocyclic ring may also be fused with aromatic ring.
• Non- limiting examples of heterocyclic rings include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, te
• heterocyclic ring may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted; substituents may be on same or different ring atom.
• heteroaryl refers to a substituted or unsubstituted 5- to 14- membered aromatic heterocyclic ring with one or more heteroatom(s) independently selected from N, O or S.
• the heteroaryl may be a mono-, bi- or tricyclic ring system.
• the heteroaryl ring may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
• Non- limiting examples of a heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridiny
• heteroaryl groups described or claimed herein may be substituted or unsubstituted.
• heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
• the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
• all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.
• heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
• the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.
• substituted refers to a group or moiety having one or more substituents attached to the structural skeleton of the group or moiety.
• the aforementioned "substituted” groups cannot be further substituted.
• substituent on “substituted alkyl” is "aryl” or “alkenyl”
• the aryl or alkenyl cannot be substituted aryl or substituted alkenyl, respectively.
• the compounds of the present invention may have one or more chiral centers. The absolute stereochemistry at each chiral centre may be 'R' or 'S'.
• the compounds of the invention include all diastereomers and enantiomers and mixtures thereof. Unless specifically mentioned otherwise, reference to one stereoisomer applies to any of the possible stereoisomers. Whenever the stereoisomeric composition is unspecified, it is to be understood that all possible stereoisomers are included.
• stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations.
• enantiomer refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
• chiral center refers to a carbon atom to which four different groups are attached.
• diastereomers refers to stereoisomers which are not enantiomers.
• racemate or “racemic mixture” refer to a mixture of equal parts of enantiomers.
• a “tautomer” refers to a compound that undergoes rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula (I).
• treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject 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; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; c) lessening the severity of a disease disorder or condition or at least one of its clinical or subclinical symptoms or (d) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
• modulate refers to an increase in the amount, quality, or effect of a particular activity or function of the receptor.
• it includes agonists, partial agonists, allosteric modulators of calcium sensing receptor (CaSR) of the present invention.
• Such modulation may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway.
• allosteric modulators of calcium-sensing receptor refers to the ability of a compound that binds to calcium sensing receptors and induces a conformational change that reduces the threshold for calcium sensing receptor activation by the endogenous ligand Ca 2+ depending on the concentration of the compound exposed to the calcium-sensing receptor.
• subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non- domestic animals (such as wildlife).
• domestic animals e.g., household pets including cats and dogs
• non- domestic animals such as wildlife.
• a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a disease, disorder, syndrome or condition, is sufficient to cause the effect in the subject which is the purpose of the administration.
• the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
• the compound of the invention may form salts.
• Non-limiting examples of pharmaceutically acceptable salts include salts derived from inorganic bases, salts of organic bases, salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.
• the invention extends to these stereoisomeric forms and to mixtures thereof.
• the different stereoisomeric forms of the invention may be separated from one another by a method known in the art, or a given isomer may be obtained by stereo specific or asymmetric synthesis or chiral HPLC (high performance liquid chromatography. Tautomeric forms and mixtures of compounds described herein are also contemplated.
• the invention relates to pharmaceutical compositions containing the compounds of the Formula (I) disclosed herein.
• pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula (I) described herein and at least one pharmaceutically acceptable excipient (such as a carrier or diluent).
• the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to modulate calcium sensing receptor (CaSR) mediated diseases described herein when administered to a subject.
• the subjects contemplated include, for example, a living cell and a mammal, including human mammal.
• the compound of the invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
• a pharmaceutically acceptable excipient includes pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
• suitable carriers or exciptients include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
• the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing.
• the pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
• the pharmaceutical compositions described herein may be prepared by conventional techniques known in the art.
• the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
• the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
• the active compound can be adsorbed on a granular solid container, for example, in a sachet.
• the pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, caplets, orally disintegrating tablets, aerosols, solutions, suspensions or products for topical application.
• the route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action.
• Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
• Solid oral formulations include, but are not limited to, tablets, caplets, capsules (soft or hard gelatin), orally disintegrating tablets, dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
• Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions formulation.
• Liquid formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, soft gelatin and sterile injectable liquids, such as aqueous or nonaqueous liquid suspensions or solutions.
• injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
• the pharmaceutical preparation is preferably in unit dosage form.
• the preparation is subdivided into unit doses containing appropriate quantities of the active component.
• the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as pocketed tablets, capsules, and powders in vials or ampoules.
• the unit dosage form can be a capsule, tablet, caplet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
• the total daily dose of the compounds of the invention depends, of course, on the mode of administration.
• oral administration may require a higher total daily dose, than an intravenous (direct into blood).
