WO2011014520A2 - Composés et compositions pouvant servir de modulateurs de l'activité du gpr119 - Google Patents

Composés et compositions pouvant servir de modulateurs de l'activité du gpr119 Download PDF

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WO2011014520A2
WO2011014520A2 PCT/US2010/043433 US2010043433W WO2011014520A2 WO 2011014520 A2 WO2011014520 A2 WO 2011014520A2 US 2010043433 W US2010043433 W US 2010043433W WO 2011014520 A2 WO2011014520 A2 WO 2011014520A2
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phenyl
methyl
pyrazolo
pyrimidin
trifluoromethyl
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PCT/US2010/043433
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WO2011014520A3 (fr
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Phillip Alper
Mihai Azimioara
Christopher Cow
Robert Epple
Gerald Lelais
Daniel Mutnick
Victor Nikulin
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Irm Llc
Mecom, John
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Publication of WO2011014520A2 publication Critical patent/WO2011014520A2/fr
Publication of WO2011014520A3 publication Critical patent/WO2011014520A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of GPRl 19.
  • GPRl 19 is a G-protein coupled receptor (GPCR) that is mainly expressed in the pancreas, small intestine, colon and adipose tissue.
  • GPCR G-protein coupled receptor
  • the expression profile of the human GPRl 19 receptor indicates its potential utility as a target for the treatment of obesity and diabetes.
  • the novel compounds of this invention modulate the activity of GPRl 19 and are, therefore, expected to be useful in the treatment of GPRl 19-associated diseases or disorders such as, but not limited to, diabetes, obesity and associated metabolic disorders.
  • the present invention provides a compound of Formula I:
  • R 1 is selected from C 2 -ioalkenyl, C 6-1 oaryl, C 6 -ioaryl-C 2 - 3 alkynyl, C 1 .
  • Y 5 is N and Y 6 is CR 2 ; or Y 5 is CR 2 and Y 6 is N;
  • R 2 is selected from hydrogen, C 1-6 alkyl, Ci_ 6 alkoxy, halo-substituted-Ci_
  • R 3 is selected from cyano, -C(O)ORi u , -C(O)R 1 la , -X 2 OC(O)R 1 la , -
  • R 4 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkenyl, C 6 -ioarylCi_ 4 alkyl, -
  • R 5 is selected from hydrogen, C 1-4 alkyl, C 6-1 oaryl, Ci ⁇ heteroaryl, C 3 - gheterocycloalkyl; wherein said alkyl, aryl, heteroaryl or heterocycloalkyl of R 5 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, - S(0)o- 2 Ri 3a , halo-substituted-Ci_ 4 alkyl, Ci_ 4 alkyl, halo-substituted-Ci_ 4 alkoxy, Ci_ 4 alkoxy, C 6-1 oaryl, -C(O)NR 13a R 13b and -C(O)OR 13a ; wherein R 13a and R 13b are independently selected from hydrogen and C 1-4 alkyl;
  • Y 2 is selected from a bond, CH 2 , C(O), NR 17 and O; wherein R 17 is selected from hydrogen, halo-substituted-Ci ⁇ alkyl and C 1-4 alkyl; or R 4 and Y 2 taken together form a double bond or a cyclopropyl ring;
  • Y 4 is selected from N and -CR 6 ; wherein Re is selected from hydrogen, halo, cyano, Ci_ 6 alkyl, X 4 NR 14a R 14b , X 4 OR 14a ; wherein X 4 is selected from a bond, C 1 .
  • R 14a and R 14b are independently selected from hydrogen and Ci_ 4 alkyl; with the proviso that when Y 4 is N, Y 1 is CH.
  • the present invention provides a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
  • the present invention provides a method of treating a disease in an animal in which modulation of GPRl 19 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula
  • the present invention provides the use of a compound of
  • GPRl 19 activity contributes to the pathology and/or symptomology of the disease.
  • the present invention provides a process for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.
  • Alkyl as a group and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, can be straight-chained, branched, cyclic or spiro.
  • C 1- ⁇ alkoxy includes methoxy, ethoxy, and the like.
  • Halo-substituted alkyl includes trifluoromethyl, pentafluoroethyl, and the like.
  • Alkylene is a divalent alkyl radical that includes -C(CH 3 ) 2 -.
  • Aryl means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms.
  • aryl can be phenyl or naphthyl, preferably phenyl.
  • Heteroaryl is as defined for aryl where one or more of the ring members are a heteroatom.
  • C ⁇ ioheteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl,
  • Heteroaryl also includes the N-oxide derivatives, for example, pyridine N-oxide derivatives with the following structure:
  • Ce-ioarylCi ⁇ alkyl means an aryl as described above connected via a alkylene grouping.
  • C 6 - 1 oarylC 1 _ 4 alkyl includes phenethyl, benzyl, etc.
  • 1 oaryl-C 2 - 3 alkynyl includes, for example, phenyl-ethynyl, etc.
  • Cycloalkyl means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated.
  • C 3 _iocycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • Enantiomers as used in this application for compounds of Formula I, describe each chiral center as labeled R or S according to a system by which its substituents are each assigned a priority, according to the Cahn Ingold Prelog priority rules (CIP), based on atomic number. If the center is oriented so that the lowest-priority of the four is pointed away from a viewer, the viewer will then see two possibilities: If the priority of the remaining three substituents decreases in clockwise direction, it is labeled R (for Rectus), if it decreases in counterclockwise direction, it is S (for Sinister).
  • CIP Cahn Ingold Prelog priority rules
  • the R enentiomer of a compound of Formula I is where R 3 has priority over the core (fused bicyclic) which has priority over Y 2 R 5 which in turn has priority over R 4 .
  • the R-enantiomer is preferred over the S-enantiomer (see examples N1-N5).
  • C 3 _ 8 heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, 2-oxo-pyrrolidin-l-yl, 2-oxo-piperidin-l-yl, etc.
  • Heterocycloalkenyl means heterocycloalkyl, as defined in this application, provided that at least one double bond exists in the ring.
  • GPRl 19 means G protein-coupled receptor 119 (GenBank ® Accession No.
  • GPRl 19 includes the human sequences found in GeneBank accession number AY288416, naturally-occurring allelic variants, mammalian orthologs, and recombinant mutants thereof.
  • Halogen (or halo) preferably represents chloro or fluoro, but can also be bromo or iodo.
  • Treatment refers to a method of alleviating or abating a disease and/or its attendant symptoms.
  • the present invention provides compounds, compositions and methods for the treatment of diseases in which modulation of GPRl 19 activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I.
  • compounds of Formula I are compounds of Formula Ia, Ib and Ic:
  • n is selected from 1, 2 and 3;
  • R 1 is selected from C 2 -ioalkenyl, C 6- ioaryl, C 6 -ioaryl-C 2 - 3 alkynyl, C ⁇ gheteroaryl, acetylenyl, C 3 .
  • alkenyl, aryl, heteroaryl, acetylenyl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl or cycloalkenyl of R 1 is optionally substituted with 1 to 3 radicals
  • R 1 Oc and R 1 Od are selected from hydrogen, C 1-6 alkyl, C 3 - iocycloalkyl optionally substituted with C 1-6 alkyl or halo;
  • R 3 is selected from cyano, - C(O)OR 1 U, -C(O)R 1 U, -X 2 OC(O)R lla , -C(O)OX 2 R 1 U, -X 2 OS(O) 0 - 2 Rii a , -X 2 S(O) 0 .
  • R 4 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkenyl, C 6 -ioarylCi_ 4 alkyl, -X 3 ORi 2 , - X 3 NRi 2 Ri 2 and -X 3 C(O)ORi 2 ; wherein X 3 is selected from a bond and Ci_ 4 alkylene; and each Ri 2 is independently selected from hydrogen and C 1-4 alkyl; Re is selected from hydrogen, halo, cyano, C 1-6 alkyl, X 4 NRi 4a Ri 4b , X 4 ORi 4a ; wherein X 4 is selected from a bond, Ci_ 6 alkylene; and Ri 4a and Ri 4b are independently selected from hydrogen and C 1- 4 alkyl; Rig is selected halo, cyano, -S(0)o- 2 Ri 3a ,halo-substituted-Ci_
  • R 1 is selected from hex-1-enyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, benzimidazolyl, styryl, l,2,4-oxadiazol-5-yl, and l,2,3,6-tetrahydropyridin-4-yl; wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, 1,2,4-oxadiazol- 5-yl, or l,2,3,6-tetrahydropyridin-4-yl Of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, methyl, methoxy, formyl, isopropyl,
  • R 3 is selected from: cyano; ethoxy-methyl; (2- methoxyethyl)(methyl)carbamoyl; (tetrahydro-2H-pyran-4-yloxy)carbonyl;
  • thiazolyl-methyl pyrazinyl-methyl; pyridinyl-methyl; (2-(dimethylamino)-2- oxoethyl)(methyl)carbamoyl; (2-(2-oxopyrrolidin- l-yl)ethoxy)carbonyl; 3- hydroxypyrrolidine-1-carbonyl; (carboxymethyl)(methyl)carbamoyl; (2,3- dihydroxypropyl)(methyl)carbamoyl; tetrahydrofuran-3-ylcarbamoyl; ((1-methyl-lH- imidazol-4-yl)methoxy)carbonyl; (azetidin-3-ylmethoxy)carbonyl; (2-hydroxy-3- (methylamino)propoxy)carbonyl; dimethoxy-ethyl-carbamoyl,
  • n is selected from 1, 2 and 3;
  • R 1 is selected from C 2 -ioalkenyl, Ce- ioaryl, C ⁇ gheteroaryl, acetylenyl, C 3 _gheterocycloalkyl, Cs.gheterocycloalkenyl, C 3 .
