Classifications

• • 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
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • 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
  • C07D471/02—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 two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• Phosphatidylinositol-4, 5-bisphosphate 3-kinases are a family of enzymes involved in various of primary cellular functions, including cell growth, proliferation, differentiation, motility, survival, metabolism and intracellular trafficking [Vanhaesebroeck, B., L. Stephens, and P. Hawkins, PI3K signalling: the path to discovery and understanding. Nat Rev Mol Cell Biol, 2012. 13 (3) : p. 195-203. ] .
• phosphatidylinositol They are kinases capable of phosphorylating phosphatidylinositol [Whitman, M., et al., Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature, 1988. 332 (6165) : p. 644-6. ; Auger, K.R., et al., PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell, 1989. 57 (1) : p. 167-75. ] .
• Phosphorylated phosphatidylinositols which are called phosphoinositides, play important roles in signaling transduction and membrane trafficking [Martin, T.F., Phosphoinositide lipids as signaling molecules: common themes for signal transduction, cytoskeletal regulation, and membrane trafficking. Annu Rev Cell Dev Biol, 1998. 14: p. 231-64. ] .
• the PI3K family is divided into three classes (I, II, and III) based on structure, regulation and substrate specificity [Vanhaesebroeck, B., et al., The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol, 2010. 11 (5) : p. 329-41. ] .
• Class I PI3Ks are further divided based on sequence similarity into class IA and class IB.
• the class IA PI3Ks comprise three closely related kinases, PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ , which exist as heterodimers composed of a catalytic subunit (p110 ⁇ , p110 ⁇ , or p110 ⁇ ) and a regulatory subunit (p85) [Yu, J., et al., Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit. Mol Cell Biol, 1998. 18 (3) : p.
• the class IB PI3K includes only PI3K ⁇ , which is composed of a p110 ⁇ [Stoyanov, B., et al., Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science, 1995. 269 (5224) : p. 690-3.
• PI3K ⁇ and PI3K ⁇ respond to signaling generally through receptor tyrosine kinases (RTKs) [Inukai, K., et al., Five isoforms of the phosphatidylinositol 3-kinase regulatory subunit exhibit different associations with receptor tyrosine kinases and their tyrosine phosphorylations.
• RTKs receptor tyrosine kinases
• GPCRs G-protein-coupled receptors
• PI3K ⁇ In contrast to PI3K ⁇ , there are no somatic mutations in the PI3K ⁇ isoform that have been identified. However, the overexpression of PI3K ⁇ has been implicated as necessary for transformation induced by the loss or inactivation of the PTEN tumor suppressor both in vitro and in vivo (Torbett NE, Luna A, Knight ZA, et al., A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isotype-selective inhibition.
• PI3K ⁇ is a promising target for cancer and other syndromes related to PTEN loss (Hollander, M. Christine; Blumenthal, Gideon M, Dennis, Phillip, PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nature reviews/Cancer 2011; 11: 289-301) . Therefore, there is a strong need of novel PI3K ⁇ inhibitors for the treatment of cancers, especially for the PTEN loss cancers.
• R 1 is halogen, C 1-6 alkyl, or C 3-6 cycloalkyl
• n 0, 1, 2, 3 or 4;
• R 2 is halogen, C 1-6 alkyl, or C 3-6 cycloalkyl
• n 0, 1 or 2;
• R 3 is halogen, C 1-6 alkyl optionally substituted with halogen, or C 3-6 cycloalkyl;
• p 0, 1, 2, 3, 4, or 5;
• L 1 is -C 1-4 alkylene-, wherein one -CH 2 -moiety is optionally replaced with -O-, -S-or -NH-;
• R 4 and R 5 are each independently hydrogen, halogen, C 3-6 cycloalkyl, -CONR 6 R 7 , or C 1- 6 alkyl optionally substituted with halogen;
• R 6 is hydrogen or C 1-6 alkyl
• R 7 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of said C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with R 7a ; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a 4-to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with one or two substituents R 8 ;
• R 7a is aryl, heteroaryl, heterocyclyl, NR a R b , C 3-6 cycloalkyl, C 1-6 alkoxy, or hydroxy, each of said aryl, heteroaryl, and heterocyclyl is optionally substituted with halogen, C 1-6 alkyl or C 1- 6 alkoxy;
• R 8 is C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with halogen, C 3-6 cycloalkyl or NR c R d ;
• R a and R b are each independently hydrogen or C 1-6 alkyl
• R c and R d are each independently hydrogen or C 1-6 alkyl.
• Disclosed herein also is a pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula (I) , or a stereoisomer thereof or a pharmaceutically acceptable salt thereof disclosed herein, and a pharmaceutically acceptable excipient.