• the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg according to the potency of the active component or mode of administration.
• Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art.
• Therapeutic doses are generally identified through a dose ranging study in subject based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects for the patient.
• the daily dosage of the CaSR modulator can range from about 0.1 to about 30.0 mg/kg.
• Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the invention.
• the invention provides compounds and pharmaceutical compositions thereof that are useful in treating, managing or lessening the severity of diseases, disorders, syndromes or conditions modulated by calcium sensing receptor (CaSR).
• the invention further provides method of treating diseases, disorders, syndromes or conditions modulated by CaSR in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the invention.
• the methods provided are also useful for diagnosis of conditions that can be treated by modulating CaSR for determining if a patient will be responsible to therapeutic agents.
• the invention provides a method for the treatment of diseases, disorders or conditions through modulating CaSR.
• a subject in need of such treatment is administered a therapeutically effective amount of a compound of Formula (I) described herein.
• the compound and pharmaceutical composition of the present invention is useful to a subject in need of the treatment having a disease, disorder, syndrome or condition characterized by one or more of the following: (a) abnormal calcium ion homeostasis, (b) an abnormal level of a messenger whose production or secretion is affected by the calcium sensing receptor (CaSR) activity or (c) an abnormal level of activity of a messenger whose function is affected by the calcium sensing receptor activity.
• a disease, disorder, syndrome or condition characterized by one or more of the following: (a) abnormal calcium ion homeostasis, (b) an abnormal level of a messenger whose production or secretion is affected by the calcium sensing receptor (CaSR) activity or (c) an abnormal level of activity of a messenger whose function is affected by the calcium sensing receptor activity.
• CaSR calcium sensing receptor
• the patient has a disease, disorder, syndrome or condition characterized by an abnormal level of one or more calcium sensing receptor-regulated components and the compound is active on a CaSR of a cell including parathyroid cell, bone cells (pre- osteoclast, osteoclast, pre-osteoblast, osteoblast), juxtaglomerular kidney cell, kidney messengial cell, glomerular kidney cell, proximal tubule kidney cell, distal tubule kidney cell, cell of the thick ascending limb of Henle's loop and/or collecting duct, parafollicular cell in the thyroid (C-cell), intestinal cell, platelet, vascular smooth muscle cell, gastrointestinal tract cell, pituitary cell or hypothalamic cell.
• the messenger of the calcium sensing receptor is Calcium.
• the compound of Formula (I), being modulators of CaSR, is potentially useful in treating, managing or lessening the severity, morbidity/mortality or complications of diseases, disorders, syndromes or conditions include but are not limited to primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyperparathyroidism, chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis) parathyroid adenoma, parathyroid hyperplasia, parathyroid carcinoma, vascular & valvular calcification, abnormal calcium homeostasis such as hypercalcemia, abnormal phosphorous homeostasis such as hypophosphatemia, bone related diseases or complications arising due to hyperparathyroidism, chronic kidney disease or parathyroid carcinoma, bone loss post renal transplantation, osteitis fibrosa cystica, adynamic bone disease, renal bone diseases, cardiovascular complications arising due to hyperparathyroidism or chronic kidney disease, certain malignancies in which (Ca 2+ ) e ions are abnormal
• Primary hyperparathyroidism is a disorder of one or more of the parathyroid glands, resulting from a hyper function of the parathyroid glands themselves (acquired sporadically or familial) resulting in PTH over secretion which could be due to single or double adenoma, hyperplasia, multigland disease or rarely, carcinoma of the parathyroid glands.
• the blood calcium rises to a level that is higher than normal (called hypercalcemia). This elevated calcium level can cause many short-term and long-term complications.
• Ca level stimulates PTH secretion.
• chronic renal insufficiency also referred to as chronic kidney disease or CKD
• CKD chronic kidney disease
• CKD chronic kidney disease
• ESRD end stage renal disease
• Excess PTH may be produced in response to hypocalcemia resulting from low calcium intake, GI disorders, renal insufficiency, vitamin D deficiency, magnesium deficiency and renal hypercalciuria.
• Tertiary hyperparathyroidism may occur after a long period of secondary hyperparathyroidism and hypercalcemia.
• the compound and composition of the present invention can be used in treating, managing or lessening the vascular or valvular calcification in a subject.
• administration of the compound of the invention retards or reverses the formation, growth or deposition of extracellular matrix hydroxyapatite crystal deposits.
• administration of the compound of the invention prevents the formation, growth or deposition of extracellular matrix hydroxyapatite crystal deposits.
• the compounds of the invention may also be used to prevent or treat atherosclerotic calcification and medial calcification and other conditions characterized by vascular calcification.