  • R 7 is selected from hydrogen, Ci- ⁇ alkyl, C 3 -iocycloalkyl optionally substituted with Ci_ 6 alkyl or halo
  • Rg is selected from -X 1 Rg; wherein X 1 is selected from a bond and Ci- 4 alkylene optionally substituted with halo
  • R 9 is selected from phenyl and pyridinyl; wherein said phenyl or pyridinyl of R 9 is optionally substituted with 1 to 3 trifluoromethyl radicals
  • R 2 is selected from hydrogen, Ci_ 6 alkyl, Ci- ⁇ alkoxy, halo-substituted-Ci- ⁇ alkyl, halo-substituted-Ci- ⁇ alkoxy, -
  • R 4 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkenyl, C 6-1 oa ⁇ ylC 1-4 alkyl, - X 3 OR 12 and -X 3 C(O)OR 12 ; wherein X 3 is selected from a bond and C 1-4 alkylene; and R 12 is selected from hydrogen and C 1-4 alkyl; R 6
  • R 1 is selected from hex-1-enyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, 1,2,4-oxadiazol- 5-yl, and l,2,3,6-tetrahydropyridin-4-yl; wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, l,2,4-oxadiazol-5-yl, or l,2,3,6-tetrahydropyridin-4-yl Of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, methyl, methoxy, formyl, isopropyl, nitro,
  • R 3 is selected from cyano, ethoxy- methyl, (2- methoxyethyl)(methyl)carbamoyl, (4-hydroxybutoxy)carbonyl, methoxy-carbonyl, ethoxy-carbonyl, (furan-2-ylmethyl)(methyl)carbamoyl, 5-methyloxazol-2-yl), (2- methoxyethoxy)carbonyl, butyl(methyl)carbamoyl, dimethyl-amino-carbonyl, isopropyl- carbamoyl, (propyl) (methyl)carbamoyl, (ethyl)methyl-amino-carbonyl, methyl((tetrahydrofuran-2-yl)methyl)carbamoyl, (2-methoxy-2- oxoethyl)(methyl)carbamoyl, methoxy-ethyl-carbamoyl, methoxy-propoxy
  • [0043] in a further embodiment are compounds selected from: ethyl (2R)-2- methyl-3-phenyl-2- ⁇ 8-[4-(trifluoromethyl)phenyl]pyrazolo[3,2-c][l,2,4]triazin-4- yljpropanoate; ethyl 2-methyl-3-phenyl-2- ⁇ 8-[4-(trifluoromethyl)phenyl]pyrazolo[3,2- c][l,2,4]triazin-4-yl ⁇ propanoate; ethyl 2- ⁇ 3-fluoro-8-[4- (trifluoromethyl)phenyl]pyrazolo[3,2-c][l,2,4]triazin-4-yl ⁇ -2-methyl-3- phenylpropanoate; ethyl 2-[8-(4-chlorophenyl)pyrazolo[3,2-c][l,2,4]triazin-4-yl]-2- methyl-3-pheny
  • R 1 is selected from C 2 -ioalkenyl, C 6-1O aTyI, C ⁇ heteroaryl, acetylenyl, Cs-sheterocycloalkyl, Cs-sheterocycloalkenyl, C3 -6 cycloalkyl, C 3 - 6 cycloalkenyl; wherein said alkenyl, aryl, heteroaryl, acetylenyl, heterocycloalkyl, heterocycloalkenyl, cycloalkyl or cycloalkenyl of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, hydroxy, C 1-4 alkyl, halo- substituted-C 1-4 alkyl, C 1-4 alkoxy, halo-substituted-C 1-4 alkoxy, C 6-1 oaryl, Ci-gheteroaryl, Cs- ⁇ hetero
  • X 5 C(O)NR 1 OaRiOb, -X 5 NR 1 ObC(O)R 1 Oa and -X 5 C(O)OR 10a wherein said X 5 is selected from a bond and C ⁇ alkylene wherein any methylene of X 5 can have a hydrogen substituted with hydroxyl, C 6-1 oaryl, C 3 _iocycloalkyl, heteroaryl or heterocycloalkyl; and R 1 Oa and R 1 Ob are independently selected from hydrogen, Ci_ 4 alkyl and Ci_ 4 alkoxy; or R 1 Oa and R 1Ob together with the nitrogen atom to which they are both attached form a 4 to 6 member ring system selected from azetidine, pyrrolidine, pyrazolidine, piperidine and morpholine; wherein said ring system can be substituted by 1 to 3 radicals selected from halo, nitro, cyano, hydroxyl, C 1-4 alkyl, halo-substituted
  • R 1 Oc and R 1 Od are selected from hydrogen, Ci_6alkyl, C 3 _iocycloalkyl optionally substituted with Ci_6alkyl or halo;
  • R 3 is selected from cyano, -C(O)OR lla , - C(O)R lla , -X 2 OC(O)R lla , -C(O)OX 2 R lla , -X 2 OS(0)o- 2 R lla , -X 2 S(O) 0-2 R 1 la , - C(0)0X 2 0R lla , -C(0)0X 2 NR lla R llb , -C(O)N R lla R llb , -X 2 NR lla R ⁇ b, -NR lla C(0)R llb , -NRiiaC(O)ORnb, -NRnaS(0)o- 2 Riib, -
  • R 1 is selected from hex-1-enyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, 1,2,4-oxadiazol- 5-yl, and l,2,3,6-tetrahydropyridin-4-yl; wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, cyclohexenyl, phenylethynyl, styryl, l,2,4-oxadiazol-5-yl, or l,2,3,6-tetrahydropyridin-4-yl Of R 1 is optionally substituted with 1 to 3 radicals independently selected from halo, methyl, methoxy, formyl, isopropyl, nitro,
  • R 3 is selected from cyano, ethoxy-methyl, (2- methoxyethyl)(methyl)carbamoyl, (4-hydroxybutoxy)carbonyl, methoxy-carbonyl, ethoxy-carbonyl, (furan-2-ylmethyl)(methyl)carbamoyl, 5-methyloxazol-2-yl), (2- methoxyethoxy)carbonyl, butyl(methyl)carbamoyl, dimethyl-amino-carbonyl, isopropyl- carbamoyl, (propyl) (methyl)carbamoyl, (ethyl)methyl-amino-carbonyl,
  • [0049] in another embodiment are compounds selected from: ethyl 2-[8-(4- chlorophenyl)imidazo[l,5-a]pyrimidin-4-yl]-2-methyl-3-phenylpropanoate; ethyl 2-[3-(4- chlorophenyl)pyrazolo[3,2-b][l,3]thiazol-6-yl]-2-methyl-3-phenylpropanoate; ethyl 2-[3- (4-chlorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl]-2,3-dihydro-lH-indene-2-carboxylate; 3- (4-chlorophenyl)-N-phenyl-N-propylpyrazolo[ 1 ,5-a]pyrimidine-7-carboxamide; 3-(4- chlorophenyl)-N-methyl-N-phenylpyrazolo[l,5-a]pyrimidine-7-carbox
  • the present invention also includes all suitable isotopic variations of the compounds of the invention, or pharmaceutically acceptable salts thereof.
  • An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that may be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include but are not limited to isotopes of hydrogen, carbon, nitrogen and oxygen such as as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S, 18 F, 36 Cl and 123 I.
  • Certain isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies.
  • 3 H and 14 C isotopes may be used for their ease of preparation and detectability.
  • substitution with isotopes such as 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.
  • Isotopic variations of the compounds of the invention or pharmaceutically acceptable salts thereof can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents. For example, the following three examples can be deuterated as shown:
  • Compounds of the invention modulate the activity of GPRl 19 and, as such, are useful for treating diseases or disorders in which the activity of GPRl 19 contributes to the pathology and/or symptomology of the disease.
  • This invention further provides compounds of this invention for use in the preparation of medicaments for the treatment of diseases or disorders in which GPRl 19 activity contributes to the pathology and/or symptomology of the disease.
  • Type II diabetes The resultant pathologies of Type II diabetes are impaired insulin signaling at its target tissues and failure of the insulin-producing cells of the pancreas to secrete an appropriate degree of insulin in response to a hyperglycemic signal.
  • Current therapies to treat the latter include inhibitors of the ⁇ -cell ATP- sensitive potassium channel to trigger the release of endogenous insulin stores, or administration of exogenous insulin. Neither of these achieves accurate normalization of blood glucose levels and both carry the risk of inducing hypoglycemia. For these reasons, there has been intense interest in the development of pharmaceuticals that function in a glucose-dependent action, i.e.
  • Physiological signaling systems which function in this manner are well-characterized and include the gut peptides GLP-I, GIP and PACAP. These hormones act via their cognate G-protein coupled receptor to stimulate the production of cAMP in pancreatic ⁇ -cells. The increased cAMP does not appear to result in stimulation of insulin release during the fasting or pre-prandial state.
  • a series of biochemical targets of c AMP signaling including the ATP- sensitive potassium channel, voltage-sensitive potassium channels and the exocytotic machinery, are modified in such a way that the insulin secretory response to a postprandial glucose stimulus is markedly enhanced. Accordingly, agonists of novel, similarly functioning, ⁇ -cell GPCRs, including GPRl 19, would also stimulate the release of endogenous insulin and
  • cAMP for example as a result of GLP-I stimulation, promotes ⁇ -cell proliferation, inhibits ⁇ -cell death and thus improves islet mass. This positive effect on ⁇ - cell mass is expected to be beneficial in both Type II diabetes, where insufficient insulin is produced, and Type I diabetes, where ⁇ -cells are destroyed by an inappropriate autoimmune response.
  • hypothalamus where they modulate hunger, satiety, decrease food intake, controlling or decreasing weight and energy expenditure.
  • agonists or inverse agonists of these receptors mitigate hunger, promote satiety and therefore modulate weight.
  • an embodiment of the invention is a method for treatment of a metabolic disease and/or a metabolic-related disorder in an individual comprising administering to the individual in need of such treatment a therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof.
  • the metabolic diseases and metabolic-related disorders are selected from, but not limited to, hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus, idiopathic type 1 diabetes (Type Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease, intermittent claudication, myocardial infarction (e.g., hyperlipidemia, type 1 diabetes, type 2 diabetes mellitus, idiopathic type 1 diabetes (Type Ib), latent autoimmune diabetes in adults (LADA), early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, coronary heart disease, ischemic stroke, restenosis after angioplasty, peripheral vascular disease,
  • necrosis and apoptosis dyslipidemia, post-prandial lipemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertrygliceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.
  • GPRl 19 activity modulators derived from increasing levels of GIP and PPY. For example, neuroprotection, learning and memory, seizures and peripheral neuropathy.
  • GLP-I and GLP-I receptor agonists have been shown to be effective for treatment of neurodegenerative diseases and other neurological disorders.
  • GLP-I and exendin-4 have been shown to stimulate neurite outgrowth and enhance cell survival after growth factor withdrawal in PC 12 cells.
  • GLP-I and exendin-4 restore cholinergic marker activity in the basal forebrain.
  • Central infusion of GLP-I and exendin-4 also reduce the levels of amyloid- ⁇ peptide in mice and decrease amyloid precursor protein amount in cultured PC 12 cells.
  • GLP-I receptor agonists have been shown to enhance learning in rats and the GLP-I receptor knockout mice show deficiencies in learning behavior.
  • the knockout mice also exhibit increased susceptibility to kainate-induced seizures which can be prevented by administration of GLP-I receptor agonists.
  • GLP-I and exendin-4 has also been shown to be effective in treating pyridoxine- induced peripheral nerve degeneration, an experimental model of peripheral sensory neuropathy.
  • Glucose-dependent insulinotropic polypeptide has also been shown to have effects on proliferation of hippocampal progenitor cells and in enhancing sensorimotor coordination and memory recognition.
  • GLP-2 and short bowel syndrome are therapeutic benefits of GPRl 19 activity modulators.
  • GLP-2 and short bowel syndrome SBS.
  • SBS short bowel syndrome
  • GLP-2 is a trophic hormone that plays an important role in intestinal adaptation. Its role in regulation of cell proliferation, apoptosis, and nutrient absorption has been well documented.
  • Short bowel syndrome is characterized by malabsorption of nutrients, water and vitamins as a result of disease or surgical removal of parts of the small intestine (eg. Crohn's disease). Therapies that improve intestinal adaptation are thought to be beneficial in treatment of this disease.
  • phase II studies in SBS patients have shown that teduglutide, a GLP-2 analog, modestly increased fluid and nutrient absorption.
  • GLP-I GLP-I
  • GIP calcitonin related gene peptide
  • osteoporosis a disease that is caharacterized by reduced bone mineral density and thus GLP-I induced increase in calcitonin might be therapeutically beneficial.
