WO2011138657A1 - Composés oléfiniques à substitution aryle en tant qu'inhibiteurs de la pde10a - Google Patents

Composés oléfiniques à substitution aryle en tant qu'inhibiteurs de la pde10a Download PDF

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WO2011138657A1
WO2011138657A1 PCT/IB2011/000948 IB2011000948W WO2011138657A1 WO 2011138657 A1 WO2011138657 A1 WO 2011138657A1 IB 2011000948 W IB2011000948 W IB 2011000948W WO 2011138657 A1 WO2011138657 A1 WO 2011138657A1
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phenyl
methyl
prop
chlorophenyl
ylmethoxy
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PCT/IB2011/000948
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Prasada Rao V. S. Lingam
Abraham Thomas
Neelima Khairatkar-Joshi
Malini Bajpai
Srinivas Gullapalli
Dnyaneshwar Harishchandra Dahale
Ajit Shankar Mindhe
Vijay Eknath Rathi
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Glenmark Pharmaceuticals S.A.
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Publication of WO2011138657A1 publication Critical patent/WO2011138657A1/fr

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    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to aryl substituted olefinic compounds and their use in treating or preventing diseases, conditions and/or disorders by inhibiting phosphodiesterase 1 OA (PDE1 OA) enzyme.
  • PDE1 OA phosphodiesterase 1 OA
  • the cyclic nucleotide phosphodiesterases are a class of intracellular enzymes related to a family of phosphohydrolases that selectively catalyze the hydrolysis of the 3' cyclic phosphate bonds of adenosine and/or guanosine 3', 5' cyclic monophosphates (cAMP/cGMP) into their respective 5' monophosphates (5'-AMP/GMP).
  • the cyclic nucleotides cAMP and cGMP act as second messengers of intracellular signal transduction in response to extracellular stimuli and are synthesized from ATP and GTP by the catalytic cyclization activity of enzymes adenylyl and guanylyl cyclases, respectively.
  • PDEs play a very important role in signal transduction by regulating the cellular levels of these second messengers (cAMP/cGMP) in the way o f controlling their rates of degradation.
  • Mammalian PDEs are composed of 21 genes and are categorized into 1 1 families (PDE 1 to PDE1 1 ), with each family typically having several different isoforms and splice variants, based on sequence homology, enzymatic properties, biochemical characteristics and sensitivity to inhibitors. These unique PDEs differ in their three-dimensional structures, kinetic properties, modes of regulation, intracellular localization, cellular expression patterns with different individual isozymes modulating distinct regulatory pathways in the cell. Furthermore, PDEs are di ferentially expressed throughout the body, including in the central nervous system, serving distinct physiological functions. Thus PDEs provide an unique opportunity of selective drug targets for the potential treatment of specific disease states.
  • PDEs are also subclassified based on different substrate specificites into cAMP selective (PDE4, 7 and 8), cGMP selective (PDE5, 6 and 9) and cAMP and cGMP dual selective (PDEl , 2, 3, 10 and 1 1 ).
  • the human PDEI OA family enzyme was reported essentially at the same time by two different groups (Fujishige K et al., J. Biol. Chem. vol. 274, p.18438- 1 8445, ( 1 999); Loughney K et al., Gene vol. 234, p.
  • mice PDEI OA 1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively.
  • PDEI OA hydrolyzes cAMP with a Km of 0.05 ⁇ and cGMP with a Km of 3 ⁇ , suggesting that the affinity of PDEI OA for cAMP is higher than for cGMP.
  • Vmax ratio of cGMP/cAMP is 4.7
  • PDE 1 OA is a unique cAMP-inhibited cGMP phosphodiesterase [Soderling, S KI et al. ' , Proc. Natl. Acad. Sci. USA vol. 96 p. 7071 -7076, ( 1 999); Fuj ishige et al ., J. Biol. Chem. vol. 274, p. 1 8438- 1 8445, (1999)].
  • the PDE I OA family of polypeptides shows a lower degree of sequence homology to previously identified PDE families. These low degrees of sequence homology of PDEI OA family of polypeptide make them insensitive to certain inhibitors that are known to be specific for other known PDE families (US 6,350,603, incorporated herein by reference).
  • PDE I OA which is one of the PDE subtypes
  • the expression of its mR A has been identified in many tissues and organs such as striatum, testis, kidney, thyroid gland, pituitary gland, thalamus, cerebellum, heart, lungs and placenta, cells such as aortic smooth m-.iscle cells and aortic endothelial cells, cells of cancers such as lung small cell carcinoma, breast cancer and large bowel cancer.
  • aortic smooth m-.iscle cells and aortic endothelial cells cells of cancers such as lung small cell carcinoma, breast cancer and large bowel cancer.
  • this enzyme is suggested to be involved in, for example, onset or progression of various disorders and diseases related to striatal, basal ganglia related dysfunctions/disorders such as schizophrenia (positive, negative & cognitive symptoms), parkinson's disease, Huntington disease, obsessive compulsive disorders, sleep disorders and disorders of changed circardian rhythm [Siuciak JA et al., Neuropharmacology, vol 51 , p. 374-385, (2006); Threlfell S ef al ., JPET, vol 328, p.
  • Neurodegenerative diseases There are very few effective treatments for neurological disorders characterized by progressive cell loss, known as neurodegenerative diseases, as well as those involving acute cell loss, such as stroke and trauma.
  • neurodegenerative diseases such as those involving acute cell loss, such as stroke and trauma.
  • neurosis which has been linked to altered striatal function relating to changes in expression of the enzyme PDE I OA [J. A. Siuciak, et al. Neuropharmacology, vol . 5 1 , p. 374- 385, (2006)].
  • Striatal dysfunction is implicated in a number of CNS disorders including psychosis, schizophrenia, obsessive-compulsive disorders, Parkinson's disease and Huntington's disease.
  • PDEI OA inhibitors are useful for treating and/or preventing various diseases caused by enhanced activity of PDE I OA, possibly with reduced side effects (for example, a neural disease such as Parkinson's disease, Huntington disease or Alzheimer's disease, dyskinesia, hypogonadism, diabetes, an ischemic heart disease, hypertension, an inflammatory disease, a disease of the digestive system, an allergic disease, osteoporosis, pain or a malignant tumor).
  • a neural disease such as Parkinson's disease, Huntington disease or Alzheimer's disease, dyskinesia, hypogonadism, diabetes, an ischemic heart disease, hypertension, an inflammatory disease, a disease of the digestive system, an allergic disease, osteoporosis, pain or a malignant tumor.
  • WO 2003/000269, WO 2003/0141 15, WO 2003/0141 16, WO 2003/0141 1 7, WO 2003/051 877, WO 2006/034491 and WO 2006/034512 describe PDE10 inhibitors for treatment of neurodegenerative diseases, cancer, diabetes and its related disorders.
  • WO 2006/072828, WO 2008/084299, WO 2003/093499, WO 2005/082883, WO 2005/120514, WO 2006/01 1 040, WO 2006/070284, WO 2007/077490, WO 2007/085954, WO 2007/096743, WO 2007/1 291 83, WO 2008/001 182, WO 2008/0041 17, WO 2008/020302, WO 2009/070584, WO 2009/068320 ; WO 2009/068246 and WO 2009/036766 describe PDE10 inhibitors for treatment of obesity, diabetes, certain central nervous system disorders, neurodegenerative and psychiatric disorders.
  • WO 2009/029214, WO 2009/025839 and WO 2009/025823 describe PDE I O inhibitors lor treatment of obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder and obsessive-compulsive disorder.
  • WO 2009/143 178, WO 2009/1 52825, WO ' 2009/1 58393, WO 2009/1 58467, WO 2009/158473, WO 2010/006130, WO 2010/017236, WO 201 0/027097 and WO 201 0/030027 describe PDE10 inhibitors for treatment of anxiety, schizophrenia, drug addiction, movement disorder, certain central nervous system disorders, neurodegenerative and psychiatric disorders.
  • the present invention relates to compounds of the formula (I):
  • A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl
  • Y is a bond, or is selected from -(CR 4 R 3 ) P - and -S0 2 -;
  • Z is selected from substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein said cyclic ring may be monocyclic, bicyclic or spirocyclic;
  • G ] and G 2 are independently selected from, hydrogen, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl , heterocyclyl, -(CR 4 R 5 ) P R 8 , -(CR 4 R 5 ) p C(0)R 8 , -(CR 4 R 5 ) P -NR 9 R 10 , -(CR 4 R 5 ) p -OR' ' , -C(0)R 8 , - C(0)(CR 4 R 5 ) p R 8 , -C(0)NR 9 R 10 , -NR 9 R 10 , -NR 3 C(0)R 8 , -NR 3 C(0)NR 9 R 10 , -N(R 3 )S0 2 R 8 , - OC(0)R 8 and -OC(0)NR 9 R 10 ; with the provis
  • R is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and -C(0)OR a ;
  • R 4 , R 5 , R 6 and R 7 which may be the same or different, are independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy.
  • R 8 is selected from hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl. cyanoalkyl. haloalkoxy, cycloalkyl.
