WO2007041634A1 - Pyrimidine amide compounds as pgds inhibitors - Google Patents

Pyrimidine amide compounds as pgds inhibitors Download PDF

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Publication number
WO2007041634A1
WO2007041634A1 PCT/US2006/038841 US2006038841W WO2007041634A1 WO 2007041634 A1 WO2007041634 A1 WO 2007041634A1 US 2006038841 W US2006038841 W US 2006038841W WO 2007041634 A1 WO2007041634 A1 WO 2007041634A1
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WIPO (PCT)
Prior art keywords
phenyl
pyrimidine
carboxylic acid
fluoro
benzylamide
Prior art date
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PCT/US2006/038841
Other languages
French (fr)
Inventor
Suzanne C. Aldous
John Ziqi Jiang
Jinqi Lu
Liang Ma
Lan Mu
Harry Randall Munson
Jeffrey Stephen Sabol
Sukanthini Thurairatnam
Christopher Loren Vandeusen
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Aventis Pharmaceuticals Inc.
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Publication date
Priority to AU2006299428A priority Critical patent/AU2006299428B2/en
Application filed by Aventis Pharmaceuticals Inc. filed Critical Aventis Pharmaceuticals Inc.
Priority to ES06816247.8T priority patent/ES2514471T3/en
Priority to CA2624749A priority patent/CA2624749C/en
Priority to JP2008534664A priority patent/JP5452925B2/en
Priority to EP06816247.8A priority patent/EP1937652B1/en
Priority to BRPI0616815-9A priority patent/BRPI0616815A2/en
Priority to NZ567208A priority patent/NZ567208A/en
Priority to KR1020087008306A priority patent/KR101457966B1/en
Publication of WO2007041634A1 publication Critical patent/WO2007041634A1/en
Priority to TNP2008000104A priority patent/TNSN08104A1/en
Priority to IL190411A priority patent/IL190411A/en
Priority to US12/062,641 priority patent/US8202863B2/en
Priority to NO20082000A priority patent/NO20082000L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is directed to pyrimidine amide compounds, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of the prostaglandin D synthase.
  • Allergic rhinitis the most common atopic disease, has an estimated prevalence ranging from about 5 to about 22 percent of the general human population and is characterized by the symptoms of sneezing, nasal discharge, and nasal congestion. These symptoms are believed to be triggered by multiple mediators released from mast cells and other inflammatory cells.
  • PGD2 prostaglandin D2
  • PGD2 is the major cyclooxygenase product of arachidonic acid produced from mast cells on immunological challenge [Lewis, RA, Soter NA, Diamond PT, Austen KF, Oates JA, Roberts LJ H, Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE, J. Immunol. 129, 1627-1631, 1982].
  • Activated mast cells are one of the key players in driving the allergic response in conditions such as asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis and other diseases [Brightling CE, Bradding P, Pavord ID, Wardlaw AJ, New Insights into the role of the mast cell in asthma, Clin. Exp. Allergy 33, 550-556, 2003].
  • PGD2 is formed by the isomerization of PGH2, a common precursor of prostanoids, by catalytic action of prostaglandin D synthase "(PGDS)".
  • PGDS prostaglandin D synthase
  • L-PGDS L-PGDS
  • H-PGDS is a cytosolic enzyme, which is distributed in the peripheral tissues, and which is localized in the antigen-presenting cells, mast cells, megakaryocytes, and Th2 lymphocytes.
  • the action of the product PGD2 is mediated by G-protein coupled receptors: D prostaglandin "(DP)" and crTH2. See (1) Prostaglandin D Synthase: Structure and Function. T. Urade and O.
  • PGDS inhibitors have been reported.
  • the compound, HQL-79 is reported to be a weak PGDS inhibitor, and is antiasthmatic in guinea pig and rat models (Matsusshita, et al., Jpn. J. Pharamcol. 78: 11, 1998).
  • the compound Tranilast is described as a PGDS inhibitor. (Inhibitory Effect of Tranilast on Prostaglandin D Synthesase. K. Ikai, M. Jihara, k. Fujii, and Y. Urade. Biochemical Pharmacology, 1989, 28, 2773-2676).
  • R 1 is aryl, heteroaryl or (C 5 -C 6 )-cycloalkyl, each of which is optionally substituted by halo, (C 1 -C 6 )- alkyl, hydroxy, (C !
  • R 2 is hydrogen or (CrC 4 )-alkyl
  • R 3 when R 3 is cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl or multicyclic alkaryl, it is also optionally substituted by oxo;
  • R , R 5 and R 6 are each independently hydrogen or alkyl
  • R 7 is alkyl optionally substituted by hydroxy, halo or alkoxy, or aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteraryl or the aryl or heteroaryl moiety of the arylalkyl or heteroarylalkyl is optionally substituted by alkyl, halolkyl, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, halo, alkoxy or haloalkoxy; and Y 1 and Y 2 are each independently: hydrogen, alkyl optionally substituted by: hydroxy, carboxy, halo, amino, alkylamino, dialkylamino, cycloalkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, alkoxy
  • Y 1 and Y 2 together with the nitrogen atom to which they are attached form a heterocyclyl optionally containing another heteroatom selected from oxygen, nitrogen or sulfur, wherein the heterocyclyl is optionally substituted with alkyl or oxo; or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention is a pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to formula (I), or a hydrate, solvate or N- oxide thereof, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier.
  • Another aspect of the present invention is directed to a method of treating allergic and/or inflammatory disorders, particularly disorders such as allergic rhinitis, asthma and/or chronic obstructive pulmonary disease (COPD) in a patient in need thereof by administering to the patient a compound according to formula (I), or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • allergic and/or inflammatory disorders particularly disorders such as allergic rhinitis, asthma and/or chronic obstructive pulmonary disease (COPD)
  • COPD chronic obstructive pulmonary disease
  • acyl means H-CO- or (aliphatic or cyclyl)-CO-. Particular acyl includes lower alkanoyl that contains a lower alkyl. Exemplary acyl includes formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl, pahnitoyl, acryloyl, propynoyl, and cyclohexylcarbonyl.
  • Alkenyl means a straight or branched aliphatic hydrocarbon group containing a carbon-carbon double bond and having 2 to about 15 carbon atoms. Particular alkenyl has 2 to about 12 carbon atoms. More particular alkenyl has 2 to about 4 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. "Lower alkenyl” means about 2 to about 4 carbon atoms in the chain that may be straight or branched.
  • Exemplary alkenyl includes ethenyl, propenyl, ra-butenyl, i-butenyl, 3-methylbut-2-enyl, «-pentenyl, heptenyl, octenyl, cyclohexylbutenyl, and decenyl.
  • Alkoxy means alkyl-O-. Exemplary alkoxy includes methoxy, ethoxy, «-propoxy, /-propoxy, n- butoxy, and heptoxy.
  • Alkoxycarbonyl means alkyl-O-CO-.
  • exemplary alkoxycarbonyl includes methoxycarbonyl, ethoxycarbonyl, and f-buryloxycarbonyl.
  • Alkyl means straight or branched aliphatic hydrocarbon having 1 to about 20 carbon atoms. Particular alkyl has 1 to about 12 carbon atoms. More particular alkyl is lower alkyl. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. "Lower alkyl” means 1 to about 4 carbon atoms in a linear alkyl chain that may be straight or branched.
  • Alkylamino means alkyl-NH-. Particular alkylamino is (Ci-C 6 )-alkylamino. Exemplary alkylamino includes methylamino and ethylamino.
  • Alkylene means a straight or branched bivalent hydrocarbon having from 1 to about 15 carbon atoms. Particular alkylene is the lower alkylene having from 1 to about 6 carbon atoms. Exemplary alkenylene includes methylene, ethylene, propylene, and butylenes.
  • Alkylsulfonyl means alkyl-SO 2 -. Particular alkylsulfonyl is (Ci-C 6 )-alkylsulfonyl. Exemplary alkylsulfonyl includes CH 3 -SO 2 -, and CH 3 CH 2 -SO 2 -.
  • Alkylthio means an alkyl-S-.
  • Exemplary alkylthio includes CH 3 -S-.
  • Alkynyl means straight or branched aliphatic hydrocarbon containing a carbon-carbon triple bond and having 2 to about 15 carbon atoms. Particular alkynyl has 2 to about 12 carbon atoms. More particular alkynyl has 2 to about 6 carbon atoms. Branched means that one or more lower alkyl such as methyl, ethyl or propyl are attached to a linear alkynyl chain. "Lower alkynyl” means 2 to about 4 carbon atoms in a linear alkynyl chain that may be straight or branched.
  • alkynyl includes ethynyl, propynyl, »-burynyl, 2-butynyl, 3-methylbutynyl, ra-pentynyl, heptynyl, octynyl, and decynyl.
  • "Aroyl” means aryl-CO-.
  • Exemplary aroyl includes benzoyl, and 1-and 2-naphthoyl.
  • Aryl means an aromatic monocyclic or multicyclic ring system of about 6 to about 14 carbon atoms. Particular aryl include about 6 to about 10 carbon atoms. Exemplary aryl include phenyl and naphthyl.
  • Arylalkoxy means arylalkyl-O-.
  • exemplary arylalkoxy includes benzyloxy and 1- or 2-naphthylenemethoxy.
  • Arylalkoxycarbonyl means arylalkyl-O-CO-.
  • exemplary arylalkoxycarbonyl includes phenoxycarbonyl and naphthoxycarbonyl.
  • Arylalkyl means aryl-alkyl-. Particular arylalkyl contains a (CrCe ⁇ alkyl moiety. Exemplary arylalkyl includes benzyl, 2-phenethyl and naphthylenemethyl. "Arylalkylsulfonyl” means aryl-alkyl-SC> 2 -. Particular arylalkylsulfonyl contains a (Ci-Ce)-alkyl moiety. Exemplary arylalkylsulfonyl includes benzylsulfonyl.
  • Arylcycloalkenyl means a fused aryl and cycloalkenyl. Particular arylcycloalkenyl is one wherein the aryl thereof is phenyl and the cycloalkenyl consists of about 5 to about 7 ring atoms. An arylcycloalkenyl is bonded through any atom of the cycloalkenyl moiety thereof capable of such bonding. Exemplary arylcycloalkenyl includes 1,2-dihydronaphthylene and indene.
  • Arylcycloalkyl means a fused aryl and cycloalkyl. Particular arylcycloalkyl is one wherein the aryl thereof is phenyl and the cycloalkyl consists of about 5 to about 6 ring atoms. An arylcycloalkyl is bonded through any atom of the cycloalkyl moiety thereof capable of such bonding. Exemplary arylcycloalkyl includes 1,2,3,4-tetrahydro-naphthylene.
  • Arylheterocyclenyl means a fused aryl and heterocyclenyl. Particular arylheterocyclenyl is one wherein the aryl thereof is phenyl and the heterocyclenyl consists of about 5 to about 6 ring atoms. An arylheterocyclenyl is bonded through any atom of the heterocyclenyl thereof capable of such bonding.
  • the designation of the aza, oxa or thio as a prefix before the heterocyclenyl portion of the arylheterocyclenyl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • the nitrogen atom of an arylheterocyclenyl may be a basic nitrogen atom.
  • the nitrogen or sulfur atom of the heterocyclenyl portion of the arylheterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Exemplary arylheterocyclenyl includes 3H- indolinyl, lH-2-oxoquinolyl, 2H-l-oxoisoquinolyl, 1,2-di-hydroquinolinyl, 3,4-dihydroquinolinyl, 1,2- dihydroisoquinolinyl, and 3,4-dihydroisoquinolinyl.
  • Arylheterocyclyl means a fused aryl and heterocyclyl.
  • Particular heterocyclylaryl is one wherein the aryl thereof is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms.
  • An arylheterocyclyl is bonded through any atom of the heterocyclyl moiety thereof capable of such bonding.
  • the designation of the aza, oxa or thio as a prefix before heterocyclyl portion of the arylheterocyclyl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • the nitrogen atom of an arylheterocyclyl may be a basic nitrogen atom.
  • the nitrogen or sulfur atom of the heterocyclyl portion of the arylheterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S s S-dioxide.
  • exemplary arylheterocyclyl includes indolinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, lH-2,3-dihydroisoindol-2-yl, 2,3- dihydrobenz[fjisoindol- 2-yl, and 1,2,3,4- tetrahydrobenz[g]-isoquinolin-2-yl.
  • Aryloxy means an aryl-O-. Exemplary aryloxy includes phenoxy and naphthoxy. “Aryloxycarbonyl” means aiyl-O-CO-. Exemplary atyloxycarbonyl includes phenoxycarbonyl and naphthoxycarbonyl.
  • Cycloalkenyl means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, particularly of about 5 to about 10 carbon atoms, and which contains at least one carbon-carbon double bond. Particular rings of the ring system include about 5 to about 6 ring atoms; and such particular ring sizes are also referred to as "lower”.
  • Exemplary monocyclic cycloalkenyl includes cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • An exemplary multicyclic cycloalkenyl is norbornylenyl.
  • Cycloalkenylaryl means a fused aryl and cycloalkenyl. Particular cycloalkenylaryl is one wherein the aryl thereof is phenyl and the cycloalkenyl consists of about 5 to about 6 ring atoms. A cycloalkenylaryl is bonded through any atom of the aryl moiety thereof capable of such bonding. Exemplary cycloalkenylaryl includes 1,2-dihydronaphthylene and indene. "Cycloalkenylheteroaryl” means a fused heteroaryl and cycloalkenyl.
  • Particular cycloalkenylheteroaryl is one wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkenyl consists of about 5 to about 6 ring atoms.
  • a cycloalkenylheteroaryl is bonded through any atom of the heteroaryl thereof capable of such bonding.
  • the designation of the aza, oxa or thio as a prefix before heteroaryl portion of the cycloalkenylheteroaryl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • the nitrogen atom of a cycloalkenylheteroaryl may be a basic nitrogen atom.
  • the nitrogen atom of the heteroaryl portion of the cycloalkenylheteroaryl may also be optionally oxidized to the corresponding N-oxide.
  • Exemplary cycloalkenylheteroaryl includes 5,6- dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6- dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5- dihydro-lH -benzimidazolyl, and 4,5-di- hydrobenzoxazolyl.
  • Cycloalkyl means a non-aromatic mono- or multicyclic saturated ring system of about 3 to about 10 carbon atoms, particularly of about 5 to about 10 carbon atoms. Particular ring systems include about 5 to about 7 ring atoms; and such particular ring systems are also referred to as "lower”.
  • Exemplary monocyclic cycloalkyl includes cyclopentyl, cyclohexyl, and cycloheptyl.
  • Exemplary multicyclic cycloalkyl includes 1-decalin, norbomyl, and adamant-(l- or 2-)yl.
  • Cycloalkylaryl means a fused aryl and cycloalkyl. Particular cycloalkylaryl is one wherein the aryl thereof is phenyl and the cycloalkyl consists of about 5 to about 6 ring atoms. A cycloalkylaryl is bonded through any atom of the cycloalkyl moiety thereof capable of such bonding. Exemplary cycloalkylaryl includes 1,2,3,4-tetrahydro-naphthylene.
  • Cycloalkylene means a bivalent cycloalkyl group having about 4 to about 8 carbon atoms. Particular cycloalkylene includes about 5 to about 7 ring atoms; and such particular ring systems are also referred to as "lower".
  • the points of binding on the cycloalkylene group include 1,1-, 1,2-, 1,3-, or 1,4- binding patterns, and where applicable the stereochemical relationship of the points of binding is either cis or trans.
  • Exemplary monocyclic cycloalkylene includes (1,1-, 1,2-, or l,3-)cyclohexylene and (1,1- or l,2-)cyclopentylene.
  • Cycloalkylheteroaryl means a fused heteroaryl and cycloalkyl.
  • Particular cycloalkylheteroaryl is one wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms.
  • a cycloalkylheteroaryl is bonded through any atom of the heteroaryl thereof capable of such bonding.
  • the designation of the aza, oxa or thio as a prefix before heteroaryl portion of the fused cycloalkylheteroaryl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • the nitrogen atom of a cycloalkylheteroaryl may be a basic nitrogen atom.
  • the nitrogen atom of the heteroaryl portion of the cycloalkylheteroaryl may also be optionally oxidized to the corresponding N-oxide.
  • Exemplary cycloalkylheteroaryl includes 5,6,7,8- tetrahydroquinolinyl, 5,6,7,8-tetra-hydroisoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8- tetrahydroquinazolyl, 4,5,6,7-tetrahydro-lH-benzimidazolyl, and 4,5,6,7-tetrahydrobenzoxazolyl.
  • Cyclyl means cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl.
  • Dialkylamino means (alkyl) 2 -N-. Particular dialkylamino is (Ci-C 6 alkyl) 2 -N-. Exemplary dialkylamino groups include dimethylamino, diethylamino and methylethylamino.
  • Halo or halogen means fluoro, chloro, bromo, or iodo. Particular halo or halogen is fluoro or chloro.
  • Haloalkoxy means alkoxy substituted by one to three halo groups. Particular haloalkoxy are loweralkoxy substituted by one to three halogens. Most particular haloalkoxy are loweralkoxy substituted by one halogen.
  • Haloalkyl means alkyl substituted by one to three halo groups. Particular haloalkyl are loweralkyl substituted by one to three halogens. Most particular haloalkyl are loweralkyl substituted by one halogen.
  • Heteroaroyl means heteroaryl-CO-.
  • exemplary heteroaroyl includes thiophenoyl, nicotinoyl, pyrrol- 2-ylcarbonyl, and pyridinoyl.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • Particular aromatic ring systems include about 5 to about 10 carbon atoms, and include 1 to 3 heteroatoms. More particular ring sizes of rings of the ring system include about 5 to about 6 ring atoms.
  • the designation of the aza, oxa or thio as a prefix before heteroaryl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • a nitrogen atom of a heteroaryl may be a basic nitrogen atom and may also be optionally oxidized to the corresponding N-oxide.
  • a heteroaryl When a heteroaryl is substituted by a hydroxy group, it also includes its corresponding tautomer.
  • Exemplary heteroaryl includes pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyL furanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, benzofuranyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, benzoazaindoly
  • Heteroarylalkyl means heteroaryl-alkyl-. Particular heteroarylalkyl contains a (Ci-C 4 )-alkyl moiety. Exemplary heteroarylalkyl includes tetrazol-5-ylmethyl.
  • Heteroarylcycloalkenyl means a fused heteroaryl and cycloalkenyl.
  • Particular heteroarylcycloalkenyl is one wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkenyl consists of about 5 to about 6 ring atoms.
  • a heteroarylcycloalkenyl is bonded through any atom of the cycloalkenyl thereof capable of such bonding.
  • the designation of the aza, oxa or thio as a prefix before heteroaryl portion of the heteroarylcycloalkenyl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • the nitrogen atom of a heteroarylcycloalkenyl may be a basic nitrogen atom.
  • the nitrogen atom of the heteroaryl portion of the heteroarylcycloalkenyl may also be optionally oxidized to the corresponding N-oxide.
  • Exemplary heteroarylcycloalkenyl includes 5,6- dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6- dihydroquinoxalinyl, 5,6-dihydroquinazolinyI, 4,5- dihydro-lH-benzimidazolyl, and 4,5-di- hydrobenzoxazolyl.
  • Heteroarylcycloalkyl means a fused heteroaryl and cycloalkyl.
  • Particular heteroarylcycloalkyl is one wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms.
  • a heteroarylcycloalkyl is bonded through any atom of the cycloalkyl thereof capable of such bonding.
  • the designation of the aza, oxa or thio as a prefix before heteroaryl portion of the fused heteroarylcycloalkyl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • the nitrogen atom of a heteroarylcycloalkyl may be a basic nitrogen atom.
  • the nitrogen atom of the heteroaryl portion of the heteroarylcycloalkyl may also be optionally oxidized to the corresponding N-oxide.
  • Exemplary heteroarylcycloalkyl includes 5,6,7,8- tetrahydroquinolinyl, 5,6,7,8-tetra-hydroisoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8- tetrahydroquinazolyl, 4,5,6,7-tetrahydro-lH-benzimidazolyl, and 4,5,6,7-tetrahydrobenzoxazolyl
  • Heteroarylheterocyclenyl means a fused heteroaryl and heterocyclenyl. Particular ' heteroarylheterocyclenyl is one wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclenyl consists of about 5 to about 6 ring atoms. A heteroarylheterocyclenyl is bonded through any atom of the heterocyclenyl thereof capable of such bonding.
  • the designation of the aza, oxa or thio as a prefix before the heteroaryl or heterocyclenyl portion of the heteroarylheterocyclenyl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • the nitrogen atom of a heteroarylazaheterocyclenyl may be a basic nitrogen atom.
  • the nitrogen or sulfur atom of the heteroaryl portion of the heteroarylheterocyclyl may also be optionally oxidized to the corresponding N-oxide.
  • the nitrogen or sulfur atom of the heteroaryl or heterocyclyl portion of the heteroarylheterocyclyl may also be optionally oxidized to the corresponding N-oxide, S- oxide or S,S- dioxide.
  • Exemplary heteroarylheterocyclenyl includes 7,8-dihydro[l,7]naphthyridinyl, 1,2- dihydro[2,7]-naphthyridinyl, 6,7-dihydro-3H -imidazo [4,5-c]pyridyl, l,2-dihydro-l,5-naphthyridinyl, 1 ,2-dihydro-l,6-naphthyridinyl, l,2-dihydro-l,7 -naphthyridinyl, 1,2-dihydro-l ,8-naphthyridinyl, and l,2-dihydro-2,6-naphthyridinyl.
  • Heteroarylheterocyclyl means a fused heteroaryl and heterocyclyl.
  • Particular heteroarylheterocyclyl is one wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclyl consists of about 5 to about 6 ring atoms.
  • a heteroarylheterocyclyl is bonded through any atom of the heterocyclyl thereof capable of such bonding.
  • the designation of the aza, oxa or thio as a prefix before the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • the nitrogen atom of a fused heteroarylheterocyclyl may be a basic nitrogen atom.
  • the nitrogen or sulfur atom of the heteroaryl portion of the heteroarylheterocyclyl may also be optionally oxidized to the corresponding N-oxide.
  • the nitrogen or sulfur atom of the heteroaryl or heterocyclyl portion of the heteroarylheterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heteroarylheterocyclyl includes 2,3-dihydro-lH-pyrrol[3,4-b]quinolin-2-yl, 1,2,3,4-tetrahydrobenz [b][l,7]naphthyridin-2-yl, l,2,3,4-tetrahydrobenz[b][l,6]naphthyridin-2-yl, l,2,3,4-tetra ⁇ hydro-9H- pyrido[3,4-b]indol-2yl, l,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2yl, 2,3-dihydro-lH-pyrrolo[3,4-b ]indol-2-yl, lH-2 5 3,4,5-tetrahydroazepino[3,4-b]indol-2-yl, lH-2,3,4,5-tetra-hydroazepino[4,3
  • Heteroaryloxy means heteroaryl-O- .
  • exemplary heteroaryloxy includes pyridyloxy.
  • Heterocyclenyl means a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond.
  • a particular non-aromatic ring system includes about 5 to about 10 carbon atoms, and 1 to 3 heteroatoms. More particular ring sizes of rings of the ring system include about 5 to about 6 ring atoms; and such particular ring sizes are also referred to as "lower”.
  • heterocyclenyl The designation of the aza, oxa or thio as a prefix before heterocyclenyl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • the nitrogen atom of a heterocyclenyl may be a basic nitrogen atom.
  • the nitrogen or sulfur atom of the heterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Exemplary monocyclic azaheterocyclenyl includes 1,2,3,4-tetrahydrohydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetra-hydropyridyl, 1,4,5,6-tetrahydro- pyrimidine, 2-pyrrolinyl, 3- pyrrolinyl, 2-imidazolinyl, and 2-pyrazolinyl.
  • Exemplary oxaheterocyclenyl includes 3,4-dihydro-2H- pyran, dihydrofuranyl, and fluorodihydro-furanyl.
  • An exemplary multicyclic oxaheterocyclenyl is 7- oxabicyclo[2.2.1]heptenyl.
  • Exemplary monocyclic thioheterocyclenyl includes dihydrothiophenyl and dihydrothiopyranyl.
  • Heterocyclenylaryl means a fused aryl and heterocyclenyl. Particular heterocyclenylaryl is one wherein the aryl thereof is phenyl and the heterocyclenyl consists of about 5 to about 6 ring atoms. A heterocyclenylaryl is bonded through any atom of the aryl thereof capable of such bonding.
  • the designation of the aza, oxa or thio as a prefix before heterocyclenyl portion of the fused heterocyclenylaryl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • the nitrogen atom of a heterocyclenylaryl may be a basic nitrogen atom.
  • the nitrogen or sulfur atom of the heterocyclenyl portion of the heterocyclenylaryl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heterocyclenylaryl include 3H- indolinyl, H ⁇ -2-oxoquinolyl, 2H-l-oxoisoquinolyl, 1,2-di-hydroquinolinyl, 3,4-dihydroquinolinyl, 1,2- dihydroisoquinolinyl, and 3,4-dihydroisoquinolinyl.
  • Heterocyclenylheteroaryl means a fused heteroaryl and heterocyclenyl.
  • Particular heterocyclenylheteroaryl is one wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclenyl consists of about 5 to about 6 ring atoms.
  • a heterocyclenylheteroaryl is bonded through any atom of the heteroaryl thereof capable of such bonding.
  • the designation of the aza, oxa or thio as a prefix before the heteroaryl or heterocyclenyl portion of the heterocyclenylheteroaryl define that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • the nitrogen atom of an azaheterocyclenylheteroaryl may be a basic nitrogen atom.
  • the nitrogen or sulfur atom of the heteroaryl portion of the heterocyclenylheteroaryl may also be optionally oxidized to the corresponding N-oxide.
  • the nitrogen or sulfur atom of the heteroaryl or heterocyclyl portion of the heterocyclenylheteroaryl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Exemplary heterocyclenylheteroaryl includes 7,8-dihydro[l,7]naphthyridinyl, 1,2- dihydro[2,7]-naphthyridinyl, 6,7-dihydro-3H-imidazo[4,5-c]pyridyl, l,2-dihydro-l,5-naphthyridinyl, 1 ,2-dihydro-l,6-naphthyridinyl, l,2-dihydro-l,7-naphthyridinyl, l,2-dihydro-l,8-naphthyridinyl and 1,2- dihydro-2,6-naphthyridinyl.
  • Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, in which one or more of the atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • a particular ring system contains about 5 to about 10 carbon atoms, and from 1 to 3 heteroatoms.
  • Particular ring sizes of the ring system include about 5 to about 6 ring atoms; and such particular ring sizes are also referred to as "lower”.
  • the designation of the aza, oxa or thio as a prefix before heterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom.
  • the nitrogen atom of a heterocyclyl may be a basic nitrogen atom.
  • the nitrogen or sulfur atom of the heterocyclyl may also be optionally oxidized to 20 the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Exemplary monocyclic heterocyclyl includes piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, THFyI, tetrahydrothiophenyl, and tetrahydrothiopyranyl.
  • Heterocyclylaryl means a fused aiyl and heterocyclyl. Particular heterocyclylaryl is one wherein the aryl thereof is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms. A heterocyclylaryl is bonded through any atom of the aryl moiety thereof capable of such bonding.
  • the designation of the aza, oxa or thio as a prefix before heterocyclyl portion of the heterocyclylaryl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • the nitrogen atom of a heterocyclylaryl may be a basic nitrogen atom.
  • heterocyclylaryl includes indolinyl, 1,2,3,4- tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, lH-2,3-dihydroisoindol-2-yl, and 2,3- dihydrobenz[fjisoindol-2-yl, and 1,2,3,4- tetrahydrobenz[g]-isoquinolin-2-yl.
  • Heterocyclylheteroaryl means a fused heteroaryl and heterocyclyl.
  • Particular heterocyclylheteroaryl is one wherein the heteoraryl thereof consists of about 5 to about 6 ring atoms and the heterocyclyl consists of about 5 to about 6 ring atoms.
  • a heterocyclylheteroaryl is bonded through any atom of the heterocyclyl thereof capable of such bonding.
  • the designation of the aza, oxa or thio as a prefix before the heteroaryl or heterocyclyl portion of the heterocyclylheteroaryl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom.
  • the nitrogen atom of a heterocyclylheteroaryl may be a basic nitrogen atom.
  • the nitrogen or sulfur atom of the heteroaryl portion of the heterocyclylheteroaryl may also be optionally oxidized to the corresponding N-oxide.
  • the nitrogen or sulfur atom of the heteroaryl or heterocyclyl portion of the heterocyclylheteroaryl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heterocyclylheteroaryl includes 2,3-dihydro-lH-pyrrol[3,4-b]quinolin-2-yl, 1,2,3,4-tetrahydrobenz [b][l,7]naphthyridin-2-yl, l,2,3,4-tetrahydrobenz[b][l,6]naphthyridin-2-yl, l,2,3,4-tetra-hydro-9H- pyrido[3,4-b]indol-2yl, l,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2yl, 2,3-dihydro-lH-pyrrolo[3,4-b ]indol-2-yl, lH-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl, lH-2,3,4,5-tetrahydroazepino[3,4-
  • Multicyclic alkaryl means a multicyclic ring system including at least one aromatic ring fused to at least one non-aromatic ring that may be saturated or unsaturated, and may also contain in the ring system one or more heteroatoms, such as nitrogen, oxygen or sulfur.
  • Exemplary multicyclic alkaryl includes arylcycloalkenyl, arylcycloalkyl, arylheterocyclenyl, arylheterocyclyl, cycloalkenylaryl, cycloalkylaryl, cycloalkenylheteroaryl, cycloalkylheteroaryl, heteroarylcycloalkenyl, heteroarylcycloalkyl, heteroarylheterocyclenyl, heteroarylheterocyclyl, heterocyclenylaryl, heterocyclenylheteroaryl, heterocyclylaryl, and heterocyclylheteroaryl.
  • Particular multicyclic alkaryl groups are bicyclic rings that include one aromatic ring fused to one non-aromatic ring and that also may contain in the ring system one or more heteroatoms, such as nitrogen, oxygen or sulfur.
  • Patient includes human and other mammals.
  • “Pharmaceutically acceptable salts” refers to the non-toxic, inorganic and organic acid addition salts, and base addition salts, of compounds of the present invention. These salts may be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. In some cases, the compounds themselves are capable of self-protonating basic sites on the molecule and forming an internal amphoteric salt.
  • Exemplary acid addition salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulfamates, malonates, salicylates, propionates, methylene-bis- ⁇ - hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and lauryl
  • Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed.
  • Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts.
  • a particular base addition salt is sodium salt or potassium salt.
  • Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, and zinc hydroxide.
  • Suitable amine base addition salts are prepared from amines which have sufficient basicity to form a stable salt, and particularly include those amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use.
  • Ammonia ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N 5 N'- dibenzy ⁇ ethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminometliane 5 tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e.g., lysine and arginine, and dicyclohexylamine.
  • Solvate means a physical association of a compound of the present invention with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and insoluble solvates. Particular solvates include hydrates, ethanolates, and methanolates. Particular Embodiments of the Invention
  • One particular embodiment of the invention is a compound of formula (I) wherein R 1 is phenyl, five or six membered heteroaryl, or (C5-C 6 )-cycloalkyl, each of which is optionally substituted by halo, (Ci-
  • R 1 is phenyl or five or six membered heteroaryl, each of which is optionally substituted by halo, (Ci-C 6 )-alkyl, hydroxy, (Ci-C 6 )-alkoxy, (Ci-C 4 )-haloalkyl or (Ci-C 4 )-haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of formula (I) wherein R 1 is phenyl or five or six membered heteroaryl, each of which is optionally substituted by halo, (Ci-C 6 )-alkyl, hydroxy, (Ci-C f i)-alkoxy, (Ci-C 4 )-haloalkyl or (CrGO-haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof, provide that when R 1 is phenyl or six membered heteroaryl, then it is only optionally substituted at the ortho or meta position.
  • R 1 is phenyl, pyridyl, thiazolyl, imidazolyl or oxodiazolyl, each of which is optionally substituted by halo, (Ci-C ⁇ )- alkyl, hydroxy, (Ci-C 6 )-alkoxy, (Ci ⁇ C 4 )-haloalkyl or (C 1 -C 4 )-haloalkoxy, or a hydrate, solvate or N- oxide thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 is phenyl or pyridyl, each of which is optionally substituted at the ortho or meta position by halo, (Q-C ⁇ alkyl, hydroxy, (CrC 6 )-alkoxy, (CrG ⁇ -haloalkyl or (Ci-C 4 )-haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of formula (I) wherein R 1 is phenyl optionally substituted by halo, (Ci-C 6 )-alkyl, hydroxy, (Ci-C 6 )-alkoxy, (Ci-C 4 )-haloalkyl or (C 1 -C 4 )- haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of formula (I) wherein R 1 is phenyl optionally substituted at the ortho or meta position by halo, hydroxy, (Ci-C 6 )-alkoxy, (Cj-C 4 )-haloalkyl or (Ci-C 4 )-haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of formula (I) wherein R 1 is phenyl optionally substituted by halo, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of formula (I) wherein R 1 is phenyl optionally substituted at the ortho or meta position by halo, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of formula (I) wherein R 1 is 2- fluorophenyl or 3 -fluorophenyl, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of formula (I) wherein R 2 is hydrogen, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of formula (I) wherein R 2 is methyl, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of formula (I) wherein L 1 is a bond, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of formula (I) wherein L 1 is (C 1 -C 3 )- alkylene, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of formula (I) wherein L 1 is -CH 2 -, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • R 3 is cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, or multicyclic alkaryl, each of which is optionally substituted by: acyl, cyano, nitro, halo, hydroxy, carboxy, amidino,
  • R 3 is phenyl, pyridyl, thiazolyl, imidazolyl, oxodiazolyl, imidazolyl, pyrimidinyl, thiophenyl, oxazolyl, cycloalkyl, benzooxazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrahydropyranyl, piperidinyl, furanyl, benzo[l,3]dioxolyl, benzothiazolyl, imidazolidinyl, indazolyl, benzoimidazolyl, indolyl, benzofuranyl, or l,3-dihydro-benzo[c]isothiazolyl, each of which is optionally substituted by: acyl, cyano, nitro, halo, hydroxy, carboxy, amidino,
  • Y 1 Y 2 N-, Y 1 Y 2 N-SO 2 -, R 7 -SO 2 -NR 6 -, aryl or heteroaryl, each of which is optionally substituted by alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, or heterocyclyl or arylheterocyclyl, each of which is optionally substituted by oxo or alkyl, or aryl, heteroaryl, aroyl, heteroaroyl, aryloxy, heteroaryloxy, or heterocyclyl, each of which is optionally substituted by alkyl, haloalkyl, halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -P( O)-(alkoxy) 2 , Y 1 Y 2 N-, or Y 1 Y 2
  • Another particular embodiment of the invention is a compound of formula (I) wherein:
  • Y 1 Y 2 N-, Y 1 Y 2 N-SO 2 -, R 7 -SO 2 -NR 6 -, aryl or heteroaryl, each of which is optionally substituted by alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, or heterocyclyl or arylheterocyclyl, each of which is optionally substituted by oxo or alkyl, or aryl, heteroaryl, aroyl, heteroaroyl, aryloxy, heteroaryloxy, or heterocyclyl, each of which is optionally substituted by alkyl, haloalkyl, halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -PC O)-Calkoxy) 2 , Y 1 Y 2 N-, or Y 1 Y 2 N-
  • Y 1 and Y 2 are each independently hydrogen, cycloalkyl, or alkyl optionally substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino, heteroaryl, or heterocyclyl optionally substituted by alkyl, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
  • Another particular embodiment of the invention is a compound of formula (T) wherein R 3 is phenyl optionally substituted by:
  • Another particular embodiment of the invention is a compound of formula (I) wherein: R 3 is phenyl optionally substituted by:
  • Another particular embodiment of the invention is a compound of formula (I), which is 2-Phenyl-pyrimidine ⁇ 5-carboxylic acid benzylamide
  • 2-Phenyl-pyrimidine-5-carboxylic acid 4-dimethylsulfamoyl-benzylamide, 2-Phenyl-pyrimidine-5-carboxylic acid (3,5-difiuoro-phenyl)-amide,
  • 2-Phenyl-pyrimidine-5-carboxylic acid (l-pyridin-3-ylmethyl-piperidin-4-yl)-araide, 2-Phenyl-pyrimidine-5-carboxylic acid [2-(2-oxo-imidazolidin-l-yl)-ethyl]-amide, 2-Phenyl-pyrimidine-5-carboxylic acid [2-(lH-imidazol-4-yl)-ethyl]-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (2H-pyrazol-3-yl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid ( 1 -methyl-piperidin-4-yl)-amide, 2-P
  • 2-Pheny-pyrimidine-5-carboxylic acid 4-methanesulfonylamino-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 4-carbamoyl-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 3-(2-hydroxy-ethylsulfamoyl)-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 4-(morpholin-4-sulfonyl)-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide,
  • 2-Pheny-pyrimidine-5-carboxylic acid [2-(2-amino-4-methyl-thiazol-5-yl)-ethyl]-amide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide, ⁇ 4- ⁇ [(2-Phenyl-pyrimidine-5-carbonyl)-amino]-benzyl ⁇ -phosphonic acid diethyl ester, ⁇ 4-[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-butyl)-phosphonic acid diethyl ester, ⁇ 4-[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-ethyl)-phosphonic acid diethyl ester,
  • 2-(Phenyl)-pyrimidine-5-carboxylic acid 3-methanesulfonylamino-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-acetylsulfamoyl-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3-oxo-piperiazine-l-sulfonyl)-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid (2-sulfamoyl-ethyl)-amide, 2-Pheny-pyrimidine-5-carboxylic acid (2-dimethylsulfamoyl-ethyl)-amide,
  • 2-Phenyl-pyrimidine-5-carboxylic acid (l-carbamimidoyl-piperidin-4-ylmethyl)-amide, S- ⁇ -Phenyl-pyrimidine-S-carbony ⁇ -aminoJ-lH-indole-S-carboxylic acid amide, 2-Phenyl-pyrimidine-5-carboxylic acid [3-(2-amino-thiazol-4-yl)-phenyl]-amide, 2-Phenyl-pyrimidine-5-carboxylic acid ⁇ 4-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-ethyl]-thiazol-2- yl ⁇ -amide,
  • 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid [2-(pyrrolidine-l-sulfonyl)-ethyl]-amide, [3-( ⁇ [2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino ⁇ -methyl)-benzyl]-carbamic acid tert-butyl ester, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[(pyridin-2-ylmethyl)-sulfamoyl]-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3 ⁇ hydroxy-2,2-dimethyl-propylsulfamoyl)- benzylamide,
  • 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(4-hydroxy-butylsulfamoyl)-benzylamide
  • 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[2-(2-hydroxy-ethoxy)-ethylsulfamoyl]- benzylamide
  • 2-(3-Fluoro-phenyl)-pyrimidme-5-carboxylic acid 3-[(tetrahydro-furan-2-yhnethyl)-sulfamoyl]- benzylamide
  • the present invention also includes within its scope a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the invention, in admixture with a pharmaceutically acceptable carrier.