• the compound of Formula (I) disclosed herein is useful as a PI3K inhibitor, in particular, a PI3K ⁇ inhibitor.
• the compound of Formula (I) disclosed herein is thus useful in treating or preventing diseases or disorders selected from the group comprising of inflammation, cancer, Restenosis, Atherosclerosis, Psoriasis, Thrombosis, immune-oncology, renal carcinoma, hepatitis C, hematological malignancies, multiple myeloma or a disease or a disorder associated with abnormal activities of PI3K signaling.
• diseases or disorders selected from the group comprising of inflammation, cancer, Restenosis, Atherosclerosis, Psoriasis, Thrombosis, immune-oncology, renal carcinoma, hepatitis C, hematological malignancies, multiple myeloma or a disease or a disorder associated with abnormal activities of PI3K signaling.
• a 1, 5-naphthyridin-4 (1H) -one derivative of Formula (I) as a PI3K inhibitor is disclosed herein.
• the first aspect comprises the following embodiments:
• Embodiment 1 A compound of Formula (I) ,
• R 1 is halogen, C 1-6 alkyl, or C 3-6 cycloalkyl
• n 0, 1, 2, 3 or 4;
• R 2 is halogen, C 1-6 alkyl, or C 3-6 cycloalkyl
• n 0, 1 or 2;
• R 3 is halogen, C 1-6 alkyl optionally substituted with halogen, or C 3-6 cycloalkyl;
• p 0, 1, 2, 3, 4, or 5;
• L 1 is -C 1-4 alkylene-, wherein one -CH 2 -moiety is optionally replaced with -O-, -S-or -NH-;
• R 4 and R 5 are each independently hydrogen, halogen, C 3-6 cycloalkyl, -CONR 6 R 7 , or C 1- 6 alkyl optionally substituted with halogen;
• R 6 is hydrogen or C 1-6 alkyl
• R 7 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of said C 1-6 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with R 7a ; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a 4-to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with one or two substituents R 8 ;
• R 7a is aryl, heteroaryl, heterocyclyl, NR a R b , C 3-6 cycloalkyl, C 1-6 alkoxy, or hydroxy, each of said aryl, heteroaryl, and heterocyclyl is optionally substituted with halogen, C 1-6 alkyl or C 1- 6 alkoxy;
• R 8 is C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with halogen, C 3-6 cycloalkyl or NR c R d ;
• R a and R b are each independently hydrogen or C 1-6 alkyl
• R c and R d are each independently hydrogen or C 1-6 alkyl.
• Embodiment 2 the compound according to Embodiment 1, wherein m is 0.
• Embodiment 3 the compound according to Embodiment 1, wherein m is 1.
• Embodiment 4 the compound according to Embodiment 3, wherein R 1 is C 1-6 alkyl, preferably methyl.
• Embodiment 5 the compound according to Embodiment 1 or 2, wherein n is 0.
• Embodiment 6 the compound according to Embodiment 1 or 2, wherein n is 1.
• Embodiment 7 the compound according to Embodiment 6, wherein R 2 is halogen, preferably chloro.
• Embodiment 8 the compound according to Embodiment 5, wherein p is 1 or 2.
• Embodiment 9 the compound according to Embodiment 8, wherein p is 2.
• Embodiment 10 the compound according to Embodiment 8 or 9, wherein R 3 , at each occurrence, is C 1-6 alkyl, C 1-6 alkyl substituted with halogen, or halogen. In one embodiment, R 3 , at each occurrence, is methyl, trifluoromethyl, or halogen. In one embodiment, R 3 , at each occurrence, is methyl, trifluoromethyl, or fluorine.
• Embodiment 11 the compound according to Embodiment 9, wherein R 3 at one occurrence is C 1-6 alkyl at position 2 of the phenyl ring and at the other occurrence is C 1-6 alkyl substituted with halogen (preferably fluoro) at position 3 of the phenyl ring.
• R 3 at one occurrence is C 1-6 alkyl substituted with one or more fluorine.
• R 3 at one occurrence is C 1-6 alkyl substituted with one or more fluorine at position 3 of the phenyl ring.
• Embodiment 12 the compound according to Embodiment 11, wherein R 3 at one occurrence is methyl at position 2 of the phenyl ring and at the other occurrence is trifluoromethyl at position 3 of the phenyl ring.
• Embodiment 13 the compound according to any one of Embodiments 8-12, wherein L 1 is -C 1-2 alkylene-.
• Embodiment 14 the compound according to Embodiment 13, wherein L 1 is -CH 2 -, -C (CH 3 ) H-, or -CH 2 CH 2 -; preferably -CH 2 -.