  • cycloalkylalkyl cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -(CR D R E ) Q R A , -C(0)R A , -C(0)NR B R C , -C(0)OR A , -NR B R C , -NR B C(0)R A , -NR B C(0)NR B R C , -N(R b )S0 2 R 8 , -OC(0)R A , -OC(0)NR B R , - S(0)R A , -S0 2 R A , -SONR B R C , -S0 2 NR B R C and -SR A ;
  • R 9 and R 1 0 which may be the same or different, are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl. hydroxyalkyl, haloalkyl, cyanoalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl .
  • R 9 and R 10 together with the nitrogen atom to which they are attached, may form an optionally substituted heterocyclyl or heteroaryl ring, wherein said heterocyclic or heteroaryl ring may contain 1 , 2, 3 or 4 hetero atom(s) selected from O, S or N;
  • R " is selected from hydrogen, nitro, substituted or unsubstituted alkyl, alkenyl. al kynyl . alkoxyalkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl.
  • R A , R D and R which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, haloalkyl , hydroxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, -C(0)OR R , -NR R R G , -C(0)N R L R E J cycloalkyl, aryl, heteroaryl and heterocyclyl;
  • R B and R C which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxy, -C(0)OR F , -C(0)NR F R E , cycloalkyl, aryl, heteroaryl and heterocyclyl : at each occurrence, R f and R 8 are independently selected from hydrogen, alkyl, alkenyl and -C(0)alkyl;
  • 'm' is an integer ranging from 0 to 5, both inclusive;
  • 'n' is an integer ranging from 0 to 4, both inclusive;
  • 'p' is an integer ranging from 1 to 3, both inclusive;
  • 'q' is an integer ranging from 1 to 3, both inclusive;
  • the compounds of formula (I) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
  • A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl
  • Y is a bond, or is selected frorn -(CR 4 R 5 ) p - and -S0 2 -;
  • Z is selected from substituted or unsubstituted alkyl, cycloalkyl, aryl, helerocyclvl and heteroaryl, wherein said cyclic ring may be monocyclic, bicyclic or spirocyclic;
  • R ! and R 2 are independently selected from halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, alkenyl. alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, arylalkyl, heterocyclyl, heterocyclylalkyl heteroaryl, heteroarylalkyl, -C(0)R A , -C(0)NR B R C , -C(0)OR A , -NR B R C , -NR H C(0)R A , - N R B C(0)NR B R C , -N(R b )S0 2 R A , -OC(0)R A , -OC(0)
  • R 3 is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and -C(0)OR A ;
  • R 4 , R 5 , R 6 and R 7 which may be the same or different, are independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(0)OR A , -NR B R C and -SR A ; or R 4 and R 5 , at each occurrence, together with the carbon atom to which they are attached, may form an optional ly substituted cycloalkyl or heterocyclyl ring;
  • R 9 and R 1 0 which may be the same or different, are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalky L - (CR D R C ) Q R ⁇ -C(0)R A , -C(0)NR B R C , -C(0)OR A , -S(0)R A , -S0 2 R A , -S(0)NR B R C and -S0 2 R B R T: ; or R 9 and R 1 0 together with the nitrogen atom to which they are attached,
  • R A , R D and R E which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, -C(0)OR F , -NR F R 8 , -C(0)NR F R 8 , cycloalkyl. aryl. heteroaryl and heterocyclyl;
  • R B and R C which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxy, -C(0)0R', -C(0)NR F R , cycloalkyl, aryl, heteroaryl and heterocyclyl; at each occurrence, R f and R s are independently selected from hydrogen, alkyl. alkenyl and -C(0)alkyl;
  • 'm' is an integer ranging from 0 to 5, both inclusive;
  • ' ⁇ ' is an integer ranging from 0 to 4, both inclusive;
  • 'p' is an integer ranging from 1 to 3, both inclusive;
  • 'q' is an integer ranging from 1 to 3, both inclusive.
  • R 1 is halogen (e.g., fluorine or chlorine), haloalkyl (e.g., trifluoromethyl), alkoxy (e.g., methoxy) or haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy); and ⁇ ' is 1 .
  • halogen e.g., fluorine or chlorine
  • haloalkyl e.g., trifluoromethyl
  • alkoxy e.g., methoxy
  • haloalkoxy e.g., difluoromethoxy or trifluoromethoxy
  • R 1 0 is hydrogen, alkyl (e.g., methyl or ethyl), cyanoalkyl (e.g., cyanoethyl), haloalkyl (e.g., trifluoromethyl, trifluoroethyl), hydroxyalkyl (e.g., hydroxyethyl), cycloalkyl (e.g., cyclopropyl), heterocyclyl (e.g., piperidinyl) or heteroaryl (e.g., thiazole).
  • alkyl e.g., methyl or ethyl
  • cyanoalkyl e.g., cyanoethyl
  • haloalkyl e.g., trifluoromethyl, trifluoroethyl
  • hydroxyalkyl e.g., hydroxyethyl
  • cycloalkyl e.g., cyclopropyl
  • heterocyclyl
  • R 1 0 is -(CR D R E ) Q R A ; wherein R D and R E are independently alkyl (e.g., methyl or ethyl), hydroxyalkyl (e.g., hydroxymethyl) or phenyl and R A is hydrogen.
  • R D and R E are independently alkyl (e.g., methyl or ethyl), hydroxyalkyl (e.g., hydroxymethyl) or phenyl and R A is hydrogen.
  • 'q' is 1.
  • R 1 0 is -(CR D R E ) Q R A ; wherein both R D and R C are hydrogen and R A is -NR R R E or -C(0)NR'R s .
  • R* and R G are independently hydrogen, alkyl (e.g., methyl or ethyl) or -C(0)alkyl (e.g., -C(O)methyl); and 'q' is 1 or 2.
  • R 1 0 is -(CR D R E ) Q R A ; wherein both R D and R E are hydrogen or alkoxy (e.g.. methoxy) and R'' is hydrogen.
  • 'q' is 2.
  • R 1 0 is -(CR D R E ) Q R A ; wherein R A is hydrogen; R D is alkyl (e.g., methyl) and R C is -C(0)OR ⁇
  • R 1 is hydrogen or alkyl (e.g., ethyl); and 'q ' is 1 .
  • A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl
  • Y is a bond, or is selected from -(CR 4 R 5 ) P - and -S0 2 -;
  • Z is selected from substituted or unsubstituted alkyl, cycloalkyl, aryl. heterocyclyl and heteroaryl, wherein said cyclic ring may be monocyclic, bicyclic or spirocyclic;
  • R 1 and R 2 which may be the same or different, are independently selected from halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, alkenyl . alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl. cycloalkylalkyl .
  • cycloalkenyl cycloalkenylalkyl, aryl, aryloxy, arylalkyl, heterocyclyl, heterocyclylalkyl , heteroaryl, heteroaryl alkyl, -C(0)R A , -C(0)NR B R C , -C(0)OR A , -NR B R C , -NR B C(0)R A , - N R B C(0)NR B R C , -N(R B )S0 2 R A , -OC(0)R A , -OC(0)NR R C , -S(0)R A , -S0 2 R A , -SON R. B R C , - S0 2 NR B R C and -SR";
  • R is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, a'kynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and -C(0)OR A ;
  • R 4 , R 5 , R 6 and R 7 which may be the same or different, are independently selected from hydrogen, halogen, nitro, cyano, hydroxy] , substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(0)OR a , -NR b R c and -SR a ; or R 4 and R ' ⁇ at each occurrence, together with the carbon atom to which they are attached, may form an optional ly substituted cycloalkyl or heterocyclyl ring;
  • R 9 and R 10 which may be the same or different, are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryl alkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylal kyl, - (CR d R e ) q R a , -C(0)R a , -C(0)NR R c , -C(0)OR a , -S(0)R a , -S0 2 R ;1 , -S(0)NR b R c and -S0 2 N R h R c ; or R 9 and R
  • R a , R d and R e which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, haloalkyl. hydroxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, -C(0)OR r , -NR r R g , -C(0) R f R , cycloalkyl, aryl, heteroaryl and heterocyclyl;
  • R b and R c which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl , alkoxy, -C(0)OR f , -C(0)NR r R , cycloalkyl, aryl, heteroaryl and heterocyclyl;
  • R f and R g are independently selected from hydrogen, alkyl, alkenyl and -C(0)alkyl;
  • ⁇ ' is an integer ranging from 0 to 5, both inclusive;
  • 'n' is an integer ranging from 0 to 4, both inclusive;
  • 'p' is an integer ranging from 1 to 3, both inclusive;
  • 'q' is an integer ranging from 1 to 3, both inclusive.
  • R is halogen (e.g., fluorine or chlorine);
  • R 10 is alkyl (e.g., methyl), cyanoalkyl (e.g., cyanoethyl) or -(Cl ⁇ R ⁇ q R 11 ; wherein R d and R c are independently alkyl (e.g., methyl or ethyl) or hydroxyalkyl (e.g.. hydoxymethyl) and R a is hydrogen.
  • R d and R c are independently alkyl (e.g., methyl or ethyl) or hydroxyalkyl (e.g.. hydoxymethyl) and R a is hydrogen.
  • 'q' is 1 .