  • Compounds of the present invention are PGDS inhibitors and thus, are useful for treating allergic and/or inflammatory disorders, particularly disorders such as allergic rhinitis, asthma and/or chronic obstructive pulmonary disease (COPD).
  • allergic and/or inflammatory disorders particularly disorders such as allergic rhinitis, asthma and/or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Another invention herein is directed to a method of treating a patient suffering from allergic rhinitis and/or asthma comprising administering to the patient a pharmaceutically effective amount of compound of formula (I).
  • References herein directed to treating should be understood to include prophylactic therapy to inhibit PGDS, as well as to treat an established acute or chronic or physiological conditions associated with PGDS to essentially cure a patient suffering therefrom, or ameliorate the physiological conditions associated therewith.
  • Physiological conditions discussed herein include some, but not all, of the possible clinical situations where an anti- allergic rhinitis and/or asthma treatment is warranted. Those experienced in this field are well aware of the circumstances requiring treatment.
  • the compound of the present invention may be administered in pharmaceutically acceptable dosage form to humans and other mammals by topical or systemic administration, including oral, inhalational, rectal, nasal, buccal, sublingual, vaginal, colonic, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), intracisternal and intraperitoneal. It will be appreciated that the particular route may vary with for example the physiological condition of the recipient.
  • “Pharmaceutically acceptable dosage forms” refers to dosage forms of the compound of the invention, and includes, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations, including suspensions, sprays, inhalants tablets, lozenges, emulsions, solutions, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition.
  • a particular aspect of the invention provides for the compound of the invention to be administered in the form of a pharmaceutical composition.
  • Pharmaceutically acceptable carriers include at least one component selected from the group comprising pharmaceutically acceptable carriers, diluents, coatings, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, emulsion stabilizing agents, suspending agents, isotonic agents, sweetening agents, flavoring agents, perfuming agents, coloring agents, antibacterial agents, antifungal agents, other therapeutic agents, lubricating agents, adsorption delaying or promoting agents, and dispensing agents, depending on the nature of the mode of administration and dosage forms.
  • suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.
  • antibacterial and antifungal agents for the prevention of the action of microorganisms include parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • Exemplary isotonic agents include sugars, sodium chloride, and the like.
  • Exemplary adsorption delaying agents to prolong absorption include aluminum monostearate and gelatin.
  • Exemplary adsorption promoting agents to enhance absorption include dimethyl sulfoxide and related analogs.
  • Exemplary diluents, solvents, vehicles, solubilizing agents, emulsifiers and emulsion stabilizers include water, chloroform, sucrose, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, tetrahydrofurfuryl alcohol, benzyl benzoate, polyols, propylene glycol, 1,3-butylene glycol, glycerol, polyethylene glycols, dimethylformamide, Tween® 60, Span® 60, cetostearyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate, fatty acid esters of sorbitan, vegetable oils (such as cottonseed oil, groundnut oil, olive oil, castor oil and sesame oil) and injectable organic esters such as ethyl oleate, and the like, or suitable mixtures of these substances.
  • vegetable oils such as cotton
  • Exemplary excipients include lactose, milk sugar, sodium citrate, calcium carbonate and dicalcium phosphate.
  • Exemplary disintegrating agents include starch, alginic acids and certain complex silicates.
  • Exemplary lubricants include magnesium stearate, sodium lauryl sulfate, talc, as well as high molecular weight polyethylene glycols.
  • the choice of pharmaceutical acceptable carrier is generally determined in accordance with the chemical properties of the active compound such as solubility, the particular mode of administration and the provisions to be observed in pharmaceutical practice.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as a solid dosage form, such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, or as a powder or granules; as a liquid dosage form such as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Solid dosage form means the dosage form of the compound of the invention is solid form, for example capsules, tablets, pills, powders, dragees or granules.
  • the compound of the invention is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or: (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used.
  • a mixture of the powdered compounds moistened with an inert liquid diluent may be molded in a suitable machine to make molded tablets.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • Solid compositions may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.
  • the compound can be microencapsulated in, or attached to, a slow release or targeted delivery systems such as a biocompatible, biodegradable polymer matrices (e.g., poly(d,l-lactide co-glycolide)), liposomes, and microspheres and subcutaneously or intramuscularly injected by a technique called subcutaneous or intramuscular depot to provide continuous slow release of the compound(s) for a period of 2 weeks or longer.
  • a biocompatible, biodegradable polymer matrices e.g., poly(d,l-lactide co-glycolide)
  • liposomes e.g., liposomes
  • microspheres subcutaneously or intramuscularly injected by a technique called subcutaneous or intramuscular depot to provide continuous slow release of the compound(s) for a period of 2 weeks or longer.
  • the compounds may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of
  • Liquid dosage form means the dose of the active compound to be administered to the patient is in liquid form, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such solvents, solubilizing agents and emulsif ⁇ ers.
  • aqueous suspensions When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
  • compositions suitable for topical administration means formulations that are in a form suitable to be administered topically to a patient.
  • the formulation may be presented as a topical ointment, salves, powders, sprays and inhalants, gels (water or alcohol based), creams, as is generally known in the art, or incorporated into a matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • Formulations suitable for topical administration in the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the oily phase of the emulsion pharmaceutical composition may be constituted from known ingredients, in a known manner.
  • the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer.
  • the emulsifier(s) with, or without, stabilizer(s) make up the emulsifying wax, and together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • the aqueous phase of the cream base may include ⁇ for example, a least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such, as, propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • a polyhydric alcohol i.e. an alcohol having two or more hydroxyl groups such, as, propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound that enhances absorption, or penetration of the active ingredient through the skin, or other affected areas.
  • a cream should particularly be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used.
  • high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • compositions suitable for rectal or vaginal administrations mean formulations that are in a form suitable to be administered rectally or vaginally to a patient and containing at least one compound of the invention.
  • Suppositories are a particular form for such formulations that can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • composition administered by injection may be by transmuscular, intravenous, intraperitoneal, and/or subcutaneous injection.
  • the compositions of the present invention are formulated in liquid solutions, in particular in physiologically compatible buffers such as Hank's solution or Ringer's solution.
  • the compositions may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms are also included.
  • formulations are sterile and include emulsions, suspensions, aqueous and non-aqueous injection solutions, which may contain suspending agents and thickening agents and anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic, and have a suitably adjusted pH, with the blood of the intended recipient.
  • compositions suitable for nasal or inhalational administration means compositions that are in a form suitable to be administered nasally or by inhalation to a patient.
  • the composition may contain a carrier, in a powder form, having a particle size for example in the range 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc.).
  • Suitable compositions wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.
  • Compositions suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. Inhalational therapy is readily administered by metered dose inhalers or any suitable dry powder inhaler, such as the Eclipse, Spinhaler®, or Ultrahaler® as described in patent application WO2004/026380, and US Patent No. 5,176,132.
  • Actual dosage levels of active ingredient(s) in the compositions of the invention may be varied so as to obtain an amount of active ingredient(s) that is (are) effective to obtain a desired therapeutic response for a particular composition and method of administration for a patient.
  • a selected dosage level for any particular patient therefore depends upon a variety of factors including the desired therapeutic effect, on the route of administration, on the desired duration of treatment, the etiology and severity of the disease, the patient's condition, weight, sex, diet and age, the type and potency of each active ingredient, rates of absorption, metabolism and/or excretion and other factors.
  • Total daily dose of the compound of this invention administered to a patient in single or divided doses may be in amounts, for example, of from about 0.001 to about 100 mg/kg body weight daily and particularly 0.01 to 10 mg/kg/day.
  • the doses are generally from about 0.01 to about 100, particularly about 0.01 to about 10, mg/kg body weight per day by inhalation, from about 0.01 to about 100, particularly 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.01 to about 50, particularly 0.01 to 10, mg/kg body weight per day by intravenous administration.
  • the percentage of active ingredient in a composition may be varied, though it should constitute a proportion such that a suitable dosage shall be obtained.
  • Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose.
  • several unit dosage forms may be administered at about the same time.
  • a dosage may be administered as frequently as necessary in order to obtain the desired therapeutic effect.
  • Some patients may respond rapidly to a higher or lower dose and may find much lower maintenance doses adequate.
  • it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. It goes without saying that, for other patients, it will be necessary to prescribe not more than one or two doses per day.
  • the formulations can be prepared in unit dosage form by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the pharmaceutically active ingredient with the carrier that constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials with elastomeric stoppers, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • sterile liquid carrier for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • a compound of formula (T), wherein R 2 is hydrogen may be prepared, as shown in Scheme I below, by reacting an amidine compound, wherein R 1 is as defined herein, with a reagent of formula (A) to form a compound of formula (B), which directly or via its hydrolyzed product of formula (C), is coupled with an amine of formula (D), wherein L 1 and R 3 are as defined herein.
  • a compound of formula (I), wherein R 2 is (Q-C ⁇ -alkyl, may be prepared, as shown in Scheme II below, by reacting an amidine compound, wherein R 1 is as defined herein, with a reagent of formula (E) to form a compound of formula (F), which directly or via its hydrolyzed product of formula (G), is coupled with an amine of formula (D), wherein L 1 and R 3 are as defined herein.
  • R 2 (C r C 4 )-alkyl
  • compounds of the invention may also be prepared by interconversion of other compounds of the invention. It will be appreciated that compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of Formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates.
  • Mass Spectra are recorded using a Micromass LCT mass spectrometer. The method is positive electrospray ionization, scanning mass m/z from 100 to 1000.
  • Step 1 A 250 mL, three-neck, round-bottom flask equipped with a magnetic stirrer and a reflux condenser is purged with N 2 .
  • the flask is charged sequentially with methyl 3,3-dimethoxypropionate (5.22 g, 35.3 mmol), anhydrous 1,2-dimethoxyethane (25 mL), anhydrous methyl formate (5 mL), 60% sodium hydride (1.7 g, 42.5 mmol), and the mixture warmed to 40 - 5O 0 C until evolution of hydrogen gas stops.
  • the reaction mixture is cooled in an ice/water bath and slowly allowed to reach room temperature overnight with stirring.
  • Step 2 To a solution of benzamidine hydrochloride hydrate (2 mmol) in anhydrous DMF (4 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylicacid methyl ester (0.46 g, 2.32 mmol) and the reaction mixture heated at 100 0 C under N2 for 1 hour. The reaction is cooled to room temperature and water (15 mL) is added. After addition of water, immediate precipitation of the product is observed. The solids are collected by filtration, washed with water (2.5 mL) and vacuum dried to yield 2-phenyl-pyrimidine-5-carboxylic acid methyl ester (0.32 g, 74%). (see: P. Zhichkin, DJ. Fairfax, S.A. Eisenbeis, Synthesis, 2002, 720-722.)
  • Step 3 A solution of 2-phenyl-pyrimidine-5-carboxylic acid methyl ester (3.15 g) and LiOH (0.71 g) in a mixture of MeOH, THF and water (1:1:1 in volume, 120 mL) is stirred at room temperature overnight. MeOH and THF are evaporated off to give an aqueous solution. The aqueous solution is acidified with 5% hydrochloric acid to adjust pH to between 2.5 and 3. The precipitate is filtered off and washed with water, dried in vacuo to yield 2.94 g ( ⁇ 100%) of 2-phenyl-pyrimidine-5-carboxylic acid as a solid. MS: 201 (M+H).
  • Step 4 A mixture of 2-phenyl-pyrimidine-5 -carboxylic acid. (80 mg), 1-hydroxybenzotriazole (92 mg) and polymer supported-carbodiimide (640 mg, 1.25 mmol/g) in 8 mL of DCM is shaken at room temperature for 30 min and benzylamine (43 mg) is added. After shaking at room temperature for 1.5 days, PS-trisamine (295 mg, 4.08 mmol/g) is added. The mixture is continually shaken at room temperature for 16 hours. The solid is filtered and washed with DCM. The filtrate is concentrated to yield of 2-phenyl-pyrimidine-5 -carboxylic acid benzylamide (98 mg, 85%) as a solid.
  • Step 1 To a solution of isonicotinamidine hydrochloride (1 g, 6.35 mmol) in anhydrous DMF (12 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylicacid methyl ester (1.46 g, 7.36 mmol) and the reaction mixture is heated at 100 0 C under nitrogen for Ih. The reaction is cooled to room temperature and water (48 mL) is added. The precipitate is collected by filtration, washed with water and vacuum dried to afford 2-pyridin-4-yl-pyrimidine-5-carboxylic acid methyl ester (1.2 g, 88%). MS: 216 (M+H); 1 H NMR (300 MHz, CD 3 OD): ⁇ 4.00 (s, 3H), 8.44 (d, 2H), 8.73 (d, 2H), 9.38 (s, 2H).
  • Step 2 A solution of 2-pyridin-4-yl-pyrimidine-5-carboxylic acid methyl ester (1.11 g, 5.18 mmol), and aqueous LiOH (1 M, 5.18 mL) in MeOH (7.25 mL) is stirred at room temperature overnight. MeOH is removed in vacuo, and the aqueous solution is treated with 3 N HCl to adjust the pH to between 2 and 3. The solid is filtered off and washed with water and dried in vacuum to yield 2z pyridin-4-yl-pyrimidine-5 -carboxylic acid (1 g, 96%) as a solid. MS: 202 (M+H). Step 3.
  • Step 1 To a solution of nicotinamidine hydrochloride (1 g, 6.35 mmol) in anhydrous DMF (12 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylicacid methyl ester (1.46 g, 7.36 mmol) and the reaction mixture is heated at 100 0 C under N 2 for 3 hours. After this time the reaction is cooled to room temperature and water (48 mL) is added. The precipitate is collected by filtration, washed with water and vacuum dried to afford 2-pyridin-3-yl-pyrimidine-5-carboxylic acid methyl ester (0.7 g, 51%). MS: 216 (M+H).
  • Step 2 A solution of 2-pyridin-3-yl-pyrimidine-5-carboxylic acid methyl ester (0.73 g, 3.32 mmol) and IM aqueous LiOH (3.32 mL) in MeOH (5 mL) is stirred at room temperature overnight. The MeOH is removed in vacuo, and the aqueous solution is treated with 3 N HCl to adjust the pH ⁇ 2-3. The solid is filtered off and washed with water and dried in vacuum to yield 2-pyridin-3 -yl-pyrimidine-5 - carboxylic acid (0.2 g, 30%) as a solid. MS: 202 (M+H).
  • Step 3 A mixture of 2-pyridin-3-yl-pyrimidine-5-carboxylic acid (110 mg, 0.55 mmol) 1- hydroxybenzotriazole (83.5 mg, 0.62 mmol) and PS-DCC (568 mg, 1.28 mmol/g, 0.73 mmol) in DMF (8 mL) is shaken at room temperature for 15 min, and aniline (34 mg, 0.36 mmol) is added. After shaking at room temperature for 18 hours, PS-trisamine (436 mg, 3.75 mmol/g, 1.64 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with DCM. The filtrate is concentrated to yield 2-pyridin-3-yl-pyrimidine-5-carboxylic acid phenylamide (41.2 mg, 41%) as a solid. MS: 277 (M+H).
  • Step 1 A solution of 2-methyl-6-nitro-benzoxazole (30 mmol), dimethyl formamide dimethyl acetal (60 mmol) and pyrrolidine (60 mmol) in DMF (45 mL) is stirred at 100 0 C for 16 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with water and brine, dried (Na 2 SO 4 ) and filtered. The filtrate is concentrated. The residue is washed with cooled EtOAc to afford 6-nitro-2-f 2-pyrrolidin- 1 -yl-vinyl Vbenzooxazole as a solid.
  • Step 2 A solution of 6-nitro-2-(2-pyrrolidin-l-yl-vinyl)-benzooxazole (8.5 mmol) and palladium/carbon (10%) (0.85 mmol) in ethanol (100 mL) is hydrogenated with the pressure of 50 psi at room temperature for 18 hours.
  • Step 3 To a solution of 2-(2-pyrrolidin-l-yl-vinyl)-benzooxazol-6-ylamine (3.2 mmol) in MeOH (40 mL) is added sodium cyanoborohydride (6.4 mmol) at room temperature. The reaction mixture is heated to reflux for 18 hours. The mixture is concentrated and the residue is dissolved in DCM. The solution is washed with water and brine, and dried (MgSO 4 ). A small amount of activated carbon is added to the solution, and the mixture is filtered. The filtrate is concentrated to afford 2-f2-pyrrolidin- l-yl-ethylVbenzooxazol-6-ylamine as a solid.
  • Step 4 Following procedures similar to those of Example 8, but substituting 2-(2-pyrrolidin-l-yl- ethyl)-benzooxazol-6-ylamine (0.3 mmol) for 2,2-dioxo2,3-dihydro ⁇ lH-21amda*6*- benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid F2-(2- Pyrrolidin-l-yl-ethylVbenzooxazol-6-yll-amide as a solid.
  • Step 1 4-Fluorobenzamidine hydrochloride (1.25 g, 7.16 mmol) is added to a solution of sodium metal (0.17 g, 7.39 mmol) in dry ethanol (25 mL) and stirred at room temperature for 20 min. Ethyl-2- acetyl-3-(dimethylamino)acrylate (1.35 g, 7.16 mmol) is added. The mixture is heated to reflux for 3 hours. The solvent is removed in vacuo.
  • Step 3 A mixture of 2-(4-fluorophenyl)-pyrimidine-5-carboxylic acid (232 mg, 1 mmol) and O-(7- azabenzotriazol-l-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (380 mg 1 mmol) in dry DMF (12 mL) is treated with diisopropylethylamine (0.18 mL) and stirred at room temperature for 30 min. A solution of 3-methylsulfamoylbenzylamine (300 mg, 1.5 mmol) in dry DMF (1.5 mL) is added and the mixture is stirred at room temperature for 24 hours.
  • a vial is charged with amine H 2 N-R' (1 mmol) followed by p-dioxane (5 mL) and piperidinomethyl polystyrene (375 mg, 1.5 mmol, 4mmol/g resin).
  • the vial is agitated in an orbital shaker for 20 min.
  • 3-Cyano-benzenesulfonyl chloride is added (181 mg, 0.9 mmol) and the reaction vial is placed into the orbital shaker for 18 hours.
  • the vial is removed from the orbital shaker, and MeOH (5mL) is added followed by the addition of 4-benzyloxybenzaldehyde polystyrene resin (100 mg, 0.3 mmol, 3 mmol/g resin). Agitation is continued in the orbital shaker for 5 hours.
  • the sample is filtered, the resin is washed with MeOH, and the combined organic fractions are concentrated to yield the sulfonamide compound 1.
  • the amine hydrochloride compound is acylated using acylation procedure W to prepare 2c (3-fluoro-phenylVpyrimidine-5-carboxylic acid 3-ethylsulfamoyl-benzylamide (449 mg) as a solid.
  • Step 1 Na 0 (0.66 g, 28.6 mmol) is added to anhydrous EtOH (100 mL) and stirred at room temperature for 15 min. 3-Fluorobenzamidine hydrochloride (4.87 g, 27.8 mmol) is added and the solution is stirred for 15 min. 2-Dimethylaminomethylene-3-oxo-butyric acid ethyl ester (5.3 g, 28.6 mmol,) is added and the reaction mixture is heated at reflux under N 2 for 1 hours. The reaction is cooled to room temperature and concentrated in vacuo.
  • Step 2 A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid ethyl ester (6.7 g, 27.2 mmol) and NaOH (2.1 g, 54.4 mmol) in a 1 : 1 : 1 solution of THF, MeOH and water (300 mL) is heated at reflux for 45 min. The THF/MeOH is evaporated, and the aqueous solution is treated with 3 N HCl to adjust the pH to between 2 and 3. The solid is filtered off, washed with water and dried in vacuo to yield 2-(3 -fluoro-phenyl)-4-methyl-pyrimidine-5 -carboxylic acid (5.4 g, 91%) as a solid.
  • Step 3 To a solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (0.195 g, 0.89 mmol) in THF (5 mL) is added carbonyl diimidazole (0.18 g, 1.1 mmol) and heated at 60 0 C for 2 hours. The mixture is cooled to room temperature. (3-Aminomethyl-benzyl)-carbamic acid tert-butyl ester (0.25 mL, 1.1 mmol) is added and the mixture is stirred for 12 hours. The mixture is diluted with EtOAc (100 mL), washed with brine (2x50 mL), dried with Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step 1 A solution of 3-bromomethyl-benzonitrile (2 g, 10.2 mmol) in EtOH (50 mL) is treated with a solution of Na 2 SOs (1.3 g, 10.3 mmol) in H 2 O (50 mL) and heated at reflux for 4 hours. The mixture is concentrated in vacuo. The residue is suspended in DCM (100 mL) and DMF (1 mL), cooled to O 0 C and treated with oxalyl chloride (8 mL, 43.4 mmol). The mixture is warmed to room temperature and stirred for 3 hours. The mixture is diluted with brine, extracted with DCM (2x100 mL), dried with Na 2 SO ⁇ filtered, and concentrated in vacuo.
  • Step 2 To a solution of C-(3-cyano-phenyl)-N-methyl-methanesulfonamide (42 mg, 0.2 mmol) in THF (4 mL) is added a solution of BH 3 THF in THF (1 M, 1 mL). The mixture is sealed and heated in a microwave reactor at 100 0 C for 120 seconds. The mixture is poured into 1 M HCl (20 mL), basified with 3 M NaOH to pH ⁇ 10, extracted with DCM (2x50 mL), dried with Na 2 SO 4 , filtered, and concentrated in vacuo to afford C-f3-aminomethyl-phenyl)-N-methyl-methanesulfonamide. which is used directly in the next without further purification.
  • Step 3 Following procedures similar to those of Example 68 (step 3) but substituiting C-(3- aminomethyl-phenyl)-N-methyl-methanesulfonamide (2.3 mmol) for (3-aminomethyl-benzyl)- carbamic acid tert-butyl ester there is prepared 2-f 3 -fluoro-phenyl)-4-methyl-pyrimidine-5 -carboxylic acid 3-methylsulfamoylmethyl-benzylamide (30 mg) as a solid.
  • Step 1 To a solution of 3-bromomethyl-benzonitrile (2 g, 10.2 mmol) in EtOH (50 mL) is added a solution OfNa 2 SO 3 (1.3 g, 10.3 mmol) in H 2 O (50 mL) and the mixture is heated at reflux for 4 hours. The mixture is concentrated in vacuo. The residue is suspended in DCM (100 mL) and DMF (1 mL), cooled to O 0 C and treated with oxalyl chloride (4.5 mL, 24.4 mmol). The mixture is warmed to room temperature for 3 hours.
  • Step 2 To a solution of C-(3-cyano-phenyl)-N-isopropyl-methanesulfonamide (0.5 g, 2.06 mmol) in THF (10 mL) is added a solution OfBH 3 THF in THF (1 M, 10.3 mL). The mixture is sealed and heated in a microwave reactor at 100 0 C for 120 seconds. The mixture is poured into 1 M HCl (50 mL), basified with 3 M NaOH to pH ⁇ 10, extracted with DCM, dried with Na 2 SO 4 , filtered, and concentrated in vacuo to afford C-(3-aminomethyl-phenyl)-N-isopropyl-methanesulfonamide.
  • Step 3 Following procedures similar to those of Example 68 (step 3) but substituting C-(3- ammomethyl-phenylVN-isopropyl-methanesulfonamide (2 mmol) for (3-aminomethyl-benzyl)- carbamic acid tert-butyl ester there is prepared 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3-[(propane-2-sulfonylamino)-methyl1-benzylamide (160 mg) as a solid.
  • Step 1 To a solution of 2-(3-fluoro-phenyl ' )-pyrunidine-5-carboxylic acid (0.5 g, 2.25 mmol) in THF (25 mL) is added carbonyl diimidazole (0.5 g, 2.7 mmol) and heated at 6O 0 C for 2 hours. The mixture is cooled to room temperature and (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester (0.67 mL, 2.7 mmol) is added. The mixture is stirred for 12 h, diluted with EtOAc (100 mL), washed with brine (2x50 mL), dried with Na 2 SO 4 , filtered and concentrated in vacuo.
  • Step 2 To [3-( ⁇ [2-(3-fluoro-phenyl)- pyrimidine-5-carbonyl]-amino ⁇ -methyl)-benzyl]-carbamic acid tert-butyl ester (0.28 g, 0.64 mmol) at O 0 C is added HCl in dioxane (6.5 mL, 4 N) and the mixture is stirred for 2.5 hours. The mixture is concentrated in vacuo. The residue is dissolved in DCM (3 mL) and Et 3 N (0.21 mL, 0.1.5 mmol) and methanesulfonyl chloride (0.105 mL, 0.1.3 mraol) are added.
  • Step 1 A solution of 2-amino-isonicotinonitrile (1 g, 8.4 mmol) and methanesulfonyl chloride (0.716 mL, 9.2 mmol) in pyridine (10 mL) is stirred at room temperature for 12 hours. The mixture is poured onto ice and stirred for 20 min. The mixture is filtered and washed with water (100 mL), followed by diethyl ether (100 mL). The solid is dried in vacuo to afford N-(4-cyanopyridin-2-yl)- methanesulfonamide (1.1 g, 66%).
  • Step 2 N-(4-Cyano-pyridin-2-yl)-methanesulfonamide (0.15 g, 0.76 mmol) is dissolved in MeOH (4 mL) and concentrated HCl (2 mL) and is treated with Pd/C (10%, 150 mg). The mixture is stirred under H 2 for 12 hours, filtered and concentrated in vacuo to afford N-(4-ammomethyl-pyridin-2-yl)- methanesulfonamide (0.15 g, 97%), which is used directly in the next step without further purification.
  • Step 3 Following procedures similar to those of Example 72 (step 1) but substituting N-(4- aminomethyl-pyridin-2-yl)-methanesulfonamide (0.75 mmol) for (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester there is prepared 2-(3-fluoro-phenylVpyrimidine-5-carboxylic acid (2- methanesulfonylamino-pyridm-4-ylmethylVamide (320 mg) as a solid.
  • Step 1 To a solution of 2-methylsulfanyl-pyrimidine-5-carboxylic acid methyl ester 1 (1 g, 5.43 mmol) in DCM (60 mL) is added MCPBA (2.81 g, 16.29 mmol) portion wise at room temperature. The resulting solution is stirred at room temperature overnight. A solution OfNa 2 S 2 O 3 (1.6 g) in water (60 mL) is added. The mixture is stirred at room temperature for 20 min. The layer is separated, and the water layer is extracted with DCM (2x20 mL).
  • Step 2 To a solution of 2-methanesulfonyl-pyrimidine-5-carboxylic acid methyl ester 2 (2.5 g, 11.56 mmol) in DCM (30 mL) is added a solution of tetrabutylammonium cyanide (3.1 g, 11.56 mmol) in water (30 mL) slowly at room temperature. The mixture is stirred for 80 min. The mixture is washed with water (2x20mL), dried (Na 2 SO 4 ), filetered and concentrated in vacuo.
  • Step 1 A flask containing DCM (90 niL) and methylamine in water (40 wt%, 7.5 mmol) is chilled in an ice water bath with magnetic stirring: 3-Cyano-benzenesulfonyl chloride (5 g, 2.49 mmol) is added along with DCM (1OmL) to wash down the sides of the flask. After 30 min, concentrated HCl in water is added at O 0 C, until the reaction is acidic (pH ⁇ 4). Water (50 mL) is added and DCM is removed in vacuo. The residue is filtered to afford 3-cyano-N-methyl-benzenesulfonamide as a solid (99%).
  • Step 2 To a solution of 3-cyano-N-methyl-benzenesulfonamide (4.88 g, 2.49 mmol) in MeOH (160 mL) is added concentrated HCl in water (16 mL) followed by the addition of Palladium on Carbon (10wt%, 50wt% water, 1.6 g). With magnetic stirring, the reaction is alternately placed under vacuum and 1 atmosphere of hydrogen (balloon) for three cycles. The reaction is then left under 1 atmosphere of hydrogen with stirring for 2 days. The reaction is filtered through celite and fresh Palladium on Carbon (10wt%, 50wt% water, 1.6 g) is added. The reaction is stirred for 24 hours under 1 atmosphere of hydrogen.
  • Step 3 To a mixture of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (545 mg, 2.5 mmol) and DCM (35 mL) is added oxalyl chloride (635 mg, 5 mmol) followed by the addition of DMF (20 ⁇ L). The reaction is stirred at room temperature for 3 hours. Anhydrous toluene (10 mL) is added and the reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc (30 mL).
  • Step 1 To a solution of potassium carbonate (13.94 mmol) and 3-aminomethyl-piperidine-l- carboxylic acid tert-butyl ester (4.65 mmol) in ethyl acetate (30 mL) and water (20 mL) is added a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylicacid chloride (4.65 mmol) in ethyl acetate (20 mL). The mixture is stirred at room temperature overnight.
  • reaction mixture is extracted with ethyl acetate, washed with water, dried (Na 2 SC ⁇ ) and concentrated in vacuo to give 3-( ⁇ [2-(3-fluoro- pheny)-pyrimidine-5-carbonyl]-amino ⁇ -methyl)-piperidine-l-carboxylic acid tert-butyl ester as a solid.
  • Step 2 Hydrogen chloride gas is bubbled into a solution of 3-( ⁇ [2-(3-fluoro-pheny)-pyrimidine-5- carbonyl]-ammo ⁇ -methyl)-piperidine-l-carboxylic acid tert-butyl ester (3.76 mmol) in DCM (20 mL) and the reaction is stirred at room temperature for 2 hours. The mixture is concentrated in vacuo to afford 2-(3-fluoro-pheny)-pyrimidine-5-carboxylic acid fpiperidin-3-ylmethviy amide hydrochloride as a solid.
  • Step 3 Methanesulfonyl chloride (0.523 mmol) is added to a stirred solution of 2-(3-fluoro-phenyl)- pyrimidine-5-carboxylic acid (piperidin-3-ylmethyl)-amide hydrochloride (0.523 mmol) and triethylamine (2.62 mmol) in DCM (20 mL) at O 0 C. The mixture is stirred at O 0 C for an hour, and then stirred at room temperature overnight. The reaction mixture is washed with water (20 mL). The organic layer is separated, dried (MgSO ⁇ , filtered and concentrated invacuo.
  • Dimethanesulfamoyl chloride (0.632 mmol) is added to a stirred solution of 2-(3-fluoro-phenyl)- pyrimidine-5-carboxylic acid (piperidin-3-ylmethyl)-amide trihydrochloride (0.632 mmol) and triethylamine (3.16 mmol) in DCM (20 mL) at O 0 C. The mixture is stirred at O 0 C for an hour, and then stirred at room temperature overnight. The reaction mixture is diluted with DCM (10 mL) and washed with water (30 mL). The organic layer is separated, dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • Methanesulfonyl chloride (0.553 mmol) is added to a stirred solution of 2-phenyl-pyrimidine-5- carboxylic acid 3-amino-benzylamide (Example 115, 0.526 mmol) and triethylamine (1.05 mmol) in DCM (20 mL) at O 0 C. The mixture is stirred at room temperature for an hour. The reaction mixture is quenched with 5% HCl and extracted with DCM (20 mL). The organic layer is separated, washed with water (20 mL) and brine (20 mL), dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • Step 1 To a solution of cyclohexanecarboxamidine hydrochloride (1 g, 7.9 mmol) in anhydrous DMF (15 mL) is added sodium 3,3-dimethoxy-2-carbomethoxyprop-l-en-l-oxide (1.82 g, 9.2 mmol) and the reaction mixture is heated at 100 0 C under N 2 for 3 hours. The reaction is cooled to room temperature and water (59 mL) is added. The mixture is extracted with EtOAc.
  • 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-isopropylsulfamoyl-pyridin-3-ylmethyl)-amide
  • 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-methylsulfamoyl-pyridin-3-ylmethyl)-amide
  • the compounds of the present invention can be tested for enzymatic inhibiting activity against PGD2
  • Prostaglandin D2-M0X express EIA kit (Caymen Chemical, Catalog No.500151) Before the assay, cool down 10 mL of acetone in polypropylene tubes and empty 96 well plates in ice. All the procedures except compound dilution are performed on ice. III. Compound dilution 1. Dilute compound in DMSO
  • reaction buffer 60 ⁇ L of reaction buffer and 6.6 ⁇ L of 5% DMSO in reaction buffer into negative control wells in the plate.
  • %Positive control (Compound value-Negative control)/(Positive value-Negative control value) xlOO. %Positive control ⁇ (Compound value-Negative control) X 100
  • Compound value PGD2 levels (pg/mL) obtained from the standard curve in EIA assay for the samples with compound
  • Negative control value PGD2 levels (pg/mL) obtained from the standard curve in EIA assay for the samples without enzyme
  • Compounds within the scope of the invention produce 50% inhibition in the Fluorescence Polarization Assay or the EIA assay at concentrations within the range of about 1 nanomolar to about 30 micromolar,
  • the IC 50 S for Examples 8, 9, 33, 34, 82, 83, 84 and 114 obtained by the Fluorescence Polarization Assay, and the IC 50 S for Examples 1, 30, 38, 40, 45, 48, 49, 51, 54, 55, 56, 63, 65, 68, 71, 85, 93, 97, 108, 109, 110, 117 and 118 obtained by the EIA assay are reported in the "EXAMPLE" section herein.

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Abstract

This invention is directed to a compound of formula (I): wherein R1, R2, R3 and L1 are as defined herein, a pharmaceutical composition comprising the compound, and the use of the compound to treat allergic and/or inflammatory disorders, particularly disorders such as allergic rhinitis, asthma and/or chronic obstructive pulmonary disease (COPD).

Description

PYRΠVUDME AMIDE COMPOUNDS AS PGDS BNIΠBΓΓORS
FEELD OF THE INVENTION
The present invention is directed to pyrimidine amide compounds, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of the prostaglandin D synthase.
BACKGROUND OF THE INVENTION
Allergic rhinitis, the most common atopic disease, has an estimated prevalence ranging from about 5 to about 22 percent of the general human population and is characterized by the symptoms of sneezing, nasal discharge, and nasal congestion. These symptoms are believed to be triggered by multiple mediators released from mast cells and other inflammatory cells. Current therapies, such as antihistamines, deal effectively with the sneezing and nasal discharge, but have little effect on congestion, which is a key symptom affecting the quality of life of patients.