• Embodiment 15 the compound according to Embodiment 13 or 14, wherein R 4 is hydrogen.
• Embodiment 16 the compound according to any one of Embodiments 13-15, wherein R 5 is halogen, preferably Br or Cl.
• Embodiment 17 the compound according to any one of Embodiments 13-15, wherein R 5 is C 1-6 alkyl optionally substituted with halogen, preferably methyl optionally substituted with halogen, more preferably methyl or trifluoromethyl.
• Embodiment 18 the compound according to any one of Embodiments 13-15, wherein R 5 is C 3-6 cycloalkyl.
• Embodiment 19 the compound according to any one of Embodiments 13-15, wherein R 5 is cyclopropyl.
• Embodiment 20 the compound according to any one of Embodiments 13-15, wherein R 5 is hydrogen.
• Embodiment 21 the compound according to any one of Embodiments 13-15, wherein R 5 is -CONR 6 R 7 , wherein R 6 and R 7 are defined as for Formula (I) .
• Embodiment 22 the compound according to Embodiment 21, wherein R 6 is hydrogen or methyl, preferably hydrogen.
• Embodiment 23 the compound according to Embodiment 21 or 22, wherein R 7 is heterocyclyl; preferably a saturated 4-to 7-membered heterocyclyl comprising one heteroatom selected from oxygen, nitrogen and optionally oxidized sulfur as ring member; more preferably a saturated 4-to 7-membered heterocyclyl comprising one nitrogen heteroatom as ring member; most preferably azetidinyl, pyrrolidinyl (e.g., pyrrolidin-3-yl) , piperidinyl, or azepanyl.
• R 7 is heterocyclyl; preferably a saturated 4-to 7-membered heterocyclyl comprising one heteroatom selected from oxygen, nitrogen and optionally oxidized sulfur as ring member; more preferably a saturated 4-to 7-membered heterocyclyl comprising one nitrogen heteroatom as ring member; most preferably azetidinyl, pyrrolidinyl (e.g., pyrrolidin-3-yl)
• Embodiment 24 the compound according to Embodiment 21 or 22, wherein R 7 is C 3- 6 cycloalkyl optionally substituted with R 7a ; preferably cyclopentyl substituted with hydroxy.
• Embodiment 25 the compound according to Embodiment 21 or 22, wherein R 7 is C 1- 6 alkyl, optionally substituted with R 7a ; preferably C 1-4 alkyl, optionally substituted with R 7a ; more preferably methyl, ethyl, propyl or isopropyl, optionally substituted with R 7a .
• Embodiment 26 the compound according to Embodiment 25, wherein R 7a is C 1-6 alkoxy (preferably methoxy) , aryl, heteroaryl, or heterocyclyl, each of said aryl, heteroaryl and heterocyclyl is optionally substituted with C 1-6 alkyl (preferably methyl) or C 1-6 alkoxy (preferably methoxy) .
• Embodiment 27 the compound according to Embodiment 25, wherein R 7a is 4-methoxyphenyl, pyridin-4-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, pyrrolidin-1-yl, 4-methylpiperazin-1-yl, or 1-methylpyrrolidin-2-yl.
• Embodiment 28 the compound according to Embodiment 25, wherein R 7 is methyl substituted with 4-methoxyphenyl, methyl substituted with pyridin-4-yl, methyl substituted with piperidin-4-yl, methyl substituted with 1-methylpiperidin-4-yl, ethyl substituted with pyrrolidin-1-yl, ethyl substituted with 4-methylpiperazin-1-yl, ethyl substituted with pyridin-4-yl, ethyl substituted with 1-methylpyrrolidin-2-yl, or ethyl substituted with 4-methoxyphenyl.
• Embodiment 29 the compound according to Embodiment 25, wherein R 7a is NR a R b , wherein R a and R b are each independently hydrogen or C 1-6 alkyl (preferably methyl) .
• Embodiment 30 the compound according to Embodiment 25, wherein R 7a is methylamino (-NH (CH 3 ) ) or dimethylamino (-N (CH 3 ) 2 ) .
• Embodiment 31 the compound according to Embodiment 25, wherein R 7 is methyl substituted with dimethylamino or methylamino, ethyl substituted with dimethylamino or methylamino, propyl substituted with dimethylamino, propan-2-yl substituted with dimethylamino, or butyl substituted with dimethylamino.
• Embodiment 32 the compound according to Embodiment 21, wherein R 6 and R 7 , together with the nitrogen atom to which they are attached, form a 4-to 8-membered monocyclic ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with one or two substituents R 8 .