  • A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl ;
  • Y is a bond, or is selected from -(CR R 5 ) P - and -S0 2 -;
  • Z is selected from substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein said cyclic ring may be monocyclic, bicyclic or spirocyclic; al each occurrence, R 1 and R 2 , which may be the same or different, are independently selected from halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, arylalkyl, heterocyclyl, heterocyclylal kyl, heteroaryl, heteroarylalkyl, -C(0)R A , -C(0)NR B R C , -C
  • R 3 is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and -C(0)OR A ;
  • R 4 , R 5 , R 6 and R 7 which may be the same or different, are independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl , aryl, heterocyclyl, heteroaryl, -C(0)OR A , -NR B R C and -SR A ; or R 4 and R 5 , at each occurrence, together with the carbon atom to which they are attached, may form an optionall y substituted cycloalkyl or heterocyclyl ring;
  • R 9 and R 1 0 which may be the same or different, are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl. hydroxyalkyl, haloalkyl, cyanoalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylal kyl, - (CR D R E ) Q R A , -C(0)R A , -C(0)NR B R C , -C(0)OR A , -S(0)R A , -S0 2 R A , -S(0)NR B R C and -S0 2 NR B R C ; or R 9 and R 1 0 together with.
  • the nitrogen atom to which they are attached may form an optionally substituted heterocyclyl or heteroaryl ring, wherein said heterocyclic or heteroaryl ring may contain 1 , 2, 3 or 4 hetero atom(s) selected from O, S or N ;
  • R A , R D and R E which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, -C(0)OR F , -NR F R G , -C(0)NR R R G , cycloalkyl, aryl, heteroaryl and heterocyclyl; at each occurrence, R and R c , which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl. cyanoalkyl, alkoxy, -C(0)OR r , -C(0)NR r R g , cycloalkyl, aryl, heteroaryl and heterocyclyl; .
  • R f and R are independently selected from hydrogen, alkyl, alkenyl and -C(0)alkyl;
  • 'm' is an integer ranging from 0 to 5, both inclusive;
  • 'n' is an integer ranging from 0 to 4, both inclusive;
  • 'p' is an integer ranging from 1 to 3, both inclusive;
  • 'q' is an integer ranging from 1 to 3, both inclusive.
  • R 1 is halogen (e.g., fluorine or chlorine); and 'm' is 1 or 2.
  • R 9 is hydrogen or alkyl, preferably methyl.
  • R 10 is alkyl (e.g., methyl), alkynyl (e.g., prop-2-nyl), -C(0)R a , cyanoalkyl (e.g., cyanoethyl) or heterocyclyl (e.g., pyrrolidinyl, pyrrolidin-2-one, piperidinyl, piperidin-2- one or ethyl piperidine- l -carboxylate).
  • R" is alkyl (e.g., methyl) or alkoxyalkyl (e.g., -CH 2 -OCH 3 ).
  • R 10 is -(CR d R e ) q R a ; wherein both R d and R e are hydrogen and R a is alkoxy (e.g., methoxy) or -NR f R 8 .
  • R 1 and R s are independently hydrogen, alkyl (e.g., methyl) or -C(0)alkyl, preferably -C(O)methy) ; and 'q ' is 2.
  • A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl
  • X is a bond, or is selected from -0-, -S-, -NR 3 -, -S(O)-, -S0 2 -, -(CR"R 5 ) P O-
  • Z is selected from substituted or unsubstituted alkyl. cycloalkyl. ary 1. helerocycl yl and heteroaryl, wherein said cyclic ring may be monocyclic, bicyclic or spirocyclic:
  • Met is selected from heteroaryl and heterocyclyl; wherein said heteroaryl and heterocyclyl may optionally be substituted with atleast one R ;
  • R 1 and R 2 which may be the same or different, are independently selected from halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, alkenyl. alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, arylalkyl, heterocyclyl, heterocyclylalkyl.
  • R 3 is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl. alkenyl . alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and -C(0)OR A ;
  • R 4 , R 5 , R 6 and R 7 which may be the same or different, are independently selected from hydrogen, halogen, nitro. cyano, hydroxyl, . substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, -C(0)OR A , -NR B R C and -SR A ; or R" and R 5 . at each occurrence, together with the carbon atom to which they are attached, may form an optional ly substituted cycloalkyl or heterocyclyl ring;
  • R 12 is selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, hydroxyalkyl, haloalkyl and alkoxy;
  • R a is selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl , haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, -C(0)OR F , -NR R R S , -C(0)NR ( R S : cycloalkyl, aryl, heteroaryl and heterocyclyl;
  • R B and R C which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl . alkoxy, -C(0)OR F , -C(0)NR , R , cycloalkyl, aryl, heteroaryl and hetei Ocyclyl ; at each occurrence, R f and R ⁇ are independently selected from hydrogen, alkyl. alkenyl and -C(0)alkyl;
  • 'm' is an integer ranging from 0 to 5, both inclusive;
  • 'n' is an integer ranging from 0 to 4, both inclusive;
  • 'p' is an integer ranging from 1 to 3, both inclusive.
  • ring A is aryl, preferably phenyl.
  • R 1 is halogen (e.g., fluorine or chlorine), haloalkyl (e.g., trifluoromethyl). alkoxy (e.g., methoxy or ethoxy) or haloalkoxy (e.g., difluoromethoxy or trifluoromethoxy); and 'nf is 1 or 2.
  • halogen e.g., fluorine or chlorine
  • haloalkyl e.g., trifluoromethyl
  • alkoxy e.g., methoxy or ethoxy
  • haloalkoxy e.g., difluoromethoxy or trifluoromethoxy
  • 'nf is 1 or 2.
  • R 2 is halogen (e.g., fluorine or chlorine) or alkoxy (e.g., methoxy or ethoxy); and ' n' is 1 .
  • substituted or unsubstituted alkyl e.g., methyl or ethyl
  • haloalkyl e.g., trifluoromethyl
  • A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl
  • Y is a bond, or is selected from -(CR 4 R ;, ) p - and -S0 2 -;
  • Z is selected from substituted or unsubstituted alky], cycloalkyl, aryl. heterocyclyl and heteroaryl, wherein said cyclic ring may be monocyclic, bicyclic or spirocyclic;
  • Met is selected from heteroaryl and heterocyclyl; wherein said heteroaryl and
  • heterocyclyl may optionally be substituted with atleast one R ;
  • R 1 and R 2 which may be the same or different, are independently selected from halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl. alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl. cycloa! ky alky L cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, arylalkyl, heterocyclyl . heterocyclylalky! .
  • R 3 is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl. alkenyl, alkynyl. alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and -C(0)OR a ;
  • R 4 , R 5 , R 6 and R 7 which may be the same or different, are independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy.
  • cycloalkyl aryl, heterocyclyl, heteroaryl, -C(0)OR a , -NR b R c and -SR a ; or R 4 and R 5 , at each occurrence, together with the carbon atom to which they are attached, may form an optional ly substituted cycloalkyl or heterocyclyl ring;
  • R 12 is selected from hydrogen, halogen, hydroxyl. cyano. substituted or unsubstituted alkyl, hydroxyalkyl, haloalkyl and alkoxy;
  • R A is selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, -C(0)OR F , -NR R R , -C(0)NR' R 5 ⁇ cycloalkyl, aryl, heteroaryl and heterocyclyl; '
  • R B and R C which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl . alkoxy, -C(0)OR F , -C(0)NR R R G , cycloalkyl, aryl, heteroaryl and heterocyclyl ;
  • R f and R 8 are independently selected from hydrogen, alkyl. alkenyl and -C(0)alkyl;
  • 'm' is an integer ranging from 0 to 5, both inclusive;
  • ' ⁇ ' is an integer ranging from 0 to 4, both inclusive;
  • 'p' is an integer ranging from 1 to 3, both inclusive.
  • R 1 is halogen, preferably chlorine; and 'm' is 1 .
  • A is selected from cycloalkyl, aryl, heteroaryl and heterocyclyl
  • R 5 ) P (R 6 )C C(R 7 )-;
  • Y is a bond, or is selected from -(CR 4 R 3 ) P - and -S0 2 -;
  • Z is selected from substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein said cyclic ring may be monocyclic, bicyclic or spirocyclic;
  • R 1 and R 2 which may be the same or different, are independently selected from halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, alkenyl. alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylal k yL cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, arylalkyl. heterocyclyl. heterocyclylalkyl .
  • R 3 is selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl. alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and -C(0)OR a ;
  • R 4 , R 3 , R 6 and R 7 which may be the same or different, are independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, haloalkyl. haloalkoxy.
  • cycloalkyl aryl, heterocyclyl, heteroaryl, -C(0)OR a , -NR b R c and -SR a ; or R 4 and R 5 , at each occurrence, together with the carbon atom to which they are attached, may form an optionally substituted cycloalkyl or heterocyclyl ring;
  • R" is selected from hydrogen, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyL cycloalkenylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl.
  • R , R D and R C which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, -C(0)OR R , -NR'R 8 , -C(0)NR R R 8 S cycloalkyl ; aryl, heteroaryl and heterocyclyl;
  • R B and R C which may be the same or different, are independent ly selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, cyanoal kyl. alkoxy, -C(0)OR.', -C(0)NR F R G , cycloalkyl, aryl, heteroaryl and heterocyclyl;
  • R 1 and R are independently selected from hydrogen, alkyl, alkenyl and -C(0)alkyl;
  • 'm' is an integer ranging from 0 to 5, both inclusive;
  • 'n' is an integer ranging from 0 to 4, both inclusive;
  • 'p' is an integer ranging from 1 to 3, both inclusive;
  • 'q' is an integer ranging from 1 to 3, both inclusive.