  • GIP has been reported to be involved in upregulation of markers of new bone formation in osetoblasts including collagen type I mRNA and in increasing bone mineral density. Like GLP-I, GIP has also been shown to inhibit bone resorption.
  • GPRl 19 activity modulators derived from increasing levels of GIP and PPY.
  • GPRl 19 located on the pancreatic polypeptide (PP) cells of the islets has been implicated in the secretion of PPY.
  • PPY has been reported to have profound effects on various physiological processes including modulation of gastric emptying and gastrointestinal motility. These effects slow down the digestive process and nutrient uptake and thereby prevent the postprandial elevation of blood glucose.
  • PPY can suppress food intake by changing the expression of hypothalamic feeding-regulatory peptides.
  • PP-overexpressing mice exhibited the thin phenotype with decreased food intake and gastric emptying rate.
  • the present invention further provides a method for preventing or ameliorating the symptamology of any of the diseases or disorders described above in a subject in need thereof, which method comprises administering to said subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositions ", infra) of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount See, "Administration and Pharmaceutical Compositions ", infra
  • the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
  • therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight.
  • An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5mg to about lOOmg, conveniently administered, e.g. in divided doses up to four times a day or in retard form.
  • Suitable unit dosage forms for oral administration comprise from ca. 1 to 50mg active ingredient.
  • Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods.
  • oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrollidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose,
  • compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.
  • the compositions can be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they can also contain other therapeutically valuable substances.
  • Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier.
  • a carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Matrix transdermal formulations can also be used.
  • Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations).
  • synergistic effects can occur with other anti-obesity agents, anorectic agents, appetite suppressant and related agents. Diet and/or exercise can also have synergistic effects.
  • Anti-obesity agents include, but are not limited to,
  • apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors MCR-4 agonists, cholescystokinin-A (CCK-A) agonists, serotonin and norepinephrine reuptake inhibitors (for example, sibutramine), sympathomimetic agents, ⁇ 3 adrenergic receptor agonists, dopamine agonists (for example, bromocriptine), melanocyte- stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists [for example, compounds described in WO2006/047516), melanin concentrating hormone antagonists, leptons (the OB protein), leptin analogues, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolip statin, i.e., Orlistat), anorectic agents (such as a bombesin agonist), Neuropeptide-Y antagonists,
  • dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.
  • a combined preparation or pharmaceutical composition can comprise a compound of the invention as defined above or a pharmaceutical acceptable salt thereof and at least one active ingredient selected from:
  • anti-diabetic agents such as insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizer such as protein tyrosine phosphatase- IB (PTP-IB) inhibitors such as PTP- 112; GSK3 (glycogen synthase kinase-3) inhibitors such as SB- 517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 and AGN- 194204; sodium-dependent glucose co-transporter inhibitors such as T-1095; glycogen phosphorylase A inhibitors such as BA
  • hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A
  • HMG-CoA reductase inhibitors e.g., lovastatin and related compounds such as those disclosed in U.S. Pat. No. 4,231,938, pitavastatin, simvastatin and related compounds such as those disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171, pravastatin and related compounds such as those disclosed in U.S. Pat. No.4,346,227, cerivastatin, mevastatin and related compounds such as those disclosed in U.S. Pat. No. 3,983,140, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and related statin compounds disclosed in U.S. Pat. No.
  • phosphinic acid compounds useful in inhibiting ⁇ MG CoA reductase suitable for use herein are disclosed in GB 2205837; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid and aspirin;
  • an anti-obesity agent or appetite regulating agent such as a CB 1 activity modulator, melanocortin receptor (MC4R) agonists, melanin-concentrating hormone receptor (MC ⁇ R) antagonists, growth hormone secretagogue receptor (G ⁇ SR) antagonists, galanin receptor modulators, orexin antagonists, CCK agonists, GLP-I agonists, and other Pre-proglucagon-derived peptides; NPYl or NPY5 antagonsist, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gamma modulators, PPAR delta modulators, acetyl- CoA carboxylase (ACC) inihibitors, 11- ⁇ -HSD-l inhibitors, adinopectin receptor modulators; beta 3 adrenergic agonists, such as AJ9677 (Taked
  • a thyroid receptor beta modulator such as a thyroid receptor ligand as disclosed in WO 97/21993 (U. CaI SF), WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), a SCD-I inhibitor as disclosed in WO2005011655, a lipase inhibitor, such as orlistat or ATL-962 (Alizyme), serotonin receptor agonists, (e.g., BVT- 933 (Biovitrum)), monoamine reuptake inhibitors or releasing agents, such as fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine or
  • anti-hypertensive agents such as loop diuretics such as ethacrynic acid, furosemide and torsemide; diuretics such as thiazide derivatives, chlorithiazide, hydrochlorothiazide, amiloride; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPase membrane pump such as digoxin; neutralendopeptidase (NEP) inhibitors e.g. thiorphan, terteo-thiorphan,
  • NEP neutralendopeptidase
  • ECE inhibitors e.g. SLV306
  • ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril
  • angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan
  • renin inhibitors such as aliskiren, terlakiren, ditekiren, RO 66-1132, RO-66-1168
  • beta-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol
  • inotropic agents such as digoxin, dobutamine and milrinone
  • calcium channel blockers such as amlodipine, bepridil,
  • thrombin inhibitors such as Ximelagatran
  • aldosterone inhibitors such as anastrazole, fadrazole, eplerenone
  • a chemotherapeutic agent such as aromatase inhibitors e.g. femara, anti- estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, antineoplastic antimetabolites, platin compounds, compounds decreasing the protein kinase activity such as a PDGF receptor tyrosine kinase inhibitor preferably Imatinib ( ⁇ N- ⁇ 5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2- methylphenyl ⁇ -4-(3-pyridyl)-2-pyrimidine-amine ⁇ ) described in the European patent application EP-A-O 564 409 as example 21 or 4-Methyl-N-[3-(4-methyl-imidazol-l-yl)-5- trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamin
  • an agent interacting with a 5-HT 3 receptor and/or an agent interacting with 5-HT 4 receptor such as tegaserod described in the US patent No. 5510353 as example 13, tegaserod hydrogen maleate, cisapride, cilansetron;
  • n) an agent for treating tobacco abuse e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename Zyban®) and nicotine replacement therapies;
  • an agent for treating tobacco abuse e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename Zyban®) and nicotine replacement therapies;
  • an agent for treating erectile dysfunction e.g., dopaminergic agents, such as apomorphine
  • ADD/ ADHD agents e.g., Ritalin®, Strattera®, Concerta® and Adderall®
  • an agent for treating alcoholism such as opioid antagonists (e.g., naltrexone (also known under the tradename Re Via®) and nalmefene), disulfiram (also known under the tradename Antabuse®), and acamprosate (also known under the tradename Campral®)).
  • opioid antagonists e.g., naltrexone (also known under the tradename Re Via®) and nalmefene), disulfiram (also known under the tradename Antabuse®), and acamprosate (also known under the tradename Campral®)
  • agents for reducing alcohol withdrawal symptoms may also be co-administered, such as benzodiazepines, beta- blockers, clonidine, carbamazepine, pregabalin, and gabapentin (Neurontin®);
  • COX-2 inhibitors COX-2 inhibitors
  • antidepressants e.g., fluoxetine hydrochloride (Prozac®)
  • cognitive improvement agents e.g., donepezil hydrochloride (Aircept®) and other
  • acetylcholinesterase inhibitors include neuroprotective agents (e.g., memantine) ; antipsychotic medications (e.g., ziprasidone (Geodon®), risperidone (Risperdal®), and olanzapine (Zyprexa®));
  • neuroprotective agents e.g., memantine
  • antipsychotic medications e.g., ziprasidone (Geodon®), risperidone (Risperdal®), and olanzapine (Zyprexa®)
  • the invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • a pharmaceutical combination e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • the kit can comprise instructions for its administration.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • the term "pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • the term "fixed combination” means that the active ingredients, e.g. a compound of Formula I and a co- agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • the term “non-fixed combination” means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
  • cocktail therapy e.g. the
  • the present invention also includes processes for the preparation of compounds of the invention.
  • reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.
  • a compound of Formula 1-1 and 1-2 can be prepared as in reaction scheme
  • a compound of the formula 4 (for example, Bioorg. Med. Chem. Lett. 2004, 14, 3669) can be coupled with a compound of the formula 3 in an appropriate solvent such as an alcohol (methanol, ethanol, and the like) or organic acid such as acetic acid and the like, in the presence of an acidic promoter such as HCl, trifluoroacetic acid or the like at an elevated temperature such as 6O 0 C to 15O 0 C to afford 1-1.
  • an appropriate solvent such as an alcohol (methanol, ethanol, and the like) or organic acid such as acetic acid and the like
  • an acidic promoter such as HCl, trifluoroacetic acid or the like
  • compound 1-1 may be further reacted with a compound of formula 5 (where X refers to a chloride, bromide, iodide, triflate, nonaflate and the like) in a solvent such as DMF, NMP, THF and the like using a base such at KOz-Bu, Cs 2 CO 3 or the like to afford 1-2.
  • a compound of formula 5 where X refers to a chloride, bromide, iodide, triflate, nonaflate and the like
  • a solvent such as DMF, NMP, THF and the like
  • a base such at KOz-Bu, Cs 2 CO 3 or the like
  • a compound of formula 4 can be prepared as in reaction scheme I by reacting a compound of formula 6 with a compound of the formula 2 (where R 49 and R 2 o are low molecular weight alkanes such as methyl, ethyl and the like) in a suitable solvent such as DMF and the like at an elevated temperature (80- 120 0 C) to generate an intermediate of the formula 7.
  • Intermediate 7 may be further reacted with hydrazine hydrochloride (8) or the like, in a suitable solvent such as a mixture of ethanol and water or the like at an elevated temperature (60- 100 0 C) to yield a compound of formula 4.
  • preparations such as described J. Het. Chem. 1977, 1(1), 65; J. Med. Chem. 1964, 7(3), 259) may be used.
  • R 4 , R 5 , Re and Y 2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
  • a compound of formula 1-3 may be prepared as in reaction scheme II.
  • a compound of formula 9 can be reacted with a compound of formula 10 (or a similar diol used in the protection of ketones) using an acid catalyst such as /7-toluenesulfonic acid and the like in a suitable solvent consisting of diol 10 and a trialkylorthoformate to generate an intermediate of formula 11.
  • Intermediate 11 can then be reacted with a base such as lithium hydroxide and the like in a high boiling alcoholic solvent such as ethylene glycol or the like at elevated temperature (50-120 0 C) to generate compounds of formula 12, which can subsequently be reduced using lithium aluminum hydride or the like to afford an intermediate of formula 13.
  • Intermediate 13 may be deprotected using an aqueous acid such as HCl and the like in an appropriate solvent such as acetone or the like at elevated temperature (40-70 0 C) to afford an intermediate of formula 14.
  • This intermediate can be reacted with a compound of formula 15 (where X refers to a chloride, bromide, iodide, triflate, nonaflate and the like) to afford a protected compound of the formula 16.