• Embodiment 33 the compound according to Embodiment 32, wherein said ring is 5-or 6-membered monocyclic ring, said ring comprising 0 or 1 additional heteroatom independently selected from nitrogen or oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with one or two substituents R 8 , wherein R 8 is C 1-4 alkyl optionally substituted with C 3-6 cycloalkyl or NR c R d , wherein R c and R d are each independently hydrogen or C 1-6 alkyl.
• Embodiment 34 the compound according to Embodiment 33, wherein said ring is piperazinyl, pyrrolidinyl or morpholinyl optionally substituted with one or two methyl groups, said methyl group is optionally substituted with cyclopropyl or NH 2 .
• Embodiment 35 the compound according to Embodiment 34, wherein said ring is 2, 6-dimethylpiperazine, 4- (cyclopropylmethyl) piperazine, (S) -3- (aminomethyl) pyrrolidine-1-yl, or 2,6-dimethylmorpholine-4-yl.
• Embodiment 36 the compound according to Embodiment 21, wherein R 6 and R 7 , together with the nitrogen atom to which they are attached, form a 7-to 12-membered bicyclic ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionally substituted with one or two substituents R 8 .
• Embodiment 37 the compound according to Embodiment 36, wherein R 6 and R 7 , together with the nitrogen atom to which they are attached, form a spiro ring selected from 2-oxa-6-azaspiro [3.3] heptane and 7-oxa-2-azaspiro [3.5] nonane.
• Embodiment 38 the compound according to Embodiment 1, wherein m is 0; n is 0; p is 2 and R 3 at one occurrence is C 1-6 alkyl at position 2 of the phenyl ring and at the other occurrence is C 1-6 alkyl substituted with halogen (preferably fluoro) at position 3 of the phenyl ring; R 4 is hydrogen; R 5 is hydrogen, Br, Cl, CF 3 , cyclopropyl, methyl, N- (2- (dimethylamino) ethyl) aminocarbonyl, N- (2- (methylamino) ethyl) aminocarbonyl, or N- (1- (dimethylamino) propan-2-yl) aminocarbonyl.
• Embodiment 39 the compound according to Embodiment 1, wherein m is 0; n is 0; p is 2 and R 3 at one occurrence is methyl at position 2 of the phenyl ring and at the other occurrence is trifluoromethyl at position 3 of the phenyl ring; R 4 is hydrogen; R 5 is hydrogen, Br, Cl, CF 3 , cyclopropyl, methyl, N- (2- (dimethylamino) ethyl) aminocarbonyl, N- (2- (methylamino) ethyl) aminocarbonyl, or N- (1- (dimethylamino) propan-2-yl) aminocarbonyl.
• Embodiment 40 the compound according to Embodiment 1, wherein the compound is selected from:
• the compounds disclosed herein are effective inhibitors against PI3K ⁇ . Particularly, the compounds disclosed herein have been found to be selective inhibitors against PI3K ⁇ over PI3K ⁇ , ⁇ and/or ⁇ . More particularly, the compounds disclosed herein show better selectivity for PI3K ⁇ over each of PI3K ⁇ , ⁇ and ⁇ .
• a pharmaceutical composition comprising a therapeutically effective amount of the compound disclosed herein, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• a method for treating or preventing the following a disorders or a disease responsive to the inhibition of PI3K ⁇ activity by using or administering the compounds disclosed herein or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is disclosed.
• a use of the compounds disclosed herein in the manufacture of a medicament for treating or preventing a disorders or a disease responsive to the inhibition of PI3K ⁇ activity is disclosed.
• the disorder or disease is selected from the group consisting of idiopathic thrombocytopenic purpura (ITP) , autoimmune hemolytic anemia, vasculitis, systemic lupus erythematosus, lupus nephritis, pemphigus, membranous nephropathy, acute lymphocytic hemolytic (ALL) , acute myeloid leukemia (AML) , chronic lymphocytic leukemia (CLL) , Non-Hodgkin lymphoma (NHL) , chronic myeloid leukemia (CML) , multiple myeloma (MM) , hairy cell leukemia, Mantle cell lymphoma (MCL) , small lymphocytic lymphoma (SLL) , follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, activated B-cell like (ABC) diffuse large B cell
• IPP
• alkyl herein refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms.
• alkyl groups comprising from 1 to 6 carbon atoms include, but not limited to, methyl, ethyl, 1-propyl or n-propyl ( “n-Pr” ) , 2-propyl or isopropyl ( “i-Pr” ) , 1-butyl or n-butyl ( “n-Bu” ) , 2-methyl-1-propyl or isobutyl ( “i-Bu” ) , 1-methylpropyl or s-butyl ( “s-Bu” ) , 1, 1-dimethylethyl or t-butyl ( “t-Bu” ) , 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-penty
• halogen herein refers to fluoro (F) , chloro (Cl) , bromo (Br) and iodo (I) .