  • R 1 is halogen, preferably fluorine or chlorine; and 'm' is 1 .
  • R 1 1 is aryl, preferably phenyl.
  • the present invention also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compounds described in the present patent application 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.
  • the compounds and pharmaceutical compositions of the present invention are useful for inhibiting PDE 1 0A, which is related to a variety of disease states.
  • the present invention further provides a method of treating a disease, condition or disorder modulated by a PDE10A, in a subject by administering to the subject in need thereof a therapeutically effective amount of a compound of formulas (I) to (If) or a pharmaceutical composition described herein.
  • the illustrative examples of the present invention are screened for 'in vivo' PDE 1 OA based efficacy in a rat model of Dizocilpine (MK-801) - induced psychotic behavior.
  • Example 91 The effect of Example 91 on MK-801 - induced psychosis behavior in female SD rats as shown in Figure 1 and the effect of Example 1 77 on MK-801 - induced psychosis behavior in female SD rats as shown in Figure 2.
  • halogen or halo means fluorine, chlorine, bromine or iodine.
  • alkyl refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n- propyl, 1 -methylethyl (isopropyl), n-butyl, n-pentyl and 1 , 1 -dimethylethyl (t-butyl). Unless set forth or recited to the contrary, all alkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkenyl refers to a hydrocarbon chain containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Examples of such alkenyl moiety includes, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl (allyl), wo-propenyl, 2-methyl- l - propenyl, 1 -butenyl and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkynyl refers to a hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 1 0 carbon atoms being preferred).
  • alkynyl moiety include, but are not limited to, ethynyl, propynyl and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxy refers an alkyl group attached via an oxygen linkage to the rest of the molecule. Examples of such alkoxy-moiety include, but are not limited to, -OCFI3 and -OC2M5. Unless set forth or recited to the contrary, all alkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxyalkyl or alkyloxyalkyl refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above. Example of such alkoxyalkyl moiety includes, but are not limited to, -CH 2 OCH 3 and -CH 2 OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkyl refers to at least one halo group (selected from F. CI, Br or I), linked to an alkyl group as defined above.
  • haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl. 2,2,2-trifluoroethyl and fluoromethyl groups. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms.
  • haloalkoxy include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifiuoroethoxy,. pentafluoroethoxy, pentachloroethoxy, chloromethoxy. dichlorormethoxy, trichloromethoxy and 1 -bromoethoxy.
  • all haloalkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
  • ' 'hydroxyalkyl refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups.
  • Examples of hydroxyalkyl moiety include, but are not limited to -CH2OH and -C 2 H 4 OH. Unless set forth or recited to the contrary, all hydroxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • cyanoalkyl refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by cyano groups.
  • Examples of cyanoalkyl moiety include, but are not limited to -CH 2 CN and -C 2 H 4 CN. Unless set forth or recited to the contrary, all cyanoalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 1 2 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl .
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g., sprio(4.4)non-2-yl, spiro
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group.
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Examples of cycloalkylalkyl moiety include, but are not limited to cyclopropylmethyl, cyclobutylethyl, and eye lopentyl ethyl. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cvclopentenyl . Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, directly attached to an al kyl group.
  • the cycloalkenylalkyl group may be attached to the main structure at any carbon atom in t he alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all cycloalkenylalkyl 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, tetrahydronapthyl, indanyl and biphenyl. Unless set forth or recited to the contrary, all aryl groups described herein may be substituted or unsubstituted.
  • aryloxy refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule.
  • Examples of aryloxy moiety include, but are not l imited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above.
  • arylalkyl moiety include, but are not limited to -CH2C6H5 and -C2H4C6H5. Unless set forth or recited to the contrary, all arylalkyl groups described herein may be substituted or unsubstituted.
  • heterocyclic ring or “heterocyclyl” unless otherwise speci fied refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may- include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sul fur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s). Examples of such heterocyclic ring radicals include, but are not limited to azepinyl.
  • azetidinyl benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl. decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl.
  • phenoxazinyl quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sul f ne. 1 ,4 azathianyl, 7-aza-spiro[3,3]heptanyl, 7-spiro[3,4]octanyl, and 7-aza- spiro[3.4]octanyl .
  • heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • al l heterocyclyl groups described 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. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described herein may be substituted or unsubstituted.
  • heteroaryl refers to substituted or unsubstituted 5 to 1 4 membered aromatic heterocyclic ring radical 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 radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl. indolyl, isoindolyl. pyrrolyl, triazolyl.
  • thiazolyl isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl.
  • benzothienyl benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl, furo[3,2-6]pyridinyl, pyrrolo[3 ,2- >] pyridinyl, thieno
  • all heteroaryl groups described 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 herein may be substituted or unsubstituted.
  • substituted or unsubstituted heterocyclylalkyl ring substituted or unsubstituted heteroarylalkyl . substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine.
  • substituted heterocyclylalkyl ring substituted or unsubstituted heteroarylalkyl, or substituted or unsiibstituted heterocyclic ring.
  • the substituents in the aforementioned "substituted” groups cannot be further substituted.
  • substituent on “substituted alkyl” is "substituted aryl”
  • the substituent on “substituted aryl” cannot be "substituted alkenyl”.
  • 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; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • subject includes mammals (especially humans). Other mammals i ncl ude domestic animals (e.g., household pets including cats and dogs) and 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 state, disorder or condition, is sufficient to effect such treatment.
  • 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.
  • salts forming part of this patent application include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydrox ide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine), salts of chiral bases (such as alkylphenylamine, glycinol, and phenyl glycinol), salts of natural amino acids (such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine), salts of non-natural amino acids (such as D
  • salts include acid addition salts (where appropriate) such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifiuoroacetate), tartrates, maleates, citrates, fumarates, succinates. palmoates. methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates and ketoglutarates.
  • acid addition salts such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifiuoroacetate), tartrates, maleates, citrates, fumarates, succinates. palmoates. methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates and ketoglutarates.
  • Compounds described herein can comprise one or more asymmetric carbon atoms and thus can occur as racemic mixtures, enantiomers and diastereomers. These compounds can also exist as conformers/rotamers. All such isomeric forms of these compounds are expressly included in the present patent application. Although the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral centre are envisioned as a part thereof. In addition, compounds of Formulas (I) to (If) can exist in different geometrical isomeric forms. Unless otherwise stated a reference to a particular compound includes al l such isomeric forms, including racemic and other mixtures thereof.
  • the pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof.
  • the compounds described herein may be associated with one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof in the form of capsule, sachet, paper or other container.
  • suitable carriers include, but are not limited to, water, salt sol utions, 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, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides. pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composition may also include one or more pharmaceutical ly acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmetic pressure, buffers, sweetening agents, flavoring agents, colorants or any combination of the foregoing.
  • the pharmaceutical composition of the patent application may be formulated so as to provide quick, sustained or delayed release of the active ingredien after administration to the subject by employing methods known in the art.
  • compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • the active compound is 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 is adsorbed on a granular solid contai ner, for example, in a sachet.
  • compositions may be in conventional forms, for example, capsules, 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 patent application 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).
  • the oral route is preferred.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), 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 arc particularly suitable for oral application. Preferable carriers for tablets, dragees. or capsules include lactose, cornstarch and/or potato starch. A syrup or elixir is used in cases where a sweetened vehicle is employed.
  • 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.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil .
  • Suitable doses of the compounds for use in treating the diseases and disorders descri bed herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in humans 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.
  • the daily dosage of the PDE 1 0A inhibitors 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 present patent application.
  • the present patent application provides a method of treating a disease, condition or disorder modulated by a PDE10A, in a subject by administering to the subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition described herein.
  • the present patent application further provides a method of treating diseases, disorders or conditions, modulated by a PDE1 0A in mammals including human., of neuropsych iatric. neurodegenerative, neurological, neuroendocrinological nature such as, but not limiting to.
  • schizophrenia, psychoses, schizoaffective disorders positive symptoms of schizophrenia including delusions, disordered thoughts and speech, and tactile, auditory, visual, olfactory and gustatory hallucinations, paranoia, paranormal behaviors, negative symptoms of schizophrenia l ike deficits of normal emotional responses or of other thought processes including flat or bl unted affect and emotion, poverty of speech (alogia), inability to experience pleasure (anhedonia), lack of desire to form relationships (asociality), and lack of motivation (avol ition) leading to poor quality of life, functional disabil ities typically regarded as manifestations of psychosis and other comorbidities like cognitive, executive, attention, learning, memory, spatial memory and social cognitive functions, Tic disorders like Tourette's syndrome, autism, autism spectrum disorders, attention deficit hyperactivity disorders (ADHD), pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), mood disorders, anxiety, depression, major depressive disorders, bipolar disorders, manias, aggression, obsessive compuls
  • neurological disorders consisting of movement disorders, ataxias, sensation disorders, cognitive disorders related to multiple sclerosis, amyotrophic lateral sclerosis, abnormalities of brain, spinal cord, nerves leading to symptoms such as paralysis, seizures, catatonias, catalepsies, muscle rigidities, muscle weakness, poor coordination, loss of sensation, confusion, mental suffering, pain and altered levels of consciousness and various other diseases, disorders or conditions related to neuroendocrinological and metabol ic mani festations like change of circardian rhythms, sleep disorders, insomnia, jet lags, eating disorders li ke anorexia nervosa, bulimia nervosa, exercise bulimia or binge eating disorder, aggressive behaviours, obsessive compulsive personality disorders, narcissistic personality disorders, sexual and gender identity disorders, various disorders related to central neurotransmission systems such as dopaminergic, glutamatergic, serotonergic, adrenergic, GABAergic.