Local allergen challenge in patients with allergic rhinitis, bronchial asthma, allergic conjunctivitis and atopic dermatitis has been shown to result in rapid elevation of prostaglandin D2 "(PGD2)" levels in nasal and bronchial lavage fluids, tears and skin chamber fluids. PGD2 has many inflammatory actions, such as increasing vascular permeability in the conjunctiva and skin, increasing nasal airway resistance, airway narrowing and eosinophil infiltration into the conjunctiva and trachea. PGD2 is the major cyclooxygenase product of arachidonic acid produced from mast cells on immunological challenge [Lewis, RA, Soter NA, Diamond PT, Austen KF, Oates JA, Roberts LJ H, Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE, J. Immunol. 129, 1627-1631, 1982]. Activated mast cells, a major source of PGD2, are one of the key players in driving the allergic response in conditions such as asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis and other diseases [Brightling CE, Bradding P, Pavord ID, Wardlaw AJ, New Insights into the role of the mast cell in asthma, Clin. Exp. Allergy 33, 550-556, 2003].
In the presence of sulfhydryl compounds, PGD2 is formed by the isomerization of PGH2, a common precursor of prostanoids, by catalytic action of prostaglandin D synthase "(PGDS)". There are two isoforms of the PGDS enzyme: L-PGDS; and H-PGDS. H-PGDS is a cytosolic enzyme, which is distributed in the peripheral tissues, and which is localized in the antigen-presenting cells, mast cells, megakaryocytes, and Th2 lymphocytes. The action of the product PGD2 is mediated by G-protein coupled receptors: D prostaglandin "(DP)" and crTH2. See (1) Prostaglandin D Synthase: Structure and Function. T. Urade and O. Hayaishi, Vitamin and Hormones, 2000, 58, 89-120, (2) J. J. Murray, N. Engl. J. Med, 1986 Sept. 25; 315(13):800, and (3) Urade et. al,, J. Immunology 168: 443-449, 2002.
We believe that inhibiting the formation of PGD2 should have an effect on nasal congestion and, therefore, be of therapeutic benefit in allergic rhinitis. In addition, we believe that a PGDS inhibitor should be of therapeutic benefit in a number of other indications such as bronchial asthma.
PGDS inhibitors have been reported. The compound, HQL-79, is reported to be a weak PGDS inhibitor, and is antiasthmatic in guinea pig and rat models (Matsusshita, et al., Jpn. J. Pharamcol. 78: 11, 1998). The compound Tranilast is described as a PGDS inhibitor. (Inhibitory Effect of Tranilast on Prostaglandin D Synthesase. K. Ikai, M. Jihara, k. Fujii, and Y. Urade. Biochemical Pharmacology, 1989, 28, 2773-2676).
SUMMARY OF THE INVENTION The present invention is directed to a compound of formula (I):
Figure imgf000003_0001
wherein: R1 is aryl, heteroaryl or (C5-C6)-cycloalkyl, each of which is optionally substituted by halo, (C1-C6)- alkyl, hydroxy, (C!-C6)-alkoxy, (Ci-C4)-haloalkyl or (Ci-C4)-haloalkoxy; R2 is hydrogen or (CrC4)-alkyl; R3 is -P(=O)-(alkoxy)2, or Y1Y2N-SO2-, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, or multicyclic alkaryl, each of which is optionally substituted by: acyl, cyano, nitro, halo, hydroxy, carboxy, amidino,
R5O-C(=O)-C(=N-OR4)-,Y1Y2N-, Y1Y2N-C(O)-, Y1Y2N-Ct=O)-O-, Y1Y2N-SO2-, R7-SO2-NR6-, R7-C(=O)-NR6-,Y1Y2N-(Ci-C4)-alkylene-SO2-(Ci-C4)-alkylene-, or alkyl, alkenyl, alkynyl, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfϊnyl, or alkylsulfonyl, each of which is optionally substituted by: halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -P(=O)-
(alkoxy)2, Y1Y2N-, Y1Y2N-SO2-, R7-SO2-NR6-, aryl or heteroaryl, each of which is optionally substituted by alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy., or alkoxycarbonyl, or heterocyclyl or arylheterocyclyl, each of which is optionally substituted by oxo or alkyl, or aryl, heteroaryl, aroyl, heteroaroyl, aryloxy, heteroaryloxy, or heterocyclyl, each of which is optionally substituted by alkyl, haloalkyl, halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, ~P(=O)-(alkoxy)2, Y1Y2N-, or Y1Y2N-SO2-
, and when R3 is cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl or multicyclic alkaryl, it is also optionally substituted by oxo;
L1 is a bond, or (Ci-CβJ-alkylene optionally substituted by hydroxy or when R3 is optionally substituted cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl or multicyclic alkaryl, then the (Ci-C6)-alkylene is also optionally substituted by -P(=O)- (alkoxy)2;
R , R5 and R6 are each independently hydrogen or alkyl, R7 is alkyl optionally substituted by hydroxy, halo or alkoxy, or aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteraryl or the aryl or heteroaryl moiety of the arylalkyl or heteroarylalkyl is optionally substituted by alkyl, halolkyl, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, halo, alkoxy or haloalkoxy; and Y1 and Y2 are each independently: hydrogen, alkyl optionally substituted by: hydroxy, carboxy, halo, amino, alkylamino, dialkylamino, cycloalkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, alkoxy optionally substituted with hydroxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted by alkyl, halo or haloalkyl, or cycloalkyl optionally substituted by carboxy, or
Y1 and Y2 together with the nitrogen atom to which they are attached form a heterocyclyl optionally containing another heteroatom selected from oxygen, nitrogen or sulfur, wherein the heterocyclyl is optionally substituted with alkyl or oxo; or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof. Another aspect of the present invention is a pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to formula (I), or a hydrate, solvate or N- oxide thereof, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier.
Another aspect of the present invention is directed to a method of treating allergic and/or inflammatory disorders, particularly disorders such as allergic rhinitis, asthma and/or chronic obstructive pulmonary disease (COPD) in a patient in need thereof by administering to the patient a compound according to formula (I), or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
As used above, and throughout the description of the invention, the following terms unless otherwise indicated, shall be understood to have the following meanings:
"Acyl" means H-CO- or (aliphatic or cyclyl)-CO-. Particular acyl includes lower alkanoyl that contains a lower alkyl. Exemplary acyl includes formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl, pahnitoyl, acryloyl, propynoyl, and cyclohexylcarbonyl.
"Alkenyl" means a straight or branched aliphatic hydrocarbon group containing a carbon-carbon double bond and having 2 to about 15 carbon atoms. Particular alkenyl has 2 to about 12 carbon atoms. More particular alkenyl has 2 to about 4 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 4 carbon atoms in the chain that may be straight or branched. Exemplary alkenyl includes ethenyl, propenyl, ra-butenyl, i-butenyl, 3-methylbut-2-enyl, «-pentenyl, heptenyl, octenyl, cyclohexylbutenyl, and decenyl.
"Alkoxy" means alkyl-O-. Exemplary alkoxy includes methoxy, ethoxy, «-propoxy, /-propoxy, n- butoxy, and heptoxy.
"Alkoxycarbonyl" means alkyl-O-CO-. Exemplary alkoxycarbonyl includes methoxycarbonyl, ethoxycarbonyl, and f-buryloxycarbonyl.
"Alkyl" means straight or branched aliphatic hydrocarbon having 1 to about 20 carbon atoms. Particular alkyl has 1 to about 12 carbon atoms. More particular alkyl is lower alkyl. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. "Lower alkyl" means 1 to about 4 carbon atoms in a linear alkyl chain that may be straight or branched.
"Alkylamino" means alkyl-NH-. Particular alkylamino is (Ci-C6)-alkylamino. Exemplary alkylamino includes methylamino and ethylamino.
"Alkylene" means a straight or branched bivalent hydrocarbon having from 1 to about 15 carbon atoms. Particular alkylene is the lower alkylene having from 1 to about 6 carbon atoms. Exemplary alkenylene includes methylene, ethylene, propylene, and butylenes.
"Alkylsulfonyl" means alkyl-SO2-. Particular alkylsulfonyl is (Ci-C6)-alkylsulfonyl. Exemplary alkylsulfonyl includes CH3-SO2-, and CH3CH2-SO2-.
"Alkylthio" means an alkyl-S-. Exemplary alkylthio includes CH3-S-.
"Alkynyl" means straight or branched aliphatic hydrocarbon containing a carbon-carbon triple bond and having 2 to about 15 carbon atoms. Particular alkynyl has 2 to about 12 carbon atoms. More particular alkynyl has 2 to about 6 carbon atoms. Branched means that one or more lower alkyl such as methyl, ethyl or propyl are attached to a linear alkynyl chain. "Lower alkynyl" means 2 to about 4 carbon atoms in a linear alkynyl chain that may be straight or branched. Exemplary alkynyl includes ethynyl, propynyl, »-burynyl, 2-butynyl, 3-methylbutynyl, ra-pentynyl, heptynyl, octynyl, and decynyl. "Aroyl" means aryl-CO-. Exemplary aroyl includes benzoyl, and 1-and 2-naphthoyl.
"Aryl" means an aromatic monocyclic or multicyclic ring system of about 6 to about 14 carbon atoms. Particular aryl include about 6 to about 10 carbon atoms. Exemplary aryl include phenyl and naphthyl.
"Arylalkoxy" means arylalkyl-O-. Exemplary arylalkoxy includes benzyloxy and 1- or 2-naphthylenemethoxy.
"Arylalkoxycarbonyl" means arylalkyl-O-CO-. Exemplary arylalkoxycarbonyl includes phenoxycarbonyl and naphthoxycarbonyl.
"Arylalkyl" means aryl-alkyl-. Particular arylalkyl contains a (CrCe^alkyl moiety. Exemplary arylalkyl includes benzyl, 2-phenethyl and naphthylenemethyl. "Arylalkylsulfonyl" means aryl-alkyl-SC>2-. Particular arylalkylsulfonyl contains a (Ci-Ce)-alkyl moiety. Exemplary arylalkylsulfonyl includes benzylsulfonyl.
"Arylcycloalkenyl" means a fused aryl and cycloalkenyl. Particular arylcycloalkenyl is one wherein the aryl thereof is phenyl and the cycloalkenyl consists of about 5 to about 7 ring atoms. An arylcycloalkenyl is bonded through any atom of the cycloalkenyl moiety thereof capable of such bonding. Exemplary arylcycloalkenyl includes 1,2-dihydronaphthylene and indene.
"Arylcycloalkyl" means a fused aryl and cycloalkyl. Particular arylcycloalkyl is one wherein the aryl thereof is phenyl and the cycloalkyl consists of about 5 to about 6 ring atoms. An arylcycloalkyl is bonded through any atom of the cycloalkyl moiety thereof capable of such bonding. Exemplary arylcycloalkyl includes 1,2,3,4-tetrahydro-naphthylene.
"Arylheterocyclenyl" means a fused aryl and heterocyclenyl. Particular arylheterocyclenyl is one wherein the aryl thereof is phenyl and the heterocyclenyl consists of about 5 to about 6 ring atoms. An arylheterocyclenyl is bonded through any atom of the heterocyclenyl thereof capable of such bonding. The designation of the aza, oxa or thio as a prefix before the heterocyclenyl portion of the arylheterocyclenyl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The nitrogen atom of an arylheterocyclenyl may be a basic nitrogen atom. The nitrogen or sulfur atom of the heterocyclenyl portion of the arylheterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary arylheterocyclenyl includes 3H- indolinyl, lH-2-oxoquinolyl, 2H-l-oxoisoquinolyl, 1,2-di-hydroquinolinyl, 3,4-dihydroquinolinyl, 1,2- dihydroisoquinolinyl, and 3,4-dihydroisoquinolinyl.
"Arylheterocyclyl" means a fused aryl and heterocyclyl. Particular heterocyclylaryl is one wherein the aryl thereof is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms. An arylheterocyclyl is bonded through any atom of the heterocyclyl moiety thereof capable of such bonding. The designation of the aza, oxa or thio as a prefix before heterocyclyl portion of the arylheterocyclyl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The nitrogen atom of an arylheterocyclyl may be a basic nitrogen atom. The nitrogen or sulfur atom of the heterocyclyl portion of the arylheterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or SsS-dioxide. Exemplary arylheterocyclyl includes indolinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, lH-2,3-dihydroisoindol-2-yl, 2,3- dihydrobenz[fjisoindol- 2-yl, and 1,2,3,4- tetrahydrobenz[g]-isoquinolin-2-yl.
"Aryloxy" means an aryl-O-. Exemplary aryloxy includes phenoxy and naphthoxy. "Aryloxycarbonyl" means aiyl-O-CO-. Exemplary atyloxycarbonyl includes phenoxycarbonyl and naphthoxycarbonyl.
"Compounds of the present invention", and equivalent expressions, are meant to embrace compounds of Formula (I) as hereinbefore described, the hydrates, solvates andN-oxides thereof, and the pharmaceutically acceptable salts thereof, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, N-oxides and solvates, where the context so permits.
"Cycloalkenyl" means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, particularly of about 5 to about 10 carbon atoms, and which contains at least one carbon-carbon double bond. Particular rings of the ring system include about 5 to about 6 ring atoms; and such particular ring sizes are also referred to as "lower". Exemplary monocyclic cycloalkenyl includes cyclopentenyl, cyclohexenyl, and cycloheptenyl. An exemplary multicyclic cycloalkenyl is norbornylenyl.
"Cycloalkenylaryl" means a fused aryl and cycloalkenyl. Particular cycloalkenylaryl is one wherein the aryl thereof is phenyl and the cycloalkenyl consists of about 5 to about 6 ring atoms. A cycloalkenylaryl is bonded through any atom of the aryl moiety thereof capable of such bonding. Exemplary cycloalkenylaryl includes 1,2-dihydronaphthylene and indene. "Cycloalkenylheteroaryl" means a fused heteroaryl and cycloalkenyl. Particular cycloalkenylheteroaryl is one wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkenyl consists of about 5 to about 6 ring atoms. A cycloalkenylheteroaryl is bonded through any atom of the heteroaryl thereof capable of such bonding. The designation of the aza, oxa or thio as a prefix before heteroaryl portion of the cycloalkenylheteroaryl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The nitrogen atom of a cycloalkenylheteroaryl may be a basic nitrogen atom. The nitrogen atom of the heteroaryl portion of the cycloalkenylheteroaryl may also be optionally oxidized to the corresponding N-oxide. Exemplary cycloalkenylheteroaryl includes 5,6- dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6- dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5- dihydro-lH -benzimidazolyl, and 4,5-di- hydrobenzoxazolyl.
"Cycloalkyl" means a non-aromatic mono- or multicyclic saturated ring system of about 3 to about 10 carbon atoms, particularly of about 5 to about 10 carbon atoms. Particular ring systems include about 5 to about 7 ring atoms; and such particular ring systems are also referred to as "lower". Exemplary monocyclic cycloalkyl includes cyclopentyl, cyclohexyl, and cycloheptyl. Exemplary multicyclic cycloalkyl includes 1-decalin, norbomyl, and adamant-(l- or 2-)yl.
"Cycloalkylaryl" means a fused aryl and cycloalkyl. Particular cycloalkylaryl is one wherein the aryl thereof is phenyl and the cycloalkyl consists of about 5 to about 6 ring atoms. A cycloalkylaryl is bonded through any atom of the cycloalkyl moiety thereof capable of such bonding. Exemplary cycloalkylaryl includes 1,2,3,4-tetrahydro-naphthylene.
"Cycloalkylene" means a bivalent cycloalkyl group having about 4 to about 8 carbon atoms. Particular cycloalkylene includes about 5 to about 7 ring atoms; and such particular ring systems are also referred to as "lower". The points of binding on the cycloalkylene group include 1,1-, 1,2-, 1,3-, or 1,4- binding patterns, and where applicable the stereochemical relationship of the points of binding is either cis or trans. Exemplary monocyclic cycloalkylene includes (1,1-, 1,2-, or l,3-)cyclohexylene and (1,1- or l,2-)cyclopentylene.
"Cycloalkylheteroaryl" means a fused heteroaryl and cycloalkyl. Particular cycloalkylheteroaryl is one wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms. A cycloalkylheteroaryl is bonded through any atom of the heteroaryl thereof capable of such bonding. The designation of the aza, oxa or thio as a prefix before heteroaryl portion of the fused cycloalkylheteroaryl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The nitrogen atom of a cycloalkylheteroaryl may be a basic nitrogen atom. The nitrogen atom of the heteroaryl portion of the cycloalkylheteroaryl may also be optionally oxidized to the corresponding N-oxide. Exemplary cycloalkylheteroaryl includes 5,6,7,8- tetrahydroquinolinyl, 5,6,7,8-tetra-hydroisoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8- tetrahydroquinazolyl, 4,5,6,7-tetrahydro-lH-benzimidazolyl, and 4,5,6,7-tetrahydrobenzoxazolyl.
"Cyclyl" means cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl.
"Dialkylamino" means (alkyl)2-N-. Particular dialkylamino is (Ci-C6alkyl)2-N-. Exemplary dialkylamino groups include dimethylamino, diethylamino and methylethylamino.
"Halo" or "halogen" means fluoro, chloro, bromo, or iodo. Particular halo or halogen is fluoro or chloro. "Haloalkoxy" means alkoxy substituted by one to three halo groups. Particular haloalkoxy are loweralkoxy substituted by one to three halogens. Most particular haloalkoxy are loweralkoxy substituted by one halogen.
"Haloalkyl" means alkyl substituted by one to three halo groups. Particular haloalkyl are loweralkyl substituted by one to three halogens. Most particular haloalkyl are loweralkyl substituted by one halogen.
"Heteroaroyl" means heteroaryl-CO-. Exemplary heteroaroyl includes thiophenoyl, nicotinoyl, pyrrol- 2-ylcarbonyl, and pyridinoyl.
"Heteroaryl" means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Particular aromatic ring systems include about 5 to about 10 carbon atoms, and include 1 to 3 heteroatoms. More particular ring sizes of rings of the ring system include about 5 to about 6 ring atoms. The designation of the aza, oxa or thio as a prefix before heteroaryl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. A nitrogen atom of a heteroaryl may be a basic nitrogen atom and may also be optionally oxidized to the corresponding N-oxide. When a heteroaryl is substituted by a hydroxy group, it also includes its corresponding tautomer. Exemplary heteroaryl includes pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyL furanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l,2-a]pyridine, imidazo[2,l-b]thiazolyl, benzofuranyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, benzoazaindolyl, 1,2,4- triazinyl, benzothiazolyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1 ,3 ,4-thiadiazolyl, thiazolyl, thienyl, and triazolyl.
"Heteroarylalkyl" means heteroaryl-alkyl-. Particular heteroarylalkyl contains a (Ci-C4)-alkyl moiety. Exemplary heteroarylalkyl includes tetrazol-5-ylmethyl.
"Heteroarylcycloalkenyl" means a fused heteroaryl and cycloalkenyl. Particular heteroarylcycloalkenyl is one wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkenyl consists of about 5 to about 6 ring atoms. A heteroarylcycloalkenyl is bonded through any atom of the cycloalkenyl thereof capable of such bonding. The designation of the aza, oxa or thio as a prefix before heteroaryl portion of the heteroarylcycloalkenyl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The nitrogen atom of a heteroarylcycloalkenyl may be a basic nitrogen atom. The nitrogen atom of the heteroaryl portion of the heteroarylcycloalkenyl may also be optionally oxidized to the corresponding N-oxide. Exemplary heteroarylcycloalkenyl includes 5,6- dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6- dihydroquinoxalinyl, 5,6-dihydroquinazolinyI, 4,5- dihydro-lH-benzimidazolyl, and 4,5-di- hydrobenzoxazolyl.
"Heteroarylcycloalkyl" means a fused heteroaryl and cycloalkyl. Particular heteroarylcycloalkyl is one wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms. A heteroarylcycloalkyl is bonded through any atom of the cycloalkyl thereof capable of such bonding. The designation of the aza, oxa or thio as a prefix before heteroaryl portion of the fused heteroarylcycloalkyl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The nitrogen atom of a heteroarylcycloalkyl may be a basic nitrogen atom. The nitrogen atom of the heteroaryl portion of the heteroarylcycloalkyl may also be optionally oxidized to the corresponding N-oxide. Exemplary heteroarylcycloalkyl includes 5,6,7,8- tetrahydroquinolinyl, 5,6,7,8-tetra-hydroisoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8- tetrahydroquinazolyl, 4,5,6,7-tetrahydro-lH-benzimidazolyl, and 4,5,6,7-tetrahydrobenzoxazolyl
"Heteroarylheterocyclenyl" means a fused heteroaryl and heterocyclenyl. Particular ' heteroarylheterocyclenyl is one wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclenyl consists of about 5 to about 6 ring atoms. A heteroarylheterocyclenyl is bonded through any atom of the heterocyclenyl thereof capable of such bonding. The designation of the aza, oxa or thio as a prefix before the heteroaryl or heterocyclenyl portion of the heteroarylheterocyclenyl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The nitrogen atom of a heteroarylazaheterocyclenyl may be a basic nitrogen atom. The nitrogen or sulfur atom of the heteroaryl portion of the heteroarylheterocyclyl may also be optionally oxidized to the corresponding N-oxide. The nitrogen or sulfur atom of the heteroaryl or heterocyclyl portion of the heteroarylheterocyclyl may also be optionally oxidized to the corresponding N-oxide, S- oxide or S,S- dioxide. Exemplary heteroarylheterocyclenyl includes 7,8-dihydro[l,7]naphthyridinyl, 1,2- dihydro[2,7]-naphthyridinyl, 6,7-dihydro-3H -imidazo [4,5-c]pyridyl, l,2-dihydro-l,5-naphthyridinyl, 1 ,2-dihydro-l,6-naphthyridinyl, l,2-dihydro-l,7 -naphthyridinyl, 1,2-dihydro-l ,8-naphthyridinyl, and l,2-dihydro-2,6-naphthyridinyl.
"Heteroarylheterocyclyl" means a fused heteroaryl and heterocyclyl. Particular heteroarylheterocyclyl is one wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclyl consists of about 5 to about 6 ring atoms. A heteroarylheterocyclyl is bonded through any atom of the heterocyclyl thereof capable of such bonding. The designation of the aza, oxa or thio as a prefix before the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The nitrogen atom of a fused heteroarylheterocyclyl may be a basic nitrogen atom. The nitrogen or sulfur atom of the heteroaryl portion of the heteroarylheterocyclyl may also be optionally oxidized to the corresponding N-oxide. The nitrogen or sulfur atom of the heteroaryl or heterocyclyl portion of the heteroarylheterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary heteroarylheterocyclyl includes 2,3-dihydro-lH-pyrrol[3,4-b]quinolin-2-yl, 1,2,3,4-tetrahydrobenz [b][l,7]naphthyridin-2-yl, l,2,3,4-tetrahydrobenz[b][l,6]naphthyridin-2-yl, l,2,3,4-tetra~hydro-9H- pyrido[3,4-b]indol-2yl, l,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2yl, 2,3-dihydro-lH-pyrrolo[3,4-b ]indol-2-yl, lH-253,4,5-tetrahydroazepino[3,4-b]indol-2-yl, lH-2,3,4,5-tetra-hydroazepino[4,3- b]indol-3-yl, lH-2,3,4,5-tetrahydroazepino[4,5-b]indol-2 yl, 5,6,7,8-tetra-hydro[l,7]naphthyridyl, l,2,3,4-tetrhydro[2,7]naphthyridyl, 2,3-dihydro[l,4]dioxino[2,3-b]pyridyl, 2,3-dihydro- [l,4]dioxino[2,3-b]pyridyl, 3,4-dihydro-2H-l-oxa[4,6]diazanaphthalenyl, 4,5,6,7- tetrahydro-3H- imidazo[4,5-c]pyridyl, 6,7-dihydro[5,8]diazanaphthalenyl, l,2,3,4-tetrahydro[l,5]-naphthyridinyl, l,2,3,4-tetrahydro[l,6]naphthyridinyl, l,2,3,4-tetrahydro[l,7]naphthyridinyl, 1,2,3,4- tetrahydro[ 1 , 8]naphthyridinyl, and 1 ,2,3 ,4-tetra-hydro [2,6]naphthyridinyl.
"Heteroaryloxy" means heteroaryl-O- . Exemplary heteroaryloxy includes pyridyloxy.
"Heterocyclenyl" means a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. A particular non-aromatic ring system includes about 5 to about 10 carbon atoms, and 1 to 3 heteroatoms. More particular ring sizes of rings of the ring system include about 5 to about 6 ring atoms; and such particular ring sizes are also referred to as "lower". The designation of the aza, oxa or thio as a prefix before heterocyclenyl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The nitrogen atom of a heterocyclenyl may be a basic nitrogen atom. The nitrogen or sulfur atom of the heterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary monocyclic azaheterocyclenyl includes 1,2,3,4-tetrahydrohydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetra-hydropyridyl, 1,4,5,6-tetrahydro- pyrimidine, 2-pyrrolinyl, 3- pyrrolinyl, 2-imidazolinyl, and 2-pyrazolinyl. Exemplary oxaheterocyclenyl includes 3,4-dihydro-2H- pyran, dihydrofuranyl, and fluorodihydro-furanyl. An exemplary multicyclic oxaheterocyclenyl is 7- oxabicyclo[2.2.1]heptenyl. Exemplary monocyclic thioheterocyclenyl includes dihydrothiophenyl and dihydrothiopyranyl. "Heterocyclenylaryl" means a fused aryl and heterocyclenyl. Particular heterocyclenylaryl is one wherein the aryl thereof is phenyl and the heterocyclenyl consists of about 5 to about 6 ring atoms. A heterocyclenylaryl is bonded through any atom of the aryl thereof capable of such bonding. The designation of the aza, oxa or thio as a prefix before heterocyclenyl portion of the fused heterocyclenylaryl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The nitrogen atom of a heterocyclenylaryl may be a basic nitrogen atom. The nitrogen or sulfur atom of the heterocyclenyl portion of the heterocyclenylaryl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary heterocyclenylaryl include 3H- indolinyl, Hϊ-2-oxoquinolyl, 2H-l-oxoisoquinolyl, 1,2-di-hydroquinolinyl, 3,4-dihydroquinolinyl, 1,2- dihydroisoquinolinyl, and 3,4-dihydroisoquinolinyl.
"Heterocyclenylheteroaryl" means a fused heteroaryl and heterocyclenyl. Particular heterocyclenylheteroaryl is one wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclenyl consists of about 5 to about 6 ring atoms. A heterocyclenylheteroaryl is bonded through any atom of the heteroaryl thereof capable of such bonding. The designation of the aza, oxa or thio as a prefix before the heteroaryl or heterocyclenyl portion of the heterocyclenylheteroaryl define that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The nitrogen atom of an azaheterocyclenylheteroaryl may be a basic nitrogen atom. The nitrogen or sulfur atom of the heteroaryl portion of the heterocyclenylheteroaryl may also be optionally oxidized to the corresponding N-oxide. The nitrogen or sulfur atom of the heteroaryl or heterocyclyl portion of the heterocyclenylheteroaryl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary heterocyclenylheteroaryl includes 7,8-dihydro[l,7]naphthyridinyl, 1,2- dihydro[2,7]-naphthyridinyl, 6,7-dihydro-3H-imidazo[4,5-c]pyridyl, l,2-dihydro-l,5-naphthyridinyl, 1 ,2-dihydro-l,6-naphthyridinyl, l,2-dihydro-l,7-naphthyridinyl, l,2-dihydro-l,8-naphthyridinyl and 1,2- dihydro-2,6-naphthyridinyl.
"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, in which one or more of the atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. A particular ring system contains about 5 to about 10 carbon atoms, and from 1 to 3 heteroatoms. Particular ring sizes of the ring system include about 5 to about 6 ring atoms; and such particular ring sizes are also referred to as "lower". The designation of the aza, oxa or thio as a prefix before heterocyclyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The nitrogen atom of a heterocyclyl may be a basic nitrogen atom. The nitrogen or sulfur atom of the heterocyclyl may also be optionally oxidized to 20 the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary monocyclic heterocyclyl includes piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, THFyI, tetrahydrothiophenyl, and tetrahydrothiopyranyl.
"Heterocyclylaryl" means a fused aiyl and heterocyclyl. Particular heterocyclylaryl is one wherein the aryl thereof is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms. A heterocyclylaryl is bonded through any atom of the aryl moiety thereof capable of such bonding. The designation of the aza, oxa or thio as a prefix before heterocyclyl portion of the heterocyclylaryl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The nitrogen atom of a heterocyclylaryl may be a basic nitrogen atom. The nitrogen or sulfur atom of the heterocyclyl portion of the heterocyclylaryl may also be optionally oxidized to the corresponding N- oxide, S-oxide or S,S-dioxide. Exemplary heterocyclylaryl includes indolinyl, 1,2,3,4- tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, lH-2,3-dihydroisoindol-2-yl, and 2,3- dihydrobenz[fjisoindol-2-yl, and 1,2,3,4- tetrahydrobenz[g]-isoquinolin-2-yl.
"Heterocyclylheteroaryl" means a fused heteroaryl and heterocyclyl. Particular heterocyclylheteroaryl is one wherein the heteoraryl thereof consists of about 5 to about 6 ring atoms and the heterocyclyl consists of about 5 to about 6 ring atoms. A heterocyclylheteroaryl is bonded through any atom of the heterocyclyl thereof capable of such bonding. The designation of the aza, oxa or thio as a prefix before the heteroaryl or heterocyclyl portion of the heterocyclylheteroaryl defines that at least a nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The nitrogen atom of a heterocyclylheteroaryl may be a basic nitrogen atom. The nitrogen or sulfur atom of the heteroaryl portion of the heterocyclylheteroaryl may also be optionally oxidized to the corresponding N-oxide. The nitrogen or sulfur atom of the heteroaryl or heterocyclyl portion of the heterocyclylheteroaryl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary heterocyclylheteroaryl includes 2,3-dihydro-lH-pyrrol[3,4-b]quinolin-2-yl, 1,2,3,4-tetrahydrobenz [b][l,7]naphthyridin-2-yl, l,2,3,4-tetrahydrobenz[b][l,6]naphthyridin-2-yl, l,2,3,4-tetra-hydro-9H- pyrido[3,4-b]indol-2yl, l,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2yl, 2,3-dihydro-lH-pyrrolo[3,4-b ]indol-2-yl, lH-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl, lH-2,3,4,5-tetra-hydroazepino[4,3- b]indol-3-yl, lH-2,3,4,5-tetrahydroazepino[4,5-b]indol-2-yl, 5,6,7,8-tetra-hydro[l,7]naphthyridyl, l,2,3,4-tetrhydro[2,7]naphthyridyl, 2,3-dihydro[l,4]dioxino[2,3-b]pyridyl, 2,3-dihydro-
[l,4]dioxino[2,3-b]pyridyl, 3,4-dihydro-2H-l-oxa[4,6]diazanaphthalenyl, 4,5,6,7- tetrahydro-3H- imidazo[4,5-c]pyridyl, 6,7-dihydro[5,8]diazanaphthalenyl, l,2,3,4-tetrahydro[l,5]-naphthyridinyl, l,2,3,4-tetrahydro[l,6]naphthyridinyl, l,2,3,4-tetrahydro[l,7]naphthyridinyl, 1,2,3,4- tetrahydro[l,8]naphthyridinyl, and l,2,3,4-tetra-hydro[2,6]naphthyridinyl. - -
"Multicyclic alkaryl" means a multicyclic ring system including at least one aromatic ring fused to at least one non-aromatic ring that may be saturated or unsaturated, and may also contain in the ring system one or more heteroatoms, such as nitrogen, oxygen or sulfur. Exemplary multicyclic alkaryl includes arylcycloalkenyl, arylcycloalkyl, arylheterocyclenyl, arylheterocyclyl, cycloalkenylaryl, cycloalkylaryl, cycloalkenylheteroaryl, cycloalkylheteroaryl, heteroarylcycloalkenyl, heteroarylcycloalkyl, heteroarylheterocyclenyl, heteroarylheterocyclyl, heterocyclenylaryl, heterocyclenylheteroaryl, heterocyclylaryl, and heterocyclylheteroaryl. Particular multicyclic alkaryl groups are bicyclic rings that include one aromatic ring fused to one non-aromatic ring and that also may contain in the ring system one or more heteroatoms, such as nitrogen, oxygen or sulfur.
"Patient" includes human and other mammals.
"Pharmaceutically acceptable salts" refers to the non-toxic, inorganic and organic acid addition salts, and base addition salts, of compounds of the present invention. These salts may be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. In some cases, the compounds themselves are capable of self-protonating basic sites on the molecule and forming an internal amphoteric salt.
Exemplary acid addition salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, sulfamates, malonates, salicylates, propionates, methylene-bis-β- hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and laurylsulfonate salts. See, for example S.M. Berge, et al., "Pharmaceutical Salts," J. Pharrn. Sci., 66, 1-19 (1977) that is incorporated herein by reference. Base addition salts can also be prepared by separately reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the salt thus formed. Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts. A particular base addition salt is sodium salt or potassium salt. Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, and zinc hydroxide. Suitable amine base addition salts are prepared from amines which have sufficient basicity to form a stable salt, and particularly include those amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N5N'- dibenzyϊethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminometliane5 tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e.g., lysine and arginine, and dicyclohexylamine.
"Solvate" means a physical association of a compound of the present invention with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and insoluble solvates. Particular solvates include hydrates, ethanolates, and methanolates. Particular Embodiments of the Invention
One particular embodiment of the invention is a compound of formula (I) wherein R1 is phenyl, five or six membered heteroaryl, or (C5-C6)-cycloalkyl, each of which is optionally substituted by halo, (Ci-
C6)-alkyl, hydroxy, (CrC6)-alkoxy, (Ci-C4)-haloalkyl or (Ci-C4)-haloalkoxy, or a hydrate, solvate or
N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein R1 is phenyl or five or six membered heteroaryl, each of which is optionally substituted by halo, (Ci-C6)-alkyl, hydroxy, (Ci-C6)-alkoxy, (Ci-C4)-haloalkyl or (Ci-C4)-haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein R1 is phenyl or five or six membered heteroaryl, each of which is optionally substituted by halo, (Ci-C6)-alkyl, hydroxy, (Ci-Cfi)-alkoxy, (Ci-C4)-haloalkyl or (CrGO-haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof, provide that when R1 is phenyl or six membered heteroaryl, then it is only optionally substituted at the ortho or meta position.