• alkyloxy herein refers to an alkyl group as defined above bonded to oxygen, represented by -Oalkyl.
• alkyloxy e.g., C 1-6 alkyloxy or C 1-4 alkyloxy includes, but not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy and hexoxy and the like.
• cycloalkyl refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups.
• the cycloalkyl group may comprise from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms.
• the cycloalkyl group may be selected from monocyclic group comprising from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms.
• Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups.
• Examples of the saturated monocyclic cycloalkyl group include, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
• the cycloalkyl is a monocyclic ring comprising 3 to 6 carbon atoms (abbreviated as C 3-6 cycloalkyl) , including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms arranged as a bicyclic ring selected from [4, 4] , [4, 5] , [5, 5] , [5, 6] and [6, 6] ring systems, or as a bridged bicyclic ring selected from bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, and bicyclo [3.2.2] nonane.
• the bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5, 6] and [6, 6] ring systems, such as and wherein the wavy lines indicate the points of attachment.
• the ring may be saturated or have at least one double bond (i.e. partially unsaturated) , but is not fully conjugated, and is not aromatic, as aromatic is defined herein.
• aryl used alone or in combination with other terms refers to a group selected from:
• bicyclic ring systems such as 7 to 12 membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl; and,
• tricyclic ring systems such as 10 to 15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, e.g., fluorenyl.
• a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 aryl) .
• Examples of a monocyclic or bicyclic aromatic hydrocarbon ring includes, but not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like.
• the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or phenyl ring.
• the aromatic hydrocarbon ring is a phenyl ring.
• heteroaryl herein refers to a group selected from:
• 5-, 6-or 7-membered aromatic, monocyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, in some embodiments, from 1 to 2, heteroatoms, selected from nitrogen (N) , sulfur (S) and oxygen (O) , with the remaining ring atoms being carbon;
• 8-to 12-membered bicyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and
• 11-to 14-membered tricyclic rings comprising at least one heteroatom, for example, from 1 to 4, or in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.
• heteroaryl is 5-to 6-membered heteroaryl comprising one nitrogen atom and 0 or 1 additional heteroatom selected from N, O and S, including but not limited to pyridinyl, isoxazolyl, and oxazolyl.
• the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
• the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring (s) of the heteroaryl group can be oxidized to form N-oxides.
• a monocyclic or bicyclic aromatic heterocyclic ring has 5-, 6-, 7-, 8-, 9-or 10-ring forming members with 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N) , sulfur (S) and oxygen (O) and the remaining ring members being carbon.
• the monocyclic or bicyclic aromatic heterocyclic ring is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N) , sulfur (S) and oxygen (O) .
• the monocyclic or bicyclic aromatic heterocyclic ring is a 5-to 6-membered heteroaryl ring, which is monocyclic and which has 1 or 2 heteroatom ring members independently selected from nitrogen (N) , sulfur (S) and oxygen (O) .
• the monocyclic or bicyclic aromatic heterocyclic ring is an 8-to 10-membered heteroaryl ring, which is bicyclic and which has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
• heteroaryl group or the monocyclic or bicyclic aromatic heterocyclic ring examples include, but are not limited to, (as numbered from the linkage position assigned priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl) , cinnolinyl, pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, or 1, 3, 4-thiadiazolyl) , tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl) , triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzoimidazo
• heterocyclic or “heterocycle” or “heterocyclyl” herein refers to a ring selected from 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-or 12-membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated rings comprising at least one carbon atoms in addition to at least one heteroatom, such as from 1-4 heteroatoms, further such as from 1-3, or further such as 1 or 2 heteroatoms, selected from nitrogen (N) , sulfur (S) , oxygen (O) , -SO-or -SO 2 -.
• a heterocyclyl group is 4-, 5-, 6-, 7-or 8-membered monocyclic ring with at least one heteroatom selected from N, O and S.
• a heterocyclyl group is a 4-, 5-, 6-, 7-or 8-membered saturated monocyclic ring comprising one nitrogen heteroatom.
• the exemplary heterocyclyl group is azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, and azocanyl.
• a heterocyclyl group is a 5-, 6-, 7-or 8-membered saturated monocyclic ring comprising one nitrogen atom and 1 additional heteroatom selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) .
• the exemplary heterocyclyl group is a morpholino, morpholinyl or piperzinyl ring.
• a heterocyclyl group is a 7-to 12-membered saturated bicyclic ring comprising one nitrogen atom and 0 or 1 or 2 additional heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring member (s) .