  • central neurotransmission systems such as dop
  • EAA excitatory amino acid
  • This patent application also provides a method of treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formulas (1) to (If) effective in treating said disorder or condition.
  • the phrase "deficiency in attention and/or cognition” as used in the phrase “disorder comprising as a symptom a deficiency in attention and/or cognition” refers to a subnormal functioning in one or more cognitive aspects such as memory, intellect, or learning and logic abi lity, in a particular indiv idual relati ve to other individuals within the same general age population.
  • "Deficiency in attention and/or cognition” also refers to a reduction in any particular individual's functioning in one or more cognitive aspects, for example as occur in age-related cognitive decline.
  • disorders that comprise as a symptom a deficiency in attention and/or cognition are dementia, for example, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, Multiple sclerosis, Amyotrophic lateral sclerosis.
  • Down's syndrome or AIDS-related dementia delirium, amnestic disorder, posttraumatic stress disorder, mental retardation, a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression, attention-deficit/hyperactivity disorder and age-related cognitive decline.
  • This patent application also provides a method of treating a mood disorder or mood episode in a mammal, including a human, comprising administerin to said mammal an amount of a compound of formulas (I) to (If) effective in treating said disorder or episode.
  • This patent application also provides a method of treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal a therapeutically effective amount of a compound of formulas (1) to (If) in inhibiting !' ⁇ )! ⁇ 1 0 ⁇ .
  • mood disorders and mood episodes that can be treated according to the present patent application include, but are not limited to, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressi ve episode with catatonic features; a mood episode with postpartum onset; post- stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia; a bipolar disorder, for example bipolar I disorder, bipolar II disorder and cyclothymic disorder.
  • This patent application further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering lo said mammal a therapeutically effective amount of a compound of the present invention in treating said disorder or condition.
  • This patent application further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal a therapeutically effective amount of a compound of formulas (1 ) to ( I f) in inhibiting PDE1 0A.
  • a neurodegenerative disorder or condition refers to a disorder or condition that is caused by the dysfunction and/or death of neurons in the central nervous system.
  • the treatment of these disorders and condi tions can be faci litated by administration of an agent which prevents the dysfunction or death of neurons at risk in these disorders or conditions and/or enhances the function of damaged or healthy neurons in such a way as to compensate for the loss of function caused by the dysfunction or death of at-risk neurons.
  • neurotrophic agent refers to a substance or agent that has some or all of these properties.
  • neurodegenerative disorders and conditions that can be treated according to the present patent application include, but are not limited to, Parkinson's disease; Huntington's disease; dementia, for example Alzheimer's disease, multi-infarct dementia.
  • dementia for example Alzheimer's disease, multi-infarct dementia.
  • a ! DS-related dementia, and Pronto temperal Dementia neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarct: hypoglycemia-induced neurodegeneration; neurodegeneration associated with epi leptic seizure: neurodegeneration associated with neurotoxin poisoning; and multi-system atrophy.
  • the neurodegenerative disorder or condition comprises neurodegeneration of striatal medium spiny neurons in a mammal, including a human.
  • this patent application provides a pharmaceutical composition for treating psychotic disorders, delusional disorders and drug induced psychosis, anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders or drug addiction, comprising a therapeutically effective amount of a compound of the present invention in treating said disorder or condition.
  • this patent application provides a method of treating a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis, anxiety disorders, movement disorders, mood disorders, and neurodegenerative disorders, which method comprises administering a therapeutically effective amount of a compound of the present invention in treating said disorder.
  • this patent application provides a method of treating the disorders above, where the disorders are selected from the group consisting of: dementia, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington ' s disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; posttraumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention- deficit/hyperactivity disorder; age-related cognitive decline, major depressive episode of the mi ld, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post- stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic
  • a method for preventing, ameliorating or treating a disease or condition selected from obesity or related diseases, conditions; diabetes (including Type 1 and Type II diabetes); diabetic complications; glucose tolerance; hyperinsulinemia; insulin sensitivity or resistance; metabolic syndromes; cardiovascular diseases including, for example, atherosclerosis, lipidemia, dyslipidemia. elevated blood pressure, microalbuminemia.
  • hyperuricaemia hypercholesterolemia, hyperlipidemias, hypertriglyceridemias, arteriosclerosis or combination thereof; respiratory diseases or disorders including, for example, sinusitis, asthma, bronchitis or combination thereof; or any combination these diseases, disorders, conditions and/or syndromes thereof; the disease or condition related to serum levels of triglyceride, LDL, HDL, VLDL, total chlolesterol, which method comprises administering to said mammal a therapeutically effective amount of a compound of formulas (I) to (If) in treating said disorder or condition.
  • the compounds of formula (la) can be prepared according to Synthetic scheme 1 .
  • The. phenyl acetic acid derivative of formula (1 ) is condensed with aromatic aldehyde of formula (2) under suitable Perkin reaction conditions [Journal of Medicinal Chemistry, 1 3, ( 1 970)] to gi ve the acrylic acid of formula (3).
  • the regioisomeric amide of formula (lb) can be prepared according to Synthetic scheme 2.
  • the acetic acid of formula (6) is condensed with benzaldehyde derivative of formula (5) under suitable Perkin reaction conditions to give the acrylic acid derivative of formula (7).
  • Coupling of this acid (7) with amine of formula (4) as described above gives the final compound of formu la (i ).
  • the regioiosmeric acrylamide of formula (ib-1 ) where X is an oxygen atom can be prepared as shown in Synthetic scheme 4.
  • 4-hydroxybenzaldehyde of the formula ( 1 4) is condensed with an aryl acetic acid derivative of formula (6) under Perkin reaction conditions in the presence of base such as N-methylmorpholine, triethylamine or diisopropylethylamine in acetic anhydride to give acrylic acid of formula (15).
  • base such as N-methylmorpholine, triethylamine or diisopropylethylamine in acetic anhydride
  • the amine of formula (Ic) can be prepared according to Synthetic scheme 5.
  • the ester of formula ( 1 2a) is reduced to corresponding alcohol of formula ( 19) using diisobutyl aluminium hydride, LiAlH or L1BH 4 in a suitable solvent.
  • the hydroxyl group of formula (1 9) is converted to an appropriate leaving group such as chloride using thionyl chloride or methane sulphonyl chloride or oxalyl chloride to give compound of formula (20).
  • Reaction of Intermediate (20) with an amine of formula (4) in the presence of a base gives the compound of general formula (lc).
  • the compound of formula (Ic) can also be prepared from the alcohol of formula ( 1 9) by its oxidation to the corresponding aldehyde of formula (21 ) using an appropriate oxidizi ng agent such as manganese dioxide followed by reductive amination using an appropriate am ine o f formula (4) in presence of sodium triacetoxyborohydride in acetic acid.
  • an appropriate oxidizi ng agent such as manganese dioxide
  • reductive amination using an appropriate am ine o f formula (4) in presence of sodium triacetoxyborohydride in acetic acid.
  • the compounds of formula (lc-1) (wherein R a is substituted or unsubstituted al kyl) can be prepared according to Synthetic scheme 6.
  • the chloro compound of formula (20) is treated with sodium azide in the presence of suitable solvent to give azide derivati ve, which on reduction with the suitable reducing agent like triphenylphosphine gives amine derivative of formula (22) via an iminophosphinone intermediate [Tetrahedron letters, 39, p. 3287-3290, ( 1 998)] .
  • Intermediate (22) can also be synthesized directly from chloride of formula (20) by treating it with potassium phthalimide followed by hydrazine hydrate in presence of a suitable solvent such as ethanol.
  • the amine derivative of formula (22) is then coupled with the carboxylic acid of formula (23a) using an appropriate coupling agent or acid chloride of formula (23b) in the presence of a base to give the amide of formula (Ic-1 ).
  • the compounds of formula (Id-1), (Id-2), (Id-3) and (Id-4) can be prepared from the aldehyde derivative (21 ) according to Synthetic scheme 7.
  • pyrazole of the formula (Id-1 ) ⁇ Tetrahedron letters, 39, p. 3287-3290, (1998)] is synthesized from aldehyde of formula (21 ) by treating it with diethyl (2- ⁇ 2-[(4-methylphenyl)sulfonyl]hydrazinylidene ⁇ ethyl)phosphonate (24) in the presence of a strong base such as sodium hydride.
  • alkylation of the pyrazole of formula (Id-1 ) with suitable alkyl halide of the formula (25) (where X is halogen) in the presence of suitable base such as K 2 CO 3 gives easily separable regioisomeric mixture of products (Id-2) and (Id-3).
  • suitable base such as K 2 CO 3
  • the aldehyde of formula (21 ) is treated with p-toluenesulphonylmethyl isocyanide (TOSJMI C) in the presence of a suitable base like potassium carbonate in refluxing methanol to give the oxazole derivative of formula (Id-4).