• vascular calcification may be associated with chronic renal insufficiency or end-stage renal disease or excess calcium or PTH itself.
• vascular calcification may be associated with pre- or post- dialysis or uremia.
• vascular calcification may be associated with diabetes mellitus I or II.
• vascular calcification may be associated with a cardiovascular disorder.
• Abnormal calcium homeostasis such as hyperparathyroidism related diseases can be characterized as described in standard medical textbooks, but not limited to Harrison's Principles of Internal Medicine.
• the compound and composition of the present invention can be used, in particular, to participate in a reduction of the serum levels in the parathyroid hormone known as PTH: these products could thus be useful for the treatment of diseases such as hyperparathyroidism.
• Abnormal phosphorous homeostasis such as hypophosphatemia can be characterized as described in standard medical textbooks, but not limited to Harrison's Principles of Internal Medicine.
• the compound and composition of the present invention can be used, in particular, to participate in a reduction of the serum levels in the parathyroid hormone known as PTH: these products could thus be useful for the treatment of diseases such as hypophosphatemia.
• the podocyte diseases or disorders treated by methods of the present invention stem from the perturbations in one or more functions of podocytes.
• functions of podocytes include: (i) a size barrier to protein; (ii) charge barrier to protein; (iii) maintenance of the capillary loop shape; (iv) counteracting the intraglomerular pressure; (v) synthesis and maintenance of the glomerular basement membrane (GMB); (vi) production and secretion of vascular endothelial growth factor (VEGF) required for the glomerular endothelial cell (GEN) integrity.
• VEGF vascular endothelial growth factor
• Such disorders or diseases include but are not limited to loss of podocytes (podocytopenia), podocyte mutation, an increase in foot process width, or a decrease in slit diaphragm length.
• the podocyte-related disease or disorder can be effacement or a diminution of podocyte density.
• the diminution of podocyte density could be due to a decrease in a podocyte number, for example, due to apoptosis, detachment, lack of proliferation, DNA damage or hypertrophy.
• the podocyte-related disease or disorder can be due to a podocyte injury.
• the podocyte injury can be due to mechanical stress such as high blood pressure, hypertension, or ischemia, lack of oxygen supply, a toxic substance, an endocrinologic disorder, an infection, a contrast agent, a mechanical trauma, a cytotoxic agent (cis-platinum, adriamycin, puromycin), calcineurin inhibitors, an inflammation (e.g., due to an infection, a trauma, anoxia, obstruction, or ischemia), radiation, an infection (e.g., bacterial, fungal, or viral), a dysfunction of the immune system (e.g., an autoimmune disease, a systemic disease, or IgA nephropathy), a genetic disorder, a medication (e.g., anti-bacterial agent, anti-viral agent, anti-fungal agent, immunosuppressive agent, anti-inflammatory agent, analgestic or anticancer agent), an organ failure, an organ transplant
• a medication
• ischemia can be sickle- cell anemia, thrombosis, transplantation, obstruction, shock or blood loss.
• the genetic disorders may include congenital nephritic syndrome of the Finnish type, the fetal membranous nephropathy or mutations in podocyte-specific proteins.
• the compounds of the invention can be used for treating abnormal intestinal motilities disorders such as diarrhea.
• the methods of the invention comprise administering to the subject a therapeutically effective amount of the compounds of Formula I.
• diarrhea can be exudative diarrhea, i.e., resulting from direct damage to the small or large intestinal mucosa. This type of diarrhea can be caused by infectious or inflammatory disorders of the gut.
• exudative diarrhea can be associated with gastrointestinal or abdominal surgery, chemotherapy, radiation treatment, inflammation or toxic traumatic injury.
• diarrhea can be secretary, means that there is an increase in the active secretion, or there is an inhibition of absorption. There is little to no structural damage. The most common cause of this type of diarrhea is cholera.
• diarrhea can be due to acceleration of intestinal transit (rapid transit diarrhea). Such condition may occur because the rapid flow-through impairs the ability of the gut to absorb water.
• the compound and composition of the present invention can be used, in particular, to participate in an augmenting gastrin or gastric acid secretion to directly or indirectly benefit certain medical conditions such as but not limited to atrophic gastritis or to improve absorption of pharmacological compounds, drugs or supplements from gastrointestinal tract by augmenting gastric acidity.
• the compounds described herein may be prepared by techniques known in the art.
• the compounds described herein may be prepared by following one or more reaction sequences as depicted in Scheme-1 to Scheme-8.
• reaction sequences as depicted in Scheme-1 to Scheme-8.
• specific bases, acids, reagents, solvents, coupling agents, etc. are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the scope of the present invention.