• the heterocyclyl group is a bicyclic bridged or spiro-ring.
• optionally oxidized sulfur used herein refer to S, SO or SO 2 .
• Heterocycle herein also refers to a 5-to 7-membered heterocyclic ring comprising at least one heteroatom selected from N, O, and S fused with 5-, 6-, and /or 7-membered cycloalkyl, carbocyclic aromatic or heteroaromatic ring, provided that the point of attachment is at the heterocyclic ring when the heterocyclic ring is fused with a carbocyclic aromatic or a heteroaromatic ring, and that the point of attachment can be at the cycloalkyl or heterocyclic ring when the heterocyclic ring is fused with cycloalkyl.
• Heterocycle herein also refers to an aliphatic spirocyclic ring comprising at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the heterocyclic ring.
• the rings may be saturated or have at least one double bond (i.e. partially unsaturated) .
• the heterocycle may be substituted with oxo.
• the point of the attachment may be carbon or heteroatom in the heterocyclic ring.
• a heterocycle is not a heteroaryl as defined herein.
• heterocyclyl is 5-to 6-membered heterocyclyl comprising one nitrogen atom and 0 or 1 additional heteroatom selected from N, O and S, including but not limited to pyrrolyl, dihydropyridine, morpholino, morpholinyl and tetrahydropyranyl.
• heterocycle examples include, but not limited to, (as numbered from the linkage position assigned priority 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2, 5-piperazinyl, pyranyl, morpholinyl, morpholino, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1, 2-dithietanyl, 1, 3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepan,
• a substituted heterocycle also includes a ring system substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1, 1-dioxo-1-thiomorpholinyl.
• oxo moieties such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1, 1-dioxo-1-thiomorpholinyl.
• Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Where the compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within the broader class of stereoisomers. All such possible stereoisomers such as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers are intended to be included. All stereoisomers of the compounds disclosed herein and /or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.
• the term “substantially pure” as used herein means that the target stereoisomer contains no more than 35%, such as no more than 30%, further such as no more than 25%, even further such as no more than 20%, by weight of any other stereoisomer (s) . In some embodiments, the term “substantially pure” means that the target stereoisomer contains no more than 10%, for example, no more than 5%, such as no more than 1%, by weight of any other stereoisomer (s) .
• keto and enol forms are also intended to be included where applicable.
• reaction products from one another and /or from starting materials.
• the desired products of each step or series of steps is separated and /or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
• separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
• Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed ( "SMB” ) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
• SMB simulated moving bed
• Diastereomers refers to stereoisomers of a compound with two or more chiral centers but which are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and /or fractional crystallization.
• Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride) , separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
• an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
• Enantiomers can also be separated by use of a chiral HPLC column.
• a single stereoisomer e.g., a substantially pure enantiomer
• Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
• “Pharmaceutically acceptable salts” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• a pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base.
• the free base can be obtained by basifying a solution of the acid salt.
• an addition salt such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
• a pharmaceutically acceptable salt thereof include salts of at least one compound of Formula (I) , and salts of the stereoisomers of the compound of Formula (I) , such as salts of enantiomers, and /or salts of diastereomers.
• administration when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, mean contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
• Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
• administration and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell.
• subject herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit) and most preferably a human.
• an effective amount refers to an amount of the active ingredient, such as compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom.
• the “therapeutically effective amount” can vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments.
• “therapeutically effective amount” is an amount of at least one compound and /or at least one stereoisomer thereof, and /or at least one pharmaceutically acceptable salt thereof disclosed herein effective to "treat” as defined above, a disease or disorder in a subject.
• the “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.
• the pharmaceutical composition comprising the compound disclosed herein can be administrated via oral, inhalation, rectal, parenteral or topical administration to a subject in need thereof.
• the pharmaceutical composition may be a regular solid formulation such as tablets, powder, granule, capsules and the like, a liquid formulation such as water or oil suspension or other liquid formulation such as syrup, solution, suspension or the like; for parenteral administration, the pharmaceutical composition may be solution, water solution, oil suspension concentrate, lyophilized powder or the like.
• the formulation of the pharmaceutical composition is selected from tablet, coated tablet, capsule, suppository, nasal spray or injection, more preferably tablet or capsule.
• the pharmaceutical composition can be a single unit administration with an accurate dosage.
• the pharmaceutical composition may further comprise additional active ingredients.
• compositions disclosed herein can be produced by the conventional methods in the pharmaceutical field.
• the active ingredient can be mixed with one or more excipients, then to make the desired formulation.