  • compound of formula (Id-5) can also be prepared by treating compound of formula (26) with anhydride (27b) or an acid chloride (27c) under suitable conditions.
  • Oxadiazolone of formula (Id-6) is synthesized, in good yields, from compound of formula (26) and trichloromethyl chloroformate in presence o a base fol lowed by alkylation ⁇ J. Heterocyclic. chem. 1 9, p. 541 , (1982)] .
  • Compound of formula (26) is reacted with carbon disulfide under basic conditions followed by alkylation to give the thio oxadiazole of formula (Id-7) [J. Heterocyclic. chem, 19, p. 541 , (1982)].
  • Triazolothione of formula (Id-8) is prepared from Intermediate (26) by its coupling with potassium thiocyanate followed by cyclization under basic conditions [J. Med, Chem. 37, p. 1 25- 1 32, ( 1 994)] .
  • Substituted and unsubstituted 1 ,3,4-triazoles derivatives of formula (Id-9) is prepared by the reaction of hydrazide (26) with appropriate amidines of formula (28) under suitable conditions.
  • compound of formula (3 1 ) can also be prepared by treating compound of formula (30) with anhydride (27b) under suitable conditions. Deprotection of the carbonate group under basic conditions gives the phenol of formula (32), which on further coupling with alky] halide of formula ( 1 l a) (where L is halogen) under basic conditions or with (l i b) under Mitsunobu reaction conditions gives the final compound of formula (Id-5).
  • the isomeric oxadiazole of formula (Id-10) can be prepared as described in Synthetic scheme ( 1 0).
  • amide of formula (la) where R 9 and R 10 are H, is condensed with N, N- dimethylformamide dimethyl acetal under reflux conditions to give the imine derivative (33).
  • Intermediate (33) on reaction with hydroxyl amine in the presence of a suitable base such as sodium hydroxide gives compound of general formula (Id-10).
  • the triazolothione compound of formula (Id-11) and its corresponding sulphur free aromatic compound of formula (Id-12) can be prepared as shown in Synthetic scheme 1 1 .
  • intermediate (26) is treated with alkylisothiocyanate of the formula (34) under reflux and the intermediate formed is cyclised under basic conditions to give the triazolothione (Id-11 ) [ . Med. Chein. 37, p. 1 25- 132, ( 1994)] .
  • Further oxidative desulphurization of (Id-11 ) by hydrogen peroxide in acetic acid gives the N-substituted triazole derivative (Id-12).
  • the lactam derivative of formula (Id-13) can be prepared according to Synthetic scheme 1 2.
  • the aldehyde of formula (21 ) undergoes wittig reaction with (carbethoxymethvlene) triphenylphosphorane to give the diene ester of formula (35).
  • Michael addition of nitromethane anion, generated by means of suitable base such as 1 , 1 ,2,2-tetramethylguanidine (TMG) gives the adduct of formula (36).
  • TMG tetramethylguanidine
  • Selective reduction of the nitro group using an appropriate reagent such as iron and ammonium chloride under aqueous conditions gives amine of the formula (37).
  • Compound of formula (37) undergoes intramolecular cyclization in refluxing xylene to
  • various regioisomeric olefins can be prepared from hydrazide of the isomeric acid (7). Preparation of one such derivative is shown in Synthetic scheme 13.
  • the acrylic acid of formula (7) was coupled with hydrazine hydrate to give hydrazide of formula (38) using a suitable coupling agent such as EDCI.
  • the oxadiazole derivative (Ie-1) can be prepared as described in Synthetic scheme 1 3 using orthoester of formula (27a) or its equivalent (27b) or (27c) under suitable reaction conditions.
  • the ether derivative of formula (If) can be prepared according to Synthetic scheme 1 4.
  • chloro compound of formula (20) is coupled with alcohol of formula (39) under basic conditions to give ether of general formula (If).
  • final compound of general formula (If) can also be prepared by itsunobu coupling reaction of alcohol ( 1 9) with appropriate aromatic alcohol of formula (39).
  • the compound of general formula (Ig) can be prepared as depicted in Synthetic scheme 1 5.
  • ethyl (4-iodophenyl)acetate derivative (40) undergoes Sonagashira coupling reaction with ethynyltrimethyl silane followed by desilylation using appropriate reagent such as TBAF.H 2 O, to give the acetylene compound of formula (41 ).
  • the coupling reaction of compound of formula (41 ) with 2-bromoquinoline under Sonagashira coupling reaction gives the compound of formula (42).
  • Catalytic reduction of the triple bond of compound of formula (42) followed by hydrolysis gives compound of formula (43).
  • Perkin reaction of compound of formula (43) with aromatic aldehyde (2) gives acid derivative which on further amide coupli ng with amine of formula (4) gives the final compound of general formaul (I ).
  • work-up includes distribution of the reaction mixture between an organic and aqueous phase, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent.
  • Purification refers to purification by silica gel chromatographic techniques, in suitable solvents o f a suitable polarity as the mobile phase or crystallization from an appropriate solvent or mixture o f solvents.
  • DMSO-i 6 hexadeuterodimethyl su lfoxide
  • CDCI3 deuterated chloroform
  • J coupling constant in units of Hz
  • T or rt room temperature (22-26°C).
  • Aq. aqueous; equiv. or eq. : equivalents.
  • fhe starling materials represented by the general formula Z-Y-X- used for the preparation intermediates and compounds of invention are in some cases commercially available or can be prepared according to suitable literature procedure or as described below.
  • the title compound was synthesized by the reaction of 2-aminothiophenol with glycolic acid using 4 hydrochloric acid as described in the literature [Journal of the Chemical Society, p.
  • Step 1 Ethyl 5-amino-6-[2-(trimethylsilyl)ethynyl] pyridine-2-carboxylate:
  • Step 2 Ethyl 5-acetamido-6-[2-(trimethylsilyl)ethynyl]pyridine-2-carboxylate: To the well stirred solution of Step 1 intermediate (5.5 g. 20.659 mmol) in DCM (1 00 ml) was added pyridine (3.3 ml) and the reaction mixture was cooled to 0 °C. Acetyl chloride (1 .76 ml. 24.79 mmol) was then added to the reaction mixture drop wise and the reaction was stirred at room temperature for 2 h. The reaction mixture was quenched with water ( 1 00 ml) and extracted with chloroform (300 ml x 3).
  • Step 3 Ethyl l H-pyrrolo[3,2-j]pyridine-5-carboxylate:
  • Step 2 intermediate 5.5 g. 1 7.84 mmol
  • TH F 50 ml
  • tetra-n-butyl ammonium fluoride 4.69 g, 17.59 mmol
  • the reaction mixture was refluxed for 8 h.
  • the reaction mixture was quenched with water ( 1 00 ml) and extracted with chloroform (300 ml x 3).
  • Step 4 l //-Pyn lo[3,2-£]pyridin-5-ylmethanol :
  • Step 3 intermediate 300 g, 1 .578 mmol in THF at 0 °C was added to the well stirred suspension of lithium aluminium hydride (359 g, 9.473 mmol) in dry ' TH F (20 ml) and the reaction mixture was stirred at same temperature for 2 h. The reaction mixture was quenched with saturated sol ution of sodium sulphate, diluted with ethyl acetate and filtered.
  • Step 5
  • Step 4 Intermediate (400 mg, 2.702 mmol) at 0 °C and the reaction mixture was stirred for 1 0 min.
  • the reaction mixture was quenched with water (50 ml) and extracted with chloroform (50 ml x 2).
  • the title compound was synthesized by esterification of indazole-6-carboxylic acid using methanol in presence of cone, sulphuric acid followed by reduction of the ester group using lithium aluminium hydride and its subsequent reaction with di-ter/-butyl dicarbonate anhydride;
  • Step 1 Ethyl 7-oxo-4,7-dihydropyrazolo[l ,5-a]pyrimidine-5-carboxylate:
  • Step 2 Ethyl 7-chloro-4,7-dihydropyrazolo
  • Step 1 intermediate (1 g, 4.830 mmol) in phosphoryl chloride (POC1 3 ) (10 ml) was added N,N-dimethylaniline ( 1 ml, 4.83 mmol) and the reaction mixture was refiuxed for 40 min.
  • the excess of POCl 3 was distilled under reduced pressure and the residue obtained was poured into crushed ice and extracted with chloroform (2 x 1 00 ml).
  • Step 3 7-Chloropyrazolo[ l ,5-a]pyrimidine-5-carbaldehyde:
  • Step 2 intermediate (1 g, 4.43 mmol) in dry THF ( 1 5 ml) was added 20 % Diisobutylaluminium hydride (DIBAL-H; 2.22 ml, 13.30 mmol) drop wise at 0°C and the reaction mixture was stirred at the same temperature for 1 h. Water was added to the reaction mixture and it was further stirred for 1 5 min. The precipitate formed was fi ltered and the filtrate was concentrated to yield 1 .3 g of the product: ⁇ N.MR (300 MHz. DMSO-ck) ⁇ 7.29 (s. I H), 7.73 (s, 1 11), 8.56 (s, 1 H), 9.91 (s, I H).
  • DIBAL-H Diisobutylaluminium hydride
  • Step 4 (7-Chloropyrazolo
  • Step 3 intermediate (1 .25 g, 5.449 mmol) in DCM ( 1 0 ml) was added sodium triacetoxyborohydride (1.154 g, 5.449 mmol) and the reaction was stirred at room temperature overnight.