Another particular embodiment of the invention is a compound of formula (I) wherein R1 is phenyl, pyridyl, thiazolyl, imidazolyl or oxodiazolyl, each of which is optionally substituted by halo, (Ci-Cβ)- alkyl, hydroxy, (Ci-C6)-alkoxy, (Ci~C4)-haloalkyl or (C1-C4)-haloalkoxy, or a hydrate, solvate or N- oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein R1 is phenyl or pyridyl, each of which is optionally substituted at the ortho or meta position by halo, (Q-Cβ^alkyl, hydroxy, (CrC6)-alkoxy, (CrG^-haloalkyl or (Ci-C4)-haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein R1 is phenyl optionally substituted by halo, (Ci-C6)-alkyl, hydroxy, (Ci-C6)-alkoxy, (Ci-C4)-haloalkyl or (C1-C4)- haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein R1 is phenyl optionally substituted at the ortho or meta position by halo,
Figure imgf000017_0001
hydroxy, (Ci-C6)-alkoxy, (Cj-C4)-haloalkyl or (Ci-C4)-haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein R1 is phenyl optionally substituted by halo, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein R1 is phenyl optionally substituted at the ortho or meta position by halo, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein R1 is 2- fluorophenyl or 3 -fluorophenyl, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein R2 is hydrogen, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein R2 is methyl, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein L1 is a bond, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein L1 is (C1-C3)- alkylene, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof. Another particular embodiment of the invention is a compound of formula (I) wherein L1 is -CH2-, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein: R3 is cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, or multicyclic alkaryl, each of which is optionally substituted by: acyl, cyano, nitro, halo, hydroxy, carboxy, amidino,
R5O-C(=O)-C(=N-OR4)-,Y1Y2N~, Y1Y2N-CC=O)-, Y1Y2N-CC=O)-O-, Y1Y2N-SO2-, R7-SO2-NR6-, R7-C(=O)-NR6-,Y1Y2N-(C1-C4)-alkylene-SO2-(Ci-C4)-alkylene-, or alkyl, alkenyl, alkynyl, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfinyl, or alkylsulfonyl, each of which is optionally substituted by: halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -PC=O)- (alkoxy)2, Y1Y2N-, Y1Y2N-SO2-, R7-SO2-NR6-, aryl or heteroaryl, each of which is optionally substituted by alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, or heterocyclyl or arylheterocyclyl, each of which is optionally substituted by oxo or alkyl, or aryl, heteroaryl, aroyl, heteroaroyl, aryloxy, heteroaryloxy, or heterocyclyl, each of which is optionally substituted by alkyl, haloalkyl, halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -P(=O)-(alkoxy)2, Y1Y2N-, Or Y1Y2N-SO2- , and when R3 is cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl or multicyclic alkaryl, it is also optionally substituted by oxo, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein R3 is phenyl, pyridyl, thiazolyl, imidazolyl, oxodiazolyl, imidazolyl, pyrimidinyl, thiophenyl, oxazolyl, cycloalkyl, benzooxazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrahydropyranyl, piperidinyl, furanyl, benzo[l,3]dioxolyl, benzothiazolyl, imidazolidinyl, indazolyl, benzoimidazolyl, indolyl, benzofuranyl, or l,3-dihydro-benzo[c]isothiazolyl, each of which is optionally substituted by: acyl, cyano, nitro, halo, hydroxy, carboxy, amidino,
R5O-C(=O)-C(=N-OR4)-,Y1Y2N-, Y1Y2N-CC=O)-, Y1Y2N-CC=O)-O-, Y1Y2N-SO2-,
R7-SO2-NR6-, R7-C(=O)-NR6-, Y1Y2N-(C1-C4)-alkylene-SO2-(Ci-C4)-alkylene-, or alkyl, alkenyl, alkynyl, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfinyl, or alkylsulfonyl, each of which is optionally substituted by: halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -P(=O)-(alkoxy)2,
Y1Y2N-, Y1Y2N-SO2-, R7-SO2-NR6-, aryl or heteroaryl, each of which is optionally substituted by alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, or heterocyclyl or arylheterocyclyl, each of which is optionally substituted by oxo or alkyl, or aryl, heteroaryl, aroyl, heteroaroyl, aryloxy, heteroaryloxy, or heterocyclyl, each of which is optionally substituted by alkyl, haloalkyl, halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -P(=O)-(alkoxy)2, Y1Y2N-, or Y1Y2N-SO2-, and when R3 is cycloalkyl, tetrahydropyranyl, piperidinyl, imidazolidinyl, or 1,3-dihydro- benzo[c]isothiazolyl, it is also optionally substituted by oxo, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein:
R3 is phenyl, pyridyl, thiazolyl, imidazolyl, oxodiazolyl, imidazolyl, pyrimidinyl, thiophenyl, oxazolyl, cycloalkyl, benzooxazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrahydropyranyl, piperidinyl, furanyl, benzo[l,3]dioxolyl, benzothiazolyl, imidazolidinyl, indazolyl, benzoimidazolyl, indolyl, benzofuranyl, or l,3-dihydro-benzo[c]isothiazolyl, each of which is optionally substituted by: nitro, halo, hydroxy, carboxy, amidino, R5O-C(=O)-C(=N-OR4)-, Y1Y2N-, Y1Y2N-CC=O)-,
Y1Y2N-SO2-, R7-SO2-NR6-, R7-C(=O)-NR6-, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, aryl, heteroaryl, or alkyl optionally substituted by: halo, carboxy, alkoxycarbonyl, aryl or heteroaryl, -P(=O)-(alkoxy)2, Y1Y2N-, Y1Y2N-SO2-, R7-SO2-NR6-, or heterocyclyl or arylheterocyclyl, each of which is optionally substituted by oxo, or heterocyclyl optionally substituted by Y1Y2N-, and when R3 is cycloalkyl, tetrahydropyranyl, piperidinyl, imidazolidinyl, or 1,3-dihydro- benzo[c]isothiazolyl, it is also optionally substituted by oxo; and Y1 and Y2 are each independently hydrogen, cycloalkyl, or alkyl optionally substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino, heteroaryl, or heterocyclyl optionally substituted by alkyl, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I) wherein R3 is phenyl optionally substituted by: acyl, cyano, nitro, halo, hydroxy, carboxy, amidino, R5O-C(=O)-C(=N-OR4)-,YIY2N-! Y1Y2N-CC=O)-, Y1Y2N-CC=O)-O-, Y1Y2N-SO2-, R7-Sθ2-NR6-5 R7-C(=0)-NR6-,Y1Y2N-(CrC4)-alkylene-Sθ2-(C,-C4)-alkylene-, or alkyl, alkenyl, alkynyl, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfinyl, or alkylsulfonyl, each of which is optionally substituted by: halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -P(=O)-(alkoxy)2,
Y1Y2N-, Y1Y2N-SO2-, R7-SO2-NR6-, aryl or heteroaryl, each of which is optionally substituted by alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, or heterocyclyl or arylheterocyclyl, each of which is optionally substituted by oxo or alkyl, or aryl, heteroaryl, aroyl, heteroaroyl, aryloxy, heteroaryloxy, or heterocyclyl, each of which is optionally substituted by alkyl, haloalkyl, halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -PC=O)-Calkoxy)2, Y1Y2N-, or Y1Y2N-SO2-, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (J) wherein: R3 is phenyl optionally substituted by: nitrp, halo, hydroxy, carboxy, amidino, R5O-C(=O)-C(=N-OR4)-,YIY2N-, Y1Y2N-CC=O)-, Y1Y2N-SO2-, R7-SO2-NR6-, R7-C(=O)-NR6-, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, aryl, heteroaryl, or alkyl optionally substituted by: halo, carboxy, alkoxycarbonyl, aryl or heteroaryl, -P(=O)-(alkoxy)2, Y1Y2N-, Y1Y2N-SO2-, R7-SO2-NR6-, or heterocyclyl or arylheterocyclyl, each of which is optionally substituted by oxo, or heterocyclyl optionally substituted by Y1Y2N-, and
Y1 and Y2 are each independently hydrogen, cycloalkyl, or alkyl optionally substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino, heteroaryl, or heterocyclyl optionally substituted by alkyl, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (T) wherein R3 is phenyl optionally substituted by:
Y1Y2N-SO2-, R7-SO2-NR6-, alkylsulfonyl, or alkyl substituted by Y1Y2N-SO2-, R7-SO2-NR6-, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof. Another particular embodiment of the invention is a compound of formula (I) wherein: R3 is phenyl optionally substituted by:
Y1Y2N-SO2-, R7-SO2-NR6-, alkylsulfonyl, or alkyl substituted by Y1Y2N-SO2-, R7-SO2-NR6-; and Y1 and Y2 are each independently hydrogen, cycloalkyl, or alkyl optionally substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino, heteroaryl, or heterocyclyl optionally substituted by alkyl, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
Another particular embodiment of the invention is a compound of formula (I), which is 2-Phenyl-pyrimidine~5-carboxylic acid benzylamide
2-Pyridin-4-yl-pyrimidine-5-carboxylic acid phenylamide,
2-Pyridin-3-yl-pyrimidine-5-carboxylic acid phenylamide,
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid phenylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide, 2-(4-Fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide,
2-(2-Fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide,
2-Phenyl-pyrimidine-5-carboxylic acid (2,2-dioxo-2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5- yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid [l-(lH-imidazol-2-ylmethyl-piperidin-4-yl]-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (6-dimethylamino-pyridin-3-ylmethyl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid [2-(2-pyrrolidin-l-yl-ethyl)-benzooxazol-6-yl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid 4-sulfamoyl-benzylamide,
2-Phenyl-pyrimidine-5-carboxylic acid [2-(4-sulfamoyl-phenyl)-ethyl]-amide,
(R)-2-Phenyl-pyrimidine-5-carboxylic acid [4-(2-oxo-oxazolidin-4-ylmethyl)-phenyl]-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (6-acetylamino-pyridin-3-yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid (3-carbamoyl-phenyl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid (3-methylcarbamoyl-phenyl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid (4-hydroxy-cyclohexyl)-amide,
4-methyl-2-[(2-phenyl-pyrimidin-5-carbonyl)-amino]-thiazole-5-carboxylic acid ethyl ester, {2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazol-4-yl}-acetic acid ethyl ester,
4-methyl-2-[(2-phenyl-pyrimidin-5-carbonyl)-amino]-thiazole-5-carboxylic acid,
{2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazol-4-yl}-acetic acid,
2-Phenyl-pyrimidine-5-carboxylic acid 4-methylsulfatnoyl-benzylamide,
2-Phenyl-pyrimidine-5-carboxylic acid 4-dimethylsulfamoyl-benzylamide, 2-Phenyl-pyrimidine-5-carboxylic acid (3,5-difiuoro-phenyl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid pyridin-2-ylamide, 2-Phenyl-pyrimidine-5-carboxylic acid thiazol-2-ylamide, 2-Phenyl-pyrimidine-5-carboxylic acid (3-sulfamoyl-phenyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (2-oxo-l,2-dihydro-pyrimidm-4-yl)-amide:> 2-Phenyl-pyrimidine-5-carboxylic acid (4-sulfamoyl-phenyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid pyrimidin-4-ylamide,
2-Phenyl-pyrimidine-5-carboxylic acid (l-pyridin-3-ylmethyl-piperidin-4-yl)-araide, 2-Phenyl-pyrimidine-5-carboxylic acid [2-(2-oxo-imidazolidin-l-yl)-ethyl]-amide, 2-Phenyl-pyrimidine-5-carboxylic acid [2-(lH-imidazol-4-yl)-ethyl]-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (2H-pyrazol-3-yl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid ( 1 -methyl-piperidin-4-yl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid pyrimidin-2-ylamide, 2-(3,5-difluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl~benzylamide, 2-(2,5-difluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-ben2ylamide,
2-(4-difluorophenyl)-4-methylpyrimidine-5-carboxylic acid-3-methylsulfamoyl-benzylamide, 2-(2-pyridyl)-pyrimidine-5-carboxylic acid-3-methylsulfamoyl-benzylamide, 2-(3-pyridyl)-4-methyl-pyrimidine-5 -carboxylic acid-3-methylsulfamoyl-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-ethylsulfamoyl-ben2ylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-ethoxy-ethylsulfamoyl)-benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-hydroxy-propylsulfamoyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxy lie acid S-cyclopropylsulfamoyl-benzylamide, 2-(3 -Fluoro-phenyl)-pyrimidine-5 -carboxylic acid 3-(3 -hydroxy-propylsulfamoyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-methoxy-ethylsulfamoyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3-methoxy-propylsulfamoyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(4-methoxy-butylsulfamoyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-cyclohexylsulfamoyl-benzylamide, 2-(3 -Fluoro-phenyl)-pyrimidine-5 -carboxylic acid 3 -(2-hydroxy- 1 , 1 -dimethyl-ethylsulfamoyl)- benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-sulfamoyl-benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-moφholin-4-yl-ethylsulfamoyl)-benzylamide, 2-(3 -Fluoro-phenyty-pyrimidine-S-carboxylic acid 3 -(2-piperidin- 1 -yl-ethylsulfamoyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[2-(l-methyl-pyrrolidin-2-yl)-ethylsulfamoyl]- benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[(l-ethyl-pyrrolidin-2-ylmethyl)-sulfamoyl]- benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[2-(lH-imidazol-4-yl)-ethylsulfamoyl]- benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[3-(2-methyl-piperidin-l-yl)-propylsulfamoyl]- benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3-pyrrolidin-l-yl-propylsulfamoyl)-benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-dimethylamino-ethylsulfamoyl)-benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-diethylamino-ethylsulfamoyl)-benzylamide,
2-(3 -Fluoro-phenyty-pyrimidine-S-carboxylic acid 3 -(3 ~dimethylamino-2,2-dimethyl- propylsulfamoyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(5-dimethylamino-pentylsulfamoyl)-benzylamide5
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-diisopropylamino-ethylsulfamoyl)- benzylamide,
2-(3 -Fluoro-phenyl)-4-methyl-pyrimidine-5 -carboxylic acid 3 -(methanesulfonylamino-methyl)- benzylamide, 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5 -carboxylic acid 3-[(propane-2-sulfonylamino)-methyl]- benzylamide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3-methylsulfamoylmethyl-benzylamide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3-(isopropylsulfamoyl-methyl)- benzylamide, 2-(3 -Fluorophenyl)- pyrimidine-5-carboxylic acid 3-(methanesulfonylamino-methyl)-benzylamide,
2-(3-Fluoro-phenyl)- pyrimidine-5-carboxylic acid 3-[(propane-2-sulfonylamino)-methyl]- benzylamide,
2-(3-Fluoro-phenyl)- pyrimidine-5-carboxylic acid 3-methylsulfamoylmethyl-benzylamide,
2-(3-Fluoro-phenyl)- pyrimidine-5-carboxylic acid 3-(isopropylsulfamoyl-methyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (2-methanesulfonylamino-pyridin-4-ylmethyl)- amide,
2-(5-Methyl-[l,2,4]oxadiazole-3-yl)-pyrimidine-5-carboxylic acid (tetrab.ydro-pyran-4-yl)-amide,
2-(5-Methyl-[l,2,4]oxadiazole-3-yl)-pyrimidine-5-carboxylic acid 4 -sulfamoyl-benzeneamide,
2-(5-Methyl-[l,2,4]oxadiazol-3-yl)-pyrimidine-5-carboxylic acid (3-phenyl-[l,2,4]thiadiazol-5-yl)- amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(morpholine-4-sulfonyl)-benzylamide,
2-Pheny-pyrimidine-5-carboxylic acid 3,4-dimethoxyl-benzylamide,
2-Pheny-pyrimidine-5-carboxylic acid (2-benzo[l,3]dioxol-5-yl-ethyl)-amide,
2-Pheny-pyrimidine-5-carboxylic acid (lH-indazol-5-yl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid 4-[l,2,3]thiadiazol-5-yl)-benzylamide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide, 4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 4-morpholin-4-ylbenzylamide,
6-[(2-Phenyl-pyrimidin-5-carbonyl)-amino]-lH-benzoimidazole-2-carboxylic acid methyl ester, 6-[(2-Phenyl-pyrimidin-5-carbonyl)-amino]-lH-benzoimidazole-2-carboxylic acid, 2-Pheny-pyrimidine-5-carboxylic acid (benzofuran-5-ylmethyl)-amide,
2-Pheny-pyrimidine-5-carboxylic acid 4-methanesulfonylamino-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 4-carbamoyl-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 3-(2-hydroxy-ethylsulfamoyl)-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 4-(morpholin-4-sulfonyl)-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide,
2-Pheny-pyrimidine-5-carboxylic acid [2-(2-amino-4-methyl-thiazol-5-yl)-ethyl]-amide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide, {4-{[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-benzyl}-phosphonic acid diethyl ester, {4-[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-butyl)-phosphonic acid diethyl ester, {4-[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-ethyl)-phosphonic acid diethyl ester,
{Phenyl-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-methyl)-phosphonic acid diethyl ester,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methanesulfonyl)-benzylamide,
2-(3 -Fluoro-phenyl)-pyrimidine-5 -carboxylic acid ( 1 -methanesulfonyl-piperidin-3 -ylmethyl)-amide,
2-(3 -Fluoro-phenyl)-pyrimidine-5 -carboxylic acid ( 1 -dimethanesulfamoyl-piperidin-3 -ylmethyl)- amide,
2-(Phenyl)-pyrimidine-5-carboxylic acid 3-methanesulfonylamino-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-acetylsulfamoyl-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3-oxo-piperiazine-l-sulfonyl)-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid (2-sulfamoyl-ethyl)-amide, 2-Pheny-pyrimidine-5-carboxylic acid (2-dimethylsulfamoyl-ethyl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid (3-phenyl-[l,2,4]thiadiazol-5-yl)-amide, 4-Methyl-2-phenyl-pyrimidine-5-carboxylic acid (3-phenyl-[l ,2,4]thiadiazol-5-yl)-amide 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (3-phenyl-[l ,2,4]thiadiazol-5-yl)amide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-yl)-amide, 2-Cyclohexyl-pyrimidine-5-carboxylic acid phenylamide,
2-Phenyl-pyrimidine-5-carboxylic acid 3-amino-benzylamide, 2-(3-Pyridyl)-pyrimidine-5-carboxylic acid-3-methylsulfamoyl-benzylamide, 2-Pyrazol-l-yl-pyrimidine-5-carboxylic acid 4-sulfamoyl-benzylamide, 2-(2-Methyl-thiazol-4-yl)-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-yl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (thiophen-2-yhnethyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (4-methyl-oxazol-2-yl)-amide, Methoxyimino-{2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thia2;ol-4-yl} -acetic acid ethyl ester, 2-Phenyl-pyrimidine-5-carboxylic acid (5-methylsulfanyl-[l,3,4]thiadiazol-2-yl)-amide, 2-[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-benzothiazole-5-carboxylic acid ethyl ester, (R)-2-Phenyl-pyrimidine-5-carboxylic acid (l-phenyl-ethyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid [3-(lH-tetrazol-5-yl)-phenyl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid (l-carbamimidoyl-piperidin-4-ylmethyl)-amide, S-^-Phenyl-pyrimidine-S-carbony^-aminoJ-lH-indole-S-carboxylic acid amide, 2-Phenyl-pyrimidine-5-carboxylic acid [3-(2-amino-thiazol-4-yl)-phenyl]-amide, 2-Phenyl-pyrimidine-5-carboxylic acid {4-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-ethyl]-thiazol-2- yl} -amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid [2-(pyrrolidine-l-sulfonyl)-ethyl]-amide, [3-({[2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[(pyridin-2-ylmethyl)-sulfamoyl]-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3~hydroxy-2,2-dimethyl-propylsulfamoyl)- benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-hydroxy-2-methyl-propylsulfamoyl)- benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3--[(tetrahydro-pyran-4-ylmethyl)-sulfamoyl]- benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(4-hydroxy-butylsulfamoyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[2-(2-hydroxy-ethoxy)-ethylsulfamoyl]- benzylamide, 2-(3-Fluoro-phenyl)-pyrimidme-5-carboxylic acid 3-[(tetrahydro-furan-2-yhnethyl)-sulfamoyl]- benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-isoburylsulfamoyl-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxy lie acid (5-isopropylsulfamoyl-pyridin-3-ylmethyl)-amide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-methylsulfamoyl-pyridin-3-ylmethyl)-amide, 2-(3 -Fluoro-phenyl)-pyrimidine-5 -carboxylic acid (2-methylsulfamoyl-pyridin-4-ylmethyl)-amide, 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (2-methylsulfamoyl-pyridin-4-yhnethyl)- amide, or
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-isopropylsulfamoyl-pyridin-3- yhnethyl)-amide, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof. The present invention also includes within its scope a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the invention, in admixture with a pharmaceutically acceptable carrier.
Compounds of the present invention are PGDS inhibitors and thus, are useful for treating allergic and/or inflammatory disorders, particularly disorders such as allergic rhinitis, asthma and/or chronic obstructive pulmonary disease (COPD).
Accordingly, another invention herein is directed to a method of treating a patient suffering from allergic rhinitis and/or asthma comprising administering to the patient a pharmaceutically effective amount of compound of formula (I).
References herein directed to treating should be understood to include prophylactic therapy to inhibit PGDS, as well as to treat an established acute or chronic or physiological conditions associated with PGDS to essentially cure a patient suffering therefrom, or ameliorate the physiological conditions associated therewith. Physiological conditions discussed herein include some, but not all, of the possible clinical situations where an anti- allergic rhinitis and/or asthma treatment is warranted. Those experienced in this field are well aware of the circumstances requiring treatment.
In practice, the compound of the present invention may be administered in pharmaceutically acceptable dosage form to humans and other mammals by topical or systemic administration, including oral, inhalational, rectal, nasal, buccal, sublingual, vaginal, colonic, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), intracisternal and intraperitoneal. It will be appreciated that the particular route may vary with for example the physiological condition of the recipient.
"Pharmaceutically acceptable dosage forms" refers to dosage forms of the compound of the invention, and includes, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations, including suspensions, sprays, inhalants tablets, lozenges, emulsions, solutions, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition.
A particular aspect of the invention provides for the compound of the invention to be administered in the form of a pharmaceutical composition. Pharmaceutically acceptable carriers include at least one component selected from the group comprising pharmaceutically acceptable carriers, diluents, coatings, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, emulsion stabilizing agents, suspending agents, isotonic agents, sweetening agents, flavoring agents, perfuming agents, coloring agents, antibacterial agents, antifungal agents, other therapeutic agents, lubricating agents, adsorption delaying or promoting agents, and dispensing agents, depending on the nature of the mode of administration and dosage forms.
Exemplary suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.
Exemplary antibacterial and antifungal agents for the prevention of the action of microorganisms include parabens, chlorobutanol, phenol, sorbic acid, and the like.
Exemplary isotonic agents include sugars, sodium chloride, and the like.
Exemplary adsorption delaying agents to prolong absorption include aluminum monostearate and gelatin.
Exemplary adsorption promoting agents to enhance absorption include dimethyl sulfoxide and related analogs.
Exemplary diluents, solvents, vehicles, solubilizing agents, emulsifiers and emulsion stabilizers, include water, chloroform, sucrose, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, tetrahydrofurfuryl alcohol, benzyl benzoate, polyols, propylene glycol, 1,3-butylene glycol, glycerol, polyethylene glycols, dimethylformamide, Tween® 60, Span® 60, cetostearyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate, fatty acid esters of sorbitan, vegetable oils (such as cottonseed oil, groundnut oil, olive oil, castor oil and sesame oil) and injectable organic esters such as ethyl oleate, and the like, or suitable mixtures of these substances.
Exemplary excipients include lactose, milk sugar, sodium citrate, calcium carbonate and dicalcium phosphate.
Exemplary disintegrating agents include starch, alginic acids and certain complex silicates. Exemplary lubricants include magnesium stearate, sodium lauryl sulfate, talc, as well as high molecular weight polyethylene glycols.
The choice of pharmaceutical acceptable carrier is generally determined in accordance with the chemical properties of the active compound such as solubility, the particular mode of administration and the provisions to be observed in pharmaceutical practice.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as a solid dosage form, such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, or as a powder or granules; as a liquid dosage form such as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
"Solid dosage form" means the dosage form of the compound of the invention is solid form, for example capsules, tablets, pills, powders, dragees or granules. In such solid dosage forms, the compound of the invention is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or: (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, (j) opacifying agents, (k) buffering agents, and agents which release the compound of the invention in a certain part of the intestinal tract in a delayed manner.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used. A mixture of the powdered compounds moistened with an inert liquid diluent may be molded in a suitable machine to make molded tablets. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Solid compositions may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.
If desired, and for more effective distribution, the compound can be microencapsulated in, or attached to, a slow release or targeted delivery systems such as a biocompatible, biodegradable polymer matrices (e.g., poly(d,l-lactide co-glycolide)), liposomes, and microspheres and subcutaneously or intramuscularly injected by a technique called subcutaneous or intramuscular depot to provide continuous slow release of the compound(s) for a period of 2 weeks or longer. The compounds may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
"Liquid dosage form" means the dose of the active compound to be administered to the patient is in liquid form, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such solvents, solubilizing agents and emulsifϊers.
When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
Pharmaceutical compositions suitable for topical administration means formulations that are in a form suitable to be administered topically to a patient. The formulation may be presented as a topical ointment, salves, powders, sprays and inhalants, gels (water or alcohol based), creams, as is generally known in the art, or incorporated into a matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. Formulations suitable for topical administration in the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. The oily phase of the emulsion pharmaceutical composition may be constituted from known ingredients, in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. In a particular embodiment, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. Together, the emulsifier(s) with, or without, stabilizer(s) make up the emulsifying wax, and together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
If desired, the aqueous phase of the cream base may include^ for example, a least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such, as, propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound that enhances absorption, or penetration of the active ingredient through the skin, or other affected areas.
The choice of suitable oils or fats for a composition is based on achieving the desired properties. Thus a cream should particularly be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used.
These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Pharmaceutical compositions suitable for rectal or vaginal administrations mean formulations that are in a form suitable to be administered rectally or vaginally to a patient and containing at least one compound of the invention. Suppositories are a particular form for such formulations that can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Pharmaceutical composition administered by injection may be by transmuscular, intravenous, intraperitoneal, and/or subcutaneous injection. The compositions of the present invention are formulated in liquid solutions, in particular in physiologically compatible buffers such as Hank's solution or Ringer's solution. In addition, the compositions may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms are also included. The - -
formulations are sterile and include emulsions, suspensions, aqueous and non-aqueous injection solutions, which may contain suspending agents and thickening agents and anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic, and have a suitably adjusted pH, with the blood of the intended recipient.
Pharmaceutical composition of the present invention suitable for nasal or inhalational administration means compositions that are in a form suitable to be administered nasally or by inhalation to a patient. The composition may contain a carrier, in a powder form, having a particle size for example in the range 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc.). Suitable compositions wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient. Compositions suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. Inhalational therapy is readily administered by metered dose inhalers or any suitable dry powder inhaler, such as the Eclipse, Spinhaler®, or Ultrahaler® as described in patent application WO2004/026380, and US Patent No. 5,176,132.
Actual dosage levels of active ingredient(s) in the compositions of the invention may be varied so as to obtain an amount of active ingredient(s) that is (are) effective to obtain a desired therapeutic response for a particular composition and method of administration for a patient. A selected dosage level for any particular patient therefore depends upon a variety of factors including the desired therapeutic effect, on the route of administration, on the desired duration of treatment, the etiology and severity of the disease, the patient's condition, weight, sex, diet and age, the type and potency of each active ingredient, rates of absorption, metabolism and/or excretion and other factors.
Total daily dose of the compound of this invention administered to a patient in single or divided doses may be in amounts, for example, of from about 0.001 to about 100 mg/kg body weight daily and particularly 0.01 to 10 mg/kg/day. For example, in an adult, the doses are generally from about 0.01 to about 100, particularly about 0.01 to about 10, mg/kg body weight per day by inhalation, from about 0.01 to about 100, particularly 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from about 0.01 to about 50, particularly 0.01 to 10, mg/kg body weight per day by intravenous administration. The percentage of active ingredient in a composition may be varied, though it should constitute a proportion such that a suitable dosage shall be obtained. Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. Obviously, several unit dosage forms may be administered at about the same time. A dosage may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much lower maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. It goes without saying that, for other patients, it will be necessary to prescribe not more than one or two doses per day.
The formulations can be prepared in unit dosage form by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the pharmaceutically active ingredient with the carrier that constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials with elastomeric stoppers, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Compounds of the invention may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature, for example those described by R.C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989.
In the reactions described hereinafter it may be necessary to protect 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 may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc., 1999.
A compound of formula (T), wherein R2 is hydrogen, may be prepared, as shown in Scheme I below, by reacting an amidine compound, wherein R1 is as defined herein, with a reagent of formula (A) to form a compound of formula (B), which directly or via its hydrolyzed product of formula (C), is coupled with an amine of formula (D), wherein L1 and R3 are as defined herein.
Scheme I
Figure imgf000033_0001
R2 = hydrogen
A compound of formula (I), wherein R2 is (Q-C^-alkyl, may be prepared, as shown in Scheme II below, by reacting an amidine compound, wherein R1 is as defined herein, with a reagent of formula (E) to form a compound of formula (F), which directly or via its hydrolyzed product of formula (G), is coupled with an amine of formula (D), wherein L1 and R3 are as defined herein.
Scheme π
Figure imgf000033_0002
(I) (G)
R2 = (CrC4)-alkyl Compounds of the invention may also be prepared by interconversion of other compounds of the invention. It will be appreciated that compounds of the present invention may contain asymmetric centers. These asymmetric centers may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of Formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates.
The compounds of the invention, their methods or preparation and their biological activity will appear more clearly from the examination of the following examples that are presented as an illustration only and are not to be considered as limiting the invention in its scope. Compounds of the invention are identified, for example, by the following analytical methods.
Mass Spectra (MS) are recorded using a Micromass LCT mass spectrometer. The method is positive electrospray ionization, scanning mass m/z from 100 to 1000.
300MHz 1H nuclear magnetic resonance spectra (1H NMR) are recorded at ambient temperature using a Varian Mercury (300 MHz) spectrometer with an ASW 5 mm probe. In the 1H NMR chemical shifts (δ) are indicated in parts per million (ppm) with reference to tetramethylsilane (TMS) as the internal standard.
As used in the examples and preparations that follow, as well as the rest of the application, the terms used therein shall have the meanings indicated: "kg" refers to kilograms, "g" refers to grams, "mg" refers to milligrams, "μg" refers to micrograms, "mol" refers to moles, "mmol" refers to millimoles, "M" refers to molar, "mM" refers to millimolar, "μM" refers to micromolar, "nM" refers to nanomolar, "L" refers to liters, "mL" or "ml" refers to milliliters, "μL" refers to microliters, "0C" refers to degrees Celsius, "mp" or "m.p." refers to melting point, "bp" or "b.p." refers to boiling point, "mm of Hg" refers to pressure in millimeters of mercury, "cm" refers to centimeters, "ran" refers to nanometers, "abs." refers to absolute, "cone." refers to concentrated, "c" refers to concentration in g/mL, "rt" refers to room temperature, "TLC" refers to thin layer chromatography, "HPLC" refers to high performance liquid chromatography, "i.p." refers to intraperitoneally, "Lv." refers to intravenously, "s" = singlet, "d" = doublet; "t" = triplet; "q" = quartet; "m" = multiplet, "dd" = doublet of doublets; "br" = broad, "LC" = liquid chromatograph, "MS" = mass spectrograph, "ESI/MS" = electrospray ionization/mass spectrograph, "Rτ" = retention time, "M" = molecular ion, "PSI" = pounds per square inch, "DMSO" = dimethyl sulfoxide, "DMF" = N,N-dimethylformamide, "DCM" = dichloromethane, "HCl" = hydrochloric acid, "SPA" = Scintillation Proximity Assay, "EtOAc" = ethyl acetate, "PBS"= Phosphate Buffered Saline, "IUPAC" = International Union of Pure and Applied Chemistry, "MHz" = megahertz, "MeOH " = methanol, "N" = normality, "THF" = tetrahydrofuran, "min" = minute(s), "N2" = nitrogen gas, "MeCN" or "CH3CN" = acetonitrile, "Et2O" = ethyl ether, "TFA" = trifluoroacetic acid, "~" = approximately, "rt" = room temperature, "MgSO4" = magnesium sulfate, "Na2SO4" = sodium sulfate, "NaHCO3" = sodium bicarbonate, "Na2CO3" = sodium carbonate, "MCPBA" = 3-Chloroperoxybenzoic acid, "NMP" = N-methylpyrrolidone, "PS- DCC" = polymer supported-dicyclohexylcarbodiimde, "LiOH" = Lithium hydroxide, "PS-trisamine" = polymer supported-trisamine, "PGH2" = prostaglandin H2, "PGD2" = prostaglandin D2; "PGE2" = prostaglandin E2, "hPGDS" = Hematopoietic PGD2 Synthase, "GSH" = glutathione (reduced), "EIA" = Enzyme immunoassay, "KH2PO4" = potassium phosphate, monobasic, "K2HPO4" = potassium phosphate, dibasic, "FeCl2" = ferrous chloride, "MOX" = methoxylamine; "EtOH" = ethanol, "DMSO" = dimethylsulfoxide.
EXAMPLES Example 1 :
2-Phenyl-pγrimidine-5-carboxylic acid benzylamide
Figure imgf000035_0001
Step 1: A 250 mL, three-neck, round-bottom flask equipped with a magnetic stirrer and a reflux condenser is purged with N2. The flask is charged sequentially with methyl 3,3-dimethoxypropionate (5.22 g, 35.3 mmol), anhydrous 1,2-dimethoxyethane (25 mL), anhydrous methyl formate (5 mL), 60% sodium hydride (1.7 g, 42.5 mmol), and the mixture warmed to 40 - 5O0C until evolution of hydrogen gas stops. The reaction mixture is cooled in an ice/water bath and slowly allowed to reach room temperature overnight with stirring. Anhydrous ether (25 mL) is added, and the resulting suspension is filtered under N2, washed with anhydrous ether (10 mL), and vacuum dried for 2 hours to yield sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylicacid methyl ester (3.51 g, 50%) as a powder. 1H NMR (CD3OD): δ 3.33 (s, 6H), 3.60 (s, 3H), 5.31 (s, IH), 8.89 (s, IH). (see: P. Zhichkin, DJ. Fairfax, S.A. Eisenbeis, Synthesis, 2002, 720-722.)
Step 2: To a solution of benzamidine hydrochloride hydrate (2 mmol) in anhydrous DMF (4 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylicacid methyl ester (0.46 g, 2.32 mmol) and the reaction mixture heated at 1000C under N2 for 1 hour. The reaction is cooled to room temperature and water (15 mL) is added. After addition of water, immediate precipitation of the product is observed. The solids are collected by filtration, washed with water (2.5 mL) and vacuum dried to yield 2-phenyl-pyrimidine-5-carboxylic acid methyl ester (0.32 g, 74%). (see: P. Zhichkin, DJ. Fairfax, S.A. Eisenbeis, Synthesis, 2002, 720-722.)
Step 3: A solution of 2-phenyl-pyrimidine-5-carboxylic acid methyl ester (3.15 g) and LiOH (0.71 g) in a mixture of MeOH, THF and water (1:1:1 in volume, 120 mL) is stirred at room temperature overnight. MeOH and THF are evaporated off to give an aqueous solution. The aqueous solution is acidified with 5% hydrochloric acid to adjust pH to between 2.5 and 3. The precipitate is filtered off and washed with water, dried in vacuo to yield 2.94 g (~100%) of 2-phenyl-pyrimidine-5-carboxylic acid as a solid. MS: 201 (M+H). Step 4: A mixture of 2-phenyl-pyrimidine-5 -carboxylic acid. (80 mg), 1-hydroxybenzotriazole (92 mg) and polymer supported-carbodiimide (640 mg, 1.25 mmol/g) in 8 mL of DCM is shaken at room temperature for 30 min and benzylamine (43 mg) is added. After shaking at room temperature for 1.5 days, PS-trisamine (295 mg, 4.08 mmol/g) is added. The mixture is continually shaken at room temperature for 16 hours. The solid is filtered and washed with DCM. The filtrate is concentrated to yield of 2-phenyl-pyrimidine-5 -carboxylic acid benzylamide (98 mg, 85%) as a solid. MS: 290 (M+H); 1H NMR (CDCl3): 9.17 (s, 2H), 8.50 (d, 2H), 7.52-7.55 (m, 3H), 7.36-7.40 (m, 5H), 6.54 (broad, H), 4.69-4.71 (d, 2H); IC50 = 10 nM. Example 2
2-Pyridin-4-yl-pyrimidine-5-carboxylic acid phenylamide
Figure imgf000036_0001
Step 1. To a solution of isonicotinamidine hydrochloride (1 g, 6.35 mmol) in anhydrous DMF (12 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylicacid methyl ester (1.46 g, 7.36 mmol) and the reaction mixture is heated at 1000C under nitrogen for Ih. The reaction is cooled to room temperature and water (48 mL) is added. The precipitate is collected by filtration, washed with water and vacuum dried to afford 2-pyridin-4-yl-pyrimidine-5-carboxylic acid methyl ester (1.2 g, 88%). MS: 216 (M+H); 1H NMR (300 MHz, CD3OD): δ 4.00 (s, 3H), 8.44 (d, 2H), 8.73 (d, 2H), 9.38 (s, 2H).
Step 2. A solution of 2-pyridin-4-yl-pyrimidine-5-carboxylic acid methyl ester (1.11 g, 5.18 mmol), and aqueous LiOH (1 M, 5.18 mL) in MeOH (7.25 mL) is stirred at room temperature overnight. MeOH is removed in vacuo, and the aqueous solution is treated with 3 N HCl to adjust the pH to between 2 and 3. The solid is filtered off and washed with water and dried in vacuum to yield 2z pyridin-4-yl-pyrimidine-5 -carboxylic acid (1 g, 96%) as a solid. MS: 202 (M+H). Step 3. A mixture of 2-pyridin-4-yl-pyrimidine-5-carboxylic acid (100 mg, 0.5 mmol), 1- hydroxybenzotriazole (76.1 mg, 0.56 mmol) and PS-DCC (539 mg, 1.25 mmol/g, 0.66 mmol) in DMF (8 mL) is shaken at room temperature for 15 min, and aniline (31 mg, 0.33 mmol) is added. After shaking at room temperature for 18 hours, PS-trisamine (398 mg, 3.75 mmol/g, 1.49 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with DCM. The filtrate is concentrated to yield 2-pyridin-4-yl-pyrimidine-5-carboxylic acid phenylamide (15 mg, 16%) as solid. MS: 277 (M+H).
Example 3
2-Pyridin-3-yl-pyrimidine-5-carboxylic acid phenylamide
Figure imgf000037_0001
Step 1. To a solution of nicotinamidine hydrochloride (1 g, 6.35 mmol) in anhydrous DMF (12 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylicacid methyl ester (1.46 g, 7.36 mmol) and the reaction mixture is heated at 1000C under N2 for 3 hours. After this time the reaction is cooled to room temperature and water (48 mL) is added. The precipitate is collected by filtration, washed with water and vacuum dried to afford 2-pyridin-3-yl-pyrimidine-5-carboxylic acid methyl ester (0.7 g, 51%). MS: 216 (M+H).