  • Compound 16 may be manipulated in an analogous manner as compound 1 in scheme I to afford intermediate 17. This intermedtiate can then be further deprotected and derivatized to afford various compounds of the formula 1-3 where R 23 refers to the definition of R 3 excluding one methylene group.
  • R 1 , R 2 , R 4 , R 5 and Y 2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
  • a compound of formula 1-4 can be prepared as in reaction scheme III by reacting a compound of formula 18 (where X refers to a group competent to be transmetallated such as chloride, bromide, triflate and the like) which can be prepared by any of the other methods mentioned in this patent with an appropriate coupling partner such as a boronic acid, organostannane, organozinc, olefin or terminal acetylene or the like using the organometallic coupling chemistry known in the art (for example, Hartwig, J. F. Handbook of Organopalladium Chemistry for Organic Synthesis, Negishi, E., Ed., Wiley- Interscience: Weinheim, 2002).
  • R 1 , R 2 , R 3 , R 4 , R 5 and Y 2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
  • a compound of formula 1-5 can be prepared as in reaction scheme IV by reacting a compound of formula 19 with an appropriate activating agent such as
  • a compound of formula 1-6 can be prepared as in reaction scheme V by reacting a compound of formula 21 with a compound of formula 22 and a metal cyanide such as KCN or the like in an appropriate solvent such as a mixture of ethanol and water or the like at an elevated temperature such as 50 0 C to afford an intermediate of formula 23.
  • This material can then be treated with an intermediate of formula 3 as described in scheme I to afford 1-6.
  • the groups designated as R 1 , R 2 , R 3 , R 4 , R 5 , Re and Y 2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
  • a compound of Formula 1-7 can be prepared as in reaction scheme VI by reacting a compound of formula 1 with a halogenating agent such as bromine or chlorine (X 2 ) in an appropriate solvent such as acetic acid to generate an intermediate of formula 24.
  • This intermediate can be reacted with a trivalent phosphorous reagent such as a trialkyl-or triarylphosphine or a trialkyl phosphite either neat or in an appropriate solvent such as tetrahydrofuran, toluene or the like to generate and intermediate with the formula 25 where Z refers to either a phosphorous ylide or a phosphonate ester.
  • a compound of the formula 4 can be diazotized with a metal nitrite such as KNO 2 in an appropriate solvent such as acetic acid to generate an intermediate of the formula 26. Then, intermediates 25 and 26 can be reacted in a biphasic solvent mixture such as DCM and water containing an aqueous base such as sodium carbonate or the like to generate 1-7 (for an example, see J. Het. Chem. 1981, 18(4), 675).
  • a biphasic solvent mixture such as DCM and water containing an aqueous base such as sodium carbonate or the like to generate 1-7 (for an example, see J. Het. Chem. 1981, 18(4), 675).
  • the groups designated as R 1 , R 2 , R 3 , R 4 , R 5 and Y 2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
  • a compound of formula 1-8 can be prepared as in reaction scheme VII by reacting a compound of formula 26 with thiourea (27) in the solvent used to generate 26 to afford an intermediate with formula 28.
  • This intermediate can be reacted with a metal hydroxide such as NaOH or the like at elevated temperature (80- 100 0 C) in an appropriate solvent such as ethanol, methanol or the like, quenched with a stoichiometric amount of acid such as HCl or the like and then reacted with a compound of the formula 24 (from scheme VI) to generate 1-8.
  • R 1 , R 2 , R 3 , R 4 , R 5 and Y 2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
  • a compound of Formula 1-9 can be prepared as in reaction scheme VIII by reacting a compound of formula 1-2 (wherein R is methyl) with a halogenating agent (R 22 X) such as N-bromosuccinimide (wherein R 22 is any group attached to a halogen as a delivery system for said halogen) in the presence of a radical initiator such as AIBN or the like in an appropriate solvent such as carbon tetrachloride or the like at an elevated temperature such as about 4O 0 C to about 100 0 C to afford an intermediate of formula 25.
  • a halogenating agent such as N-bromosuccinimide (wherein R 22 is any group attached to a halogen as a delivery system for said halogen)
  • a radical initiator such as AIBN or the like
  • an appropriate solvent such as carbon tetrachloride or the like
  • an elevated temperature such as about 4O 0 C to about 100 0 C to afford an intermediate of formula 25.
  • This intermediate can be reacted with a nucleophile of structure R 23 Z r- H, where Z represents a heteroatom such as N, O, S, or the like (and R 23 is any alkyl, aryl, heteroalkyl or heteroaryl sidechain attached to a nucleophilic atom like N, O or S) in the presence of a base like cesium carbonate in an appropriate solvent such as acetonitrile,
  • R 1 , R 3 , R 4 , R 5 , R 6 and Y 2 may be protected versions of the radicals defined in formula I which may be deprotected and manipulated to the final compound after completion of this scheme or in the middle of the scheme.
  • a compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from,
  • a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, and the like.
  • a compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).
  • Compounds of the invention in unoxidized form can be prepared from N- oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 0 C.
  • a suitable inert organic solvent e.g. acetonitrile, ethanol, aqueous dioxane, or the like
  • Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).
  • a suitable carbamylating agent e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
  • Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3 rd edition, John Wiley and Sons, Inc., 1999.
  • Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the
  • diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by
  • the compounds of Formula I can be made by a process, which involves:
  • Step A A mixture of ethyl 2-benzyl-3-oxobutanoate Ala (510 mg, 2.3 mmol) and dimethylformamide diethyl acetal (341 mg, 2.3 mmol) is heated to 100 0 C overnight. The solvent is removed to afford ethyl 2-benzyl-5-(dimethylamino)-3- oxopent-4-enoate Alb; ESIMS calcd. for Ci 6 H 22 NO 3 ([M+H]+) 276.2, found 276.0. The compound is used without purification.
  • Step B A microwave vial charged with a solution of Intermediate Alb
  • Example Al A solution of Example Al (33.4 mg, 83 ⁇ mol) in tetrahydrofuran (1 niL) is added to a solution of potassium tert-butoxide (9.4 mg, 83 ⁇ mol) in tetrahydrofuran (1 mL) at 0 0 C.
  • the reaction is then treated with iodomethane (14 mg, 100 ⁇ mol) and allowed to come to room temperature and stir overnight.
  • the reaction is then evaporated to dryness and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO 4 , filtered, evaporated and purified on a reversed phase HPLC
  • Step A A solution of Intermediate AlOa (6.58g, 28.08 mmol) in a mixture of ethylene glycol (25 ml) and triethyl orthoformate (20 mL) is treated with p- toluenesulfonic acid (200 mg, 1.3 mmol) and heated to 55 0 C overnight. The reaction is then cooled to room temperature and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO 4 , filtered and evaporated to afford ethyl 2-methyl- 2-(2-methyl-l,3-dioxolan-2-yl)-3-phenylpropanoate AlOb; ESIMS calcd. for Ci 6 H 23 O 4 ([M+H] + ) 279.2, found 279.1. The product is used without purification.
  • Step B A solution of Intermediate AlOb in ethylene glycol (50 ml) is treated with lithiumhydroxide (3 g, 71 mmol) and heated to 200 0 C for 30 minutes using conventional heating. At this point, the reaction solidifies. After cooling to room temperature, the solid mass is repeatedly digested with hot IM NaOH until all of the material dissolves. The resulting aqueous solution is extracted once with ethyl acetate and the organics are discarded. The aqueous solution is adjusted to pH 4 with concentrated HCl and extracted twice with ethyl acetate. The combined organic extracts are dried over MgSO 4 , filtered and evaporated.
  • lithiumhydroxide 3 g, 71 mmol
  • Step C A solution of Intermediate AlOc (3.36 g, 13.44 mmol) in IN HCl is extracted with ethyl acetate five times. The combined organics are dried over Na 2 SO 4 , filtered and evaporated. The resulting acid is then dissolved in tetrahydrofuran (100 mL) and is slowly added to a pre-cooled (0 0 C) solution of lithiumaluminiumhydride (2.0 g, 53.76 mmol) in tetrahydrofuran (100 niL). After stirring for 10 minutes the ice-bath is removed and the contents heated to reflux for 2 hours.
  • Step D A solution of Intermediate AlOd (1.8 g, 7.62 mmol) in acetone
  • Step E A solution of intermediate AlOe (110 mg, 0.573 mmol) in dichloromethane (1 mL) is treated with triethylamine (120 ⁇ L, 0.860 mmol), benzoyl chloride (80 ⁇ L, 0.688 mmol), and DMAP (5 mg, 0.04 mmol). After stirring for 2 hours the reaction is quenched with water and the aqueous layer extracted with
  • Step F A solution of Intermediate AlOf (1.34 g, 4.53 mmol) and dimethylformamide diethyl acetal (3.9 mL, 22.63 mmol) is heated at 125 0 C for 16 hours. Excess dimethylformamide diethyl acetal is removed and the crude is purified by flash chromatography (80 g SiO 2 , hexanes/ethyl acetate gradient) to afford 2-benzyl-5- (dimethylamino)-2-methyl-3-oxopent-4-enyl benzoate AlOg as a yellow oil.
  • Step G In a Smith Process vial charged with Intermediate AlOg (1.34 g,
  • Step H To a solution of Intermediate AlOh (1.34 g, 2.79 mmol) in methanol (120 mL) is added sodium methoxide (2M solution in methanol, 6 mL, 12 mmol) and the mixture is stirred for 1.5 hours. Methanol is removed under vacuum and the residue partitioned between saturated aqueous NH 4 Cl and ethyl acetate. The aqueous layer is extracted with ethyl acetate (2x). The combined organic phase is washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step I To a solution of Intermediate AlOi (20 mg, 0.053 mmol) in dichloromethane (1 rnL) is added diisopropylethylamine (13 ⁇ L, 0.080 mmol) followed by methanesulfonyl chloride (5 ⁇ L, 0.064 mmol). After 1 hour the reation is quenched with water and the aqueous layer is extracted with dichloromethane. The organic layer is washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step A To a mixture of tetrabutyl ammonium bromide (247 mg, 0.768 mmol) in 50% aqueous NaOH (7 mL) is added a solution of dibromo-oxylene (4.05 g, 15.36 mmol) in toluene (20 mL) and stirred vigourosly. Next, a solution of
  • Step B A solution of Intermediate A13b (432 mg, 1.86 mmol) in dimethylformamide diethyl acetal (683 ⁇ L, 3.72 mmol) is heated at 120 0 C for 16 hours.
  • Step C In a Smith Process vial charged with Intermediate A13c (45 mg,
  • Step A A solution of Intermediate AlOa (2.1 g, 9 mmol) and
  • Step B A solution of Intermediate A14a (2.48 g, 8.6 mmol) in ethanol
  • Step A To a solution of intermediate A14a (720 mg, 2.49 mmol) in chloroform (20 mL) is added iV-chlorosuccinimide (366 mg, 2.75 mmL) and the mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the residue is purified by flash chromatography (80 g SiO 2 , hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-4-chloro-5-(dimethylamino)-2-methyl-3-oxopent-4-enoate A15a as a yellow solid.
  • Step B In a Smith Process vial charged with Intermediate A15a (458 mg,
  • Example A16 is obtained.