• Variations in reaction conditions, for example, temperature and/or duration of the reaction which may be used as known in the art are also within the scope of the present invention. All the isomers of the compounds are described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
• the compound of Formula (la), where ring A, L, X, 3 ⁇ 4, Ri, R 2 , R5, R9, Rio, 'p' and are defined herein above, can be prepared by following the procedure as depicted in Scheme-2.
• the compound of Formula (2a) is reacted with amine of Formula (a) in presence of trimethyl aluminium to obtain compound of Formula (5).
• This compound of Formula (5) undergoes carbon-nitrogen (C-N) coupling reaction with Formula (b) by following the methods known in the art for example Buchwald coupling reaction (when L is a bond) using suitable reagents known in the art, or the coupling reaction (when L is not a bond) is carried out by using suitable base for example TEA, DIPEA or K 2 CO 3 etc., and in suitable solvent for example DCM, THF etc., to give compound of Formula (6).
• This compound of Formula (6) undergoes reduction using suitable reducing agents for example borane-dimethyl sulfide (Journal of Medicinal Chemistry, 1998, 46, 3142-3158) complex to give compound of Formula (la).
• This compound of Formula (la) undergoes Boc protection on nitrogen then oxidation with suitable oxidizing agent for example KMn0 4, in suitable solvent like acetonitrile, acetone; etc., to give compound of Formula (7b),
• suitable oxidizing agent for example KMn0 4, in suitable solvent like acetonitrile, acetone; etc.
• This oxidized compound of Formula (7b) undergoes deprotection to give compound of Formula (lb), if ester, which can be hydrolyzed to give corresponding acid derivative.
• the compound of Formula (la) is prepared from Formula (4) or Formula (5) by carrying out reduction reaction using suitable reducing agents such as NaBH 4 , borane- dimethyl sulfide complex, LiAlH etc., and in suitable solvent(s).
• This compound of Formula (7) undergoes carbon-nitrogen (C-N) coupling reaction with Formula (b) by following the methods known in the art for example Buchwald coupling reaction (when L is a bond) using suitable reagents known in the art, or the coupling reaction (when L is not a bond) is carried out by using suitable base for example TEA, DIPEA or K 2 CO 3 etc., and in suitable solvent for example DCM, THF etc., to give compound of Formula (la).
• suitable base for example TEA, DIPEA or K 2 CO 3 etc.
• suitable solvent for example DCM, THF etc.
• the compound of Formula (3) is reacted with Formula (b) in presence of suitable solvent for example DCM to give compound of Formula (8) which further undergoes reduction reaction using suitable reducing agents such as NaBH 4 , borane-dimethyl sulfide complex, LiAlH 4 etc., (Journal of Medicinal Chemistry, (1998), 46, 3142-3158) to give compound of Formula (Ie) where ring A, X, Ri, R 2 , R5, R9, Rio, 'p' and 'q' are defined herein above.
• compound of Formula (3) undergoes reduction using suitable reducing to give compound of Formula (9) which further carried out C-N coupling reaction by using suitable base like triethyl amine in suitable solvent like DCM to give compound of Formula (Ie).
• the compound of Formula (2b) is reacted with amine of Formula (a) in presence of trimethyl aluminium in suitable solvent such as toluene, THF etc., to obtain compound of Formula (10).
• suitable solvent such as toluene, THF etc.
• the compound of Formula (15) undergoes reduction using borane- dimethyl sulfide (Journal of MedicinalChemistry, (1998), 46, 3142-3158) to afford compound of Formula (11).
• This compound of Formula (11) undergoes carbon-nitrogen (C-N) coupling reaction with Formula (b) by following the methods known in the art for example Buchwald coupling reaction (when L is a bond) using suitable reagents known in the art, or the coupling reaction (when L is not a bond) carried out by using suitable base for example TEA, DIPEA or K 2 CO 3 and in suitable solvent for example DCM, THF etc., to give compound of Formula (If) where ring A, L, X, 3 ⁇ 4, i, R 2 , R5, R9, Rio, 'p' and 'q' are defined herein above.
• the compound of Formula (2a) or Formula (2b) is coupled with Formula (b) in presence of base for example triethylamine, to give compound of Formula (12).
• base for example triethylamine
• Reduction of the ester group in compound of Formula (12) by using suitable reducing agents for example sodium borohydride in suitable solvent for example alcohols or acetone etc., to afford compound of Formula (13), which further protected with p-toluene sulfonyl chloride in presence of base for example triethylamine to give corresponding O- tosylated compound of Formula (14).