Step 2. A solution of 2-pyridin-3-yl-pyrimidine-5-carboxylic acid methyl ester (0.73 g, 3.32 mmol) and IM aqueous LiOH (3.32 mL) in MeOH (5 mL) is stirred at room temperature overnight. The MeOH is removed in vacuo, and the aqueous solution is treated with 3 N HCl to adjust the pH ~ 2-3. The solid is filtered off and washed with water and dried in vacuum to yield 2-pyridin-3 -yl-pyrimidine-5 - carboxylic acid (0.2 g, 30%) as a solid. MS: 202 (M+H).
Step 3. A mixture of 2-pyridin-3-yl-pyrimidine-5-carboxylic acid (110 mg, 0.55 mmol) 1- hydroxybenzotriazole (83.5 mg, 0.62 mmol) and PS-DCC (568 mg, 1.28 mmol/g, 0.73 mmol) in DMF (8 mL) is shaken at room temperature for 15 min, and aniline (34 mg, 0.36 mmol) is added. After shaking at room temperature for 18 hours, PS-trisamine (436 mg, 3.75 mmol/g, 1.64 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with DCM. The filtrate is concentrated to yield 2-pyridin-3-yl-pyrimidine-5-carboxylic acid phenylamide (41.2 mg, 41%) as a solid. MS: 277 (M+H). Example 4
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid phenylamide
Figure imgf000037_0002
A mixture of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (100 mg, 0.5 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (76.1 mg, 0.56 mmol) and PS-DCC (518 mg, 1.28 mmol/g, 0.66 mmol) in 8 mL of DMF is shaken at room temperature for 15 minutes, and aniline (31 mg, 0.33 mmol) is added. After shaking at room temperature for 18 hours, PS-trisamine (400 mg, 3.75 mmol/g, 1.5 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with DCM. The filtrate is concentrated to yield 2-pyridin-2-yl-pyrimidine-5-carboxylic acid phenylamide (21 mg, 23%) as a solid. MS: 277 (MH-H). Example 5
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide
Figure imgf000038_0001
A mixture of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (107 mg, 0.49 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (75 mg, 0.56 mmol) and PS-DCC (511 mg, 1.28 mmol/g, 0.65 mmol) in DMF (8 mL) is shaken at room temperature for 15 min. Aniline (30.4 mg, 0.33 mmol) is added. The mixture is shaken at room temperature for 18 hours. PS-trisamine (392 mg, 3.75 mmol/g, 1.47 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with EtOAc. The filtrate is concentrated to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide as a solid in quantitative yield. MS: 294 (M+H). Example 6 2-(4-Fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide
Figure imgf000038_0002
A mixture of 2-(4-fluoro-phenyl)-pyrimidine-5-carboxylic acid (107 mg, 0.49 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (75 mg, 0.56 mmol) and PS-DCC (511 mg, 1.28 mmol/g, 0.65 mmol) in DMF (8 mL) is shaken at room temperature for 15 min. Aniline (30.4 mg, 0.33 mmol) is added. The mixture is shaken at room temperature for 18 hours. PS-trisamine (392 mg, 3.75 mmol/g, 1.47 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with EtOAc. The filtrate is concentrated to afford 2-(4-fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide (83.4 mg, 86%) as a solid. MS: 294 (M+H). Example 7
2-(2-Fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide
Figure imgf000038_0003
A mixture of 2-(2-fluoro-phenyl)-pyrimidine-5-carboxylic acid (105 mg, 0.48 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (74 mg, 0.54 mmol) and PS-DCC (501 mg, 1.28 mmol/g, 0.64 mmol) in DMF (8 mL) is shaken at room temperature for 15 min. Aniline (29.9 mg, 0.32 mmol) is added. The mixture is shaken at room temperature for 18 hours. PS-trisamine (385 mg, 3.75 mmol/g, 1.44 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with EtOAc. The filtrate is concentrated to afford 2-f2-fluoro-phenyiypyrimidine-5-carboxylic acid phenylamide (60 mg, 63%) as a solid. MS: 294 (M+H). Example 8 2-Phenyl-pyrimidine-5-carboxylic acid ('2.2-dioxo-2.3-dihvdro-lH-21amda*6*-benzorclisothiazol-5-
Figure imgf000039_0001
A mixture of 2-phenyl-pyrimidine-5-carboxylic acid (60 mg, 0.3 mmol), 1-hydroxybenzotriazole (69 mg, 0.51 mmol), and PS-DCC (469 mg, 1.21 mmol/g, 0.6 mmol in DMF (8 mL) is shaken at room temperature for 60 min. 2,2-Dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine (55 mg, 0.3 mmol) is added. The mixture is shaken at room temperature for 2 days. PS-trisamine (221 mg, 4.08 mmol/g, 0.9 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with MeOH. The filtrate is concentrated to yield 2-phenyl- pyrimidine-5-carboxylic acid r2,2-dioxo-2.3-dihydro-lH-21amda*6*-benzofc1isothiazol-5-ylVamide (57 mg) as a solid. MS: 367 (M+H); 1HNMR(SOO MHz, CD3C)D): δ 4.58 (s, 2H), 6.86 (d, H), 7.53- 7.65 (m, 4H), 7.76 (s, H), 8.46 (t, 2H), 9.33 (d, 2H), 10.41 (broad, H), 10.54 (s, H); IC50 = 2.5 nM. Example 9 2-Phenyl-pyrimidine-5-carboxylic acid [l-(lH-imidazol-2-ylmethyl-piperidin-4-yl]-amide
Figure imgf000039_0002
Following procedures similar to those of Example 8 but substituting l-(lH-imidazol-2-ylmethyl)- piperidin-4-ylamine for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid |" 1 -( 1 H-imidazol-2-yhnethyl-piperidin-4-yl] -amide (74 mg) as a solid. MS: 363 (M+H); 1HNMR (300 MHz, DMSO-d6): δ 1.80-1.89 (m, 2H), 2.05-2.16 (m, 2H), 3.21-3.37 (m, 2H), 3.50-3.60 (m, 2H), 4.14 (m, H)3 4.66 (s, 2H), 7.49-7.58(m, 3H), 7.80 (s, 2H), 8.44 (m, 2H), 8.69 (d, H), 9.23 (s, 2H); IC50 = 2 nM. Example 10 2-Phenyl-pyrimidine-5-carboxylic acid (6-dimethylamino-pyridin-3 -ylmethyD-amide
Figure imgf000040_0001
Following procedures similar to those of Example 8 but substituting 6-dimethylamino-pyridin-3- ylmethylamine (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid (6-dimethylamino-pyridin-3-ylmethyl)-amide as a solid. MS: 334 (M+H).
Example 11
2-Phenyl-pyrimidine-5-carboxylic acid r2-(2-pyrrolidin-l-yl-ethyl)-benzooxazol-6-yl1 -amide
Figure imgf000040_0002
Step 1: A solution of 2-methyl-6-nitro-benzoxazole (30 mmol), dimethyl formamide dimethyl acetal (60 mmol) and pyrrolidine (60 mmol) in DMF (45 mL) is stirred at 1000C for 16 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with water and brine, dried (Na2SO4) and filtered. The filtrate is concentrated. The residue is washed with cooled EtOAc to afford 6-nitro-2-f 2-pyrrolidin- 1 -yl-vinyl Vbenzooxazole as a solid. 1H NMR (300 MHz, CDCl3): δ 1.80-2.25 (broad, 4H), 3.10-3.80 (broad, 4H), 5.06 (d, H), 7.44 (d, H), 7.96 (d, H), 8.21 (m, 2H). Step 2: A solution of 6-nitro-2-(2-pyrrolidin-l-yl-vinyl)-benzooxazole (8.5 mmol) and palladium/carbon (10%) (0.85 mmol) in ethanol (100 mL) is hydrogenated with the pressure of 50 psi at room temperature for 18 hours. The mixture is filtered and the filtrate is concentrated in vacuo to afford 2-r2-pyrrolidin-l-yl-vinylVbenzooxazol-6-ylamine as a solid. 1HNMR (300 MHz, CDCl3): δ 1.82 (m, 4H), 3.2 (broad, 4H), 3.65 (broad, 2H), 4.92 (d, H), 6.49 (d, H), 6.64 (d, H), 7.19 (d, H), 7.60 (d, H).
Step 3: To a solution of 2-(2-pyrrolidin-l-yl-vinyl)-benzooxazol-6-ylamine (3.2 mmol) in MeOH (40 mL) is added sodium cyanoborohydride (6.4 mmol) at room temperature. The reaction mixture is heated to reflux for 18 hours. The mixture is concentrated and the residue is dissolved in DCM. The solution is washed with water and brine, and dried (MgSO4). A small amount of activated carbon is added to the solution, and the mixture is filtered. The filtrate is concentrated to afford 2-f2-pyrrolidin- l-yl-ethylVbenzooxazol-6-ylamine as a solid. 1HNMR (300 MHz, CDCl3): δ 1.79 (m, 4H), 2.61(m, 4H), 3.00-3.18 (m, 4H), 4.78 (broad, 2N-H), 6.68 (q, H), 6.80 (d, H), 7.43 (d, H). Step 4: Following procedures similar to those of Example 8, but substituting 2-(2-pyrrolidin-l-yl- ethyl)-benzooxazol-6-ylamine (0.3 mmol) for 2,2-dioxo2,3-dihydro~lH-21amda*6*- benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid F2-(2- Pyrrolidin-l-yl-ethylVbenzooxazol-6-yll-amide as a solid. MS: 414 (M+H); 1H NMR (300 MHz, DMSOd6): δ 1.70 (broad, 4H), 2.44-2.78 (m, 2H), 2.95-3.30 (m, 6H), 7.55-7.75 (m, 5H), 8.27 (s, H), 8.5 (q, 2H), 8.38 (s, 2 H), 10.8 (s, H); IC50 = 18 nM. Example 12 2-Phenyl-pyrimidine-5-carboxylic acid 4-sulfamoyl-benzylamide
Figure imgf000041_0001
Following procedures similar to those of Example 8 but substituting 4-aminomethyl- benzenesulfonamide (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5- ylamine, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid 4-sulfamoyl-benzylamide as a solid. MS: 369 (M+H); 1HNMR (300 MHz, DMSO-d6): δ 4.60 (d, 2H), 7.34 (s, 2H), 7.54-7.64 (m, 5H), 7.78 (d, 2H), 8.45 (m, 2H), 9.30 (s, 2H), 9.46 (t, H). Example 13
2-Phenyl-pyrimidine-5-carboxylic acid [2-f4-sulfamoyl-phenyl>ethyr|-amide
Figure imgf000041_0002
Following procedures similar to those of Example 8 but substituting 4-(2-amino~ethy)- benzenesulfonamide (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5- ylamine, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid r2-(4-sulfamoyl-phenyl)-ethyl]- amide as a solid. MS: 383 (M+H). Example 14 (Ry2-Phenyl-pwirnidine-5-carboxylic acid r4-(2-oxo-oxazolidm-4-ylmethylVphenvll-amide
Figure imgf000041_0003
Following procedures similar to those of Example 8 but substituting 4-(4-amino-benzyl)-oxazolidin-2- one (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared (RV2-phenyl-pyrimidine-5 -carboxylic acid [4-f 2-oxo-oxazolidin-4-ylmethyl Vphenyl] -amide - -
as a solid. MS: 375 (M+H); 1HNMR (300 MHz3 CD3OD): δ 2.85-2.94 (m, 2H), 4.13-4.24 (m, 2H), 4.36 (m, H)3 7.30 (d, 2H)3 7.46-7.60 (m, 3H)3 7.70 (d, 2H)3 8.44-8.56 (m, 2H)3 9.23 (d, 2H). Example 15
2-Phenyl-pyrimidine-5-carboxylic acid (6-acetylamino-pyridϊn-3-ylVamid
Figure imgf000042_0001
Following procedures similar to those of Example 8 but substituting N-(5-amino-pyridin-2yl)- acetamide (0.3 mmol) for 232-dioxo233-dihydro-lH-21amda*6*-benzo[c]isotb.iazol-5-ylamine, there is prepared 2-phenyl-pyrimidme-5-carboxylic acid (6-acetylamino-pyridin-3-ylVamide as a solid. MS: 334 (M+H); 1HNMR (300 MHz3 DMSOd6): δ 2.09(s, 3H), 7.47-7.66 (m3 3H), 8.09 (s, 2H), 8.40-8.53 (m, 2H)3 8.72 (s, H), 9.36 (s, 2H)3 10.29 (s N-H)3 10.70 (s, N-H). Example 16
2-Phenyl-pyrimidine-5-carboxylic acid (3-carbamoyl-phenylVamide
Figure imgf000042_0002
Following procedures similar to those of Example 8 but substituting 3-amino-benzamide (0.3 mmol) for 232-dioxo233-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl- pyrimidine-5-carboxylic acid (3-carbamoyl-phenyl)-amide as a solid. MS: 319 (M+H). Example 17 2-Phenyl-pyrimidine-5-carboxylic acid (3-methylcarbamoyl-phenylVamide
Figure imgf000042_0003
Following procedures similar to those of Example 8 but substituting 3-amino-N-methyl-benzamide (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine3 there is prepared 2-phenyl-pyrimidine-5-carboxylic acid G-metfaylcarbamoyl-phenylVamide as a solid. MS: 333 (M+H); 1HNMR (300 MHz3 DMSOd6): δ 2.79 (d, 3H), 7.47 (t, H), 7.54-7.65 (m, 3H), 7.96 (d, 2H), 8.23 (s, H), 8.37-8.54 (m, 3H), 9.37 (s, 2H), 10.70 (s, IH). Example 18
2-Phenyl-pyrimidine-5-carboxylic acid (4-hydroxy-cyclohexyD-amide
Figure imgf000043_0001
Following procedures similar to those of Example 8 but substituting 4-amino-cyclohexanol (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl- pyrimidine-5-carboxylic acid (4-hydroxy-cycloheχyiyamide as a solid. MS: 298 (M+H). Example 19 4-methyl-2-[(2-phenyl-pyrimidin-5-carbonylVaminol-thiazole-5-carboxylic acid ethyl ester
Figure imgf000043_0002
Following procedures similar to those of Example 8 but substituting 2-amino-4-methyl-thiazole-5- carboxylic acid ethyl ester (0.3 mmol) for 2,2-dioxo253-dihydro-lH-21amda*6*-benzo[c]isothiazol-5- ylamine, there is prepared 4-methyl-2-[r2-phenyl-pyrimidin-5-carbonyl)-amino]-thiazole-5-carboxylia acid ethyl ester as a solid. MS: 369 (M+H). Example 20 {2-[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-thiazol-4-yl}-acetic acid ethyl ester
Figure imgf000043_0003
Following procedures similar to those of Example 8 but substituting (2-amino-thiazol-4-yl)-acetic acid ethyl ester (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared {2-[(2-phenyl-pyrimidine-5-carbonylVamino1-thiazol-4-yll -acetic acid ethyl ester as a solid. MS: 369 (M+H). Example 21 4-Methyl-2-[(2-phenyl-pyrimidin-5-carbonyl)-aminol-thiazole-5-carboxylic acid
Figure imgf000043_0004
A mixture of 4-methyl-2-[(2-phenyl-pyrimidin-5-carbonyl)-amino]-thiazole-5-carboxylic acid ethyl ester (0.15 mmol) and 10% aqueous NaOH solution (4 mL) in THF (10 mL) is stirred at 6O0C for 18 hours. THF is evaporated and the residue is acidified with 5% hydrochloric acid to pH ~ 2.0-2.5. The precipitate is filtered and dried to afford 4-methyl-2-[(2-phenyl-pyrimidin-5-carbonvD-amino'l- thiazole-5-carboxylic acid as a solid. MS: 341 (M+H).. Example 22 {2-[r2-phenyl-pyrimidine-5-carbonyl)-aminol-thiazol-4-yU-acetic acid
Figure imgf000044_0001
Following procedures similar to those of Example 21 but substituting {2-[(2-phenyl-pyrimidine-5- carbonyl)-amino]-thiazol-4-yl} -acetic acid ethyl ester for 4-methyl-2-[(2-phenyl-pyrimidin-5- carbonyl)-amino]-thiazole-5-carboxylic acid ethyl ester, there is prepared {2-[(2-phenyl-pyrimidine-5- carbonyl)-amino]-thiazol-4-yU -acetic acid as a solid. MS: 341 (M+H). Example 23
2-Phenyl-pyrimidine-5-carboxylic acid 4-methylsulfamoyl-benzylamide
Figure imgf000044_0002
Following procedures similar to those of Example 8 but substituting 3-aminomethyl-N-methyl- benenesulfonamide hydrochloride (1.5 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*~ benzo[c]isothiazol-5-ylamine there is prepared 2-phenyl-pyrimidine-5-carboxylic acid 4- methylsulfamoyl-benzylamide as a solid. MS: 383 (M+H); 1H NMR (300 MHz, CD3OD): δ 3.36 (s, 3H), 4.51 (s, 2H)3 7.48-7.57 (m, 3H), 7.59 (d, 2H), 7.84 (d, 2H), 8.50 (m, 2H), 9.25 (s, 2H). Example 24
2-Phenyl-pyrimidine-5-carboxylic acid 4-dimethylsulfamoyl-benzylamide
Figure imgf000044_0003
A mixture of 2-phenyl-pyrimidine-5-carboxylic acid sulfamoyl-benzylamide (Example 12, 0.3 mmol), iodomethane (0.3 mmol) and potassium carbonate (0.9 mmol) in DMF (8 mL) is stirred at room temperature for 18 hours. The mixture is concentrated in vacuo and the residue is dissolved in EtOAc (30 mL). The resulting solution is washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue is purified by column chromatography eluting with 5-10% EtOAc in DCM to afford Iz phenyl-pyrimidine-S-carboxylic acid 4-dimethylsulfamoyl-benzylamide as a solid. MS: 397 (M+H); 1HNMR (300 MHz, CD3OD): δ 2.70 (s, 6H), 4.74(s, 2H), 7.46-7.57 (m, 3H), 7.65 (d, 2H), 7.77 (d, 2H), 8.43-8.56 (m, 2H), 9.25 (s, 2H). Example 25
2-Phenyl-pyrimidine-5-carboxylic acid (3,5-difluoro-phenyfl-amide
Figure imgf000045_0001
Following procedures similar to those of Example 8 but substituting 3,5-difluoroaniline (0.3 mmol) for 2,2-dioxo2,3-dmydro-lH-21amda*6*-benzo[c]isomiazol-5-ylamine, there is prepared 2-phenyl- pyrimidine-5-carboxylic acid (3,5-difluoro-phenyl)-amide as a solid. MS: 312 (M+H). Example 26 2-Phenyl-pyrimidine-5-carboxylic acid pyridin-2-ylamide
Figure imgf000045_0002
Following procedures similar to those of Example 8 but substituting 2-aminopyridine (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl- pyrimidine-5-carboxylic acid pyridin-2-ylamide as a solid. MS: 277 (M+H). Example 27
2-Phenyl-pyrimidine-5-carboxylic acid thiazol-2-ylamide
Figure imgf000045_0003
Following procedures similar to those of Example 8 but substituting 2-aminothiazole (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl- pyrimidine-5-carboxylic acid thiazol-2-ylamide as a solid. MS: 283 (M+H). Example 28 2-Phenyl-pyrimidine-5-carboxylic acid (3-sulfamoyl-phenyl)-amide
Figure imgf000045_0004
Following procedures similar to those of Example 8 but substituting 3-amino-benzenesufonamide (0.3 mmol) for 2,2~dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine5 there is prepared 2z phenyl-pyrimidine-5-carboxylic acid (3-sulfamoyl-phenyl)-amide as a solid. MS: 355 (M+H). - -
Example 29
2-Phenyl-pyrimidine-5-carboxylic acid (2-oxo-l,2-dihydro-pyrimidin-4-yl)-amide
Figure imgf000046_0001
Following procedures similar to those of Example 8 but substituting 4-amino-lH-pyrimidin-2-one (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2r_ phenyl-pyrimidine-5-carboxylic acid (2-oxo-l .2-dihydropyrimidin-4-yl)-amide as a solid. MS: 294 (M+H); 1HNMR (300 MHz, DMSO-d6): δ 7.17 (bs, N-H), 7.47-7.68 (m, 4H), 7.90 (d, H), 8.46 (d, 2H)5 9.35 (s, 2H), 11.65 (bs, N-H); IC50 = 15 nM. Example 30
2-Phenyl-pyrimidine-5-carboxylic acid (4-sulfamoyl-phenyl)-amide
Figure imgf000046_0002
Following procedures similar to those of Example 8 but substituting 4-amino-benzenesufonamide (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2z phenyl-pyrimidine-5-carboxylic acid (4-sulfamoyl-phenyl)-amide as a solid. MS: 355 (M+H). IC5O = 5 nM.
Example 31
2-Phenyl-pyrimidine-5-carboxylic acid pyrimidin-4-ylamide
Figure imgf000046_0003
Following procedures similar to those of Example 8 but substituting 4-aminopyrimidine (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl- pyrimidine-5-carboxylic acid pyrimidin-4-ylamide as a solid. MS: 278 (M+H); Example 32 2-Phenyl-pyrimidine-5-carboxylic acid ( 1 -pyridin-3 -ylmethyl-piperidin-4-yl Vamide
Figure imgf000046_0004
Following procedures similar to those of Example 8 but substituting l-pyridin-3-ylmethyl-piperidin-4- ylamine (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid π-pyridin-3-ylmethyl-piperidin-4-yl)-amide as a solid. MS: 374 (M+H). Example 33
2-Phenyl~pyrirnidine-5-carboxylic acid ["2-f 2-oxo-imidazolidin- 1 -ylVethyl]-amide
Figure imgf000047_0001
Following procedures similar to those of Example 8 but substituting l-(2-amino-ethyl)-imidazolidin-2- one (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid [2-(2-oxo-imidazolidin- 1 -yl)-ethyl]-amide as a solid. MS: 312 (M+H); 1HNMR(SOO MHz, CDC13): δ 3.47-3.58 (m, 4H), 4.60-4.73 (m, 4H), 4.52 (s, N-H)3 7.46-7.57 (m, 3H), 8.02 (bs, N-H), 8.53 (m, 2H), 9.24 (s, 2H); IC50 = 32 nM. Example 34
2-Phenyl-pyrimidine-5-carboxylic acid [2-( lH-imidazol-4-yl)~ethyl]-amide
Figure imgf000047_0002
Following procedures similar to those of Example 8 but substituting 2-(lH-imidazol-4-yl)-ethylamine
(0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid [2-(lH-imidazol-4-ylVethyl]-amide as a solid; MS: 294 (M+H); IC50 = 35 nM. Example 35
2-Phenyl-pyrimidine-5-carboxylic acid (terrahydro-pyran-4-ylmethyiy amide
Figure imgf000047_0003
Following procedures similar to those of Example 8 but substituting (terrahydro-pyran-4-yl)- methylamine (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid ftetrahydro-pyran-4-ylmethylVamide as a solid.
MS: 298 (M+H).
Example 36
2-Phenyl-pyrimidine-5-carboxylic acid (3-trifluoromethyl-phenyl)-amide
Figure imgf000048_0001
Following procedures similar to those of Example 8 but substituting 3-trifluoromethyl-aniline (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2z phenyl-pyrimidine-5-carboxylic acid (3-trifluoromethyl-phenylVamide as a solid. MS: 344 (M+H). Example 37
2-Phenyl-pyrimidine-5-carboxylic acid (2H-pyrazol-3-ylVamide
Figure imgf000048_0002
Following procedures similar to those of Example 8 but substituting 2H-pyrazol-3-ylamine (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl- pyrimidine-5-carboxylic acid (2H-pyrazol-3-yl)-amide as a solid. MS: 266 (M+H).
Example 38
2-Phenyl-pyrimidine-5-carboxylic acid (l-methyl-piperidin-4-yl)-amide
Figure imgf000048_0003
Following procedures similar to those of Example 8 but substituting l-methyl-piperidin-4-ylamine (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2_i phenyl-pyrirnidine-5-carboxylic acid (l-methyl-piperidin-4-yl)-amide as a solid. MS: 297 (M+H); IC50 = 96 nM. Example 39
2-Phenyl-pyrimidine-5-carboxylic acid pyrimidin-2-ylamide
Figure imgf000048_0004
- -
Following procedures similar to those of Example 8 but substituting 2-aminopyrimidine (0.3 mmol) for 2s2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl- pyrimidine-5-carboxylic acid pyrimidin-2-ylamide as a solid. MS: 278 (M+H). Example 40
2-f3,5-Difluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide
Figure imgf000049_0001
A mixture of 2-(3,5-difluoro-phenyl)-pyrimidine-5-carboxylic acid (118 mg, 0.5 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2) and O~(7-azabenzotriazol-l- yI)-N,N,N,N-tetramemyluronium hexafluorophosphate (190 mg, 0.5 mmol) in dry DMF (5 mL) is treated with diisopropylethylamine (0.09 mL) and stirred at room temperature for 30 min. A solution of 3-memylsulfamoylbenzylamine (150 mg, 0.75 mmol.) in dry DMF (1 mL) is added and the mixture stirred at room temperature for 24 hours. The solvent is removed and the residue is partitioned between EtOAc and water. The organic phase is separated and washed with saturated NaHCO3, water and brine, dried (MgSC^), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 30% EtOAc in DCM to afford 2-(3,5-difluorophenylVpyrimidine-5- carboxylic acid 3-methylsulfamoyl-benzylamide (125 mg, 62%) as a solid. MS: 419 (M+H); 1H NMR (300MHz, DMSO-d6): δ 2.41(d, 3H)5 4.64 (d, 2H)5 7.43-7.75 (m5 5H)5 7.80 (s, IH)5 8.05 (d, 2H)5 9.37 (s5 2H), 9.60 (t, IH); IC50 = 49 nM. Example 41 2-(2,5-Difluoro-phenylVpyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide
Figure imgf000049_0002
A mixture of 2-(2,5-difluoro-phenyl)-pyrimidine-5-carboxylic acid (118 mg, 0.5mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), and O-(7-azabenzotriazol- l-yl)-N5N5N,N-tetramethyluronium hexafluorophosphate (190 mg, 0.5 mmol) in dry DMF (5 mL) is treated with 0.09 mL of diisopropylethylamine and stirred at room temperature for 30minutes. A solution of 3-methylsulfamoylbenzylamine (150 mg, 0.75 mmol) in dry DMF (1 mL) is added and the mixture stirred at room temperature for 24 hours. The solvent is removed and the residue partitioned between EtOAc and saturated NaHCO3. The organic phase is separated and washed with water and - -
brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 20% EtOAc in DCM to afford 2-(2.5-difluoro-phenyl)-pyrimidine-5- carboxylic acid 3-methylsulfamoyl-benzylamide (135 mg, 65%) as a solid. MS: 419 (M+H); 1HNMR (300MHz5 DMSO-d6): δ 2.41 (d, 3H), 4.64 (d, 2H), 7.43-7.78 (m, 5H), 7.89 (s, IH) 7.90 (t, IH), 9.37 (s, 2H), 9.60 (t, IH). Example 42
2-f4-Difluorophenyl)-4-methylpyrimidine-5-carboxylic acid-3-methylsulfamoyl-benzylamide
Figure imgf000050_0001
Step 1: 4-Fluorobenzamidine hydrochloride (1.25 g, 7.16 mmol) is added to a solution of sodium metal (0.17 g, 7.39 mmol) in dry ethanol (25 mL) and stirred at room temperature for 20 min. Ethyl-2- acetyl-3-(dimethylamino)acrylate (1.35 g, 7.16 mmol) is added. The mixture is heated to reflux for 3 hours. The solvent is removed in vacuo. The residue is dissolved in EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to afford ethyl-2-(4-fluorophenyl)-4-methyl- pyrirnidine-5-carboxylate (1.65 g, 87%) as a solid. MS: 261 (M+H) 261. Step 2: A solution of ethyl-2-(4-fluorophenyl)pyrimidine-5-carboxylate (1.65 g, 6.35 mmol) in MeOH (75mL) is treated with 2 N aqueous sodium hydroxide (10 mL) and heated to reflux for 30 min. MeOH is removed in vacuo and the residue is diluted with water (50 mL). The solution is adjusted to pH ~ 2 with 2 M hydrochloric acid. The precipitated is collected by filtration, washed with water and vacuum dried to afford 2-(4-fluorophenylV4-methylpyrimidme-5-carboxylic acid (1.3 g, 88%) as a solid. MS: 233 (M+H).
Step 3: A mixture of 2-(4-fluorophenyl)-pyrimidine-5-carboxylic acid (232 mg, 1 mmol) and O-(7- azabenzotriazol-l-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (380 mg 1 mmol) in dry DMF (12 mL) is treated with diisopropylethylamine (0.18 mL) and stirred at room temperature for 30 min. A solution of 3-methylsulfamoylbenzylamine (300 mg, 1.5 mmol) in dry DMF (1.5 mL) is added and the mixture is stirred at room temperature for 24 hours. The solvent is removed and the residue is partitioned between EtOAc and water. The organic phase is separated, washed with saturated NaHCOj, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 60% EtOAc in heptane to afford 2-(4-fluorophenyl)-pyrimidine-5- carboxylic acid 3-methylsulfamoyl-benzylamide (210 mg, 52%) as a solid. MS: 415 (M+H); 1HNMR (300MHz, DMSO-de): δ 2.42 (s, 3H), 2.63 (s, 3H), 4.60 (d, 2H), 7.37-7.40 (t, 2H), 7.50 (s, IH), 7.60- 7.75 (m, 3H), 7.80 (s, IH), 8.45-8.50 (dd, 2H), 8.88 (s, IH), 9.30 (t, IH). Example 43 l-^-PyridylVpyrimidine-S-carboxylic acid-S-methylsulfamoyl-benzylamide
Figure imgf000051_0001
Following procedures similar to those of Example 40 but substituting 2-(2-pyridyl)-pyrimidine-5- carboxylic acid hydrochloride for 2-(3,5-difluoro-phenyl)-pyrimidine-5-carboxylic acid there is prepared 2-(2-pyridyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide (183 mg, 48%) as a solid. MS: 384 (M+H); 1HNMR (300MHz, DMSO-d6): δ 2.42 (d, 3H), 4.64 (d, 2H), 7.46-7.54 (m, IH), 7.51-7.70 (m, 4H), 7.80 (s, IH), 8.00-8.07 (t, IH), 8.44-8.50 (d, IH), 8.80 (d, IH), 9.37 (s, 2H), 9.55 (t, IH). Example 44 2-( 3 -Pyridyl)-4-methyl-pyrimidine-5 -carboxylic acid-3 -methylsulfamoyl-benzylamide
Figure imgf000051_0002
A mixture of 2-(3-pyridyl)-4-methylpyrimidine-5 -carboxylic acid (215 mg, 1 mmol, prepared according to the general procedure described in Example 42, steps 1 and 2) and O-(7-azabenzotriazol- l-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol) in dry DMF (12 mL) is treated with of diisopropylethylamine (0.18 mL) and stirred at room temperature for 30 min. 3- Methylsulfamoylbenzylamine hydrochloride (355 mg, 1.5 mmol) is added and the mixture is stirred at room temperature for 24 hours. The solvent is removed and the residue partitioned between EtOAc and saturated NaHCO3. The organic phase is separated, washed with water and brine, dried (MgSC^), filtered and concentrated in vacuo. The residue is purfϊed by column chromatography eluting with 2% MeOH in EtOAc to afford 2-(3-pyridyl)-4-methyl-pyrimidine-5-carboxylic-acid-3-methylsulfamoyl- benzylamide (180 mg, 45%) as a solid. MS: 398 (M+H); 1HNMR (300MHz, DMSO-d6): δ 2.43 (s, 3H), 2.65 (s, 3H), 4.60 (d, 2H), 7.57-7.71 (m, 4H), 7.79 (s, IH), 8.68-8.72 (d, IH), 8.72-8.78 (d, IH), 8.93 (s, IH), 9.34 (t, IH), 9.53 (s, IH). General Procedures for Examples 45 - 67 Procedure
Figure imgf000052_0001
Figure imgf000052_0003
General procedure X: Sulfonamide Formation
A vial is charged with amine H2N-R' (1 mmol) followed by p-dioxane (5 mL) and piperidinomethyl polystyrene (375 mg, 1.5 mmol, 4mmol/g resin). The vial is agitated in an orbital shaker for 20 min. 3-Cyano-benzenesulfonyl chloride is added (181 mg, 0.9 mmol) and the reaction vial is placed into the orbital shaker for 18 hours. The vial is removed from the orbital shaker, and MeOH (5mL) is added followed by the addition of 4-benzyloxybenzaldehyde polystyrene resin (100 mg, 0.3 mmol, 3 mmol/g resin). Agitation is continued in the orbital shaker for 5 hours. The sample is filtered, the resin is washed with MeOH, and the combined organic fractions are concentrated to yield the sulfonamide compound 1.
General procedure Y: Sulfonamide Formation
A vial is charged with amine H2N-R' (1 mmol) followed by p-dioxane (5 mL) and triethylamine (202 mg, 2 mmol). 3-Cyano-benzenesulfonyl chloride is added (181 mg, 0.9 mmol) and the reaction vial is placed into an orbital shaker for 18 hours. The solvents are removed in vacuo. The residue is partitioned between IN HCl in water (5 mL) and EtOAc (10 mL). The organic phase is separated, dried filtered, and concentrated in vacuo to yield the sulfonamide compound 1. General Procedure Z: Hydrogenation.
To a solution of the sulfonamide compound (0.9 mmol) in MeOH (9 mL) is added palladium on carbon (200 mg, 10 wt% on carbon, 50 wt% water, ACROS) followed by concentrated HCl in water (1 mL). The reaction is alternately placed under vaccum and hydrogen (1 atm) for 3 cycles before being left under an atmosphere of hydrogen with magnetic stirring for 24 hours. The reaction is filtered through a plug of celite and the filtrate is concentrated in vacuo to yield the amine hydrochloride compound 2. General Procedure W: Parallel Acylation
To a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (196 mg, 0.9 mmol) in DCM (5 mL) is added oxalyl chloride (229 mg, 1.8 mmol) followed by DMF (2 μL). The reaction is stirred for 3 hours. Anhydrous toluene is added (0.5 mL) and the mixture is concentrated in vacuo. The residue is dissolved in EtOAc (7 mL) and the resulting solution is added to a mixture of the amine hydrochloride compound 2 (1 mmol), Na2CO3 (212 mg) in water (5 mL) a vial with rapid stirring. The reaction is stirred for 18 h, and the organic phase is separated and concentrated in vacuo. The residue is suspended in DMSO (3 mL), filtered, purified via reverse phase HPLC (water and acetonitrile mobile phase with 0.1% TFA buffer) to afford the desried product.
Example 45
2-r3-Fluoro-phenylVpyrimidine-5-carboxylic acid 3-ethylsulfamoyl-benzylamide
Figure imgf000053_0001
A solution of ethylamine (2 M in MeOH, 6 mmol) in DCM (40 mL) is cooled in an ice water bath and 3-cyano-benzenesulfonyl chloride (402 mg, 2 mmol) is added. The reaction is rapidly stirred for 2 hours. Water (40 mL) is added, and the reaction is acidified to approximately pH 4 via the careful addition of concentrated HCl. The DCM is removed in vacuo. The precipitate is collected via filtration. The precipitate is hydrogenated using general method Z to afford the amine hydrochloride compound. The amine hydrochloride compound is acylated using acylation procedure W to prepare 2c (3-fluoro-phenylVpyrimidine-5-carboxylic acid 3-ethylsulfamoyl-benzylamide (449 mg) as a solid. MS: 415 (M+H); 1HNMR (300 MHz, CDCl3): δ = 0.95(t, 3H), 2.75-2.9(m, 2H), 4.65(d, 2H), 7.47 (t, IH), 7.55-7.75 (m, 4H), 7.81(s, IH), 8.17(d, IH), 8.32(d, IH), 9.27(bs, IH), 9.35(s, 2H), 9.58(t, IH); IC50 = 58 nM. Example 46 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-r2-ethoxy-ethylsulfamoyl)-benzylamide
Figure imgf000053_0002
Following general procedures Y, Z, and W, but using 2-ethoxy-ethylamine as the amine in procedure Y, there is prepared 2-(3-fluoro-phenyπ-pyrimidine-5-carboxylic acid 3-(2-ethoxy-ethylsulfamoylV benzylamide (210 mg) as a powder. MS: 457 (M-H); 1HNMR (300 MHz, CDCl3): δ 1.0 (t, 3H), 2.9 (t, 2H), 4.6 (s, 2H), 7.45 (t, IH), 7.5-7.7 (m, 4H), 7.8 (s, IH)5 8.16 (d, IH), 8.31 (d, IH), 9.3 (s, IH). Example 47 2-(3-Fluoro-phenylVpyrimidine-5-carboxylic acid 3-(2-hydroxy-propylsulfamoyl)-benzylamide
Figure imgf000054_0001
Following general procedures Y, Z5 and W5 but using l-amino-propan-2-ol as the amine in procedure Y5 there is prepared 2-(3-fluoro-phenylVpyrimidine-5-carboxylic acid 3-(2-hydroxy-propylsulfamoylV benzylamide (265 mg) as a solid. MS: 443 (M-H); 1HNMR (300 MHz, CDCl3): δ 0.97 (d, 3H)5 2.57- 2.71 (m, 2H)5 3.55-3.61 (q, IH)5 4.6 (s, 2H), 7.45 (t, IH)5 7.54-7.77 (m, 4H), 7.8 (s, IH)5 8.16 (d, IH)5 8.31 (d, IH)5 9.34 (s, 2H). Example 48 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-cvclopropylsulfamoyl-benzylamide
Figure imgf000054_0002
Following general procedures Y, Z5 and W, but using cyclopropylamine as the amine in procedure Y, there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-cvclopropylsulfamoyl- benzylamide (265 mg) as a solid. MS: 425 (M-H); 1HNMR (300 MHz, CDCl3): δ 0.35-0.49 (m, 4H)5
2.07-2.14 (m5 IH)5 4.65(d, 2H)5 7.46 (dt, IH)5 7.57-7.73 (m, 4H)5 7.81 (s, IH)5 7.94 (d, IH), 8.16 (d,
IH)5 8.31 (d, IH)5 9.33 (s, 2H)5 9.55 (t, IH); IC50 = 132 nM.