  • Step A A solution of Intermediate A14a (204 mg, 0.71 mmol) in dichloromethane (7 rnL) cooled to -15 0 C is treated with a solution of N-fluoro benzenesulfonamide (267 mg, 0.85 mmL) in acetonitrile (10 mL). The mixture is then allowed to stir at room temperature overnight. The solvent is removed in vacuo and the residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-5-(dimethylamino)-4-fluoro-2-methyl-3-oxopent-4-enoate A17a as a yellow oil.
  • Step B By following a similar procedure as the one used for preparing
  • Step A A solution of diisopropylamine (589 mg, 5.8 mmol) in tetrahydrofuran (10 niL) is cooled to -78 0 C (dry ice/acetone bath) and treated with butyllithium (2.46 M in hexane, 1.73 rnL, 4.3 mmol) dropwise and allowed to stir cold for 15 minutes. The reaction is then treated dropwise with a solution of Intermediate A18a (870 mg, 3.9 mmol) in tetrahydrofuran (2 mL) and stirred cold for 20 minutes.
  • Step B A solution of Intermediate A18b (489 mg, 0.19 mmol) and hydrazine hydrate (133 mg, 1.9 mmol) in ethanol (10 mL) and water (2 mL) is heated to 60 0 C for 2 hours. The reaction is then cooled to room temperature and the solvent is removed to afford tert-butyl 4-(5-amino-lH-pyrazol-4-yl)piperidine-l-carboxylate A18c; ESIMS calcd. for Ci 3 H 23 N 4 O 2 ([M+H] + ) 267.2, found 267.1. The product is used without purification.
  • Step C A solution of Intermediate A18c (94.3 mg, 0.35 mmol) and
  • Step A A solution of Intermediate A21a (1 g, 6.94 mmol) in
  • tetrahydrofuran (5 rnL) is added slowly to a pre-cooled (O 0 C) mixture of 60% NaH (333 mg, 8.33 mmol) in tetrahydrofuran (20 mL) and stirred for 1 hour. The mixture is then cooled to -78 0 C, NBS (1.35 g, 7.63 mmol) is added in one portion and the mixture is allowed to stir for an additional 1 hour. The reaction is quenched with water and allowed to warm to room temperature at which time tetrahydrofuran is removed under reduced pressure. The remaining residue is partitioned between water and ethyl acetate and the aqueous layer is extracted with ethyl acetate.
  • Step B To a solution of Intermediate A21b (100 mg, 0.45 mmol) in toluene (2 rnL) is added Cs 2 CO 3 (176 mg, 0.54 mmol) followed by phenol (42 mg, 0.45 mmol). The mixture is then heated to 120 0 C for 2 hours, the contents cooled, and partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate and the organic phase is washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to afford ethyl 2-methyl-3-oxo-2-phenoxybutanoate A21c.
  • Step C A solution of Intermediate A21c (70 mg, 0.297) and
  • dimethylformamide diethyl acetal (3 mL) is heated at 100 0 C for 16 hours. Excess dimethylformamide diethyl acetal is removed in vacuo and the crude is purified by flash chromatography (12 g SiO 2 ) to afford ethyl 5-(dimethylamino)-2-methyl-3-oxo-2- phenoxypent-4-enoate A21d as an orange oil.
  • Step D In a Smith Process vial charged with Intermediate A21d (43 mg,
  • Step A A solution of Intermediate A22a (1 g, 4.58 mmol) and
  • dimethylformamide-DEA (1.6 rnL, 9.33 mmol) is heated at 120 0 C for 16 hours. Excess dimethylformamide-DEA is removed and the crude is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzylidene-5-(dimethylamino)-3- oxopent-4-enoate A22b as a 1.5:1 mixture of isomers.
  • Step B In a Smith Process vial charged with Intermediate A22b (69 mg,
  • Step A A solution of Intermediate A23a (260 mg, 1.12 mmol; prepared following experimental procedure from Synthesis 1992, 884-887) and
  • dimethylformamide-DEA (1 mL, 5.83 mmol) is heated at 80 0 C for 16 hours and then at 120 0 C for another 16 hours. Excess dimethylformamide-DEA is removed and the crude is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl l-(3- (dimethylamino)acryloyl)-2-phenylcyclopropanecarboxylate A23b as an orange oil.
  • ESIMS calcd. for Ci 7 H 22 NO 3 ([M+H] + ) 288.1, found 288.2.
  • Step B A solution of Intermediate A23b (233 mg, 0.81 mmol) and 4-(4-
  • Step C A solution of Intermediate A23c (33 mg, 0.07 mmol) in
  • Step A To a O 0 C solution of intermediate A14a (300 mg, 1.04 mmol) in ethanol (1 niL) is added dropwise a solution of hydroxylamine hydrochloride (72 mg, 1.04 mmol) and sodium acetate (128 mg, 1.56 mmol) in water (1 mL). The mixture is then stirred for 17 hours while allowed to warm to room temperature. The solvent is evaporated and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-5-(hydroxyimino)-2-methyl-3-oxopentanoate A26a as a white oil.
  • ESIMS calcd. for Ci 5 H 20 NO 4 ([M+H] + ) 278.1, found 278.1.
  • Step B A solution of Intermediate A26a (153 mg, 0.55 mmol) and dimethylformamide-DEA (0.5 mL, 2.92 mmol) is stirred at room temperature for 16 hours. Excess dimethylformamide-DEA is removed and the crude is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-4-cyano-5- (dimethylamino)-2-methyl-3-oxopent-4-enoate A26b as a yellow oil.
  • Step C In a Smith Process vial charged with Intermediate A26b (58 mg,
  • Step A A solution of Intermediate A27a (486 mg, 2.55 mmol; prepared following experimental procedure from Synthesis 1989, 688-690) and
  • dimethylformamide-DEA (2 mL, 11.7 mmol) is heated at 120 0 C for 16 hours. Excess dimethylformamide-DEA is removed and the crude material is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford 5-(dimethylamino)-2,2- dimethyl- l-phenylpent-4-ene-l,3-dione A27b as an orange oil.
  • ESIMS calcd. for
  • Step B In a Smith Process vial charged with Intermediate A27b (54 mg,
  • Step A To a solution of Intermediate A14a (80 mg, 0.27 mmol) in CHCl 3
  • N-bromo succinimide 60 mg, 0.37 mmL
  • N-bromo succinimide 60 mg, 0.37 mmL
  • the solvent is removed and the remaining contents partitioned between water and ethyl acetate.
  • the organic layer is washed with 10% aqueous NaHSO 3 , dried over Na 2 SO 4 , and volatiles are removed to afford 2-benzyl-4- bromo-5-(dimethylamino)-2-methyl-3-oxopent-4-enoate A28a.
  • the product is used without further purification.
  • Step B In a Smith Process vial charged with Intermediate A28a (1.90 g,
  • Step A By following a similar procedure as the one used for preparing
  • Step B By following a similar procedure as the one used for preparing
  • Step C By following a similar procedure as the one used for preparing
  • Step A Into a 50 ml round bottom flask is placed methyl 2-((l,3- dioxoisoindolin-2-yl)methyl)-3-oxobutanoate A31a (500 mg, 1.18 mmol), K 2 CO 3 (376 mg, 2.27 mmol), benzyl bromide (258 ⁇ L, 2.17 mmol), and acetonitrile (20 ml) and the mixture is stirred for 24 hours. The mixture is partitioned between water and ethyl acetate and the aqueous layer is extracted with ethyl acetate. The organic layer is washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step B A 20 ml vial is charged with Intermediate A3 Ib (134 mg, 0.367 mmol) and dimethylformamide-dimethylacetal (1.5 ml) and the mixture is heated to 110 0 C for 24 hours. The solvent is removed and the crude material is purified by flash chromatography (12 g SiO 2 , hexanes/ethyl acetate gradient) to afford methyl 2-benzyl-5- (dimethylamino)-2-((l,3-dioxoisoindolin-2-yl)methyl)-3-oxopent-4-enoate A31c as a dark yellow oil.
  • Step C Into a 20 ml vial is placed 4-(4-trifluoromethylphenyl)- IH- pyrazol-5-amine (60 mg, 0.262 mmol), Intermediate A31c (110 mg, 0.262 mmol), acetic acid (200 ⁇ L), and methanol (2 ml).
  • Step D Into a 20 ml vial is placed Intermediate A3 Id (13 mg, 0.022 mmol), hydrazine monohydrate (5 ⁇ L, 0.089 mmol), methanol (200 ⁇ L), and
  • Step A A solution of 3-methyl-lH-pyrazol-5-amine A32a (1 g, O.Olmol) in acetic acid (10 niL) is treated with cyclohexanone (1.2 rnL, 0.012 mol) and stirred at 7O 0 C overnight. The reaction is cooled to room temperature, concentrated, and the crude material is purified by reversed-phase HPLC (acetonitrile/water gradient) to afford 4- cyclohexenyl-3-methyl-lH-pyrazol-5-amine A32b.
  • acetic acid 10 niL
  • cyclohexanone 1.2 rnL, 0.012 mol
  • Step B By following a similar procedure as the one used for preparing
  • Example A34 is obtained: ESIMS calcd. for C 20 H 19 F 3 N 3 O 4 ([M+H] + ) 422.1, found 422.1.
  • Example A35
  • Example A36 ESIMS calcd. for C 27 H 25 F 3 N 3 O 4 ([M+H] + ) 511.2, found 511.1.
  • Step A A mixture of methanesulfonyl acetone A37a (2.0 g, 14.7 mmol), potassium carbonate (2.0 g, 14.7 mmol) and methyl iodide (916 ⁇ L, 14.7 mmol) in acetone (50 mL) is stirred at room temperature for 2h. The mixture is then filtered, concentrated, and the crude material is purified by flash chromatography (SiO 2 , hexanes/ethyl acetate gradient) to provide 3-(methylsulfonyl)butan-2-one A37b.
  • ESIMS calcd. for C 5 H 11 O 3 S ([M+H] + ) 151.0, found 151.0.
  • Step B A mixture of Intermediate A37b (753 mg, 5.0 mmol), benzyl bromide (566 ⁇ L, 4.8 mmol) and potassium carbonate (1.38 g, 10.0 mmol) is stirred in acetone (25 mL) at room temperature for 3h.
  • Step C A solution of Intermediate A37c (300 mg, 1.25 mmol) and N,N- dimethylformamide dimethyl acetal (167 ⁇ L, 1.25 mmol) are heated to 100 0 C for 12h. The mixture is concentrated to provide (E)-l-(dimethylamino)-4-methyl-4- (methylsulfonyl)-5-phenylpent-l-en-3-one A37d, which is used directly in the next step without further purification.
  • ESIMS calcd. for C15H22NO3S ([M+H]+) 296.1, found 296.0.
  • Step D A mixture of 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-5-amine
  • Step A Ethyl 2-methyl-3-oxobutanoate A21a (1.25 g, 8.7 mmol) is dissolved in acetone (10 niL), then potassium carbonate (1.43 g, 10.4 mmol) and 3- fluorobenzyl chloride (2.1 mL, 17.3 mmol) are added and the mixture is heated for 12h at 60 0 C. The mixture is cooled, filtered, concentrated, and the crude material is purified by flash chromatography (SiO 2 , hexanes/ethyl acetate gradient) to provide ethyl 2-(3- fluorobenzyl)-2-methyl-3-oxobutanoate A38a: ESIMS calcd. for Ci 4 Hi 8 FO 3 ([M+H] + ) 253.1, found 253.1.