  • the reaction mixture was diluted with water and the pH was made neutral with sodium bicarbonate.
  • the compound was extracted with chloroform and the organic layer was washed with water, brine, dried, filtered and concentrated to yield the 81 0 mg of the product; ⁇ NMR (300 MHz, DMSO- ⁇ ) ⁇ 4.59 (s, 2H), 5.75 (br s, 1 H), 6.79 (s, 1 H), 7.38 (s, 1T1), 8.3 1 (s, l H).
  • Step 5 Pyrazolo[l ,5-o]pyrimidin-5-ylmethanol :
  • Step 4 To the well stirred solution of Step 4 Intermediate (800 mg, 4.312 mmol) in a mixture of ethanol ( 12 ml) and ethyl aceatate (27 ml) was added sodium acetate (424 mg, 5. 1 74 mmol) and pal ladium on activated carbon (20 mg) and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 5 h. The reaction mixture was diluted with ethyl acetate fi ltered and washed with saturated solution of sodium bicarbonate, water and brine.
  • Step 6 Pyrazolo[l ,5-o]pyrimidin-5-ylmethyl me hanesulfonate:
  • Step 5 intermediate 100 mg, 0.662 mmol
  • DCM 1 0 ml
  • TEA tri ethyl amine
  • Methanesulphonyl chloride was added drop wise to the reaction mixture at this temperature and the reaction mixture was stirred for 30 min.
  • Step 1 2-[4-(Acetyloxy)phenyl]-3-(4-chlorophenyl)prop-2-enoic acid:
  • Step 2 Ethyl -3 -(4-chloro phenyl)-2-(4-hydroxyphenyl)prop-2-enoate:
  • Step 2 Intermediate ( 10 g, 33.05 mmol) in dimethyl formamide (60 ml), were added potassium carbonate (6.85 g, 49.57 mmol) and 2-(ch!oromethyl)im idazo
  • Step 4 3-(4-Chlorophenyl)-2-[4-(imidazo[l ,2-a]pyridin-2-ylmethoxy)phenyl]prop-2-enoic acid : To a well stirred solution of Step 3 Intermediate (8.5 g, 19.63 mmol) in ethanol (60 ml) was added aqueous solution of 1 N sodium hydroxide and the reaction mixture was stirred for 1 6 h at room temperature. The excess of ethanol was distilled off and the reaction mass was di l uted wi th water (50 ml).
  • Step 1 Ethyl -2-[4-(l ,3-benzothiazol-2-ylmethoxy)phenyl]-3-(4-chlorophenyl)prop-2-enoate: To the well stirred solution of ethyl-3-(4-chlorophenyl)-2-(4-hydroxyphenyl)prop-2-enoate (Step 2 of intermediate 1 , 1 .5 g, 4.958 mmol) in dry tetrahydrofuran (30 ml), were added 1 ,3- benzothiazol-2-ylmethanol (81 9 mg, 4.958 mmol) and triphenyl phosphine (,1 .95 g, 7.438 mmol) followed by dropwise addition of diethyl azodicarboxylate ( 1 .01 ml, 6.446 mmol).
  • Step 2 2-[4-(l,3-Benzothiazol-2-ylmethoxy)phenyl]-3-(4-chlorophenyl)prop-2-enoic acid:
  • Step 1 To a well stirred solution of the Step 1 Intermediate (650 mg, 1.445 mmol) in ethanol (15 ml) was added aqueous solution of IN sodium hydroxide and the reaction mixture was stirred for 16 h at room temperature. The excess of ethanol was distilled off and the reaction mass was diluted with water (25 ml).
  • Intemediates 4 to 38 were prepared using appropriate starting materials as described in Intermediate 1. Their structure, names and ⁇ NMR data are given in the Table 1.
  • Ethyl-2-(4-hydroxyphenyl)-3-(pyridin-4-yl)prop-2-enoate was synthesized from 4-hydroxy phenylacetic acid and 4-pyridine carboxaldehyde as described in Steps 1 and 2 of Intermediate 1.
  • Step 1 Ethyl ⁇ 4-[(trimethylsilyl)ethynyl]phenyl ⁇ acetate:
  • Step 1 intermediate (4.9 g, 1 8.82 mmol) in dich loromethane (30 ml) was added tetrabutyl ammonium fluoride hydrate (2.461 g, 9.413 mmol) and the reaction mixture was stirred at room temperature for 10 min.
  • the reaction mixture was quenched with water ( 1 00 ml) and extracted with chloroform (2 x 250 ml). The combined organic layers were washed with water (2 x 50 ml) and brine (50 ml), dried over anhydrous a?S0 4 and concentrated to yield the crude product.
  • Step 3 Ethyl [4-(quinolin-2-ylethynyl)phenyl]acetate:
  • Step 2 intermediate (1 .44 g, 7.6 mmol) in TEA (20 ml) were added dichlorobis(triphenylphosphine) palladium (II) (54 mg, 0.076 mmol), copper iodide (44 mg, 0.23 mmol) and 2-bromoquinoline (1 .6 g, 7.69 mmol) and the reaction was stirred at room temperature overnight.
  • the reaction mixture was diluted with water ( 1 00 ml) and chloroform (300 ml), given charcoal treatment and filtered.
  • Step 3 intermediate (1.40 g, 4.44 mmol) in ethanol (30 ml) was added palladium on activated carbon (400 mg) and the reaction was carried for 4 h under 40 psi pressure of hydrogen gas. The reaction mixture was diluted with ethyl acetate and filtered.
  • Step 5 ⁇ 4-[2-(Quinolin-2-yl)ethyl]phenyl ⁇ acetic acid:
  • Step 4 intermediate 500 mg, 1.566 mmol
  • aqueous solution of sodium hydroxide 313 mg, 7.83 mmol
  • the reaction mixture was stirred at room temperature overnight.
  • the solvent was distilled out and reaction mass was diluted with water and then neutralized with dil. HQ.
  • the aqueous layer was extracted with ethyl acetate (2 x 100 ml).
  • Step 6 3-(4-Chlorophenyl)-2- ⁇ 4-[2-(quinolin-2-yl)ethyl]phenyl ⁇ prop-2-enoic acid:
  • Step 5 intermediate 460 mg, 1.580 mmol
  • acetic anhydride 15 ml
  • triethylamine 0.33 ml, 2.370 mmol
  • 4-chlorobenzaldehyde 222 mg, 1.580 mmol
  • the reaction mixture was quenched with water (50 ml) and was further refluxed for half hour after which the aqueous layer was extracted with ethyl acetate.
  • Step 1 3-(4-Chlorophenyl)-2-[4-(quinolin-2-ylmethoxy)phenyl]prop-2-en- l -ol :
  • Step 2 3-(4-Chlorophenyl)-2-[4-(quinolin-2-ylmethoxy)phenyl]prop-2-enal:
  • Step 1 intermediate (1 .1 5 g, 2.287 mmol) in THF (40 ml) was carried out at room temperature and the reaction mixture was further stirred for 4 h.
  • Step 1 3-(4-Chlorophenyl)-2-[4-(quinolin-2-ylmethoxy)phenyl]pi p-2-en- 1 -ol :
  • Step_2 2-( ⁇ 4-[3-Chloro-l -(4-chlorophenyl)prop- l -en-2-yl]phenoxy ⁇ methyl)quinoline:
  • Step 1 intermediate To a well stirred solution of the Step 1 intermediate (580 mg, 1 .03 mmol) in DCM ( 1 0 ml) was added triethylamine (0.28 ml, 2.06 mmol) followed by methanesulfonylchloride (0. 1 2 ml, 1 .558 mmol) at 0 °C and was stirred overnight.
  • Step 2 4-( ' l -(4-Chlorophenyl)-3-hydrazinyl-3-oxoprop-l-en-2-yl]phenyl ethyl carbonate:
  • Step 1 intermediate 750 mg, 2.73 mmoi
  • THF THF
  • TEA ethyl chloroformate
  • ethyl chloroformate 0.78 ml, 8.19 mmoi
  • Step 3 4-
  • Step 2 intermediate 700 mg, 1.94 mmoi
  • triethyl orlhoformale 15 ml
  • PTSA 74 mg, 0.388 mmoi
  • the reaction mixture was heated at 90-100 °C for 2 h.
  • Step 4 4-J " 2-(4-Chlorophenyl)-l-(l,3,4-oxadiazol-2-yl)ethenyl]phenol:
  • Step 3 intermediate 320 mg, 0.863 mmoi
  • ethanol 10 ml
  • aqueous solution of sodium hydroxide 173 mg, 4.318 mmoi
  • the reaction mixture was stirred at room temperature for 15 min.
  • the reaction mixture was diluted with water (25 ml) and the pH was made slightly acidic.
  • Intemediates 48 to 82 were prepared using appropriate propenoic acid and hydrazine hydrate as described in Intermediate 47. Their structure, names and H NMR data are given in the Table 3. fable 3 : Structure and characterization data for Intermediates 48 - 82
  • Example 36 A / -(2-Cyanoethy])-3-[4-(difluoromethoxy)phenyl]-2-[4-(quinolin-2-ylmethoxy)phenyl] prop-2- enamide
  • Example 1 To the well stirred solution of Example 1 (500 mg, 1.206 mmol) in THF (15 ml) was added TEA (0.26 ml, 1.929 mmol) and the reaction mixture was cooled to 0 °C. Trifluoroacetic anhydride was added to this cooled reaction mixture and was further stirred at the same temperature for 2 h.