Example 49
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3-hydroxy-propylsulfamoylVbenzylamide
Figure imgf000054_0003
Following general procedures Y, Z, and W, but using 3-aminopropanol as the amine in procedure Y, there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3-hydroxy-propylsulfamoyl)- benzylamide (175 mg) as a powder. MS: 443 (M-H); 1HNMR (300 MHz, CDCl3): δ 1.51 (p, 2H),
2.79 (t, 2H), CH2 hidden in water peak, 4.64 (s, 2H), 7.45 (dt, IH), 7.55-7.70 (m, 4H), 7.79 (s, IH),
8.135 (d, IH)3 8.31 (d, IH), 9.29 (s, N-H), 9.33 (s, IH); IC50 = 22 nM.
Example 50
2-f3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-methoxy-ethylsulfamoyl)-benzylamide
Figure imgf000055_0001
Following general procedures Y, Z, and W, but using 2-methoxyethylamine as the amine in procedure
Y, there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-f2-methoxy-ethylsulfamoyl)- benzylamide (190 mg) as a powder. MS: 443 (M-H); 1H NMR (300 MHz, CDC13): δ 2.90 (t, 2H),
3.14 (s, 3H), CH2hidden under water peak, 4.63 (s, 2H), 7.45 (dt, IH), 7.54-7.71 (m, 4H), 7.80 (s,
IH), 8.15 (d, IH), 8.31 (d, IH), 9.33 (s, 2H), 9.57 (bs, N-H).
Example 51
2-(3 -Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3 -( 3 "methoxy-propylsulfamovD-benzylamide
Figure imgf000055_0002
Following general procedures Y, Z, and W, but using 3-methoxypropylamine as the amine in procedure Y, there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3-methoxy- propylsulfamoylVbenzylamide (201 mg) as a powder. MS: 457 (M-H); 1H NMR (300 MHz, CDCl3): δ 1.57 (p, 2H), 2.77 (t, 2H), 3.13 (s, 3H), 3.24 (t, 2H), 4.63 (s, 2H), 7.45 (dt, IH), 7.55-7.70 (m, 4H),
7.79 (s, IH), 8.15 (d, IH), 8.31 (d, IH), 9.33 (s, 2H), 9.58 (bs, N-H); IC50 = 37 nM.
Example 52
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3~f4-methoxy-butylsulfamoyl)-benzylamide
Figure imgf000055_0003
Following general procedures Y, Z, and W, but using 4-methoxyburylamine as the amine in procedure Y, there is prepared 2-r3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-r4-methoxy-butylsulfamoylV benzylamide (220 mg) as a powder. MS: 471 (M-H); 1HNMR (300 MHz, CDCl3): δ 1.01 (t, 2H), 1.57 (p, 2H), 2.78 (t, 2H), CH2 and CH3 hidden under water peak, 4.63 (s, 2H), 7.45 (dt, IH), 7.55-7.70 (m, 4H), 7.79 (s, IH), 8.16 (d, IH), 8.31 (d, IH), 9.33 (s, 2H), 9.59 (bs, N-H). Example 53 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-cvclohexylsulfamoyl-benzylamide
Figure imgf000056_0001
Following general procedures Y, Z, and W, but but using cyclohexylamine as the amine in procedure Y, there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-cyclohexylsulfamoyl- benzylamide (240 mg) as a powder. MS: 467 (M-H); 1HNMR (300 MHz, CDCl3): δ 1.07 (t, 6H), 1.41 (bs, IH), 1.53-1.55 (m, 4H), 2.90 (bs, IH), 4.63 (d, 2H), 7.45 (dt, IH), 7.53-7.72 (m, 4H), 7.80 (s, IH), 8.15 (dd, IH), 8.30 (d, IH), 9.33 (s, 2H), 9.55 (t, IH). Example 54
2-(3-Fluoro-phenyπ-pyrimidine-5-carboxylic acid 3-(2-hydroxy-l,l-dirflethyl-ethylsulfamoyl)- benzylamide
Figure imgf000056_0002
Following general procedures Y, Z, and W, but using 2-Amino-2-methyl-propan-l-ol as the amine in procedure Y, there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-hydroxy-l.l- dimeτhyl-ethylsulfamovn-benzylamide (90 mg) as a solid. MS: 457 (M-H); 1H NMR (300 MHz, CDCl3): δ 1.00 (s, 6H)3 3.19 (d, 2H), 4.63 (d, 2H), 4.75 (t, IH), 7.35 (s, IH), 7.45 (dt, IH), 7.52-7.67 (m, 3H), 7.75 (d, IH), 7.84 (s, IH), 8.16 (d, IH), 8.31 (d, IH), 9.33 (s, 2H), 9.54 (t, IH); IC50 = 60 nM. Example 55 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-sulfamoyl-benzylamide
Figure imgf000057_0001
Following general procedures Y, Z, and W, but using tert-butylamine as the amine in procedure Y, there is prepared 2-(3-fluoro-phenyπ-pyrimidine-5-carboxylic acid 3-sulfamoyl-benzylamide (25 mg) as a powder. MS: 385 (M-H); 1H NMR (300 MHz3 CDCl3): δ 4.62 (d, 2H), 7.38 (s, IH)5 7.45 (t, IH), 7.53-7.75 (m, 5H), 7.83 (s, IH), 8.16 (d, IH), 8.32 (d, IH), 8.34 (s, IH), 9.32 (s, 2H), 9.55 (t, IH); IC50 = 31 nM. Example 56 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-f2-morpholm-4-yl-ethylsulfamoyl)-benzylamide
Figure imgf000057_0002
Following general procedures X, Z, and W, but using 2-moφholin-4-yl-ethylamine as the amine in procedure X, there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-morpholin-4-yl- ethylsulfamoylVbenzylamide (150 mg) containing small amount of TFA. MS: 500 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.0-3.4 (m, 8H), 3.5-3.75 (m, 2H), 3.85-4.1 (m, 2H), 4.64 (d, 2H), 7.45 (dt, IH), 7.60-7.75 (m, 4H), 7.82 (s, IH), 8.01 (s, IH), 8.16 (d, IH), 8.30 (d, IH), 9.33 (s, 2H), 9.56 (t, IH), 9.69 (m, IH); IC50 = 37 nM. Example 57 2-(3 -Fluoro-phenyl)-ρyrimidine-5-carboxylie acid 3 -(2-piperidin- 1 -yl-ethylsulfamoylVbenzylamide
Figure imgf000057_0003
Following general procedures X, Z, and W, but using 2-piperidin- 1-yl-ethylamine as the amine in rocedure X, there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3 -f 2-piperidin- 1-yl- ethylsulfamoylVbenzylamide (125 mg) containing small amount of TFA. MS: 498 (M+H); 1H NMR (300 MHz, CDCl3): δ 1.2-1.8 (m, 6H), 2.8-2.95 (m, 2H), 3.11 (bs, 4H), 3.3-3.5 (m, 2H), 4.64 (d, 2H), 7.46 (dt, IH), 7.60-7.75 (m, 4H), 7.82 (s, IH), 8.00 (bs, IH), 8.16 (d, IH), 8.31 (d, IH)5 9.08 (m, IH), 9.33 (s, 2H), 9.56 (t, IH). Example 58
2-(3-Fluoro-phenyl)-pyrJjnidine-5-carboxylic acid 3-[2-(l-methyl-pyrrolidin-2-yl)-ethylsulfamoyll- benzylamide
Figure imgf000058_0001
Following general procedures X, Z, and W, but using 2-(l-methyl-pyrrolidin-2-yl)-ethylamine as the amine in procedure X, there is prepared 2-G-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[2-(l- methyl-pyrrolidin-2-vn-ethylsulfamovn-benzylamide (110 mg). MS: 498 (M+H); 1H NMR (300 MHz, CDCl3): δ 1.4-1.7 (m, 2H), 1.7-2.2 (m, 4H), 2.7-2.9 (m, 5H), 3.0-3.1 (m, IH), 3.1-3.3 (m, IH),
3.4-3.6 (m, IH), 4.64 (d, 2H), 7.46 (dt, IH), 7.58-7.72 (m, 4H), 7.79 (s, IH), 8.16 (d, IH), 8.31 (d, IH),
9.33 (s, 2H), 9.56 (t, IH).
Example 59
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[(l-ethyl-pyrrolidm-2-yunethyl)-sulfamoyl]- benzylamide
Figure imgf000058_0002
Following general procedures X, Z, and W, but using C-(l-ethyl-pyrrolidin-2-yl)-methylamine as the amine in procedure X there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[(l-ethyl- pyrrolidin-2-ylmethyl)-sulfamoyl]-benzylamide (85 mg) containing small amount of TFA. MS: 498 (M+H); 1HNMR (300 MHz, CDCl3): δ 1.20 (t, 3H)3 1.6-2.2 (m, 4H), 2.95-3.2 (m, 4H), 3.25-3.45 (m, 2H), 3.45-3.6 (m, IH), 4.65 (d, 2H), 7.46 (dt, IH), 7.60-7.76 (m, 4H), 7.83 (s, IH), 8.09-8.17 (m, 2H), 8.31 (d, IH), 9.13 (bs, IH), 9.34 (s, 2H), 9.57 (t, IH). Example 60
2-r3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[2-flH-imidazol-4-yl)-ethylsulfamoyl]- benzylamide
Figure imgf000059_0001
Following general procedures X5 Z, and W, but using 2-(lH-imidazol-4-yl)-ethylamine as the amine in procedure X, there is prepared 2-(3-fluoro-phenylVpwimidine-5-carboxylic acid 3-[2-flH-imidazol-4- vn-ethylsulfamoyli-benzylamide (30 mg) as a solid. MS: 481 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.77 (t, 2H), 3.06 (t, 2H), 4.63 (d, 2H), 7.40 (s, IH), 7.46 (t, IH), 7.56-7.96 (m, 4H), 7.77 (s, IH), 7.86 (t, IH), 8.16 (d, IH), 8.31 (d, IH), 9.32 (s, 2H), 9.55 (t, IH); IC50 = 61 nM. Example 61
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[3-f2-methyl-piperidin-l-yl)-propylsulfamoyl]- benzylamide
Figure imgf000059_0002
Following general procedures X, Z, and W, but using 3-(2-methyl-piperidin-l-yl)-propylamine as the. amine in procedure X there is prepared 2-f3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[3-f2- methyl-piperidin-1-ylVpropylsulfamoyll-benzylamide (155 mg) containing small amount of TFA. MS: 526 (M+H); 1HNMR (300 MHz, CDCl3): δ 1.19 (dd, 3H), 1.3-1.9 (m, 8H), 2.75-3.25 (m, 6H), 3.3-3.6 (m, IH), 4.64 (d, 2H), 7.46 (dt, IH), 7.58-7.72 (m, 4H), 7.79-7.85 (m, 2H), 8.16 (d, IH), 8.31 (d, IH), 8.9-9.2 (m, IH), 9.34 (s, 2H), 9.57 (t, IH). Example 62 2-f3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-f3-pyrrolidin-l -yl-propylsulfamoyl)-benzylamide
Figure imgf000059_0003
Following general procedures X, Z, and W, but using 3-pyrrolidin-l-yl-propylamine as the amine in procedure X, there is prepared 2-r3-fluoro-phenylVpyrimidine-5-carboxylic acid 3-f3-pyrrolidin-l-yl- propylsulfamoylVbenzylamide (105 mg). MS: 498 (M+H); 1HNMR (SOO MHz, CDCl3): δ 1.7-1.9 (m, 4H), 1.9-2.1 (m, 2H), 2.8-3.0 (m, 4H), 3.05-3.15 (m, 2H), 3.2-3.35 (m, 2H), 4.64 (d, 2H), 7.46 (dt, IH), 7.58-7.77 (m, 4H), 7.79 (m, IH), 8.16 (d, IH), 8.31 (d, IH), 9.34 (s, 2H), 9.41 (bs, IH), 9.56(t, IH). Example 63 2-r3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-dimethylamino-ethylsulfamoylVbenzylamide
Figure imgf000060_0001
Following general procedures X, Z, and W, but using N^N^dimethyl-ethane-l^-diamine as the amine in procedure X there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2- dimethylamino-ethylsulfamoylVbenzylamide (38 mg) as a solid. MS: 458 (M+H); 1H NMR (300
MHz, CDC13): δ 2.78 (s, 6H), 3.0-3.2 (m, 4H), 4.65 (d, 2H), 7.46 (dt, IH)3 7.60-7.76 (m, 4H), 8.01 (t,
IH), 8.16 (d, IH), 8.31 (d, IH), 9.33 (bs, 3H), 9.56 (t, IH); IC50 = 45 nM.
Example 64
2-f 3 -Fluoro-phenyl)-pyrimidine-5 -carboxylic acid 3 -(2-diethylamino-ethylsulfamoyl)-benzylamide
Figure imgf000060_0002
Following general procedures X, Z, and W, but using N^N^diethyl-ethane-l^-diamine as the amine in procedure X there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-diethylamino- ethylsulfamoylVbenzylamide (128 mg) containing small amount of TFA. MS: 486 (M+H); 1HNMR (300 MHz, CDCl3): δ 1.16 (t, 6H), 3.0-3.2 (m, 8H), 4.65 (d, 2H), 7.46 (dt, IH), 7.60-7.76 (m, 4H), 7.83 (s, IH), 8.02 (t, IH), 8.16 (d, IH), 8.31 (d, IH), 9.17 (bs, IH), 9.33 (s, 2H), 9.57 (t, IH). Example 65
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3-dimethylamino-2,2-dimethyl- propylsulfamovD-benzylarnide
Figure imgf000060_0003
Following general procedures X, Z, and W, but using 2,2,N1,N1-Tetramethyl-propane-l,3-diamine as the amine in procedure X there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-f3- dimethylamino-2.2-dimethyl-propylsulfamoyl)-benzylamide (190 mg) containing small amount of TFA. MS: 500 (M+H); 1HNMR (300 MHz, CDCl3): δ 0.95 (s, 6H), 2.68 (d, 2H), 2.84 (d, 6H), 3.03 (d, 2H), 4.64 (d, 2H), 7.46 (dt, IH), 7.58-7.74 (m, 4H), 7.80 (s, IH), 7.85 (t, IH), 8.16 (d, IH), 8.31 (d, IH), 8.85 (bs, IH), 9.34 (s, 2H), 9.57 (t, IH); IC50 = 35 nM. Example 66 2-(3-Fluoro-phenylVpyrimidine-5-carboxylic acid 3-(5-dimethylamino-pentylsulfamoyl)-benzylamide
Figure imgf000061_0001
Following general procedures X, Z, and W, but using N^N^dimethyl-pentane-ljS-diamine as the amine in procedure X there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(5- dimethylamino-pentylsulfamoylVbenzylamide (175 mg). MS: 500 (M+H); 1HNMR (300 MHz, CDCl3): δ 1.22-1.27 (m, 2H), 1.34-1.44 (m, 2H), 1.44-1.57 (m, 2H), 2.70-2.74 (m, 8H), 2.92-2.99 (m,
2H), 4.63 (d, 2H), 7.46 (dd, IH), 7.56-7.70 (m, 4H), 7.78 (s, IH), 8.16 (d, IH), 8.31 (d, IH), 9.33 (s,
2H), 9.56 (t, IH).
Example 67
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-diisopropylamino-ethylsulfamoyiy benzylamide
Figure imgf000061_0002
Following general procedures X, Z, and W, but using N^N^diisopropyl-ethane-l^-diamine as the amine in procedure X there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2- diisopropylamino-ethylsulfamoylVbenzylamide (150 mg). MS: 514 (M+H); 1HNMR (SOO MHZ, CDCl3): δ 1.21 (t, 12H), 3.06-.308 (m, 4H), 3.58-3.65 (m, 2H), 4.64 (d, 2H), 7.46 (dd, IH), 7.60-7.75 (m, 4H), 7.82 (s, IH), 8.07 (t, IH), 8.16 (d, IH), 8.31 (d, IH), 9.34 (s, 2H), 9.59 (t, IH). Example 68
Σ-fS-Fluoro-phenyD^-methyl-pyrimidine-S-carboxylic acid S-fmethanesulfonylamino-methyl)- benzylamide
Figure imgf000062_0001
Step 1. Na0 (0.66 g, 28.6 mmol) is added to anhydrous EtOH (100 mL) and stirred at room temperature for 15 min. 3-Fluorobenzamidine hydrochloride (4.87 g, 27.8 mmol) is added and the solution is stirred for 15 min. 2-Dimethylaminomethylene-3-oxo-butyric acid ethyl ester (5.3 g, 28.6 mmol,) is added and the reaction mixture is heated at reflux under N2 for 1 hours. The reaction is cooled to room temperature and concentrated in vacuo. The residue is dissolved in EtOAc (300 mL), washed with brine (2x100 mL), dried (Na2SO4), filtered, and concentrated to afford 2-(3-fluoro-phenyl)-4-methyl- pyrimidine-5-carboxylic acid ethyl ester (6.8 g, 99%). MS: 261 (M+H); 1HNMR (300 MHz, CDCl3): δ 1.43 (t, J= 7.0 Hz, 3H), 2.92 (s, 3H), 4.42 (q, J= 7.0 Hz, 2H), 7.24 (m, IH), 7.45 (m, IH), 8.27 (m, IH), 8.37 (m, IH), 9.21 (s, IH).
Step 2. A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid ethyl ester (6.7 g, 27.2 mmol) and NaOH (2.1 g, 54.4 mmol) in a 1 : 1 : 1 solution of THF, MeOH and water (300 mL) is heated at reflux for 45 min. The THF/MeOH is evaporated, and the aqueous solution is treated with 3 N HCl to adjust the pH to between 2 and 3. The solid is filtered off, washed with water and dried in vacuo to yield 2-(3 -fluoro-phenyl)-4-methyl-pyrimidine-5 -carboxylic acid (5.4 g, 91%) as a solid. MS: 233 (M+H); 1HNMR (300 MHz, CD3OD): δ 2.85 (s, 3H), 7.24 (m, IH), 7.50 (m, IH), 8.17 (m, IH), 8.32 (m, IH), 9.20 (s, IH).
Step 3. To a solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (0.195 g, 0.89 mmol) in THF (5 mL) is added carbonyl diimidazole (0.18 g, 1.1 mmol) and heated at 600C for 2 hours. The mixture is cooled to room temperature. (3-Aminomethyl-benzyl)-carbamic acid tert-butyl ester (0.25 mL, 1.1 mmol) is added and the mixture is stirred for 12 hours. The mixture is diluted with EtOAc (100 mL), washed with brine (2x50 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography eluting with 20%-80% EtOAc/heptane to afford r3-({[2-G-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino>-methyl)-benzyl]-carbamic acid tert-butyl ester (0.32 g, 80%) as a solid. MS: 451 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 1.38 (s, 9H), 2.65 (s, 3H), 4.14 (d, J= 6.1 Hz, 2H), 4.50 (d, J= 5.6 Hz, 2H), 7.15 (m, IH), 7.24 (m, IH), 7.31 (m, IH), 7.43 (m, IH), 7.62 (m, IH), 8.13 (m, IH), 8.28 (m, IH), 8.89 (s, IH), 9.23 (m, IH). Step 4. To a solution of [3-({[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-methyl)- benzyl]-carbamic acid tert-butyl ester (0.05 g, 0.111 mmol) in DCM (2 mL) at 0 0C is added TFA (0.013 mL. 0.111 mmol) and the mixture is stirred for 2.5 hours. The mixture is concentrated in vacuo. The residue is dissolved in THF (2 mL). Et3N (0.05 mL, 0.333 mmol) and methanesulfonyl chloride (0.010 mL, 0.133 mmol) are added and the mixture is stirred for 12 hours. The mixture is diluted with EtOAc (100 niL), washed with saturated aqueous NH4CI (2x50 mL), dried with Na2SO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography eluting with 20%- 80% EtO Ac/heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3- (methanesulfonylamino-methyl)-benzylamide (0.03 g, 64%) as a powder. MS: 429 (M+H); 1H NMR (300 MHz, DMSO-ds): δ 2.65 (s, 3H)5 2.86 (s, 3H), 4.18 (d, J= 6.3 Hz, 2H), 4.50 (d, J= 5.9 Hz, 2H), 121-1 AS (m, 3H), 7.62 (m, 2H), 8.13 (m, IH), 8.28 (m, IH), 8.90 (s, IH), 9.25 (m, IH); IC50 = 48.5 nM.
Example 69 2-r3-Fluoro-phenyl)-4-methyl-ρyrimidme-5-carboxylic acid 3-rrpropane-2-sulfonylamino)-methyll- benzylamide
Figure imgf000063_0001
Following procedures similar to those of Example 68 (step 3) but substituting isopropanesulfonyl chloride (0.57 mmol) for (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester there is prepared 2-(3- fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3-[rpropane-2-sulfonylamino)-methyl1- benzylamide (100 mg) as a solid. MS: 456 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 1.22 (d, J= 6.8 Hz, 6H), 2.65 (s, 3H), 3.10 (m, IH), 4.18 (d, J= 6.2 Hz, 2H), 4.51 (s, 2H), 121-1 AS (m, 3H), 7.62 (m, 2H), 8.14 (m, IH), 8.26 (m, IH), 8.90 (s, IH), 9.25 (m, IH). Example 70 2-(3-Fluoro-phenylV4-methyl-pyrimidine-5-carboxylic acid 3-methylsulfamoylmethyl-benzylamide
Figure imgf000063_0002
Step 1: A solution of 3-bromomethyl-benzonitrile (2 g, 10.2 mmol) in EtOH (50 mL) is treated with a solution of Na2SOs (1.3 g, 10.3 mmol) in H2O (50 mL) and heated at reflux for 4 hours. The mixture is concentrated in vacuo. The residue is suspended in DCM (100 mL) and DMF (1 mL), cooled to O0C and treated with oxalyl chloride (8 mL, 43.4 mmol). The mixture is warmed to room temperature and stirred for 3 hours. The mixture is diluted with brine, extracted with DCM (2x100 mL), dried with Na2SO^ filtered, and concentrated in vacuo. The residue is dissolved in THF (25 mL), methylamine (2 M3 12.5 mL, 25 mmol) is added and the misture is stirred for 12 hours. The mixture is diluted with EtOAc (100 mL), washed with saturated aqueous NEJ4Cl (2x100 mL), dried with Na2SO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography eluting with 20%-80% EtOAc/heptane to afford C-(3-cyano-phenylVN-methyl-methanesulfonamide (1.5 g, 69%) as a powder. MS: 209 (M+H); 1H ΝMR (300 MHz, DMSO-d6): δ 2.60 (d, J= 4.8 Hz, 3H), 4.44 (s, 2H), 7.02 (m, IH), 7.61 (m, IH), 7.74 (m, IH), 7.85 (m, 2H).
Step 2: To a solution of C-(3-cyano-phenyl)-N-methyl-methanesulfonamide (42 mg, 0.2 mmol) in THF (4 mL) is added a solution of BH3 THF in THF (1 M, 1 mL). The mixture is sealed and heated in a microwave reactor at 1000C for 120 seconds. The mixture is poured into 1 M HCl (20 mL), basified with 3 M NaOH to pH ~ 10, extracted with DCM (2x50 mL), dried with Na2SO4, filtered, and concentrated in vacuo to afford C-f3-aminomethyl-phenyl)-N-methyl-methanesulfonamide. which is used directly in the next without further purification.
Step 3: Following procedures similar to those of Example 68 (step 3) but substituiting C-(3- aminomethyl-phenyl)-N-methyl-methanesulfonamide (2.3 mmol) for (3-aminomethyl-benzyl)- carbamic acid tert-butyl ester there is prepared 2-f 3 -fluoro-phenyl)-4-methyl-pyrimidine-5 -carboxylic acid 3-methylsulfamoylmethyl-benzylamide (30 mg) as a solid. MS: 429 (M+H); 1H ΝMR (300 MHz, DMSO-de): δ 2.58 (d, J= 4.8 Hz, 3H), 2.65 (s, 3H), 4.34 (s, 2H), 4.53 (d, J= 5.7 Hz, 2H), 6.92 (m, IH), 7.27-7.45 (m, 3H), 7.62 (m, 2H), 8.14 (m, IH), 8.28 (m, IH), 8.90 (s, IH), 9.23 (m, IH). Example 71 2-f3-Fluoro-phenyπ-4-methyl-pyrimidine-5-carboxylic acid 3-(isopropylsulfamoyl-methyl)- benzvlamide
Figure imgf000064_0001
Step 1: To a solution of 3-bromomethyl-benzonitrile (2 g, 10.2 mmol) in EtOH (50 mL) is added a solution OfNa2SO3 (1.3 g, 10.3 mmol) in H2O (50 mL) and the mixture is heated at reflux for 4 hours. The mixture is concentrated in vacuo. The residue is suspended in DCM (100 mL) and DMF (1 mL), cooled to O0C and treated with oxalyl chloride (4.5 mL, 24.4 mmol). The mixture is warmed to room temperature for 3 hours. The mixture is diluted with brine (100 mL), extracted with DCM (2x100 mL), dried with Na2SO4, filtered, and concentrated in vacuo. The residue is dissolved in THF (100 mL), and treated with isopropyl amine (3.5 mL, 40.8 mmol). The mixture is stirred for 12 h, diluted with EtOAc (200 mL), washed with saturated aqueous NH4Cl (2x100 mL), dried with Na2SO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography eluting with 20%-80% EtOAc/heptane to afford C-G-cyano-phenyD-N-isopropyl-methanesulfonamide as a powder. MS: 237 (M+H); 1HNMR (300 MHz, DMSO-d6): δ 1.10 (d, J= 6.6 Hz, 6H), 3.36 (m, IH), 4.42 (s, 2H), 7.09 (m, IH), 7.57 (m, IH), 7.74 (m, IH), 7.85 (m, 2H).
Step 2: To a solution of C-(3-cyano-phenyl)-N-isopropyl-methanesulfonamide (0.5 g, 2.06 mmol) in THF (10 mL) is added a solution OfBH3THF in THF (1 M, 10.3 mL). The mixture is sealed and heated in a microwave reactor at 1000C for 120 seconds. The mixture is poured into 1 M HCl (50 mL), basified with 3 M NaOH to pH ~ 10, extracted with DCM, dried with Na2SO4, filtered, and concentrated in vacuo to afford C-(3-aminomethyl-phenyl)-N-isopropyl-methanesulfonamide. which is used directly in the next step without further purification. Step 3: Following procedures similar to those of Example 68 (step 3) but substituting C-(3- ammomethyl-phenylVN-isopropyl-methanesulfonamide (2 mmol) for (3-aminomethyl-benzyl)- carbamic acid tert-butyl ester there is prepared 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3-[(propane-2-sulfonylamino)-methyl1-benzylamide (160 mg) as a solid. MS: 457 (M+H); 1H ΝMR (300 MHz, DMSOd6): δ 1.09 (d, J= 6.4, 6H), 2.65 (s, 3H), 3.37 (m, IH), 4.31 (s, 2H), 4.53 (d, J= 5.8, 2H), 6.99 (d, J= 7.1 Hz, IH), 7.27-7 '.45 (m, 3H), 7.62 (m, IH), 8.13 (m, IH), 8.28 (m, IH), 8.90 (s, IH), 9.24 (m, IH); IC50 = 34 nM. Example 72 2-(3-Fluoro-phenylV pyrimidine-5-carboxylic acid 3-(methanesulfonylamino-methylVbenzylamide
Figure imgf000065_0001
Step 1. To a solution of 2-(3-fluoro-phenyl')-pyrunidine-5-carboxylic acid (0.5 g, 2.25 mmol) in THF (25 mL) is added carbonyl diimidazole (0.5 g, 2.7 mmol) and heated at 6O0C for 2 hours. The mixture is cooled to room temperature and (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester (0.67 mL, 2.7 mmol) is added. The mixture is stirred for 12 h, diluted with EtOAc (100 mL), washed with brine (2x50 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography eluting with 20%-80% EtOAc/heptane to
Figure imgf000065_0002
pyrimidine-5-carbonyl]-amino>-methylVbenzyl]-carbamic acid tert-butyl ester (0.8 g, 80%) as a solid. MS: 437 (M+H); 1HNMR (300 MHz, DMSO-de): δ 1.35 (s, 9H), 4.13 (d, J= 6.1 Hz, 2H), 4.54 (d, J= 5.9 Hz, 2H), 7.27-7.48 (m, 4H), 7.62 (m, IH), 8.16 (m, IH), 8.31 (m, IH), 9.32 (s, 2H), 9.43 (m, IH). Step 2. To [3-({[2-(3-fluoro-phenyl)- pyrimidine-5-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester (0.28 g, 0.64 mmol) at O0C is added HCl in dioxane (6.5 mL, 4 N) and the mixture is stirred for 2.5 hours. The mixture is concentrated in vacuo. The residue is dissolved in DCM (3 mL) and Et3N (0.21 mL, 0.1.5 mmol) and methanesulfonyl chloride (0.105 mL, 0.1.3 mraol) are added. The mixture is stirred for 12 hours, diluted with EtOAc (100 mL), washed with saturated aqeous NH4C (2x50 mL)l, dried with Na2SO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography eluting with 20%-80% EtOAc/heptane to afford 2-(3-fluoro-phenyD- pyrimidine-5- carboxylic acid 3-(methanesulfonylamino-methylVbenzylamide (0.25 g, 94%) as a powder. MS: 459 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.85 (s, 3H), 4.17 (d, J= 6.2 Hz, 2H), 4.56 (d, J= 5.9 Hz, 2H), 7.27-7.62 (m, 5H), 8.17 (m, IH), 8.32 (m, IH), 9.32 (s, 2H), 9.45 (m, IH). Example 73 2-(3-fluoro-phenyl)- pyrimidine-5-carboxylic acid 3-[φropane-2-sulfonylammo)-methvH-benzylamide
Figure imgf000066_0001
Following procedures similar to those of Example 72 (step 2) but substituting isopropanesulfonyl chloride (1.3 mmol) for methanesulfonyl chloride there is prepared 2-(3 -fluoro-phenyl)-4-methyl- pyrimidine-S-carboxylic acid S-^propane^-sulfonylaminoVmethyli-benzylamide (7 mg) as a solid. MS: 443 (M+H); 1H NMR (SOO MHZ3 DMSO^6): δ 1.20 (d, J= 6.8 Hz, 6H), 3.05 (m, IH), 4.17 (d, J = 6.4 Hz3 2H)3 4.55 (d, J= 5.9 Hz, 2H)3 7.27-7.62 (m, 5H)3 8.17 (m, IH), 8.32 (m, IH), 9.32 (s, 2H), 9.45 (m, IH). Example 74 2-(3-Fluoro-phenvD- pyrimidine-5-carboxylic acid 3-methylsulfamoylmethyl-benzvlamide
Figure imgf000066_0002
Following procedures similar to those of Example 72 (step 1) but substituting C-(3-aminomethyl- phenyl)-N-methyl-methanesulfonamide (1.17 mmol) for (3-aminomethyl-benzyl)-carbamic acid tert- butyl ester there is prepared 2-(3-fluoro-phenylV pyrimidine-5-carboxylic acid 3- methylsulfamoylmethyl-benzylamide (105 mg) as a solid. MS: 415 (M+H); 1H ΝMR (300 MHz, DMSO-d6): δ 2.57 (d, J= 4.8 Hz, 3H), 4.32 (s, 2H), 4.57 (d, J= 5.9 Hz, 2H), 6.92 (m, IH), 7.28-7.67
(m, 5H), 8.17 (m, IH), 8.32 (m, IH), 9.32 (s, 2H), 9.46 (m, IH).
Example 75
2-(3 -Fluorophenyl)- pyrimidine-5-carboxylic acid 3-risopropylsulfamoyl-methyl)-benzylamide
Figure imgf000067_0001
Following procedures similar to those of Example 72 (step 1) but substituting C-(3-aminomethyl- phenyl)-N-isopropyl-methanesulfonamide (1.45 mmol) for (3-aminomethyl-benzyl)-carbamic acid tert- butyl ester there is prepared 2-(3-fluoro-phenyl)- pyrimidine-5-carboxylic acid 3-(isopropylsulfamoyl- methylVbenzylamide (140 mg) as a solid. MS: 443 (M+H); 1HNMR (300 MHz, DMSOd6): δ 1.07 (d, J= 6.4, 6H), 3.39 (m, IH), 4.29 (s, 2H), 4.56 (d, J= 5.9, 2H), 6.99 (d, J= 7.1 Hz, IH), 7.28-7.45 (m, 3H), 7.62 (m, IH), 8.17 (m, IH), 8.32 (m, IH), 9.32 (s, 2H), 9.45 (m, IH). Example 76
2-f3-Fluoro-phenyl)-pyrimidme-5-carboxylic acid (2-methanesulfonylamino-pyridin-4-ylmethyl)- amide
Figure imgf000067_0002
Step 1: A solution of 2-amino-isonicotinonitrile (1 g, 8.4 mmol) and methanesulfonyl chloride (0.716 mL, 9.2 mmol) in pyridine (10 mL) is stirred at room temperature for 12 hours. The mixture is poured onto ice and stirred for 20 min. The mixture is filtered and washed with water (100 mL), followed by diethyl ether (100 mL). The solid is dried in vacuo to afford N-(4-cyanopyridin-2-yl)- methanesulfonamide (1.1 g, 66%). MS: 198 (M+H); 1HNMR (300 MHz, DMSO-d6): δ 3.32 (s, 3H), 7.27 (s, IH), 7.48 (d, J= 5.1 Hz, IH), 8.53 (d, J= 5.3 Hz, IH).
Step 2: N-(4-Cyano-pyridin-2-yl)-methanesulfonamide (0.15 g, 0.76 mmol) is dissolved in MeOH (4 mL) and concentrated HCl (2 mL) and is treated with Pd/C (10%, 150 mg). The mixture is stirred under H2 for 12 hours, filtered and concentrated in vacuo to afford N-(4-ammomethyl-pyridin-2-yl)- methanesulfonamide (0.15 g, 97%), which is used directly in the next step without further purification. Step 3: Following procedures similar to those of Example 72 (step 1) but substituting N-(4- aminomethyl-pyridin-2-yl)-methanesulfonamide (0.75 mmol) for (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester there is prepared 2-(3-fluoro-phenylVpyrimidine-5-carboxylic acid (2- methanesulfonylamino-pyridm-4-ylmethylVamide (320 mg) as a solid. MS: 402 (M+H); 1HNMR (300 MHz, DMSO-de): δ 3.24 (s, 3H), 4.53 (d, J= 5.7 Hz5 2H), 6.97 (s, br, 2H), 7.43 (m, IH), 7.63 (m, IH), 8.18 (m, 2H), 8.33 (m, IH), 9.33 (s, 2H)5 9.52 (m, IH). Example 77 2-(5-Methyl-fl.2.4]oxadiazole-3-yl)-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-yl)-amide ,
Figure imgf000068_0001
Step 1. To a solution of 2-methylsulfanyl-pyrimidine-5-carboxylic acid methyl ester 1 (1 g, 5.43 mmol) in DCM (60 mL) is added MCPBA (2.81 g, 16.29 mmol) portion wise at room temperature. The resulting solution is stirred at room temperature overnight. A solution OfNa2S2O3 (1.6 g) in water (60 mL) is added. The mixture is stirred at room temperature for 20 min. The layer is separated, and the water layer is extracted with DCM (2x20 mL). The combined DCM layer is washed with saturated NaHCO3 (3x20 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford 2-methanesulfonyl- pyrimidine-5-carboxylic acid methyl ester as a solid (1.05 g, 90%). MS: 217 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.41 (s, 3H), 4.06 (s, 3H), 9.44 (s, 2H).