  • Step B A solution of Intermediate A38a (1.93 g, 7.65 mmol) and N,N- dimethylformamide diethyl acetal (1.31 mL, 7.65 mmol) are heated at 100 0 C for 12h. The mixture is concentrated to afford (E)-ethyl 5-(dimethylamino)-2-(3-fluorobenzyl)-2- methyl-3-oxopent-4-enoate A38b as a red-brown oil.
  • ESIMS calcd. for Ci 7 H 23 FNO 3 ([M+H] + ) 308.2, found 308.1. The product is used in the next step without purification.
  • Step C A solution of 4-trifluoromethylphenylacetonitrile (0.54 g, 2.9 mmol) and N,N-dimethylacetamide dimethyl acetal (0.42 niL, 2.9 mmol) is heated to 100 0 C for 2h. The mixture is concentrated to afford (Z)-3-(dimethylamino)-2-(4- (trifluoromethyl)phenyl)but-2-enenitrile A38c, which is used in the next step without further purification.
  • ESIMS calcd. for Ci 3 H 14 F 3 N 2 ([M+H] + ) 255.1, found 255.1.
  • Step D A solution of Intermediate A38c (2.9 mmol) and hydrazine-HCl
  • Step E A mixture of Interemediate A38b (209 mg, 0.68 mmol) and
  • Step A By following a similar procedure as the one used for preparing
  • Step B A mixture of Intermediate BIa (65 mg, 0.17 mmol),
  • Step A By following a similar procedure as the one used for preparing
  • Example Al from intermediate Alb except substituting 4-bromo-lH-pyrazol-5-amine for 4-(4-chlorophenyl)-lH-pyrazol-5-amine, Example B4a is obtained; ESIMS calcd. for Ci 8 Hi 9 BrN 3 O 2 ([M+H] + ) 388.1, found 388.1.
  • Step B By following a similar procedure as the one used for preparing
  • a Smith Process vial charged with Intermediate B4a (48 mg, 0.12 mmol), biphenylboronic acid (30 mg, 0.12 mmol) and cesium fluoride (57 mg, 3.7 mmol) in dioxane (1 mL) is treated with Pd 2 dba 3 (2.3 mg, 2.5 ⁇ mol) and tri-tert-butylphosphonium tetrafluoroborate (2.2 mg, 7.5 ⁇ mol).
  • the vial is then sealed and the mixture is subjected to microwave irradiation (120 0 C, 20 min).
  • the reaction mixture is cooled and partitioned between ethyl acetate and water.
  • Example A14 38 mg, 0.08 mmol
  • pyridin-3-yl boronic acid 30 mg, 0.2 mmol
  • powdered potassium carbonate 50 mg, 0.36 mmol
  • dimethoxyethane 2.5 mL
  • water 0.5 mL
  • Tetrakis(triphenylphosphino)-palladium(II) 30 mg, 0.03 mmol
  • Example B19 from Example A14 except substituting pyridin-4-yl boronic acid for pyridin-3-yl boronic acid, Example B20 is obtained; ESIMS calcd. for C 29 H 27 N 4 O 2 ([M+H] + ) 463.2, found 463.1.
  • Example B21 from Example A14 except substituting 1-phenylethanamine for (6- (trifluoromethyl)pyridin-3-yl)methanamine, Example B22 is obtained; ESIMS calcd. for C 32 H 33 N 4 O 2 ([M+H] + ) 505.2, found 505.1.
  • Step A By following a similar procedure as the one used for preparing
  • Step B By following a similar procedure as the one used for preparing
  • Step A A solution of Intermediate B23a (109 mg, 0.25 mmol) in tetrahydrofuran (250 ⁇ L) is cooled to 0 0 C (ice/water bath) and treated isopropyl magnesium chloride (2M in tetrahydrofuran, 163 ⁇ L, 0.33 mmol) over 2 minutes and allowed to stir cold for 1 hour. The reaction is then treated with a 1 M zinc chloride in diethyl ether (0.376 mL, 0.38 mmol), stirred cold for an additional hour and then warmed to room temperature. The reaction is then treated with a solution of 2-trifluoromethyl-5- bromopyridine (85 mg, 0.38 mmol) and Pd(PPh 3 ) 4 (5.8 mg, 5.0 ⁇ mol) in
  • Step A By following a similar procedure as the one used for preparing
  • Step B A solution of intermediate B27a (51 mg, 0.13 mol) in
  • dimethylformamide (1 mL) is treated with dimethylamine (2M in tetrahydrofuran, 0.13 mL), sealed and heated to 100 0 C overnight. The reaction mixture is cooled and partitioned between ethyl acetate and water.
  • Example B28 A solution of Example B28 (41.6 mg, 85 ⁇ mol) in dichloromethane (0.5 niL) and trifluoroacetic acid (0.5 niL) is aged for 1 hour and the solvent is removed. The reaction is then treated with dichloromethane (1 mL), 1-methylcyclopropyl 4-nitrophenyl carbonate (21 mg, 89 ⁇ mol) and triethylamine (30 ⁇ L, 0.21 mmol). The reaction mixture is stirred for 1.5 hours and partitioned between ethyl acetate and water.
  • Example B31 To a solution of Example B31 (41 mg, 0.1 mmol) in dichloromethane (0.3 mL) is added deoxo-fluor (31 ⁇ L, 0.17 mmol) and stirred at room temperature for 4 h. Another portion of deoxo-fluor (31 ⁇ L, 0.17 mmol) is added and the reaction mixture stirred at room temperature overnight. The excess of reagent is quenched with saturated aqueous NaHCO 3 (1 mL), extracted with dichloromethane (3 x 10 mL), dried (Na 2 SO 4 ) and concentrated.
  • Step A By following a similar procedure as the one used for preparing
  • Step B A cold (O 0 C) solution of Intermediate B41a (50.1 mg, 0.113 mmol) in tetrahydrofuran (1 rnL) is treated with methyl magnesium bromide (3M in diethyl ether, 0.79 mL) and stirred for 2.5 hours. The reaction mixture is then quenched with water and extracted with ethyl actetate.
  • Example B41 from Intermediate B41a except substituting pentamethylene (bis) magnesium bromide for methyl magnesium bromide, Example B42 is obtained; ESIMS calcd. for C 30 H 34 N 3 O 3 ([M+H] + ) 484.6, found 484.1.
  • Example B43
  • Step A By following a similar procedure as the one used for preparing
  • Step B A solution of Intermediate CIa (129 mg, 0.36 mol) in dimethylformamide (1.5 mL) is treated with N-hydroxysuccinimide (59 mg) and EDC (91 mg, 0.47 mmol) and stirred overnight at room temperature. The reaction mixture is cooled and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO 4 , filtered, evaporated and the residue is purified by flash chromatography
  • Step C A solution of Intermediate CIb (137 mg, 0.30 mmol) and N'- hydroxyisobutyrimidamide in dioxane (2 mL) is sealed and heated to 110 0 C overnight. The reaction mixture is cooled and partitioned between ethyl acetate and water. The organics are isolated, dried over MgSO 4 , filtered, evaporated and the residue is purified on a reversed phase HPLC (H 2 O/MeCN gradient) to provide the title compound
  • Step A Asolution of diisopropylamine (3.08 g, 30.5 mmol) in tetrahydrofuran (20 rnL) is cooled in a dry ice/acetone bath and treated with a solution of butyllithium (6.7 rnL of a 2.5 M solution, 16.8 mmol) and allowed to stir cold for 15 minutes. The reaction is then treated with Intermediate DIa (2.0 g, 15.3 mmol) and allowed to stir for 15 minutes cold. The reaction is then allowed to come to room temperature over 30 minutes and treated with ethyl acetate (669 mg, 7.6 mmol) and stirred for an additional 30 minutes.
  • dimethylformamide dimethyl acetal (3.5 ml, excess) is heated to 100 0 C for 1 hour and the solvent is removed in vacuo. The residue is coevaporated with ethanol twice and then dissolved in ethanol (5 mL) and treated with 4-(4-chlorophenyl)-lH-pyrazol-5-amine (726 mg, 3.75 mmol) and 4M HCl in dioxane (1 mL, 4 mmol). The reaction is heated to 150 0 C for 30 minutes, cooled to room temperature, diluted with ethyl acetate and washed with water (3x).
  • Example Dl 75 mg, 0.36 mol
  • methanol 1 mL
  • a 50% aqueous solution of hydroxylamine N-hydroxysuccinimide 50 ⁇ L, 0.76 mmol
  • the reaction is then cooled to room temperature and the solvent was removed.
  • the residue is co evaporated with dioxane and treated with dioxane (1 mL) followed by acetic anhydride (42 mg, 0.42 mmol).
  • the reaction is heated to 120 0 C for 2 hours.
  • 50 ⁇ L of acetic acid is added and the reaction is heated to 120 0 C for 3 days.
  • the reaction is cooled to room temperature and the solvent is removed.
  • Step A A solution of Intermediate EIa (250 mg, 1.8 mmol), amidine hydrochloride (157 mg, 2.0 mmol) and potassium cyanide (122 mg, 1.9 mmol) in a mxture of ethanol (3 mL) and water (3 mL) is heated to 50 0 C overnight. The reaction is then diluted with ethyl acetate and the organics are extracted twice with 1 M NaOH. The aqueous phase is discarded and the organics are extracted twice with 1 M HCl and discarded. The combined aqueous layers are made basic with solid Na 2 CO 3 , extracted twice with ethyl acetate.
  • Step B By following a similar procedure as the one used for preparing
  • Step A A solution of Intermediate AlOa (600 mg, 2.6 mmol) in acetic acid (8 mL) is treated with bromine (409 mg, 2.6 mmol) and stirred at room temperature overnight. The reaction is then diluted with ethyl acetate and the organics are extracted with IM NaOH (Ix) and with saturated aqueous sodiumhydrogencarbonate (2x). The organics are isolated, dried over MgSO 4 , filtered, evaporated and the residue is purified by flash chromatography (hexanes/ethyl acetate gradient) to afford ethyl 2-benzyl-4- bromo-2-methyl-3-oxobutanoate FIa; ESIMS calcd. for Ci 4 Hi 8 BrO 3 ([M+H] + ) 313.0, found 313.0.
  • Step B A solution of Intermediate FIa (95 mg, 0.30 mmol) in tetrahydrofuran (3 rnL) is treated with triphenylphosphine (180 mg, 0.69 mmol) and heated to 50 0 C overnight. The reaction is then evaporated to dryness and the residue is treated with ether and the ether is decanted. This procedure is repeated a total of 6 times and the resulting residue is dissolved in dichloromethane. A separate flask is charged with 4-(4-chlorophenyl)-lH-pyrazol-5-amine (194 mg, lmmol) followed by cone. HCl (0.5 mL) and water (2 mL).
  • the resulting suspension is then treated with sodium nitrite (69 mg, 1 mmol) in water (0.3 mL) and stirred for 30 minutes.