• the “pharmaceutically acceptable excipient” refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, for example: a diluent, a vehicle such as water, various organic solvents, etc., a filler such as starch, sucrose, etc.
• a binder such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP) ; a wetting agent such as glycerol; a disintegrating agent such as agar, calcium carbonate and sodium bicarbonate; an absorption enhancer such as quaternary ammonium compound; a surfactant such as hexadecanol; an absorption carrier such as Kaolin and soap clay; a lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc.
• PVP polyvinylpyrrolidone
• the pharmaceutical composition further comprises other pharmaceutically acceptable excipients such as a decentralized agent, a stabilizer, a thickener, a complexing agent, a buffering agent, a permeation enhancer, a polymer, aromatics, a sweetener, and a dye.
• other pharmaceutically acceptable excipients such as a decentralized agent, a stabilizer, a thickener, a complexing agent, a buffering agent, a permeation enhancer, a polymer, aromatics, a sweetener, and a dye.
• disease refers to any disease, discomfort, illness, symptoms or indications, and can be interchangeable with the term “disorder” or “condition” .
• C n-m indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C 1-8 , C 1-6 , and the like.
• the reaction for preparing compounds disclosed herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
• suitable solvents can be substantially non-reactive with the starting materials, the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent’s boiling temperature.
• a given reaction can be carried out in one solvent or mixture of solvents.
• Reactions can be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS and TLC.
• Compounds can be purified by a variety of methods, including HPLC and normal phase silica chromatography.
• Chiral analytic HPLC was used for the retention time analysis of different chiral examples, the conditions were divided into the methods as below according to the column, mobile phase, solvent ration used.
• compounds of Formula (I) can be formed as shown in scheme I.
• the compound (i) can be subject to the condensation reaction to give compound (ii) followed by cyclization under heat to get compound (iii) which is used for SN2 reaction to form compound (iv) , the compound (iv) is reacted with substituted morpholine under transitional metal catalyzed reaction to give compound (v) which is hydrolyzed to give the acid compound (vi) , the compound (vi) is used for coupling with different amines under EDCI, HOBt, HATU, PyBOP and etc. to give compound (vii) (i.e., Formula (I) ) .
• the compounds of Formula (I) can also be synthesized by the route in Scheme II. Decarboxylation while halogenation of compound (vi) or direct halogenation of compound (vi-II) can give compound (viii) which is used for Suzuki, Buchwald and etc. reaction under transitional metal to give compound ix (i.e., Formula (I) ) .
• Step 1 diethyl 2- ( ( (5-bromopyridin-3-yl) amino) methylene) malonate (Compound 1-1)
• Step 2 ethyl 7-bromo-4-oxo-1, 4-dihydro-1, 5-naphthyridine-3-carboxylate (Compound 1-2)
• Step 3 ethyl 7-bromo-1- (2-methyl-3- (trifluoromethyl) benzyl) -4-oxo-1, 4-dihydro-1, 5- naphthyridine-3-carboxylate (Compound 1-3)
• Step 4 ethyl 1- (2-methyl-3- (trifluoromethyl) benzyl) -7-morpholino-4-oxo-1, 4-dihydro- 1, 5-naphthyridine-3-carboxylate (Compound 1-4)
• Step 5 1- (2-methyl-3- (trifluoromethyl) benzyl) -7-morpholino-4-oxo-1, 4-dihydro-1, 5- naphthyridine-3-carboxylic acid (Compound 1-5)
• Step 6 N- (2- (dimethylamino) ethyl) -1- (2-methyl-3- (trifluoromethyl) benzyl) -7- morpholino-4-oxo-1, 4-dihydro-1, 5-naphthyridine-3-carboxamide
• Step 1 ethyl (R) -1- (2-methyl-3- (trifluoromethyl) benzyl) -7- (2-methylmorpholino) -4- oxo-1, 4-dihydro-1, 5-naphthyridine-3-carboxylate (Compound 30-1)
• Step 2 (R) -1- (2-methyl-3- (trifluoromethyl) benzyl) -7- (2-methylmorpholino) -4-oxo-1, 4- dihydro-1, 5-naphthyridine-3-carboxylic acid (Compound 30-2)
• Step 3 (R) -3-bromo-1- (2-methyl-3- (trifluoromethyl) benzyl) -7- (2-methylmorpholino) - 1, 5-naphthyridin-4 (1H) -one
• Step 1 ethyl (S) -1- (2-methyl-3- (trifluoromethyl) benzyl) -7- (2-methylmorpholino) -4- oxo-1, 4-dihydro-1, 5-naphthyridine-3-carboxylate (Compound 32-1)
• Step 2 (S) -1- (2-methyl-3- (trifluoromethyl) benzyl) -7- (2-methylmorpholino) -4-oxo-1, 4- dihydro-1, 5-naphthyridine-3-carboxylic acid (Compound 32-2)
• Step 3 (S) -3-bromo-1- (2-methyl-3- (trifluoromethyl) benzyl) -7- (2-methylmorpholino) - 1, 5-naphthyridin-4 (1H) -one
• Step 1 7-bromo-1- (2-methyl-3- (trifluoromethyl) benzyl) -1, 5-naphthyridin-4 (1H) -one (Compound 34-1)
• Step 2 1- (2-methyl-3- (trifluoromethyl) benzyl) -7-morpholino-1, 5-naphthyridin-4 (1H) - one
• Step 1 3-iodo-1- (2-methyl-3- (trifluoromethyl) benzyl) -7-morpholino-1, 5-naphthyridin- 4 (1H) -one (Compound 37-1)
• the Compound 37-1 (500 mg, 63%, brown solid) was prepared in a manner similar to that described in Example 35 from N-Iodosuccinimide.