• This compound of Formula (14) undergoes coupling reaction with amine of Formula (a) in basic conditions such as Hunig's base and in suitable solvent to give compound of Formula (Ig) ring A, X, Ri, R 2 , R5, R9, Rio, 'p' and 'q' are defined herein above.
• the compound of Formula (10) is reacted with Formula (b) in presence of suitable coupling agents and in suitable solvent to give compound of Formula (15) which further undergoes reduction with borane-dimethyl sulfide complex (Journal of Medicinal Chemistry, (1998), 46, 3142-3158) to give compound of Formula (Ih) ring A, X, R b , R R 2 , R5, R9, Rio, 'p' and 'q' are defined herein above.
• the compound of Formula (19) undergoes carbon-nitrogen (C-N) coupling reaction with Formula (b) by following the methods known in the art for example Buchwald coupling reaction (when L is a bond) using suitable reagents known in the art, or the coupling reaction (when L is not a bond) carried out by using suitable base for example TEA, DIPEA or K 2 C0 3 etc, and in suitable solvent for example DCM, THF etc. to afford compound of Formula (Ii) ring A, L, X, 3 ⁇ 4, i, 2, R5, R9, Rio, 'p' and 'q' are defined herein above.
• Formula (Ii) is an ester compound it can be hydrolyzed to give corresponding acid and further converted to corresponding amide by reacting with suitable amine using suitable amide coupling agents known in the art.
• the compound of Formula (Ij), ring A, L, X, Ri, R2, R5, R9, Rio, 'p' and 'q' are defined herein above, can be prepared by following the procedure as depicted in Scheme - 8.
• the commercially available 2-aminophenol is reacted with trifluoroacetic anhydride in presence of suitable base for example pyridine in suitable solvent for example ether (US5550125).
• a protected amide of Formula (20) is reacted with 4-bromo 2-butenoate in the presence of suitable base such as sodium methoxide, sodium ethoxide etc., and in suitable solvent to give corresponding ethyl 2-(3,4-dihydro-2H-benzo[b] [l,4]oxazin-3- yl)acetate (21).
• suitable base such as sodium methoxide, sodium ethoxide etc.
• suitable solvent to give corresponding ethyl 2-(3,4-dihydro-2H-benzo[b] [l,4]oxazin-3- yl)acetate (21).
• the compound of Formula (21) is further reduced in presence of suitable reducing agents for example lithium aluminium hydride to obtain corresponding alcohol of Formula (22) which is Boc protected using (Boc) 2 0 in suitable solvent to give compound of Formula (23).
• the compound of Formula (26) undergoes carbon-nitrogen (C-N) coupling reaction with Formula (b) by following the methods known in the art for example Buchwald coupling reaction (when L is a bond) using suitable reagents known in the art, or the coupling reaction (when L is not a bond) carried out by using suitable base for example TEA, DIPEA or K 2 CO 3 etc., and in suitable solvent for example DCM, THF etc. afford compound of Formula (Ij) .
• C-N carbon-nitrogen
• the resultant brown color oily product was purified by flash chromatography on a silica gel column eluted with mixture of 5% ethylacetate in hexane to give compound of la (25 g) as an oily mass and compound of lb was eluted in 3% ethylacetate in hexane as an oil (15 g); (m/z 208.1).
• reaction mixture was heated to 110°C and maintained for 5 h. The reaction progress was monitored by TLC. The reaction was quenched with dilute HC1 and the product extracted with ethylacetate. Organic layer was washed with water followed by brine solution. The organic layers were combined, dried over sodium sulfate and concentrated to get the crude compound. Further this crude compound was purified by flash chromatography by using mixture of ethylacetate/hexane to get the title compound (1.45 g, 90.06%). m/z 333.2.
• Step-1 Reacting a fluoro substituted amino phenol with maleic anhydride by following the similar procedure as described in Intermediate- 15;
• Step-2 Cyclization of Step-1 intermediate using triethylamine by following the similar procedure as described in Intermediate- 16
• Step-3 Coupling of Step-2 intermediate with (R)-l-(naphthalen-l-yl) ethanamine by following the similar procedure as described in Intermediate- 17
• Step-4 Reduction of Step-3 intermediate using borane dimethyl sulphide complex by following the similar procedure as described in Intermediate- 18
• Step-1 Condensation reaction of Intermediate- 16- with (S)-l -(naphthalen -1-yl) ethanamine by following the similar procedure as described in intermediate- 17;
• Step-2 Reduction of step-1 intermediate with borane dimethyl complex by following similar procedure as described in Intermediate-18; m/z 333.5.