  • Step 1 ter/-Butyl 4-( ⁇ 3-(4-chlorophenyl)-2-[4-(quinolin-2-ylmethoxy)phenyl]prop-2-enoyl ⁇ amino)piperidine- 1 -carboxylate:
  • Step 2 3-(4-Chlorophenyl)-N-(piperidin-4-yl)-2-[4-(quinolin-2-ylmethoxy)phenyl]prop-2- enamide di (trifluoroacetic acid):
  • Step 1 To a well stirred solution of Step 1 Intermediate (170 mg, 0.284 mmol) in dichloromethane (4 ml) was added trifluoroacetic acid (0.5 ml) at 0 °C and the reaction was continued for 4 h. The reaction mixture was concentrated under reduced pressure and dried well under high vacuum.
  • Step 1 eri-bu ⁇ y ⁇ [2-( ⁇ 3-(4-Chlorophenyl)-2-[4-(quinolin-2-ylmethoxy)phenyl]prop-2-en-l -yl ⁇ amino)et ' hyl]carbamale:
  • Step 2 N- ⁇ 3-(4-Chlorophenyl)-2-[4-(quinolin-2-ylmethoxy)phenyl]prop-2-en-l-yl ⁇ ethane- 1 ,2- diamine di(trifluoro acetic acid) salt:
  • Step 1 To a well stirred solution of Step 1 Intermediate (115 mg, 0.211 mmol) in dichloromethane (4 ml) was added trifluoroacetic acid (0.5 ml) at 0°C and the reaction was continued for 4 h. The reaction mixture was concentrated under reduced pressure and dried well under high vacuum.
  • Step 1 3-(4-ChIorophenyl)-N-(2-methoxyethyl)-2-[4-(quinolin-2-ylmethoxy)pheny]] prop-2-en- 1 -amine:
  • Step 2 3-(4-Chlorophenyl)-N-(2-methoxyethyl)-2-[4-(quinolin-2-ylmethoxy)phenyl]prop-2-en- 1 -amine dihydrochloride:
  • Step 1 2-( ⁇ 4-[l-(4-Fluoi phenyl)-3-(piperazin-l-yl)prop-l-en-2-yl]phenoxy ⁇ methyl)quinoline: The title compound was prepared from Intermediate 43 (590 mg, 1.302 mmol) and N-BOC piperazine (485 mg, 2.604 mmol) as described in Example 82.
  • Step 2 2-( ⁇ 4-[l-(4-Fluorophenyl)-3-(piperazin-l-yl)prop-l-en-2-yl]phenoxy ⁇ methylquinoline trihydrochloride:

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Abstract

La présente invention concerne des composés oléfiniques à substitution aryle en tant qu'inhibiteurs de la phosphodiestérase 10A (PDE10A). En particulier, lesdits composés sont utiles pour le traitement ou la prévention de maladies, d'affections et/ou de troubles par inhibition de l'enzyme phosphodiestérase 10A. L'invention a également pour objet des procédés de préparation desdits composés, des intermédiaires utilisés dans leur synthèse, leurs compositions pharmaceutiques.
PCT/IB2011/000948 2010-05-04 2011-05-03 Composés oléfiniques à substitution aryle en tant qu'inhibiteurs de la pde10a WO2011138657A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012112946A1 (fr) 2011-02-18 2012-08-23 Allergan, Inc. Dérivés de 6,7-dialkoxy-3-isoquinolinol substitués en tant qu'inhibiteurs de la phosphodiestérase 10 (pde10a)
WO2014004064A1 (fr) 2012-06-29 2014-01-03 E. I. Du Pont De Nemours And Company Carboxamides hétérocycliques fongicides
WO2014071044A1 (fr) 2012-11-01 2014-05-08 Allergan, Inc. Dérivés de 6,7-dialcoxy-3-isoquinoline substitués à titre d'inhibiteurs de phosphodiestérase 10 (pde10a)
WO2014172190A1 (fr) 2013-04-15 2014-10-23 E. I. Du Pont De Nemours And Company Amides fongicides
EP2940022A1 (fr) * 2014-04-30 2015-11-04 Masarykova Univerzita Furopyridines comme inhibiteurs de protèines kinases
US9200016B2 (en) 2013-12-05 2015-12-01 Allergan, Inc. Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
CN107216334A (zh) * 2017-06-29 2017-09-29 上海吉尔多肽有限公司 一种6‑氯呋喃[3,2‑b]吡啶的合成方法
EP3305786A2 (fr) 2018-01-22 2018-04-11 Bayer CropScience Aktiengesellschaft Dérivés d'hétérocyclène bicycliques condensés en tant que pesticides
EP3498273A1 (fr) * 2017-12-14 2019-06-19 Universität Wien Composition pharmaceutique pour la modulation de la reponse du recepteur gaba-a
CN114213424A (zh) * 2021-12-30 2022-03-22 杭州澳赛诺生物科技有限公司 一种呋喃[3，2-b]并吡啶衍生物的合成方法
US20230285331A1 (en) * 2022-01-24 2023-09-14 University Of South Carolina Tyrosine and resveratrol derivatives as novel modulators of cellular serine-adp-ribosylation
JP7443414B2 (ja) 2017-01-20 2024-03-05 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア アンドロゲン受容体のｎ末端ドメインの阻害剤

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WO1991011999A1 (fr) * 1990-02-13 1991-08-22 Merck & Co., Inc. Antagonistes d'angiotensine ii incorporant un element benzylique substitue
EP0669333A1 (fr) * 1994-02-24 1995-08-30 J. URIACH & CIA. S.A. Dérivés d'imidazopyridine comme antagonistes de l'angiotensine II
CN1109057A (zh) * 1993-11-23 1995-09-27 默克专利股份有限公司 咪唑并哒嗪

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Publication number Priority date Publication date Assignee Title
WO1991011999A1 (fr) * 1990-02-13 1991-08-22 Merck & Co., Inc. Antagonistes d'angiotensine ii incorporant un element benzylique substitue
CN1109057A (zh) * 1993-11-23 1995-09-27 默克专利股份有限公司 咪唑并哒嗪
EP0669333A1 (fr) * 1994-02-24 1995-08-30 J. URIACH & CIA. S.A. Dérivés d'imidazopyridine comme antagonistes de l'angiotensine II

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012112946A1 (fr) 2011-02-18 2012-08-23 Allergan, Inc. Dérivés de 6,7-dialkoxy-3-isoquinolinol substitués en tant qu'inhibiteurs de la phosphodiestérase 10 (pde10a)
US8772316B2 (en) 2011-02-18 2014-07-08 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE10A)
US9670181B2 (en) 2011-02-18 2017-06-06 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
WO2014004064A1 (fr) 2012-06-29 2014-01-03 E. I. Du Pont De Nemours And Company Carboxamides hétérocycliques fongicides
WO2014071044A1 (fr) 2012-11-01 2014-05-08 Allergan, Inc. Dérivés de 6,7-dialcoxy-3-isoquinoline substitués à titre d'inhibiteurs de phosphodiestérase 10 (pde10a)
WO2014172190A1 (fr) 2013-04-15 2014-10-23 E. I. Du Pont De Nemours And Company Amides fongicides
US9902710B2 (en) 2013-12-05 2018-02-27 Exonhit Therapeutics, Sa Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US9200016B2 (en) 2013-12-05 2015-12-01 Allergan, Inc. Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
JP2017513915A (ja) * 2014-04-30 2017-06-01 マサリコヴァ ユニヴェルジタ プロテインキナーゼのインヒビターとしてのフロピリジン
WO2015165428A1 (fr) * 2014-04-30 2015-11-05 Masarykova Univerzita Furopyridines utilisées en tant qu'inhibiteurs de protéine kinases
EP2940022A1 (fr) * 2014-04-30 2015-11-04 Masarykova Univerzita Furopyridines comme inhibiteurs de protèines kinases
US9902733B2 (en) 2014-04-30 2018-02-27 Masarykova Univerzita Furopyridines as inhibitors of protein kinases
JP7443414B2 (ja) 2017-01-20 2024-03-05 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア アンドロゲン受容体のｎ末端ドメインの阻害剤
CN107216334A (zh) * 2017-06-29 2017-09-29 上海吉尔多肽有限公司 一种6‑氯呋喃[3,2‑b]吡啶的合成方法
EP3498273A1 (fr) * 2017-12-14 2019-06-19 Universität Wien Composition pharmaceutique pour la modulation de la reponse du recepteur gaba-a
EP3305786A2 (fr) 2018-01-22 2018-04-11 Bayer CropScience Aktiengesellschaft Dérivés d'hétérocyclène bicycliques condensés en tant que pesticides
CN114213424A (zh) * 2021-12-30 2022-03-22 杭州澳赛诺生物科技有限公司 一种呋喃[3，2-b]并吡啶衍生物的合成方法
US20230285331A1 (en) * 2022-01-24 2023-09-14 University Of South Carolina Tyrosine and resveratrol derivatives as novel modulators of cellular serine-adp-ribosylation

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