  • the reaction is quenched with a saturated aqueous solution of sodium carbonate and when the bubbling subsides, the ylide solution prepared above is added to the reaction and stirring is maintained for 1 hour.
  • the entire reaction is then poured onto a silica gel plug and eluted with
  • Step A Into a 100 ml round bottom flask containing methyl 3- oxopentanoate (3.0 g, 23.0 mmol) in acetonitrile (40 ml) is added K 2 CO 3 (4.76 g, 34.5 mmol) followed by benzyl bromide (2.6 ml, 21.9 mmol). After stirring for 72 hours the mixture is partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate (2x), the combined organic layers are washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. Purification of the crude material by flash
  • Step B To a 100 ml round bottom flask containing Intermediate F2b (2.3 g, 10.45 mmol) in acetonitrile (30 ml) is added K 2 CO 3 (2.16 g, 15.67 mmol) followed by methyl iodide (1.62 ml, 26.12 mmol). The mixture is refluxed for 24 hours and acetonitrile is removed under vacuum. The contents are partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate (2x), the combined organic layers are washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step C To a 20 ml vial containing Intermediate F2c (500 mg, 2.13 mmol) in acetic acid (3 ml), bromine (109 ⁇ L, 2.13 mmol) is added dropwise at room temperature
  • Step D To a 20 ml vial containing Intermediate F2d (625 mg, 1.99 mmol) in toluene (5 ml) is added triethyl phosphite (1.74 ml, 9.98 mmol) and the mixture is heated at 130 0 C for 18 hours. The solvent is removed and the crude material is purified by flash chromatography (40 g SiO 2 , hexanes/ethyl acetate gradient) to yield methyl 2- benzyl-4-(diethoxyphosphoryl)-2-methyl-3-oxopentanoate F2e as a clear oil.
  • ESEVIS calcd. for Ci 8 H 28 O 6 P ([M+H] + ) 371.1, found 371.1.
  • Step E To a 20 ml vial containing 4-(4-trifluoromethylphenyl)- IH- pyrazol-5-amine (100 mg, 0.440 mmol) in acetic acid (1 ml) is added a solution Of NaNO 2 (30 mg, 0.440 mmol) in water (100 ⁇ L). After 10 minutes the reaction is diluted with dichloromethane (3 ml) and treated with saturated aqueous Na 2 CO 3 until p ⁇ > 8. A solution of Intermediate F2e (125 mg, 0.338 mmol) in dichloromethane (1 ml) is then added and the mixture is stirred for 6 hours. The mixture is then partitioned between brine and dichloromethane.
  • Example F2 The aqueous layer is extracted with dichloromethane (Ix) and the combined organic layers are washed with brine, dried over MgSO 4 and evaporated in vacuo.
  • the crude material is dissolved in MeOH (2 ml) and is then subjected to microwave irradiation (150 0 C, 2 hours). The solvent is removed and the crude material is purified by flash chromatography (12 g SiO 2 , hexanes/ethyl acetate gradient) to afford the title compound (Example F2) as a yellow semi-solid.
  • Step A A sample of Intermediate F5a is prepared from Intermediate FIa in an analogous manner as the preparation of Intermediate F2e from Intermediate F2d.
  • a solution of potassium tert-butoxide (234 mg, 2.43 mmol) in tetrahydrofuran (3.5 mL) is treated with a solution of Intermediate F5a (850 mg, 2.43 mmol) in tetrahydrofuran (7 mL) and added to a cooled (ice/water) suspension of Selectfluor (1.72 g, 4.86 mmol) in acetonitrile (7 mL). The cooling bath is removed and the reaction is allowed to stir for 3 hours at room temperature.
  • Step B A solution of 4-(4-trifluoromethylphenyl)-lH-pyrazol-5-amine
  • Step A A solution of Intermediate GIa (100 mg, 0.51 mmol) in acetic acid (1 niL) is treated with a solution of sodium nitrite (37 mg, 0.51 mmol) in water (0.5 mL). After stirring for 15 minutes, the reaction is treated with thiourea (80 mg, 1.1 mmol) and stirred for 30 minutes. The reaction immediately evolves gas and becomes thick with solid. The solvent is removed and the residue is purified on a reversed phase HPLC (H 2 OZMeCN gradient) to provide 4-(4-chlorophenyl)-lH-pyrazol-3-yl
  • Step B In a microwave vial a solution of Intermediate GIb (50 mg, 0.14 mmol) in ethanol (2 mL) is treated with potassium hydroxide (38 mg, 0.68 mmol). The vial is sealed and the mixture is subjected to microwave irradiation (100 0 C, 5 min). The reaction is then treated with 4 M HCl in dioxane (187 ⁇ L, 0,75 mmol) followed by a solution of Intermediate FIa (100 mg, 0.32 mmol) in ethanol (1 niL) and the reaction is subjected to microwave irradiation (165 0 C, 20 min).
  • Step A In a Smith Process vial charged with Example N8 (29 mg, 0.06 mmol) in iV,./V-dimethylacetamide (1.5 ml) is added Pd 2 dba 3 (2 mg, 0.0023 mmol), dppf (2.6 mg, 0.0048 mmol), zinc (1 mg, 0.012 mmol), and zinc cyanide (9 mg, 0.072 mmol). The mixture is purged with nitrogen, the vial sealed, and then evacuated and re-purged with nitrogen. The mixture is then subjected to microwave irradiation (160 0 C, 1 hour). The solution is partitioned between water and ethyl acetate.
  • Step A In a Smith Process vial charged with Example N8 (30 mg, 0.062 mmol) in dioxane (1 ml) is added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (85 ⁇ L, 0.62 mmol), Pd(dppf)Cl 2 - dichloromethane complex (5 mg, 0.0062 mmol), and IM aqueous cesium carbonate (124 ⁇ L, 0.124 mmol). The mixture is purged with nitrogen, the vial sealed, and then evacuated and re-purged with nitrogen. The mixture is then subjected to microwave irradiation (160 0 C, 10 minutes).
  • Step A In a Smith Process vial charged with Example N8 (60 mg, 0.082 mmol) in dioxane (3 ml) and water (300 ⁇ L) is added potassium
  • Step A A cold (O 0 C) solution of Intermediate B23a (141 mg, 0.323 mmol) tetrahydrofuran (2 niL) is treated with the dropwise addition of isopropylmagnesium chloride (2.0M in tetrahydrofuran, 178 ⁇ L, 0.356 mmol) and stirred for 15 minutes. Dimethylformamide (100 ⁇ L) is then added. After 30 minutes, water is added and the reaction extracted with ethylacetate. The organics are dried (MgSO 4 ), filtered, concentrated, and the crude material is purified by flash chromatography
  • Step B A mixture of Intermediate Ha (77 mg, 0.23 mmol) and sodium metabisulfite (43 mg, 0.23 mmol) in dimethylformamide (1.5 mL) is heated to HO 0 C and maintained for 10 min. 4-(trifluoromethyl)benzene-l,2-diamine (35 mg, 0.20 mmol) is added and the reaction stirred at 11O 0 C for 3 hours. The reaction is cooled to room temperature, diluted with water and extracted with ethylacetate. The organics are dried (MgSO 4 ), filtered, concentrated, and the crude material is purified by flash
  • Step A A solution of Intermediate JIa (346 mg, 1 mmol) (prepared according to S.Pirc, D. Bevk, A. Golobic, B.Stanovnik, J.Svete, HeIv. Chim. Acta, 2006, 89, 30-44) and 4-(4-(trifluoromethyl)phenyl)-lH-pyrazol-3-amine (250 mg, 1.1 mmol) in ethanol (8 mL) and 37% aq HCl (100 ⁇ L, 1.2 mmol) is heated to 7O 0 C overnight. The reaction mixture is then cooled to -30 0 C. The resulting precipitate is filtered and washed with cold ethanol to afford tert-butyl 2-phenyl-l-(3-(4-
  • Step C To a solution of Intermediate JIc (46 mg, 0.12 mmol) in dichloromethane (2 rnL) is added diisopropylethylamine (128 ⁇ L, 0.72 mmol) followed by acetyl chloride (32 ⁇ L, 0.45 mmol) and the mixture is stirred overnight at room temperature. Dichloromethane is then added and the reaction mixture is washed with brine, 10% aqueous citric acid solution, brine, saturated aqueous NaHCO 3 solution, and brine.
  • the organic phase is dried (Na 2 SO 4 ), filtered, evaporated and the residue is purified by chiral chromatography using a Chiral Technologies 10x250mm ChiralPak IC column with a 7 minute isocratic elution using CO 2 /75:25 THF:MeOH (80:20) as mobile phase at 10 mL per minute.
  • the second eluting peak is collected and reanalyzed on a using a Chiral Technologies 4.6xl00mm ChiralPak IC column with 5 minute isocratic elution using CO 2 /75:25 THF:MeOH (80:20) as mobile phase at 2 mL per minute and 30 0 C.
  • Step A A solution of Intermediate J4a (0.91 g, 2.96 mmol) in anhydrous toluene is cooled to -78°C and treated dropwise with diisobutylaluminium hydride (IM in toluene, 7.4 rnL, 7.4 mmol). After stirring the reaction mixture at -78°C for 2 hours methanol (0.75 mL) is added followed by saturated NaHCO 3 (20 mL). The flask is warmed to RT, water (10 mL) and ether (10 mL) are added and stirred for another 1 hour. Organics are extracted with ether, dried with Na 2 SO 4 and concentrated.
  • IM in toluene 7.4 rnL, 7.4 mmol
  • the mixture consists mostly of tert-butyl l-hydroxy-2-methyl-3-phenylpropan-2-ylcarbamate J4c (ESIMS calcd. for Ci 5 H 23 NNaO 3 ([M+Na] + ) 288.2, found 288.2) with some tert-butyl 2- methyl-l-oxo-3-phenylpropan-2-ylcarbamate J4b (ESIMS calcd. for Ci 5 H 2I NNaO 3 ([M+Na] + ) 286.1, found 286.2) and is used without purification.
  • Step B To a solution of Dess-Martin periodinane (1.506 g, 3.55 mmol) in dichloromethane (10 mL) is added a solution of Intermediates J4b and J4c (0.793 g, 2.96 mmol) in dichloromethane (10 mL) and the mixture is stirred at ROOM
  • Step C A solution of Intermediate J4b (500 mg, 1.9 mmol) in anhydrous THF (4 mL) is cooled to -78°C and ethynylmagnesium bromide (0.5 M solution in THF, 15.2 mL, 7.6 mmol) is slowly added. The cooling bath is removed and the reaction mixture is stirred for 2 hours at room temperature. The excess of
  • ethynylmagnesium bromide is quenched by addition of saturated NH 4 Cl (10 mL). The mixture is extracted with ethylacetate, the organic phase is dried (Na 2 SO 4 ) and concentrated to yield tert-butyl 3-hydroxy-2-methyl-l-phenylpent-4-yn-2-ylcarbamate J4d as a mixture of diastereomers; ESIMS calcd. for Ci 7 H 23 NNaO 3 ([M+Na] + ) 312.2, found 312.1. The crude material is used without purification.