Step 2. To a solution of 2-methanesulfonyl-pyrimidine-5-carboxylic acid methyl ester 2 (2.5 g, 11.56 mmol) in DCM (30 mL) is added a solution of tetrabutylammonium cyanide (3.1 g, 11.56 mmol) in water (30 mL) slowly at room temperature. The mixture is stirred for 80 min. The mixture is washed with water (2x20mL), dried (Na2SO4), filetered and concentrated in vacuo. The residue is purified by column chromatography eluting with 5-60% EtOAc in heptane to afford 2-cyano-pyrimidine-5- carboxylic acid methyl ester (1.16 g, 61%) as a solid. MS: 164 (M+H); 1HNMR (300 MHz, CDCl3): δ 4.05 (s, 3H), 9.37 (s, 2H). Step 3. To a solution of 2-cyano-pyrimidine-5-carboxylic acid methyl ester 3 (1 g, 6.13 mmol) in MeOH (20 mL) at room temperature is added hydroxylamine hydrochloride (0.64g, 9.2mmol) and sodium acetate (0.76 g, 9.2 mmol). The resulting mixture is heated to reflux for 2 hours. The mixture is cooled to room temperature and concentrated in vacuo. Water (30 mL) is added to the residue, and the solid is filtered, and washed with water twice. The solid is dried in vacuum oven overnight to afford 2-(N-hydroxycarbamimidoyl)-pyrimidine-5-carboxylic acid methyl ester (1.09 g, 91%) as a solid. MS: 197 (M+H). Step 4. To a solution of 2-(N-hydroxycarbamimidoyl)-pyrimidine-5-carboxylic acid methyl ester (900 mg, 4.59 mmol) in pyridine (15 mL) is added acetyl chloride (432 mg, 5.5 mmol) dropwise. The resulting solution is stirred at room temperature for 1 hour, and heated to reflux for 3h. The solution is cooled to room temperature and concentrated in vacuo. Water (30 mL) is added to the residue, and the mixture is extracted with EtOAc (3x20 mL). The combined organic layer is washed with saturated
NaHCO3, dried (Na2SO4), filetered and concentrated in vacuo to afford 2-(5-methyl-[1.2.3"loxadiazo-3- yl)-pyrimidine-5-carboxylic acid methyl ester (900 mg, 89%) as a solid. MS: 221 (M+H). Step 5. To a solution of 2-(5-methyl-[l,2,3]oxadiazo-3-yl)-pyrimidine-5-carboxylic acid methyl ester (900 mg) in MeOH (20 mL) is added a solution of LiOH (100 mg) in water (20 mL) at O0C. The ice- bath is removed, and the mixture is stirred for another 10 min. The solvent is evaporated, and water (20 mL) is added. The water solution is washed with ether (2x20mL), and acidified with 2 N HCl to pH ~ 3. The resulting precipitate is filtered, washed with water and dried in vacuum oven overnight to afford 2-(5-methyl-ri,2,41oxadiazol-3-ylVpyrimidine-5-carboxylic acid (350 mg, 37%) as a solid. MS: 207 (M+H); 1HNMR (300 MHz, DMSO-dβ): δ 2.73 (s, 3H), 9.39 (s, 2H). Step 6. To a solution of 2-(5-methyl-[l,2,4]oxadiazol-3-yl)-pyrimidine-5-carboxylic acid (50 mg, 0.24 mmol) in DCM (10 mL) is added l-[3-(dimethylamino)propyl-3-ethylcarbodiimide (50 mg, 0.26 mmol) and N-hydroxybenzotriazole (35 mg, 0.26 mmol) at room temperature. The mixture is stirred for 10 min, and tetrahydro-pyran-4-ylamine (27 mg, 0.26 mmol) is added. The mixture is stirred overnight, washed with 2N HCl (lx5mL), saturated NaHCO3, (1x5 mL), water (Ix 5mL), dried (Na2SO4), filetered and concentrated in vacuo. The residue is purified by column chromatography eluting with 5% MeOH in DCM to affrod 2-r5-methyl-n.2.41oxadiazole-3-ylVpyrimidine-5- carboxylic acid (tetrahvdro-pyran-4-ylVamide (33 mg) as a solid. MS: 290 (M+H); 1HNMR (300 MHz, CDCl3): δ 1.70 (m, 2H), 2.04 (m, 2H), 2.76 (s, 3H), 3.59 (m, 2H), 4.06 (m, 2H), 4.28 (m, IH), 9.26 (s, 2H); IC50 = 513.5 nM. Example 78
2-(5-Methyl-[1.2.4]oxadiazole-3-yl)-pyrimidine-5-carboxylic acid 4 -sulfamoyl-benzeneamide.
Figure imgf000069_0001
Following procedures similar to those of Example 77 (step 6) but substituting 4-aminomethyl- benzenesulfonamide for tetrahydro-pyran-4-ylamine there is prepared 2-(5-methyl-|~1.2.4]oxadiazole- 3-yl)-pyrimidine-5-carboxylic acid 4 -sulfamoyl-benzeneamide as a solid. MS: 375 (M+H); 1HNMR (300 MHz, DMSO-d6): δ 2.72 (s, 3H), 4.61 (d, 2H), 7.33 (s, 2H), 7.56 (d, 2H), 7.80 (d, 2H)3 9.39 (s, 2H).
Example 79
2-r5-Methyl-[1.2.4]oxadiazol-3-yl)-pyrimidine-5-carboxylic acid r3-phenyl-[l,2,4]thiadiazol-5-yl)- amide
Figure imgf000070_0001
Following procedures similar to those of Example 77 (step 6) but substituting 3-phenyl- [l,2,4]thiadiazol-5-ylamine for tetrahydro-pyran-4-ylamine there is prepared 2-(5-methyl- ri.2.41oxadiazol-3-yl)-pyrimidine-5-carboxylic acid (3-phenyl-[1.2,4]thiadiazol-5-yl)-amide as a solid. MS: 366 (M+H); 1HNMR (300 MHz, DMSO-d6): δ 2.74 (s, 3H), 7.56 (m, 3H), 8.24 (m, 2H), 9.63 (s, 2H).
Example 80 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-fmorpholine-4-sulfonyl)-benzylamide
Figure imgf000070_0002
Following procedures similar to those of Example 5 but substituting 3-(morpholinesulfonyl)- benzylamine for aniline, there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3- (morpholine-4-sulfonylVbenzylamide as a solid. MS: 457 (M+H); 1HNMR (300 MHz, CDCl3): δ 2.88-3.10 (m, 4H), 3.65-3.85 (m, 4H), 4.78 (d, 2H), 6.88-7.05(bs, N-H), 7.18-7.35 (m, H), 7.40-7.60 (m, 2H), 7.60-7.80 (m, 3H), 8.10-8.35 (q, 4H), 9.21 (s, 2H). Example 81
2-Pheny-pyrimidine-5-carboxylic acid 3.4-dimethoxyl-benzylamide
Figure imgf000070_0003
Following procedures similar to those of Example 8 but substituting 3,4-dimethoxyl-benzylamine (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2z pheny-pyrimidine-5-carboxylic acid 3.4-dimethoxyl-benzylamide as a solid. MS: 350 (M+H). Example 82
2-Pheny-pyrimidine-5-carboxylic acid (2-benzof 1 ,3]dioxol-5-yl-ethyl)-amide
Figure imgf000071_0001
Following procedures similar to those of Example 8 but substituting 2-benzo[l,3]dioxol-5-yl- ethylamine hydrochloride (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5- ylamine, there is prepared 2-pheny-pyrimidine-5-carboxylic acid (2-benzo[1.3]dioxol-5-yl-ethylV amide as a solid. MS: 348 (M+H); 1HlSlMR (300 MHz, CDCl3): δ 2.91 (t, 2H), 3.74(m, 2H), 5.98 (s, 2H), 6.20 (bs, N-H), 6.65-6.83 (m, 3H), 7.54 (m, 3H), 8.49 (m, 2H), 9.08 (s, 2H); IC50 = 2 nM. Example 83 2-Pheny-pyrimidine-5-carboxylic acid flH-indazol-5-vD-amide
Figure imgf000071_0002
Following procedures similar to those of Example 8 but substituting lH-indazol-5-amine (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-pheny- pyrimidine-5-carboxylic acid αH-indazol-5-ylVamide as a solid. MS: 316 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.99 (d, H), 7.06 (q, H), 7.52-7.63 (m, 4H), 8.10 (s, H), 8.38 (d, H), 8.57 (m, 3H), 9.53 (s, H); IC50 = 23 nM. Example 84
2-Phenyl-pyrimidine-5-carboxylic acid 4-[ 1 ,2,31thiadiazol-5-yl)-benzylamide
Figure imgf000071_0003
Following procedures similar to those of Example 8 but substituting 4-[l,2,3]thiadiazol-5-yl- benzylamine (0.3 mmol) for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl-pyrimidine-5 -carboxylic acid 4-[ 1.2.31thiadiazol-5 -yl Vbenzylamide as a solid. MS: 374 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 4.25 (d, 2H), 7.52-7.60 (m, 5H), 8.12 (d, 2H), 8.45 (m, 2H), 9.31 (s, 2H), 9.46 (bs, N-H), 9.59 (s, H); IC50 = 6.5 nM. Example 85
2-r3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzvlamide
Figure imgf000072_0001
Following procedures similar to those of Example 5, but substituting 2-(3-fluoro-phenyl)-4-methyl- pyrimidine-5-carboxylic acid for 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, and substituting 3- aminomethyl-N-methyl-benenesulfonamide hydrochloride for aniline, there is prepared 2-f3-fluoro- phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide as a solid. MS: 415 (M+H); 1HNMR (300 MHz, CDCl3): δ 2.73 (s, 3H), 4.72 (d, 2H), 6.70 (bs, N-H), 7.15-7.26 (m, H), 7.41-7.65 (m, 3H), 7.77 (d, H), 7.85 (s, N-H), 8.15 (d, H), 8.24 (d, H), 9.76 (s, H). IC50 = 106 nM. Example 86 4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide
Figure imgf000072_0002
Following procedures similar to those of Example 5 but substituing 4-methyl-2-pyridin-2-yl- pyrimidine-5-carboxylic acid for 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, and substituting 3- aminomethyl-N-methyl-benenesulfonamide for aniline, there is prepared 4-methyl-2-pyridin-2-yl- pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide as a solid. MS: 398 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.54 (s, 3H), 2.59 (s, 3H), 4.62 (d, 2H), 7.23-7.42 (m, 3H), 7.48-7.60 (m, H), 7.61-7.68 (d, H), 7.78-7.93 (m, 2H), 8.37-8.44 (d, H), 8.51-8.62 (m, H), 8.67 (s, H). Example 87 2-Pheny-pyrimidine-5-carboxylic acid 4-morpholin-4-ylbenzylamide
Figure imgf000072_0003
Following procedures similar to those of Example 8 but substituting 4-morpholin-4-yl-benzylamine for for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-pheny- pyrimidine-5-carboxylic acid 4-morpholin-4-ylbenzylamide as a solid. MS: 375 (M+H); 1HNMR (300 MHz, CDCl3): δ 3.18 (t, 4H), 3.88 (t, 4H), 4.62 (d, 2H)5 6.48 (bs, N-H), 6.92 (m, 2H), 7.29 (m,
2H), 7.47-7.58 (m, 3H), 8.50 (m, 2H), 9.16 (s, 2H); IC50 = 12 nM.
Example 88 ά-fr∑-Phenyl-pyrimidin-S-carbonylVaminoj-lH-benzoimidazole-Σ-carboxylic acid methyl ester.
Figure imgf000073_0001
Following procedures similar to those of Example 8 but substituting 6-amino-lH-benzoimidazole-2- carboxylic acid methyl ester for 2,2-dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 6-rr2-phenyl-pyrimidin-5-carbonyl)-aminol-lH-benzoimidazole-2-carboxylic acid methyl ester as a solid. MS: 374 (M+H); 1HNMR (300 MHz, DMSOd6): δ 3.95 (s, 3H), 7.52-7.63 (m, 5H), 7.70-7.82 (m, H), 8.29 (s, H), 9.38 (s, 2H), 10.68 (d, H). Example 89 6-[(2-Phenyl-pyrimidin-5-carbonyl)-amino]-lH-benzoimidazole-2-carboxylic acid
Figure imgf000073_0002
A solution of 6-[(2-phenyl-pyrimidin-5-carbonyl)-amino]-lH-benzoimidazole-2-carboxylic acid methyl ester (0.44 mmol) and LiOH (4.40 mmol) in MeOH/water/tetrahydrofuran (1:1:1, 60 mL) is stirred at room temperature overnight. MeOH and THF are evaporated in vacuo and the aqueous mixture is acidified with 5% HCl to pH ~ 2. The resulting precipitate is filtered, washed with water (10 mL) and dried to give 6-[(2-phenyl-pyrimidin-5-carbonylVamino]-lH-benzoimidazole-2- carboxylic acid as a solid (115 mg). MS: 360 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 7.52-7.70 (m, 5H), 8.30 (s, H), 8.48 (m, 3H), 9.28 (S, H), 9.38 (s, 2H), 10.73 (s, N-H). Example 90
2-Pheny-pyrimidine-5-carboxylic acid (benzofuran-5-ylmethylVamide
Figure imgf000073_0003
Following procedures similar to those of Example 5 but substituting 2-phenyl-pyrimidine-5-carboxylic acid for 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, and substituting C-benzofuran-5- ylmethylamine for aniline, there is prepared 2-phenv-pyrimidine-5-carboxylic acid (benzofuran-5- VlmethylVamide as a solid. MS: 330 (M+H); 1H NMR (300 MHz, CDCl3): δ 4.79 (d, 2H), 6.58 (bs, N- H), 6.78 (m, H), 7.32 (q, H), 7.49-7.56 (m, 4H), 7.64 (s, H), 7.66 (d, 2H), 8.48 (m, 2H), 9.18 (s, 2H); IC50 = 7 nM. Example 91
2-Pheny-pyrimidine-5-carboxylic acid 4-rnethanesulfonylamino-benzylamide
Figure imgf000074_0001
Following procedures similar to those of Example 5 but substituting 2-phenyl-pyrimidine-5-carboxylic acid for 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, and substituting N-(4-aminomethyl~ phenyl)-methanesulfonamide for aniline, there is prepared 2-pheny-pyrimidine-5-carboxylic acid 4- methanesulfonylamino-benzylamide as a solid. MS: 383 (M+H); 1H NMR (300 MHz, DMSOd6): δ 2.96 (s, 3H), 4.89 (d, 2H), 7.18 (d, 2H), 7.33 (d, 2H)5 7.51-7.63 (m, 3H), 78.43 (m, 2H), 8.27 (s, 2H), 9.36 (bs, N-H).
Example 92
2-Pheny-pyrimidine-5-carboxylic acid 4-carbamoyl-benzylamide
Figure imgf000074_0002
Following procedures similar to those of Example 5 but substituting 2-phenyl-pyrimidine-5-carboxylic acid for 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, and substituting 4-aminomethyl-benzamide for aniline there is prepared 2-pheny-pyrimidine-5-carboxylic acid 4-carbamoyl-benzylamide as a solid. MS: 333 (M+H); 1H NMR (300 MHz, DMSOd6): δ 4.59 (d, 2H), 7.32 (s, N-H), 7.43 (d, 2H), 7.50-7.63 (m, 4H), 7.85 (d, 2H), 7.94 (s, H), 8.47 (m, 2H), 9.37 (s 2H), 9.43 (t, N-H); IC50 = 16 nM. Example 93 2-Phenv-pyrimidine-5-carboxylic acid 3-(2-hvdroxy-ethylsulfamoylVbenzylamide
Figure imgf000074_0003
Following procedures similar to those of Example 5 but substituting 2-phenyl-pyrimidine-5-carboxylic acid for 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, and substituting 3-aminomethyl-N-(2- hydroxy-ethyl)-benzenesulfonamide hydrochloride for aniline, there is prepared 2-pheny-pyrimidine- 5-carboxylic acid 3-(2-hydroxy-ethylsulfamoyl)-benzylamide as a solid. MS: 413 (M+H); IHNMR (300 MHz, CD3OD): δ 2.96 (t, 2H), 3.53 (t, 2H), 4.78 (d, 2H), 7.42-7.91 (m, 9H), 8.46 (m, 2H), 9.22 (s, 2H), 9.40 (bs, N-H). Example 94
2-Pheny-pyrimidine-5-carboxylic acid 4-(morpholin-4-sulfonyl')-benzylamide
Figure imgf000075_0001
Following procedures similar to those of Example 5 but substituing 2-phenyl-pyrimidine-5-carboxylic acid (0.35 mmol) for 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, and substituting 4-(morpholin- 4-sulfonyl)-benzylamine hydrochloride for aniline, there is prepared 2-pheny-pyrimidine-5 -carboxylic acid 4-fmorpholin-4-sulfonylVbenzylamide as a solid. MS: 439 (M+H); 1HNMR (300 MHz, CD3OD): δ 2.96 (t, 4H), 3.70 (t, 4H), 4.73 (s, 2H), 7.53 (m, 3H), 7.65 (d, 2H), 7.77 (d, 2H), 8.49 (d, 2H), 9.26 (s, 2H). Example 95
2-Pheny-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide
Figure imgf000075_0002
Following procedures similar to those of Example 5 but substituting 2-phenyl-pyrimidine-5 -carboxylic acid for 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, and substituting 3-aminomethyl-N-methyl- benenesulfonamide hydrochloride for aniline, there is prepared 2-pheny-pyrimidine-5-carboxylic acid
3-methylsulfamoyl-benzylamide as a solid. MS: 383 (M+H); 1HNMR (300 MHz, CD3OD): δ 2.53 (s,
3H), 4.71 (s, 2H), 7.26 (m, H), 7.46-7.80(m, 7H), 7.87 (s, H), 8.49 (m, 2H), 9.24 (s, 2H).
Example 96
2-Pheny-pyrimidine-5-carboxylic acid r2-(2-amino-4-methyl-thiazol-5-yl)-ethyll-amide
Figure imgf000076_0001
Following procedures similar to those of Example 5 but substituting 2-phenyl-pyrimidine-5-carboxylic acid (0.12 mmol) for 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, and substituting 5-(2-amino- ethyl-thiazol-2-ylamine dihydrobromide for aniline, there is prepared 2-pheny-pyrimidine-5-carboxylic acid r2-r2-amino-4-methyl-thiazol-5-ylVethyll-amide as a solid. MS: 340 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.11 (s, 3H), 2.92 (t, 2H), 3.61 (q, 2H), 6.70 (bs, N-H), 7.40-7.58 (m, 3H), 8.37-8.54 (m, 2H), 9.12 (s, 2H). Example 97
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide
Figure imgf000076_0002
Step 1: A flask containing DCM (90 niL) and methylamine in water (40 wt%, 7.5 mmol) is chilled in an ice water bath with magnetic stirring: 3-Cyano-benzenesulfonyl chloride (5 g, 2.49 mmol) is added along with DCM (1OmL) to wash down the sides of the flask. After 30 min, concentrated HCl in water is added at O0C, until the reaction is acidic (pH < 4). Water (50 mL) is added and DCM is removed in vacuo. The residue is filtered to afford 3-cyano-N-methyl-benzenesulfonamide as a solid (99%). MS: 195 (M+H); 1HNMR (300 MHz, CDCl3): δ 2.76 (d, 3H), 4.48 (broad-s, N-H), 7.7 (t, IH), 7.9 (d, IH), 8.13 (d, IH), 8.19 (s, IH).
Step 2: To a solution of 3-cyano-N-methyl-benzenesulfonamide (4.88 g, 2.49 mmol) in MeOH (160 mL) is added concentrated HCl in water (16 mL) followed by the addition of Palladium on Carbon (10wt%, 50wt% water, 1.6 g). With magnetic stirring, the reaction is alternately placed under vacuum and 1 atmosphere of hydrogen (balloon) for three cycles. The reaction is then left under 1 atmosphere of hydrogen with stirring for 2 days. The reaction is filtered through celite and fresh Palladium on Carbon (10wt%, 50wt% water, 1.6 g) is added. The reaction is stirred for 24 hours under 1 atmosphere of hydrogen. The reaction is filtered through celite and the filtrate is concentrated in vacuo to provide 3-aminomethyl-N-methyl-benzenesulfonamide hydrochloride, as a solid (99%). MS: 201 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.41 (d, 3H), 4.12 (d, 2H), 7.23-7.57 (m, 2H), 7.70 (d, IH), 7.81 (d, IH), 8.49 (broad-s, 3H). r
-76-
Step 3: To a mixture of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (545 mg, 2.5 mmol) and DCM (35 mL) is added oxalyl chloride (635 mg, 5 mmol) followed by the addition of DMF (20 μL). The reaction is stirred at room temperature for 3 hours. Anhydrous toluene (10 mL) is added and the reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc (30 mL). The resulting solution is added to a mixture of 3-aminomethyl-N-methyl-benzenesulfonamide hydrochloride (590 mg, 2.5 mmol), sodium carbonate (530 mg, 5 mmol) and water (10 mL) at O0C. The resulting reaction mixture is warmed to room temperature and stirred overnight. Approximately 80% of EtOAc is removed in vacuo, and heptane is added to precipitate the product. The precipitate is collected by fϊlteration, and recrystallized twice in EtOAc to afford 2-f3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide (400 mg). The mother liquors are concentrated and the residue is purified by flash chromatography to afford additional 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide (130 mg) as a powder. MS: 401 (M + H); 1HNMR (300 MHz, DMSO-de): δ 2.41 (d, 3H)3 4.64 (d, 2H), 7.42-7.50 (m, 2H), 7.57-7.70 (m, 4H), 7.78 (s, IH), 8.16 (d, IH), 8.31 (d, IH), 9.33 (s, 2H), 9.53 (t, IH). IC50 = 9.5 nM. Example 98
{4-{[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-benzyl}-phosphonic acid diethyl ester
Figure imgf000077_0001
Following procedures similar to those of Example 5 but substituting 2-phenyl-pyrimidine-5-carboxylic acid for 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, and substituting (4-amino-benzyl)- phosphonic acid diethyl ester for aniline, there is prepared f4-{[(2-phenyl-pyrimidine-5-carbonyl)- amino]-methyl}-benzyl)-phosphonic acid diethyl ester as a solid. MS: 426 (M+H); 1H NMR (300 MHz, CDCl3): δ 1.13 (t, 3H), 1.32(t, 3H), 3.79 (q, H), 3.99 (q, H), 4.20 (m, 2H), 5.91(q, 4.62 (d, H), 7.27 (d, 3H), 7.48 (s, 3H), 7.67 (d, 2H), 8.42 (d, 2H), 9.28 (s, H), 9.53 (s, H); IC50 = 38 nM. Example 99 {4-r(2-Phenvl-pvrimidine-5-carbonvl)-ammo1-butyl)-phosphonic acid diethyl ester
Figure imgf000077_0002
Following procedures similar to those of Example 5 but substituting 2-phenyl-pyrimidine-5-carboxylic acid for 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, and substituting (4-aminobutyl)-phosphonic acid diethyl ester oxalate for aniline, there is prepared {4-[(2-phenyl-pyrimidine-5-carbonyl>amino~|- butylVphosphonic acid diethyl ester as a solid. MS: 392 (M+H); 1H NMR (300 MHz, CDCl3): δ 1.31
(t, 6H)5 1.77 (m, 6H)5 3.48 (q, 2H), 3.97-4.19 (m, 4H)5 7.40-7.58 (m, 3H)5 7.84 (bs, N-H), 8.40-8.57
(m, 2H)5 9.23 (s5 2H); IC50 = 23.5 nM.
Example 100
(4-[(2-Phenyl-pyrimidine-5-carbonylVamino]-ethyl)-phosphonic acid diethyl ester
Figure imgf000078_0001
Following procedures similar to those of Example 5 but substituting 2-phenyl-pyrimidine-5-carboxylic acid for 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, and substituting (4-aminoethyl)-phosphonic acid diethyl ester oxalate for aniline, there is prepared {4-[(2-phenyl-pyrimidme-5-carbonyl)-amino]- ethylVphosphonic acid diethyl ester as a solid. MS: 364 (M+H); 1HNMR (SOO MHz, CDCl3): δ 1.38 (t, 6H)52.16 (m, 2H)5 3.78 (m, 2H), 4.03-4.22 (m, 4H)5 7.50 (m, 3H)5 8.09 (bs, N-H)5 8.48 (m, 2H)5 9.24 (s5 2H). Example 101 |Phenyl-r(2-phenyl-pyrimidine-5-carbonylVaminol-methylVphosphonic acid diethyl ester
Figure imgf000078_0002
Following procedures similar to those of Example 5 but substituting 2-phenyl-pyrimidine-5-carboxylic acid for 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid, and substituting (amino-phenyl-methyl)- phosphonic acid diethyl ester hydrochloride for aniline, there is prepared {phenyl-[(2-phenyl- pyrimidine-5-carbonyl)-amino]-methyl)-phosphonic acid diethyl ester as a solid. MS: 426 (M+H); 1H NMR (300 MHz5 CDCl3): δ 1.13 (t, 3H), 1.32 (t, 3H), 3.70-3.90 (m, H), 3.90-4.08 (m, H)5 4.09-4.31 (m, 2H), 5.88 (q, H), 7.27 (m, 3H), 7.47 (m, 3H), 7.65 (d, H)5 8.43 (m, 2H), 9.27 (s5 2H), 9.35(d, N-H); IC50 = 48 nM. Example 102 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methanesulfonyl)-benzylamide - -
Figure imgf000079_0001
Following procedures similar to those of Example 5 but substituting 3-methanesulfonyl-benzylamine for aniline, there is prepared 2-(3 -fluoro-phenyll-pyrimidine-S-carboxylic acid 3 -methanesulfonylV benzylamide as a solid. MS: 386 (M+H); 1HNMR (300 MHz, CD3OD): δ 3.12(s, 3H), 4.93 (d, 2H)5
7.24-7.37 (m, H), 7.48-7.70 (m, 2H), 7.77 (d, H), 7.88 (d, H), 7.98 (s, H), 8.20 (d, H), 8.34 (d, H), 9.25
(S, 2H).
Example 103
2-(3-Fluoro-phenyl>pyrimidine-5-carboxylic acid (l-methanesulfonyl-piperidin-3-γlmethyl)amide
Figure imgf000079_0002
Step 1: To a solution of potassium carbonate (13.94 mmol) and 3-aminomethyl-piperidine-l- carboxylic acid tert-butyl ester (4.65 mmol) in ethyl acetate (30 mL) and water (20 mL) is added a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylicacid chloride (4.65 mmol) in ethyl acetate (20 mL). The mixture is stirred at room temperature overnight. The reaction mixture is extracted with ethyl acetate, washed with water, dried (Na2SC^) and concentrated in vacuo to give 3-({[2-(3-fluoro- pheny)-pyrimidine-5-carbonyl]-amino}-methyl)-piperidine-l-carboxylic acid tert-butyl ester as a solid. MS 415 (M+H); 1HNMR(SOO MHz, CDCl3): δ 1.47 (s, 9H), 1.55-2.22 (m, 5H), 2.90-4.90 (m, 6H), 7.15-7.25 (m, H), 7.41-7.53 (m, H), 7.56 (bs, NH), 8.18 (d, H), 8.29 (d, H), 9.21 (s, 2H). Step 2: Hydrogen chloride gas is bubbled into a solution of 3-({[2-(3-fluoro-pheny)-pyrimidine-5- carbonyl]-ammo}-methyl)-piperidine-l-carboxylic acid tert-butyl ester (3.76 mmol) in DCM (20 mL) and the reaction is stirred at room temperature for 2 hours. The mixture is concentrated in vacuo to afford 2-(3-fluoro-pheny)-pyrimidine-5-carboxylic acid fpiperidin-3-ylmethviy amide hydrochloride as a solid. MS 415 (M+H); 1H NMR (SOO MHZ, CD3OD): δ 1.22-1.50 (m, 2H), 1.68-1.90 (m, H), 1.90- 2.06 (bs, 2H), 2.06-2.17 (bs, 6H), 2.73-3.04 (m, 2H), 3.24-3.50 (m, H), 7.24-7.35 (m, H), 7.48-7.60 (m, H), 8.19 (d, H), 8.34 (d, H), 9.23 (s, 2H). Step 3: Methanesulfonyl chloride (0.523 mmol) is added to a stirred solution of 2-(3-fluoro-phenyl)- pyrimidine-5-carboxylic acid (piperidin-3-ylmethyl)-amide hydrochloride (0.523 mmol) and triethylamine (2.62 mmol) in DCM (20 mL) at O0C. The mixture is stirred at O0C for an hour, and then stirred at room temperature overnight. The reaction mixture is washed with water (20 mL). The organic layer is separated, dried (MgSO^, filtered and concentrated invacuo. The residue ispurified by silica gel column chromatography eluting with EtOAc to afford 2-(3-fluoro-phenyl)-pyτimidme-S- carboxylic acid fl-methanesulfonyl-piperidin-3-ylmethyiy amide as a solid. MS: 393 (M+H); 1H NMR (300 MHz, CD3OD): δ 1.43-1.95 (m, 4H), 2.10-2.23 bs, H), 3.04-3.50 (m, 5H), 3.60-3.78(m, H), 6.71-6.90 (bs, N-H), 7.18-7.23 (m, H), 7.42-7.57 (m, H), 8.18-8.37(q, 2H), 9.20 (s, 2H). Example 104
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (l-dimethanesulfamoyl-piperidin-3-ylmethyl)- amide
Figure imgf000080_0001
Dimethanesulfamoyl chloride (0.632 mmol) is added to a stirred solution of 2-(3-fluoro-phenyl)- pyrimidine-5-carboxylic acid (piperidin-3-ylmethyl)-amide trihydrochloride (0.632 mmol) and triethylamine (3.16 mmol) in DCM (20 mL) at O0C. The mixture is stirred at O0C for an hour, and then stirred at room temperature overnight. The reaction mixture is diluted with DCM (10 mL) and washed with water (30 mL). The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with EtOAc to afford 2-(3-fluoro-phenylVpyrimidine-5-carboxylic acid (1- dimethanesulfamoyl-piperidin-3-ylmethyl)-amide (245 mg) as a solid. MS: 422 (M+H); 1H NMR (300 MHz, CDCl3): δ 1.37-1.69 (m, 2H), 1.74-1.92 (m, 2H), 2.03-2.17 (bs, H), 2.81 (s, 6H), 3.09-3.20 (m, H), 3.21-3.50(m, 4H), 3.60-3.75 (m, H), 6.83-6.98 (bs, N-H), 7.16-7.28 (m, H), 7.42-7.55 (m, H), 8.16- 8.33(q, 2H), 9.20 (s, 2H). Example 105
2-(Phenyl)-pyrimidine-5-carboxylic acid 3-methanesulfonylamino-benzylamide
Figure imgf000080_0002
Methanesulfonyl chloride (0.553 mmol) is added to a stirred solution of 2-phenyl-pyrimidine-5- carboxylic acid 3-amino-benzylamide (Example 115, 0.526 mmol) and triethylamine (1.05 mmol) in DCM (20 mL) at O0C. The mixture is stirred at room temperature for an hour. The reaction mixture is quenched with 5% HCl and extracted with DCM (20 mL). The organic layer is separated, washed with water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with 0-5% MeOH in DCM to afford 2-(phenyD- pyrimidine-5-carboxylic acid 3-methanesulfonylamino-benzylamide (200 mg) as a solid. MS: 383 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.41 (s, 3H), 4.76-4.72 (m, 2H)3 7.00 (bs, N-H), 7.05-7.23 (m, 2H), 7.27-7.60 (m, 5H), 8.40-8.53(m, 2H), 9.16 (s, 2H). Example 106
2-r3-Fluoro-phenylVpyrimidine-5-carboxylic acid 3-acetylsulfamoyl-benzylamide
Figure imgf000081_0001
To a solution of potassium carbonate (1.22 mmol) and N-acetyl-3-aminomethyl-benzenesulfonamide (1.22 mmol) in EtOAc (10 mL) and water (10 mL) is added a solution of 2-(3-fluoro-phenyl)~ pyrimidine-5-carboxylic acid chloride (1.22 mmol) in acetate (10 mL) at O0C, and the mixture is stirred at room temperature overnight. The mixture is acidified with 5% HCl to pH 2-3 and extracted with EtOAc. The organic layer is separated, washed with water and brine, dried (MgSO^, filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with EtOAc to afford 2-f3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-acetylsulfamoyl-benzylamide as a solid. MS: 429 (M+H); 1HNMR (SOO MHz, CD3OD): δ 3.95-4.00 (d, 3H), 4.85 (s, 3H), 7.22-7.34 (m, H), 7.41-7.62(m, H), 7.66-7.83 (d, 2H), 7.88-7.95 (d, H), 8.04 (s, H), 8.12-8.23(m, H), 8.26-8.37 (d, H), 9.26-9.34 (m, 2H). Example 107 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-f3-oxo-piperiazine-l-sulfonyl)-benzylamide
Figure imgf000081_0002
Following procedures similar to those of Example 106, but substituting 4-(3-aminomethyl- benzenesulfonyl)-piperazin-2-one for N-acetyl-3-aminomethyl-benzenesulfonamide, there is prepared 2-(3-fluoro-phenylVpyrimidine-5-carboxylic acid 3-(3-oxo-piperiazme-l-sulfonylVbenzylamide as a solid. MS: 470 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 3.16 (s, 4H), 3.57 (s, 2H), 4.63 (d, 2H), 7.34-7.47 (m, H), 7.56-7.77 (m, 4H), 7.80 (s, N-H), 8.01-8.18 (m, 2H), 8.28 (d, H), 9.29 (S, 2H), 9.45 (t, N-H). Example 108
2-Phenv-pyrimidine-5-carboxylic acid f2-sulfamoyl-ethyl*)-amide
Figure imgf000082_0001
To a solution of 2-phenyl-pyrimidine-5-carboxylic acid chloride (1.51 mmol) and 2-amino- ethanesulfonicacid amide (1.51 mmol) in DCM (15 mL) is added diisopropylethylamine (4.53 mmol). The mixture is stirred at room temperature overnight. The mixture is concentrated in vacuo. The residue is washed with water and DCM to afford 2-pheny-pyrimidine-5-carboxylic acid (2-sulfamoyl- ethvD-amide as a solid. MS: 307 (M+H); 1H NMR (300 MHz, DMSOd6): δ 3.25 (q, 2H), 3.67 (m, 2H), 6.93 (s, N-H), 7.47-7.60 (m, 3H), 8.36-8.48 (m, 2H), 8.92-9.15 (m, N-H), 9.16-9.36 (m, 2H); IC50 = 55 nM.
Example 109
2-Phenv-pyrimidine-5-carboxylic acid (2-dimethylsulfamoyl-ethyl)-amide
Figure imgf000082_0002
Following procedures similar to those of Example 108 but substituting 2-dimethylamino- ethanesulfonicacid amide for 2-amino-ethanesulfonicacid amide, there is prepared 2-pheny- pyrimidine-5-carboxylic acid C2-dimethylsulfamoyl-ethyl)-amide as a solid. MS: 334 (M+H); 1H
NMR (300 MHz, DMSOd6): δ 2.76 (s, 6H), 3.29 (t, 2H), 3.62-3.73 (m, 2H), 7.45-7.60 (m, 3H), 8.42
(m, 2H), 9.06 (bs, N-H), 9.20 (s, 2H); IC50 = 82 nM.