• LC-MS (M+H) + 529.9.
• Step 2 1- (2-methyl-3- (trifluoromethyl) benzyl) -7-morpholino-3- (trifluoromethyl) -1, 5- naphthyridin-4 (1H) -one
• Step 1 ethyl 7-bromo-1- (3-fluoro-2-methylbenzyl) -4-oxo-1, 4-dihydro-1, 5- naphthyridine-3-carboxylate (Compound 39-1)
• Step 2 ethyl 1- (3-fluoro-2-methylbenzyl) -7-morpholino-4-oxo-1, 4-dihydro-1, 5- naphthyridine-3-carboxylate (Compound 39-2)
• Step 3 1- (3-fluoro-2-methylbenzyl) -7-morpholino-4-oxo-1, 4-dihydro-1, 5- naphthyridine-3-carboxylic acid (Compound 39-3)
• Step 1 ethyl 7-bromo-1- (4-fluorophenethyl) -4-oxo-1, 4-dihydro-1, 5-naphthyridine-3- carboxylate (Compound 40-1)
• LC-MS (M+H) + 418.7, 420.7.
• Step 2 ethyl 1- (4-fluorophenethyl) -7-morpholino-4-oxo-1, 4-dihydro-1, 5- naphthyridine-3-carboxylate (Compound 40-2)
• Compound 40-2 was prepared in a manner similar to that described in compound 1-4 from ethyl 7-bromo-1- (4-fluorophenethyl) -4-oxo-1, 4-dihydro-1, 5-naphthyridine-3-carboxylate. 50 mg. 38%.
• LC-MS (M+H) + 427.8.
• Step 3 7-morpholino-4-oxo-1-phenethyl-1, 4-dihydro-1, 5-naphthyridine-3-carboxylic acid (Compound 40-3)
• Step 4 N- (2- (dimethylamino) ethyl) -1- (4-fluorophenethyl) -7-morpholino-4-oxo-1, 4- dihydro-1, 5-naphthyridine-3-carboxamide
• Example 40 (10 mg, 42%) was prepared in a manner similar to that described in Step 6 of Example 1 from 7-morpholino-4-oxo-1-phenethyl-1, 4-dihydro-1, 5-naphthyridine-3-carboxylic acid and N1, N1-dimethylethane-1, 2-diamine.
• Step 1 ethyl 7-bromo-1- (1- (2, 3-dimethylphenyl) ethyl) -4-oxo-1, 4-dihydro-1, 5- naphthyridine-3-carboxylate (Compound 41-1)
• Step 2 ethyl 1- (1- (2, 3-dimethylphenyl) ethyl) -7-morpholino-4-oxo-1, 4-dihydro-1, 5- naphthyridine-3-carboxylate (Compound 41-2)
• Step 3 1- (1- (2, 3-dimethylphenyl) ethyl) -7-morpholino-4-oxo-1, 4-dihydro-1, 5- naphthyridine-3-carboxylic acid (Compound 41-3)
• Step 4 N- (2- (dimethylamino) ethyl) -1- (1- (2, 3-dimethylphenyl) ethyl) -7-morpholino-4- oxo-1, 4-dihydro-1, 5-naphthyridine-3-carboxamide
• kinase detection reagent was added to simultaneously convert ADP to ATP and allow the newly synthesized ATP to be measured using a luciferase/luciferin reaction. After incubation for 0.5hr at room temperature, the light generated was measured on a PHERAstar FS plate reader (BMG LABTECH) . The IC 50 values were calculated based on inhibition of Enzymatic activity in the presence of increasing concentrations of compounds disclosed herein.

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