  • Step D To a solution of Intermediate J4d (1.9 mmol) in
  • dichloromethane (5 mL) is added Dess-Martin periodinane (967 mg, 2.28 mmol) in dichloromethane (15 mL) and the mixture is stirred at room temperature overnight. Aqueous solution of NaHCO 3 and Na 2 S 2 O 3 is added, the mixture is stirred for 20 min, extracted with dichloromethane (3x), dried (Na 2 SO 4 ), and concentrated to afford tert- butyl 2-methyl-3-oxo-l-phenylpent-4-yn-2-ylcarbamate J4e; ESIMS calcd. for
  • the crude material is used in without purification.
  • Step E Diethylamine (204 ⁇ L, 2 mmol) is added to a cold (0 0 C) solution of Intermediate J4e (1.9 mmol) in dichloromethane (20 mL). The reaction mixture is stirred at room temperature overnight, the solvent is evaporated and the crude material is purified by flash chromatography (hexane/ethylacetate gradient) to afford tert-butyl 5- (diethylamino)-2-methyl-3-oxo-l-phenylpent-4-en-2-ylcarbamate J4f; ESIMS calcd. for C 2I H 33 N 2 O 3 ([M+H] + ) 361.3, found 361.2.
  • Step G A solution of Intermediate J4g (160 mg, 0.32 mmol) in dichloromethane (4 mL) is treated with trifluoroacetic acid (2 mL) and stirred at room temperature overnight. The solvent is removed, the crude material is treated with saturated aqueous NaHCO 3 and extracted with dichloromethane (3x). the combined organic phase is dried (Na 2 SO 4 ) and concentrated to yield l-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[ 1 ,5-a]pyrimidin-7-yl)propan-2-amine J4h; ESIMS calcd. for C 22 H 20 F 3 N 4 ([M+H] + ) 397.2, found 397.2. The crude material is used in without purification.
  • Step A A sample of Example K4a is subjected to chiral chromatography using a Chiral Technologies 21x250mm ChiralPak AD-H column with a 2.5 minute stacked injections, 5 minute isocratic elution using methanol/CO 2 (30:70) as mobile phase at 8Og/ min and 40 0 C.
  • the first eluting peak is collected and reanalyzed using a Chiral Technologies 4.6x100mm ChiralPak AD-H column with 10 minute isocratic elution using methanol/CO 2 (30:70) as mobile phase at 2 mL/min and 30 0 C.
  • Intermediate J5a comes off at 1.98 min.
  • the 1 H NMR and ESIMS data for Intermediate J5a are identical to Intermediate K4a.
  • Step B To a solution of Intermediate J5a (217 mg, 0.51 mmol) in toluene (3.5 rnL) is added diisopropylethylamine (106 ⁇ L, 0.61 mmol) followed by diphenyl phosphoryl azide (132 ⁇ L, 0.61 mmol) and the reaction mixture is stirred at room temperature for 2 hours. Tert-buthanol (488 ⁇ L, 5.1 mmol) is then added and the reaction mixture is stirred at 110 0 C overnight. Water is added and the mixture is extracted with dichloromethane. The organic phase is dried (Na2SO4), concentrated in vacuo and the crude material is purified by flash chromatography (hexane/ethylacetate gradient). The 1 H NMR and ESIMS data for Intermediate J5b are identical to
  • Step C By following a similar procedure as the one used for preparing
  • Step D By following a similar procedure as the one used for preparing
  • Step A To a solution of Intermediate AlOi (116 mg, 0.308 mmol) in dichloromethane (5 mL) are added pyridine (50 ⁇ L, 0.615 mmol) and Dess-Martin reagent (261 mg, 0.615 mmol). The mixture is then stirred at room temperature for 3 hours. The mixture is quenched with 10% aqueous Na 2 S 2 O 3 and saturated aqueous Na 2 CO 3 and the aqueous layer is extracted with dichloromethane. The combined organic phase is washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step B To a solution of dimethylamine in tetrahydrofuran (2M, 0.4 mL,
  • Example K2 Kl from Intermediate KIa except substituting morpholine for dimethylamine, Example K2 is obtained.
  • Step A To a solution of Intermediate K3a (25 mg, 0.061 mmol; prepared by following a similar procedure as the one used for preparing Intermediate KIa from Intermediate AlOg except substituting 4-(4-trifluoromethylphenyl)-lH-pyrazol-5-amine for 4-(4-chlorophenyl)-lH-pyrazol-5-amine in step G) in methanol (1.5 mL) is added K 2 CO 3 (25 mg, 0.183 mmol) followed by p-toluenesulfonylmethyl isocyanide (13 mg, 0.067 mmol) and the mixture is heated to 80 0 C for 16 hours.
  • K 2 CO 3 25 mg, 0.183 mmol
  • p-toluenesulfonylmethyl isocyanide 13 mg, 0.067 mmol
  • Step A To a solution of Intermediate K3a (25 mg, 0.061 mmol) in a mixture of tetrahydrofuran (300 ⁇ L), /-BuOH (500 ⁇ L), and water (100 ⁇ L) is added 2- methyl-2-butene (28 ⁇ L, 0.268 mmol) followed by NaH 2 PO 4 (25 mg, 0.213 mmol). The mixture is cooled to 0 0 C and a solution of NaClO 2 (15 mg, 0.165 mmol) in water (200 ⁇ L) is added.
  • Step B To a solution of Intermediate K4a (12 mg, 0.028 mmol) in dichloromethane (200 ⁇ L) is added oxalyl chloride (8 ⁇ L, 0.084 mmol) followed by catalytic amounts of dimethylformamide (50 ⁇ L). Reaction progress is monitored by diluting an aliquot of the reaction mixture with methanol and analyzing the conversion of K4a to the corresponding methyl ester by ESIMS. After 30 minutes, the solvent is evaporated in vacuo to afford 2-methyl-3-phenyl-2-(3-(4-
  • Step C To a solution of Intermediate K4b (45 mg, 0.027 mmol) in tetrahydrofuran (200 ⁇ L) is added an excess of 28% ammonium hydroxide and stirred at room temperature. After 10 minutes, the contents is partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic phase is washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step D To a Smith Process vial charged with Intermediate K4c (12 mg,
  • Step A To a solution of Intermediate K4b (50 mg, 0.113 mmol) in pyridine (1 rnL) is added N-hydroxysuccinimide (20 mg, 0.169 mmol) and the mixture is stirred for 1 hour. The solvent is removed in vacuo and the residue is purified by flash chromatography (12 g SiO 2 ) to yield 2,5-dioxopyrrolidin-l-yl 2-methyl-3-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[l,5- ⁇ ]pyrimidin-7-yl)propanoate K6a as a yellow solid.
  • Step B To a solution of Intermediate K6a (34 mg, 0.065 mmol) in dioxane
  • Step A To a solution of Intermediate K6a (120 mg, 0.230 mmol) in dioxane (1 rnL) is added hyrdrazine (73 ⁇ L, 2.30 mmol) and the mixture is stirred for 30 min. The solvent is removed in vacuo and the residue is purified by flash chromatography (12 g SiO 2 , dichloromethane/methanol gradient) to yield 2-methyl-3-phenyl-2-(3-(4- (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyrimidin-7-yl)propanehydrazide K7a as a yellow glass.
  • Step B To a Smith Process vial charged with Intermediate K7a (15 mg,
  • Step A A mixture of Intermediate A21a (4mL, 20 mmol) and dimethylformamide diethyl acetal (3.35 rnL, 20 mmol) is heated to 100 0 C overnight. The solvent is removed and the resulting residue of Intermediate LIa is used without further purification; ESIMS calcd. for Ci 0 H 18 NO 3 ([M+H] + ) 200.1, found 200.1.
  • Step B A solution of Intermediate LIa (1.75 mL, 8.8 mmol) in ethanol
  • Step C A mixture of Intermediate Lib (23 mg, 0.07 mmol), 4- methylbenzylbromide (16.8 mg, 0.09 mmol) and Cs 2 CO 3 (68 mg, 0.21 mmol) in acetonitrile (3 mL) is heated at 60 0 C for 3h. The mixture is cooled, filtered, and concentrated.
  • Step A A microwave vial charged with Intermediate Lib (40 mg, 0.12 mmol), Boc-4-(bromomethyl)-piperidine (56 mg, 0.18 mmol) and Cs 2 CO 3 (118 mg, 0.36 mmol) in dimethylformamide (1 mL) is subjected to microwave irradiation (180 0 C, 5 min). The mixture is then cooled, extracted with ethyl acetate, washed with water and brine, dried (MgSO 4 ), filtered, and concentrated.
  • Step B A solution of Intermediate L15a (85 mg, 0.15 mmol) in a mixture of trifluoroacetic acid (1 mL) and dichloro methane (3 mL) is stirred at room temperature for 1 hour.
  • Step C A solution of Intermediate L15b (21 mg, 0.05 mmol) and diisopropylethylamine (26 ⁇ L, 0.15 mmol) in dichloromethane (3 mL) is treated with methanesulfonyl chloride (5 ⁇ L, 0.06 mmol) and stirred at room temperature for 1 hour. The mixture is concentrated and the residue is purified by flash chromatography
  • Step A A solution of Intermediate MIa (5.28 g, 33.4 mmol) in acetone
  • Step B A solution of Intermediate MIb (8.6 g, 50 mmol) in N,N- dimethylformamide-di-te/t-butyl acetal (11.97 g, 50 mmol) is heated to 100 0 C for 3 hours. The solvent is removed and the resulting residue of MIc is used without further purification;
  • Step C A solution of Intermediate MIc (0.60 g, 2.6 mmol) in tert- butanol (6 mL) is treated with 4-(4-chlorophenyl)-lH-pyrazol-5-amine (0.51 g, 2.6 mmol) followed by trifluoroacetic acid (0.3 mL) and heated to 60 0 C for Ih.
  • Step D A mixture of Intermediate MId (280 mg, 0.78 mmol), benzyl bromide (280 ⁇ L, 2.35 mmol) and Cs 2 CO 3 (767 mg, 2.35 mmol) in acetonitrile (5 mL) is heated at 80 0 C for 3 hours. The mixture is cooled to room temperature, and

Abstract

L'invention concerne des composés, des compositions pharmaceutiques contenant de tels composés et des méthodes d'utilisation de tels composés pour traiter ou prévenir des maladies ou des troubles associés à l'activité du GPR119.
PCT/US2010/043433 2009-07-29 2010-07-27 Composés et compositions pouvant servir de modulateurs de l'activité du gpr119 WO2011014520A2 (fr)

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WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
JP2014532058A (ja) * 2011-10-04 2014-12-04 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ ５−［２−［７−（トリフルオロメチル）−５−［４−（トリフルオロメチル）フェニル］ピラゾロ［１，５−ａ］ピリミジン−３−イル］エチニル］−２−ピリジンアミンの製造方法
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US20150299206A1 (en) * 2012-11-20 2015-10-22 Discoverybiomed, Inc. Small molecule cftr correctors
US9546176B2 (en) 2012-11-20 2017-01-17 Discoverybiomed, Inc. Small molecule bicyclic and tricyclic CFTR correctors
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CN114315899A (zh) * 2020-09-30 2022-04-12 上海美迪西生物医药股份有限公司 3-（芳环并咪唑基）吡唑并嘧啶类衍生物及其应用

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