• the title compound was prepared by following the similar reduction procedure as described in Example- 1 by taking Intermediate-6 and borane dimethyl sulphide complex. The diastereomers were separated by flash chromatography using a mixture of 20% ethylacetate/hexane. m/z 453.1 ;
• HCl salts of these isomers were prepared by following the similar HCl salt procedure as described in Example- 1.
• Step-1 To a mixture of Intermediate-2 (0.5g, 0.96mmol) and methyl 3-bromo benzoate (0.23g, 1.06mmol) Cs 2 C0 3 (0.47g, 1.44mmol) in toluene (7mL) was degassed for 15 minutes by purging nitrogen. Then bis (tri-tert-butyl phosphine palladium(O) (0.025g, 0.048mmol) and tris dibenzylideneacetone dipalladium (0) (0.044g, 0.048 mmol) were added. The reaction mixture was heated to 110°C and further maintained for 20 h at the same temperature. The reaction mixture was cooled to RT and progress of reaction monitored by TLC.
• Example-3b was prepared by taking isomer-b.
• Example-3a *H NMR (400 MHz, CDC1 3 ): ⁇ 9.47 (bs, 1H), 7.9 (m, 2H), 7.32 (m, 1H), 7.23 (m, 2H), 7.13-7.10 (m, 2H), 7.04-7.00 (m, 2H), 6.96-6.94 (m, 2H), 6.81 (m, 1H), 4.43 (m, 1H), 4.05 (m, 1H), 3.82 (m, 3H), 3.53-3.48 (m, 2H), 3.02-3.01 (m, 2H), 1.59 (m, 3H);
• Example-3b *H NMR (400 MHz, CDC1 3 ): ⁇ 7.82 (m, 1H), 7.71-7.69 (m, 1H), 7.38-7.36 (m, 2H), 7.21 (m, 1H), 6.92-6.88 (m, 2H), 6.78-6.85 (m, 2H), 6.79-6.74 (m, 3H), 4.25 (m, 1H), 3.90 (m, 3H), 3.3.79 (m, 3H), 3.78-3.70 (m, 1H), 3.68-3.46 (m, 2H), 2.83-2.62 (m, 2H), 1.36-1.34 (m, 3H);
• Step-1 To a mixture solution of Intermediate-3 (0.3g, 0.90mmol) and methyl 3-bromo benzoate (0.21g, 0.99mmol), CS 2 CO 3 (0.44 g, 1.35mmol) in toluene (7 mL) was degassed for 15 min by purging nitrogen. Then bis (tri-tert-butylphosphine palladium (0) (0.023 g, 0.045 mmol) and tris dibenzylidene acetone dipalladium (0) (0.041 g, 0.045 mmol) were added. The reaction mixture was heated to 110°C and further maintained for 20 h at the same temperature. The reaction mixture was cooled to room temperature and progress of reaction monitored by TLC.
• Example- 1 0.2 g, 0.46 mmol
• MeOH MeOH
• water (2 mL) lithium hydroxide monohydrate 0.094 g, 2.31 mmol
• Example-5 0.1 g, 0.24 mmol
• DMF dry DMF
• 1 , - carbonyldiimidazole 0.048 g, 0.3 mmol
• dimethylamine 0.25 mL, 0.48 mmol, 2M solution in THF
• the reaction mixture was stirred at room temperature for overnight.
• the progress of reaction was monitored by TLC.
• Product extracted with diethyl ether (10mLX2) Organic layer was washed with water (5mL) followed by brine (5mL) solution. The organic layer was dried over sodium sulfate and concentrated under vacuum. This crude compound was purified by preparative HPLC to give title compound of 0.045 g as solid, m/z 446.2.
• Example-6 O. lg, 0.23 mmol
• DMF dry DMF
• 1 , - carbonyldiimidazole 0.046 g, 0.29 mmol
• DEA Dimethylamine
• THF 2M 0.23 mL, 0.46 mmol
• the reaction mixture was stirred at room temperature for overnight.
• the progress of reaction was monitored by TLC and diluted with diethyl ether and the organic layer washed with water followed by brine solution. The organic layer was dried over sodium sulfate and concentrated under vacuum.
• the crude compound was purified by preparative HPLC to give title compound of 0.045 g as solid, m/z 466.1 ;
• Example-5 The title compound were prepared by following the similar hydrolysis procedure as described in Example-5 by taking racemic compound of Example-3 and LiOH monohydrate. Further HC1 salt was prepared by following the similar HC1 salt procedure as described in Example- 1.
• Example-40b The title compound was prepared by following the similar procedure as described in Example-lOa, 10b by using Intermediate-26 and methyl 5-bromo-2-methylbenzoate. The crude compound obtained was further purified by flash chromatography using a mixture of 15% ethylacetate in hexane to get the tilte compound. Mass (m/z) 465.2.
• Example-40b
• Step 1 - Boc protection by using di-tert-butyl dicarbonate:
• Example-31b 0.3g, 0.64mmol in acetonitrile (10 mL) was added di- tert-b tyl dicarbonate (0.21g, 0.96mmol) at 0°C. The reaction was stirred at room temperature for overnight. Reaction was monitored by TLC then the reaction mixture quenched with 10% citric acid. Extracted with Ethyl acetate (10 mLX2), washed with water (15 mLX2) followed by brine solution (5mL), dried over Na 2 S0 4 , filtered and concentrated to get the crude product. This crude product was further purified by flash chromatography (10% Ethyl acetate :n-hexane) to give the title compound (0.32g, 88 % yield), m/z 567.5.
• step-1 intermediate (0.120 g, 0.212 mmol) in acetonitrile (lOmL) KMn0 4 (0.234g, 1.482mmol) and benzyl triethyl ammonium chloride (0.072 g, 0.318 o
• step-2 intermediate (0.07 g, 0.12mmol) was dissolved in DCM (5mL) and MeOH/HCl (10 mL, 3N). The reaction mixture was stirred at 35°C for overnight. The progress of reaction was monitored by TLC. The reaction was evaporated under reduced pressure then added saturated Na 2 C0 3 solution (5mL). The mixture was extracted with ethylacetate (10mLX2) and washed with water (5mLX2) followed by brine solution (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. This was further purified by flash chromatography (15% Ethyl acetate -hexane) to give the title compound (0.02g, 51.8%). m/z 481.5.
• the title compound was prepared by following the similar hydrolysis procedure as described in Example-6 by taking Example-4 using lithium hydroxide monohydrate.
• Example 42 to 47 were prepared by following the similar procedure as described in Example-7 by taking acid compound and appropriate amine. Further, HC1 salts were prepared by following the similar HC1 salt procedure as described in Example- 1.
• Examples 48 to 82 given in Table-4 were prepared by following the similar ester hydrolysis procedure as described in Example-6 by taking corresponding ester compound and lithium hydroxide monohydrate. Further HCl salts were prepared by 5 following the similar Hal salt procedure as described in Example- 1.
• the title compound was prepared in two steps.
• Step-1 Example-71b was reacted with methyl 2-aminoacetate following the similar as described in Example-8.
• Step-2 Step-1 compound was hydrolyzed by following the similar procedure as in Example-6 by using LiOH monohydrate.
• the mixture was diluted with ethylacetate, filtered through celite and concentrated under vacuum to get the crude product.
• the crude product was purified by flash chromatography using a mixture of 20% ethylacetate in hexane (0.14g, 64%). m/z 481.2.
• Step-1 Intermediate-3 (0.7 g, 2.1 mmol) was dissolved in DMF (5 mL) and cooled to 0°C. To this solution K 2 CO 3 (0.58g ,4.21mmol) was added and stirred for 15 min then methyl 3-(bromomethyl)benzoate (0.72 g, 3.16 mmol) was added slowly. The reaction mixture was allowed to RT and further stirred for 20h. The progress of reaction was monitored by TLC. The mixture was diluted with Ethyl acetate. Organic layer was washed with water followed by brine solution. The organic layer was dried over sodium sulfate and concentrated to get crude compound. This was further purified by flash chromatography using a mixture of ethyl acetate/hexane as eluent to give title compound as an oily mass (0.8 g, 80%). m/z 480.10.
• Step2 Methyl 3-((2-((((R)-l-(naphthalen-l -yl)ethyl)amino)methyl)-2H-benzo[3 ⁇ 4] [l ,4] oxazin-4(3H)-yl)methyl)benzoate
• the title compound was prepared by following the similar coupling reaction procedure as described in Example-lOa, 10b by taking Intermediate- 12 and methyl 5-bromo-2- methylbenzoate. Further, the compound was purified by flash chromatography using a mixture of 15% ethylacetate in hexane. m/z 485.1.
• Example-6a The title compound was prepared by following the similar hydrolysis procedure as described in Example-6a, 6b by taking Example- 83.
• the title compound was prepared by following the similar coupling reaction procedure as described in Example-lOa, 10b by taking Intermediate-9 and methyl 5-bromo-2- methylbenzoate. Further diastereomers were separated by using flash chromatography using a mixture of 15% ethylacetate in hexane. m/z 482.2.
• Example-86b was prepared from Example-85b by following the similar procedure as described in Example-6a, 6b.
• Example-40b 0.050g, O. lOmmol
• MeOH MeOH
• THF 5.00mL
• water 0.5mL
• lithium hydroxide monohydrate 0.075g, 0.31mmol
• the reaction mixture was heated to 50°C and further maintained for 2h. The progress of reaction was monitored by TLC.
• the product was extracted into Ethyl acetate (10mLX2), washed with water (5 mL X2) followed by brine solution (5 mL), dried over sodium sulfate and concentrated under vacuum to get solid compound.
• Racemic mixture of Intermediate- 18 (0.35g, 1.05mmol) and methyl 5-bromo-2- methylbenzoate (0.29g, 1.26 mmol), CS 2 CO 3 (0.52 g, 1.58 mmol) were added in toluene (7 mL) and degassed for 15 min by purging nitrogen. Then, bis (tri-tert-butylphosphine palladium (0) (0.027 g, 0.053 mmol) and tris dibenzylidene acetone dipalladium (0) (0.048 g, 0.053 mmol) were added. The reaction mixture was heated to 110°C and further maintained for 20 hr at the same temperature.
• the reaction mixture was cooled to room temperature and progress of reaction monitored by TLC.
• the mixture was diluted with ethylacetate, filtered through celite and concentrated under vacuum to get the crude product.
• the crude product was purified by flash chromatography using a mixture of 20% ethylacetate in hexane (0.18g, 86%).
• the title compound was prepared by following the similar procedure as described in Example-88a, 88b by taking Intermediate-22 and methyl 5-bromo-2-methylbenzoate. Further, diastereomers were separated by using chiral chromatographycolumn: CHIRAL PAK ID, 250 x 4.6 MM 5u Mobile Phase : A: hexane/IPA (90: 10, %v/v, 0.1 %DEA) B :IPA(100%) A:B 90/10%v/v: flow is 1.0 ml/min m z 498.36.
• Examples 116 to 132 given in Table-6 were prepared by following the similar procedure as described in Example-88a, 88b by taking appropriate intermediate and appropriately substituted halobenzene. Further diastereomers were separated by using chiral preparative HPLC; column: CHIRAL PAK 1C, 250x4.65u mobile Phase:
• Example-133b was prepared from Example-88b by using this procedure.
• Examples 159 to 172 given in Table-8 were prepared by following the similar ester hydrolysis procedure as described in Example-133a, 133b by using appropriate ester compound. Further HCl salt of this amino compound was prepared by following the similar HCl salt procedure as described in Example- 1.
• oxazin-4(3H)-yl) 161b:m/z 501.2: *H NMR(400 MHz, phenoxy)aceticacid DMSO-d6): ⁇ 13.02 (bs, IH), 9.20 (bs, hydrochloride IH), 9.07 (bs, IH), 8.25 (d, 7 8 Hz,
• 164a, 118a, 164a m/z 501.2; ⁇ NMR (400MHz, 164b 118b DMSO-d6): ⁇ 13.02(bs, lH), 9.73 (bs,
• phenoxy)aceticacid 164b 1 HNMR (400 MHz, DMSO-d6): ⁇ hydrochloride 13.02 (bs, 1H), 9.80 (bs, 1H), 9.25 (bs,
• Example-173a (0.09g, 0.18mmol) in MeOH (15mL)
• THF 5mL
• water 0.5mL
• lithium hydroxide monohydrate 0.013g, 0.55mmol
• the reaction mixture was heated to 80°C and further maintained for 2 h. The progress of reaction was monitored by TLC.
• Extracted the product into Ethyl acetate (10mLX2) washed with water (5 mLX2) followed by brine solution (5 mL), dried over sodium sulfate and concentrated under vacuum to get solid compound.
• Further HC1 salt of this amino compounds were prepared by following the similar HC1 salt procedure as described in Example-1 (0.057g, 65.2% yield), (m/z) 481.11 ;
• Example-133a The title compound was prepared following the similar hydrolysis procedure as described in Example-133a, 133b by taking Example-80 and LiOH monohydrate.
• Example- 182a The title compound of Example- 182a was prepared by following the similar ester hydrolysis procedure as described in Example-133a, 133b by using Example- 129a and LiOH monohydrate. Similarly, Example- 182b was prepared from Example- 129b.
• Example- 183a The title compound of Example- 183a was prepared by following the similar ester hydrolysis procedure as described in Example-133a, 133b by using Example- 122a and LiOH monohydrate.
• Example-183b was prepared from Example-122b.
• Examples 184 to 221 given in Table-l la and Table- l ib are prepared by following the similar procedure as described in Example-88a, 88b by taking appropriate halo benzene (ester) followed by ester hydrolysis using LiOH monohydrate by following the procedure as described in Example- 133a, 133b by taking appropriately substituted intermediates further hydrochloride salt is prepared as described in Example- 1.

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