Example 110 2-Phenyl-pyrimidine-5-carboxylic acid r3-phenyl-ri.2,41thiadiazol-5-ylVamide
Figure imgf000082_0003
To a suspension of 2-phenyl-pyrimidine-5-carboxylic acid (400 mg, 2 mmol) in DCM (10 mL), oxalyl chloride (0.2 mL, 2.3 mmol) is added at O0C followed by DMF (0.23 mL, 3 mmol). The mixture is stirred at O0C for 20 minutes, warmed to room temperature and stirred for 20 additional min. The mixture is concentrated in vacuo. The residue is dissolved in DCM and 3-phenyl-[l,2,4]thiadiazol-5- ylamine (248 mg, 1.4 mmol) is added followed by NMP (0.5 mL). The mixture is stirred at room temperature for two hours, and cooncnetrated in vacuo. The residue is triturated in DCM to afford 2z -o -
phenyl-pyrimidine-5-carboxylic acid ('3-phenyl-[l,2.4]thiadiazol-5-ylVamide (300 mg) as a solid. MS: 360 (M+H); IC50 = 30 nM. Example 111 4-Methyl-2-phenyl-pyrimidine-S-carboxylic acid (3-phenyl-[1.2.41thiadiazol-5-yl)-amide
Figure imgf000083_0001
Following procedures similar to those of Example 110 but substituting 4-methyl-2-phenyl-pyrimidine- 5-carboxylic acid for 2-phenyl-pyrimidine-5-carboxylic acid, there is prepared 4-methyl-2-phenyl-pyrimidine-5-carboxylic acid f3-phenyl-[1.2.41thiadiazol-5-ylVamide MS: 374 (M+H); 1H NMR (300 MHz, DMSOd6): δ 2.77 (s, 3H), 7.54-7.60 (m, 6H), 8.23 (d, 2H), 8.48 (d, 2H), 9.22 (s, IH), 13.88 (s, IH). Example 112 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (3-phenyl-[1.2,4]thiadiazol-5-yl)amide
Figure imgf000083_0002
Following procedures similar to those of Example 110 but substituting 2-(3-fluoro-phenyl) pyrimidine- 5-carboxylic acid for 2-phenyl-pyrimidine-5-carboxylic acid, there is prepared 2-(3-fluoro-phenyl)- pyrimidine-5-carboxylic acid (3-phenyl-[l,2,41thiadiazol-5-yl)amide. MS: 378 (M+H). Example 113 2-(3 -Fluoro-phenyl)-pyrimidine-5-carboxylic acid ("tetrahydro-pyran-4-yl)-amide
Figure imgf000083_0003
Following procedures similar to those of Example 110 but substituting 2-(3-fluoro-phenyl) pyrimidine- 5-carboxylic acid for 2-phenyl-pyrirnidine-5-carboxylic acid, and substituting tetrahydro-pyran-4- ylamine for 3-phenyl-[l,2,4]thiadiazol-5-ylamine, there is prepared 2-(3 -fluoro-phenyl)-pyrimidine-5 - carboxylic acid (tetrahvdro-pyran-4-vn-amide. MS: 302 (M+H); 1H NMR (300 MHz, CD3OD): δ 1.60-1.64 (m, 2H)5 1.81-1.84 (d, 2H), 3.33 (s, 2H), 3.38-3.45 (t, 2H), 3.88-3.92 (d, 2H), 4.02-4.06 (m, IH), 7.46 (t, IH) 7.62 (q, IH), 8.14 (d, IH), 8.29 (d, IH), 8.70 (d, IH), 9.27 (s, 2H). Example 114 2-Cvclohexyl-pyrimidine-5-carboxylic acid phenylamide -O-J"*
Figure imgf000084_0001
Step 1. To a solution of cyclohexanecarboxamidine hydrochloride (1 g, 7.9 mmol) in anhydrous DMF (15 mL) is added sodium 3,3-dimethoxy-2-carbomethoxyprop-l-en-l-oxide (1.82 g, 9.2 mmol) and the reaction mixture is heated at 1000C under N2 for 3 hours. The reaction is cooled to room temperature and water (59 mL) is added. The mixture is extracted with EtOAc. The organic layer is washed with saturated aqueous brine, dried (MgSO^, filtered and concentrated in vacuo to afford 2-cyclohexyl- pyrimidine-5-carboxylic acid methyl ester (0.5 g, 29%) as a solid. MS: 221 (M+H). Step 2. A solution of 2-cyclohexyl-pyrimidine-5-carboxylic acid methyl ester (0.97 g, 4.39 mmol) and aqueous LiOH (1 M, 4.39 mL) MeOH (6 mL) is stirred at room temperature overnight. MeOH is evaporated in vacuo, and the aqueous solution is treated with 3 N HCl to adjust the pH to between 2 and 3. The resulting precipitate is filtered off, washed with water and dried in vacuo to afford 2^ cyclohexyl-pyrimidine-5-carboxylic acid (0.2 g, 22%) as a solid. MS: 207 (M+H). Step 3. A mixture of 2-cyclohexyl-pyrimidine-5-carboxylic acid (100 mg, 0.48 mmol), 1- hydroxybenzotriazole (74.2 mg, 0.55 mmol), and PS-DCC (505 mg, 1.28 mmol/g, 0.65 mmol) in DMF (8 mL) is shaken at room temperature for 15 minutes, and aniline (30 mg, 0.32 mmol) is added. The mixture is shaken at room temperature for 18 hours, PS-trisamine (388 mg, 3.75 mmol/g, 1.45 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with DCM. The filtrate is concentrated in vacuo to afford 2-cyclohexyl-pyrimidine-5- carboxylic acid phenylamide (45.6 mg, 51%) as a solid. MS: 282 (M+H); IC50 = 4960 nM. Example 115
2-Pphenyl-pyrimidine-5-carboxylic acid 3-amino-benzylamide
Figure imgf000084_0002
Following procedures similar to those of Example 8, but substituting 3-amino-benzylamine for 2,2- dioxo2,3-dihydro-lH-21amda*6*-benzo[c]isothiazol-5-ylamine there is prepared 2-phenyl-pyrimidine- 5-carboxylic acid 3-amino-benzylamide as a solid. MS: 305 (M+H); 1H NMR (300 MHz, CD3OD): δ 4.52 (s, 2H)5 6.60-6.75 (m, 2H), 6.77 (bs, N-H), 7.07 (t, H), 7.47-7.59 (m, 3H), 8.44-8.53 (m, 2H), 9.23 (s, 2H). Example 116 2-("3-PyridylVpyrimidme-5-carboxylic acid-3-methylsulfamoyl-benzylamide
Figure imgf000085_0001
A mixture of 2-(3-pyridyl)-pyrimidine-5-carboxylic acid hydrochloride (237 mg 1 mmol) and O-(7- azabenzotriazol-l-yl)-N,N,N,N-tetramethyluronium hexafhlorophosphate (380 mg, 1 mmol) in dry DMF (15 mL) is treated with diisopropylethylamine (0.36 mL) and stirred at room temperature for 30 min. 3-Methylsulfamoylbenzylamine hydrochloride (355 mg, 1.5 mmol) is added and the mixture is stirred at room temperature for 24 hours. The solvent is removed and the residue is partitioned between EtOAc and saturated aqeous NaHCO3. The organic phase is separated, washed with water and brine, dried (MgSO^, filtered and concentrated in vacuo. The residue is triturated with EtOAc. The resulting solid is filtered, washed with ether to afford 2-(3-pyridyl)-pyrimidme-5-carboxylic-acid- 3-methylsulfamoyl-benzylamide (185 mg, 48%). MS: 384 (M+H); 1HNMR (300MHz, DMSO-d6): δ 2.43 (d, 3H), 4.65 (d, 2H), 7.45-7.55 (q, IH), 7.60-7.75 (m, 3H), 7.80 (s, IH), 8.72-8.80 (m, 2H), 9.35 (s, 2H), 9.55 (m, 2H). Example 117
2-Pyrazol-l-yl-pyrimidine-5-carboxylic acid 4-sulfamoyl-benzylamide
Figure imgf000085_0002
Following procedures similar to those of Example 116 but substituting 2-pyrazol- 1 -yl-pyrimidine-5- carboxylic acid for 2-(3-pyridyl)pyrimidine-5-carboxylic acid hydrochloride, and substituting 4- aminomethyl-benzenesulfonamide hydrochloride for 3-methylsulfamoylbenzylamine hydrochloride there is prepared 2-pyrazol-l-yl-pyrimidine-5-carboxylic acid 4-sulfamoyl-benzylamide as a solid. MS: 359 (M+H); IC50 = 266 nM. Example 118
2-r2-Methyl-thiazol-4-yl)-pyrimidine-5-carboxylic acid (tetrahvdro-pyran-4-ylVamide -OJ-
Figure imgf000086_0001
Following procedures similar to those of Example 116 but substituting 2-(2-methyl-thiazol-4-yl)- pyrimidine-5-carboxylic acid for 2-(3-pyridyl)pyrimidine-5-carboxylic acid hydrochloride, and substitutinh tetrahydro-pyran-4-ylamine for 3-methylsulfamoylbenzylamine hydrochloride there is prepared 2-(2-methyl-thiazol-4-yl)-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-yl)-amide as a solid. MS: 305 (M+H); IC50 = 82 nM.
Following the general procedures described in the above examples, the following compounds can be made:
2-Phenyl-pyrimidine-5-carboxylic acid (thiophen-2-yhnethyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (4-methyl-oxazol-2-yl)-amide,
Methoxyimino-{2-[(2-phenyl-pyrimidine-5--carbonyl)-amino]-thiazol-4-yl}-acetic acid ethyl ester,
2-Phenyl-pyrimidine-5-carboxylic acid (5-methylsulfanyl-[l ,3,4]thiadiazol-2-yl)-amide,
2-[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-benzothiazole-5-carboxylic acid ethyl ester,
(R)-2-Phenyl-pyrimidine-5-carboxylic acid (l-phenyl-ethyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid [3-(lH-tetrazol-5-yl)-phenyl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid ( 1 -carbamimidoyl-piperidin-4-yhnethyl)-amide,
S-^-Phenyl-pyrimidine-S-carbony^-aminoJ-lH-indole^-carboxylic acid amide,
2-Phenyl-pyrimidine~5-carboxylic acid [3-(2-amino-thiazol-4-yl)-phenyl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid {4-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-ethyl]-thiazol-2- yl} -amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid [2-(pyrrolidine-l-sulfonyl)-ethyl]-amide,
[3-({[2-(3-Fluoro-phenyl)-4-memyl-pyrimidine-5-carbonyl]-amirio}-methyl)-benzyl]-carbamic acid tert-butyl ester,
2-(3-Fluoro-phenyl)-pyrimidme-5-carboxylic acid 3-[(pyridin-2-ylmethyl)-sulfamoyl]-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3-hydroxy-2,2-dimethyl-propylsulfamoyl)- benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-hydroxy-2-methyl-propylsulfamoyl)- berLzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[(tetrahydro-pyran-4-ylmethyl)-sulfamoyl]- benzylamide,
2-(3 -Fluoro-phenyl)-pyrimidine-5 -carboxylic acid 3 -(4-hydroxy-burylsulfamoyl)-beri2ylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[2-(2-hydroxy-ethoxy)-ethylsulfamoyl]- benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[(tetrahydro-foraii-2-ylmethyl)-sulfamoyl]- benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-isobutylsulfamoyl-benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-isopropylsulfamoyl-pyridin-3-ylmethyl)-amide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-methylsulfamoyl-pyridin-3-ylmethyl)-amide,
2-(3 -Fluoro-pheny^-pyrimidine-S-carboxylic acid (2-methylsulfamoyl-pyridin-4-ylmethyl)-amide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (2-methylsulfamoyl-pyridin-4-ylmethyl)- amide, and
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-isopropylsulfamoyl-pyridin-3- ylmβthyl)-amide.
IN VITRO ASSAY PROTOCOLS TO IDENTIFY INHIBITORS OF HEMATOPOIETIC PGD2 SYNTHASE
The compounds of the present invention can be tested for enzymatic inhibiting activity against PGD2
Synthase according to either one of the following assays. Assay 1: Fluorescence Polarization Assay
As described in PCT publication WO 2004/016223, Example II.
Assay 2: Enzyme Immunoassay (EIA) method
I. Assay solutions a. Preparation of 0. IM K2HPO4ZKH2PO4 buffer (pH 7.4) Prepare 0.1 M KH2PO4 from IM KH2PO4 (Sigma, Cat* P-8709)
Prepare 0.1 M K2HPO4 from powder OfK2HPO4 (Fisher, BP363-500) Mix 0.1 M K2HPO4 with 0.1 M KH2PO4 to adjust pH to 7.4. b. Preparation of 0.5% γ-globulin
Add 0.1 g of γ-globulin (Sigma, Cat# G-5009) to 20 mL 0.1 M K2HPO4ZKH2PO4 buffer (pH 7.4) and make 1-mlZvial aliquots and store in -8O0C. c. Preparation of 100 roM GSH
Add 307 mg of GSH (Sigma, Cat# G-6529) to 10 mL 0.1 M K2HPO4Z KH2PO4 buffer (pH 7.4) and store at - 800C. d. Preparation of Reaction buffer: 198 mL of 0.1M K2HPO4ZKH2PO4 buffer (pH 7.4)
2 mM GSH - Prepared from 100 mM GSH
0.4 g Glycerol
2 mL of 0.5% γ-globulin
Add 0.4 g of glycerol and 2 mL of 0.5% γ-globulin to 198 mL of 0.1 M K2HPO4Z KH2PO4 buffer (pH7.4). - -
Add 0.4 mL of 100 mM GSH to 19.6 ml reaction buffer before the assay (enough for two 96- well plates), e. Preparation of FeC^/citric acid stopping solution: (8 mg/mL FeCl2, 0.1 M citric acid)
Add 40 mg fresh FeCl2 (IGN, Cat# 158046) to 5 ml 0.1 M citric acid (Sigma, Cat# C0759). f. Preparation of MOX reagent:
10% EtOH - Add 1 mL of EtOH to 9 mL of ultra pure H2O
Dissolve 0.1 g of methoxylamine (Cayman, Cat# 400036/) in 10% EtOH (10 mL). Add 0.82 g of sodium acetate (Cayman, Cat#400037) to MOX solution and dissolve. II. Materials and Method
Dimethylsulfoxide (DMSO; Sigma; Cat# D2650)
Prostaglandin D2-M0X express EIA kit (Caymen Chemical, Catalog No.500151) Before the assay, cool down 10 mL of acetone in polypropylene tubes and empty 96 well plates in ice. All the procedures except compound dilution are performed on ice. III. Compound dilution 1. Dilute compound in DMSO
Figure imgf000088_0001
2. Dilute 2 μL of each above concentration of compound to 38 μL of reaction buffer in 96-well plates and mix. IV. Enzyme and substrate solution preparation
1. Preparation of 0.39 ng/μL enzyme solution (0.35 ng/uL at final after compound addition). Mix 4 μL of 4 mg/mL human h-PGDS with 396 μL of reaction buffer (to give enzyme concentration 40 μg/mL). Add 46.8 μL of 40 μg/mL h-PGDS to 4.753 mL of reaction buffer to give a total volume of 4.8 mL
2. Preparation of Substrate Solution (PGH2): Add 0.375 mL of 0.1 mg/mL of PGH2 to 1.625mL acetone. V. Enzyme reaction:
1. Add 60 μL of enzyme solution to compound well and positive control (without compound) in U-bottom polypropylene plate on ice.
2. Add 60 μL of reaction buffer and 6.6 μL of 5% DMSO in reaction buffer into negative control wells in the plate.
3. Add 6.6 μL of diluted compound in reaction buffer to the compound wells and mix.
4. Add 6.6 μL of 5% DMSO in reaction buffer to the positive control well.
5. Incubate the plate in ice for at least 30 min.
6. Add 20 μL of substrate (PGH2) solution to compound, negative and positive control wells in the U-bottom 96 well plate on ice.
7. Dry the plate in cold room for about 25-28 min.
8. Pipette 45 μL of enzyme solution (above) into 96-wells with dried PGH2 and mix 3 times. Incubate on the ice for 1 min.
9. Add 45 μL OfFeCl2 solution into each wells and mix. 10. Add 90 μL of MOX solution and mix.
11. Incubate for 30 min at 600C.
12. Dilute the samples 2500X with EIA buffer. VL EIA assay
Perform the assay according to the procedure in EIA kit provided by Cayman. Total PGD2 levels (pg/mL) were determined in the samples by EIA kits (Caymen Chemical, Catalog No. 500151)
Calculate amount of PGD2 as below
Calculated % Positive control according to the equation below;
%Positive control= (Compound value-Negative control)/(Positive value-Negative control value) xlOO. %Positive control^ (Compound value-Negative control) X 100
(Positive value-Negative control value)
Compound value = PGD2 levels (pg/mL) obtained from the standard curve in EIA assay for the samples with compound
Negative control value = PGD2 levels (pg/mL) obtained from the standard curve in EIA assay for the samples without enzyme
Positive control value = PGD2 levels (pg/mL) obtained from the standard curve in EIA assay for the samples with enzyme but without compound IC50S are determined by excel fit to get the x value when y=l/2Ymax using 4 parameter logistic model for the IC50 curves. Results
Compounds within the scope of the invention produce 50% inhibition in the Fluorescence Polarization Assay or the EIA assay at concentrations within the range of about 1 nanomolar to about 30 micromolar, The IC50S for Examples 8, 9, 33, 34, 82, 83, 84 and 114 obtained by the Fluorescence Polarization Assay, and the IC50S for Examples 1, 30, 38, 40, 45, 48, 49, 51, 54, 55, 56, 63, 65, 68, 71, 85, 93, 97, 108, 109, 110, 117 and 118 obtained by the EIA assay are reported in the "EXAMPLE" section herein.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof.

Claims

We claim:
1. A compound of formula (I):
Figure imgf000091_0001
(I)
wherein:
R1 is aiyl, heteroaryl, or (C5-C6)-cycloalkyl, each of which is optionally substituted by halo, (C1-
C6)-alkyl, hydroxy, (CrC6)-alkoxy, (CrC4)-haloalkyl or (CrC4)-haloalkoxy; R2 is hydrogen or (Q-C^-alkyl;
Figure imgf000091_0002
cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, or multicyclic alkaryl, each of which is optionally substituted by: acyl, cyano, nitro, halo, hydroxy, carboxy, amidino,
Figure imgf000091_0003
Y1Y2N-CC=O)-, Y1Y2N-CC=O)-O-, Y1Y2N-SO2-, R7-SO2-NR6-, R7-CC=O)-NR6-,Y1Y2N-(Ci-C4)-alkylene-SO2-(C1-C4)-alkylene-, or alkyl, alkenyl, alkynyl, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfinyl, or alkylsulfonyl, each of which is optionally substituted by: halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -P(=O)- Calkoxy)2, Y1Y2N-, Y1Y2N-SO2-, R7-SO2-NR6-, aryl or heteroaryl, each of which is optionally substituted by alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, or heterocyclyl or arylheterocyclyl, each of which is optionally substituted by oxo or alkyl, or aryl, heteroaryl, aroyl, heteroaroyl, aryloxy, heteroaryloxy, or heterocyclyl, each of which is optionally substituted by alkyl, haloalkyl, halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -P(=O)-(alkoxy)2, Y1Y2N-, OrY1Y2N-SO2- , and when R3 is cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl or multicyclic alkaryl, it is also optionally substituted by oxo; L1 is a bond, or (CrC6)-alkylene optionally substituted by hydroxy or when R3 is optionally substituted cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, or multicyclic alkaryl, then the (CrC6)-alkylene is also optionally substituted by -P(=O)- (alkoxy)2; R4, R5 and R6 are each independently hydrogen or alkyl,
R7 is alkyl optionally substituted by hydroxy, halo or alkoxy, or aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteraryl or the aryl or heteroaryl moiety of the arylalkyl or heteroarylalkyl is optionally substituted by alkyl, halolkyl, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, halo, alkoxy or haloalkoxy; and
Y1 and Y2 are each independently: hydrogen, alkyl optionally substituted by: hydroxy, carboxy, halo, amino, alkylamino, dialkylamino, cycloalkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, alkoxy optionally substituted with hydroxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted by alkyl, halo or haloalkyl, or cycloalkyl optionally substituted by carboxy, or Y1 and Y2 together with the nitrogen atom to which they are attached form a heterocyclyl optionally containing another heteroatom selected from oxygen, nitrogen or sulfur, wherein the heterocyclyl is optionally substituted with alkyl or oxo; or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R1 is phenyl, five or six-membered heteroaryl, or (C5-C6)~cycloalkyl, each of which is optionally substituted by halo, (CrC6)-alkyl, hydroxy, (C1-C6)- alkoxy, (CrGO-haloalkyl or (CrC4)-haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1, wherein R1 is phenyl or five or six membered heteroaryl, each of which is optionally substituted by halo, (CrC^-alkyl, hydroxy, (C1-C6)-alkoxy, (C1-C4)- haloalkyl or (Ci-C4)-haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1, wherein R1 is phenyl or five or six membered heteroaryl, each of which is optionally substituted by halo, (
Figure imgf000092_0001
Q-C^-alkyl, hydroxy, (C1-C4)- haloalkyl or (Q-C^-haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof, provide that when R1 is phenyl or six membered heteroaryl, then it is only optionally substituted at the ortho or meta position.
5. The compound according to claim I3 wherein R1 is phenyl, pyridyl, thiazolyl, or imidazolyl, oxodiazolyl, each of which is optionally substituted by halo, (CVC^-alkyl, hydroxy, (C1-C6)-alkoxy, (Ci-C4)-haloalkyl or
Figure imgf000093_0001
or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1, wherein R1 is phenyl or pyridyl, each of which is optionally substituted at the ortho or meta position by halo, (CrC6)-alkyl, hydroxy, (Ci-CβJ-alkoxy, (Ci-C4)-haloalkyl or (Ci-GO-haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1, wherein R1 is phenyl optionally substituted by halo, (Ci- C6)-alkyl, hydroxy, (Ci-C6)-alkoxy, (Ci-C^-haloalkyl or (Ci-C4)-haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1, wherein R1 is phenyl optionally substituted at the ortho or meta position by halo, (CrC6)-alkyl, hydroxy, (Ci-C6)-alkoxy, (CrC^-haloalkyl or (Ci-C4)- haloalkoxy, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1, wherein R1 is phenyl optionally substituted by halo, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1, wherein R1 is phenyl optionally substituted at the ortho or meta position by halo, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1, wherein R1 is 2-fluorophenyl or 3 -fluorophenyl, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1, wherein R2 is hydrogen, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 1, wherein R2 is methyl, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 1, wherein L1 is a bond, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 1, wherein L1 is (CrC3)-alkylene, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 1, wherein L1 is -CH2-, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 1, wherein
R3 is cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, heterocyclenyl, or multicyclic alkaryl, each of which is optionally substituted by: acyl, cyano, nitro, halo, hydroxy, carboxy, amidino,
R5O-C(=O)-C(=N-OR4)-,Y1Y2N-, Y1Y2N-CC=O)-, Y1Y2N-CC=O)-O-, Y1Y2N-SO2-, R7-SO2-NR6-, R7-C(=O)-NR6-,Y1Y2N-CCrC4)-alkylene-SO2-(Ci-C4)-alkylene-, or alkyl, alkenyl, alkynyl, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfinyl, or alkylsulfonyl, each of which is optionally substituted by: halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -P(=O)-
(alkoxy)2, Y1Y2N-, Y1Y2N-SO2-, R7-SO2-NR6-, aryl or heteroaryl, each of which is optionally substituted by alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, or heterocyclyl or arylheterocyclyl, each of which is optionally substituted by oxo or alkyl, or aryl, heteroaryl, aroyl, heteroaroyl, aryloxy, heteroaryloxy, or heterocyclyl, each of which is optionally substituted by alkyl, haloalkyl, halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -P(=O)-(alkoxy)2, Y1Y2N-, or Y1Y2N-SO2-
, and when R3 is cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl or multicyclic alkaryl, it is also optionally substituted by oxo, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
18. The compound according to claim 1, wherein R3 is phenyl, pyridyl, thiazolyl, imidazolyl, oxodiazolyl, imidazolyl, pyrimidinyl, thiophenyl, oxazolyl, cycloalkyl, benzooxazolyl, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, tetrahydropyranyl, piperidinyl, fiiranyl, benzo[l,3]dioxolyl, benzothiazolyl, imidazolidinyl, indazolyl, benzoimidazolyl, indolyl, benzofuranyl, or 1,3-dihydro- benzo[c]isothiazolyl, each of which is optionally substituted by: acyl, cyano, nitro, halo, hydroxy, carboxy, amidino,
R5O-C(=O)-C(=N-OR4)-,Y1Y2N-, Y1Y2N-CC=O)-, Y1Y2N-CC=O)-O-, Y1Y2N-SO2-, R7-SO2-NR6-, R7-C(=O)-NR6-,Y1Y2N-(Ci-C4)-alkylene-Sθ2-(Ci-C4)-alkylene-, or alkyl, alkenyl, alkynyl, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfinyl, or alkylsulfonyl, each of which is optionally substituted by: halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -P(=O)-(alkoxy)2,
Y1Y2N-, Y1Y2N-SO2-, R7-SO2-NR6-, aryl or heteroaryl, each of which is optionally substituted by alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, or heterocyclyl or arylheterocyclyl, each of which is optionally substituted by oxo or alkyl, or aryl, heteroaryl, aroyl, heteroaroyl, aryloxy, heteroaryloxy, or heterocyclyl, each of which is optionally substituted by alkyl, haloalkyl, halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -P(=O)-(alkoxy)2, Y1Y2N-, or Y1Y2N-SO2-, and when R3 is cycloalkyl, tetrahydropyranyl, piperidinyl, imidazolidinyl, or 1,3-dihydro- benzo[c]isotbiazolyl, it is also optionally substituted by oxo, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
19. The compound according to claim 1, wherein:
R3 is phenyl, pyridyl, thiazolyl, imidazolyl, oxodiazolyl, imidazolyl, pyrimidinyl, thiophenyl, oxazolyl, cycloalkyl, benzooxazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrahydropyranyl, piperidinyl, furanyl, benzo[l,3]dioxolyl, benzothiazolyl, imidazolidinyl, indazolyl, benzoimidazolyl, indolyl, benzofuranyl, or l,3-dihydro-benzo[c]isothiazolyl, each of which is optionally substituted by: nitro, halo, hydroxy, carboxy, amidino, R5O-C(=O)-C(=N-OR4)-,Y1Y2N-, Y1Y2N-CC=O)-,
Y1Y2N-SO2-, R7-SO2-NR6-, R7-CC=O)-NR6-, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, aryl, heteroaryl, or alkyl optionally substituted by: halo, carboxy, alkoxycarbonyl, aryl or heteroaryl, -PC=O)-Calkoxy)2, Y1Y2N-, Y1Y2N-SO2-, R7-SO2-NR6-, or heterocyclyl or arylheterocyclyl, each of which is optionally substituted by oxo, or _ _
heterocyclyl optionally substituted by Y1Y2N-, and when R3 is cycloalkyl, tetrahydropyranyl, piperidinyl, imidazolidinyl, or 1,3-dihydro- benzo[c]isothiazolyl, it is also optionally substituted by oxo; and
Y1 and Y2 are each independently hydrogen, cycloalkyl, or alkyl optionally substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino, heteroaryl, or heterocyclyl optionally substituted by alkyl, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
20. The a compound according to claim 1, wherein R3 is phenyl optionally substituted by: acyl, cyano, nitro, halo, hydroxy, carboxy, amidino, R5O-C(=O)-C(=N-OR4)-,Y1Y2N-, Y1Y2N-CC=O)-, Y1Y2N-CC=O)-O-, Y1Y2N-SO2-,
R7-SO2-NR6-, R7-C(=O)-NR6-,Y1Y2N-(C1-C4)-alkylene-SO2-(C1-C4)-alkylene-, or alkyl, alkenyl, alkynyl, alkoxy, alkoxycarbonyl, alkyltbio, alkylsulfinyl, or alkylsulfonyl, each of which is optionally substituted by: halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -PC=O)-Calkoxy)2, Y1Y2N-, Y1Y2N-SO2-, R7-SO2-NR6-, aryl or heteroaryl, each of which is optionally substituted by alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, amino, alkylamino, dialkylamino, carboxy, or alkoxycarbonyl, or heterocyclyl or arylheterocyclyl, each of which is optionally substituted by oxo or alkyl, or aryl, heteroaryl, aroyl, heteroaroyl, aryloxy, heteroaryloxy, or heterocyclyl, each of which is optionally substituted by alkyl, haloalkyl, halo, alkoxy, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, -PC=O)-(alkoxy)2, Y1Y2N-, Or Y1Y2N-SO2-, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
21. The compound according to claim 1 , wherein: R3 is phenyl optionally substituted by: nitro, halo, hydroxy, carboxy, amidino, R5O-CC=O)-CC=N-OR4KY1Y2N-, Y1Y2N-CC=O)-, Y1Y2N-SO2-, R7-SO2-NR6-, R7-CC=O)-NR6-, alkoxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, aryl, heteroaryl, or alkyl optionally substituted by: halo, carboxy, alkoxycarbonyl, aryl or heteroaryl, -P(=O)-(alkoxy)2, Y1Y2N-, Y1Y2N-SO2-, R7-SO2-NR6-, or heterocyclyl or arylheterocyclyl, each of which is optionally substituted by oxo, or heterocyclyl optionally substituted by Y1Y2N-, and _ _
Y1 and Y2 are each independently hydrogen, cycloalkyl, or alkyl optionally substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino, heteroaryl, or heterocyclyl optionally substituted by alkyl, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
22. The compound according to claim 1, wherein R3 is phenyl optionally substituted by: Y1Y2N-SO2-, R7-SO2-NR6-, alkylsulfonyl, or alkyl substituted by Y1Y2N-SO2-, R7-SO2-NR6-, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
23. The compound according to claim 1, wherein: R3 is phenyl optionally substituted by:
Y1Y2N-SO2-, R7-SO2-NR6-, alkylsulfonyl, or alkyl substituted by Y1Y2N-SO2-, R7-SO2-NR6-; and
Y1 and Y2 are each independently hydrogen, cycloalkyl, or alkyl optionally substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino, heteroaryl, or heterocyclyl optionally substituted by alkyl, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
24. The compound according to claim 1, which is 2-Phenyl-pyrimidine-5-carboxylic acid benzylamide
2-Pyridm-4-yl-pyrimidine-5-carboxylic acid phenylamide,
2-Pyridin-3-yl-pyrimidine-5-carboxylic acid phenylamide,
2-Pyridin-2-yl-pyrimidine-5-carboxylic acid phenylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide, 2-(4-Fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide,
2-(2-Fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide,
2-Phenyl-pyrimidine-5-carboxylic acid (2,2-dioxo-2,3-dihydro-l H-21amda*6*-benzo[c]isothiazol-5- yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid [l-(lH-imidazol-2-ylmethyl-piperidin-4-yl]-amide, 2-Phenyl-ρyrimidine-5-carboxylic acid (6-dimethylamino-pyridin-3-yhnethyl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid [2-(2-pyrrolidin- 1 -yl-ethyl)-benzooxazol-6-yl] -amide,
2-Phenyl-pyrimidine-5-carboxylic acid 4-sulfamoyl-benzylamide,
2-Phenyl-pyrimidine-5-carboxylic acid [2-(4-sulfamoyl-phenyl)-ethyl] -amide,
(R)-2-Phenyl-pyrimidine-5-carboxylic acid [4-(2-oxo-oxazolidin-4-yhnethyl)-phenyl]-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (6-acetylamino-pyridin-3-yl)-amide,
2-Phenyl-pyrimidine-5-carboxylic acid (3-carbamoyl-phenyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (3-methylcarbamoyl-phenyl)-amide, 2-Phenyl-pyrimidine-5 -carboxylic acid (4-hydroxy-cyclohexyl)-amide, 4-methyl-2-[(2Lphenyl-pyrimidin-5-carbonyl)-amino]-thiazole-5-carboxylic acid ethyl ester, {2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazol-4-yl}-acetic acid ethyl ester, 4-methyl-2-[(2-phenyl-pyrimidin-5-carbonyl)-amino]-thiazole-5-carboxylic acid, {2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazol-4-yl}-acetic acid, 2-Phenyl-pyrimidine-5-carboxylic acid 4-methylsulfamoyl-benzylamide, 2-Phenyl-pyrimidine-5-carboxylic acid 4-dimethylsulfamoyl-benzylamide, 2-Phenyl-pyrimidine-5-carboxylic acid (3,5-difluoro-phenyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid pyridin-2-ylamide, 2-Phenyl-pyrimidine-5-carboxylic acid thiazol-2-ylamide, 2-Phenyl-pyrimidine-5-carboxylic acid (3-sulfamoyl-phenyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (2-oxo-l,2-dihydro-pyrimidin-4-yl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (4-sulfamoyl-phenyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid pyrimidin-4-ylamide,
2-Pheny l-pyrimidine-5 -carboxylic acid ( 1 -pyridin-3 -ylrnethyl-piperidin~4-yl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid [2-(2-oxo-imidazolidin- 1 -yl)-ethyl]-amide, 2-Phenyl-pyrimidine-5-carboxylic acid [2-(lH-imidazol-4-yl)-ethyl]-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (2H-pyrazol-3-yl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (l-methyl-piperidin-4-yl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid pyrimidin-2-ylamide, 2-(3,5-difluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide, 2-(2,5-difluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide,
2-(4-difluorophenyl)-4-methylpyrimidine-5-carboxylic acid-3-meth^ylsulfamoyl-beii2ylamide, 2-(2-pyridyl)-pyrimidine-5 -carboxylic acid-3 -methylsulfamoyl-benzylamide, 2-(3-pyridyl)-4-methyl-pyrimidine-5-carboxylic acid-3-methylsulfarnoyl-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-ethylsulfamoyl-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-ethoxy-ethylsulfamoyl)-benzylamide,
2-(3 -Fluoro-phenylJ-pyrimidine-S-carboxylic acid 3 -(2-hydroxy-propylsulfamoyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxy lie acid 3-cyclopropylsulfamoyl-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3-hydroxy-propylsulfamoyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-methoxy-ethylsulfamoyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3-methoxy-propylsulfamoyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyiimidine-5-carboxylic acid 3-(4-methoxy-butylsulfamoyl)-benzylamide, _
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-cyclohexylsulfamoyl-benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-hydroxy-l,l-dimethyl-ethylsulfamoyl)- benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-sulfamoyl-benzylamide, 2-(3 -Fluoro-phenyl)-pyrimidine-5 -carboxylic acid 3 -(2-morpholin-4-yl-ethylsulfaraoyl)-benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-piperidin-l-yl-ethylsulfamoyl)-benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[2-(l -methyl-pyrrolidin-2-yl)-ethylsulfamoyl]- benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[(l-ethyl-pyrrolidin-2-ylmethyl)-sulfamoyl]- benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[2-(lH-imidazol-4-yl)-etb.ylsulfamoyl]- benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[3-(2-methyl-piperidin-l-yl)-propylsulfamoyl]- benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3-pyrrolidin-l-yl-propylsulfamoyl)-benzylamide,
2-(3-Fluoro-phenyl)-pyrmiidme-5-carboxylic acid 3-(2-dimemylamino-ethylsulfamoyl)-benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-diethylamino-ethylsulfamoyl)-benzylamide,
2-(3 -Fluoro-phenyty-pyrimidine-S-carboxylic acid 3 -(3 -dimethylamino-2,2-dimethyl- propylsulfamoyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(5-dimethylamino-pentylsulfamoyl)-benzylamide,
2-(3 -Fluoro-phenyl)-pyrimidine-5 -carboxylic acid 3 -(2-diisopropylamino-ethylsulfamoyl)- benzylamide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidme-5-carboxylic acid 3-(methanesulfonylammo-methyl)- benzylamide, 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3-[(propane-2-sulfonylamino)~methyl]- benzylamide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3-methylsulfamoylmethyl-benzylamide,
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3-(isopropylsulfamoyl-methyl)- benzylamide, 2-(3-Fluoro-phenyl)- pyrimidine-5-carboxylic acid 3-(methanesulfonylamino-methyl)-benzylamide,
2-(3-Fluoro-phenyl)- pyrimidine-5-carboxylic acid 3-[(propane-2-sulfonylamino)-methyl]- benzylamide,
2-(3-Fluoro-phenyl)- pyrimidine-5-carboxylic acid 3-methylsulfamoylmethyl-benzylamide,
2-(3-Fluoro-ρhenyl)- pyrimidine-5-carboxylic acid 3-(isopropylsulfamoyl-methyl)-benzylamide 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (2-methanesulfonylamino-pyridin-4-ylmethyl)- amide, _ _
2-(5-Methyl-[l,2,4]oxadiazole-3-yl)-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-yl)-amide, 2-(5-Methyl-[l,2,4]oxadiazole-3-yl)-pyrimidine-5-carboxylic acid 4 -sulfamoyl-benzeneamide, 2-(5-Methyl-[l,2,4]oxadiazol-3-yl)-pyrimidine-5-carboxylic acid (3-phenyl-[l,2,4]thiadiazol-5-yl)- amide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(morpholine-4-sulfonyl)-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 3,4-dimethoxyl-ben2ylamide, 2-Pheny-pyrimidine-5-carboxylic acid (2-benzo[l,3]dioxol-5-yl-ethyl)-amide, 2-Pheny-pyrimidine-5-carboxylic acid (lH-indazol-5-yl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid 4-[l,2,3]thiadiazol-5-yl)-benzylamide, 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide, 4-Metiiyl-2-pyridm-2-yl-pyrimidme-5-carboxylic acid 3-methylsulfamoyl-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 4-morpholin-4-ylbenzylamide, ό-^-Phenyl-pyrimidin-S-carbony^-aminoJ-lH-benzoimidazole^-carboxylic acid methyl ester, 6-[(2-Phenyl-pyrimidin-5-carbonyl)-amino]- lH-benzoimidazole-2-carboxylic acid, 2-Pheny-pyrimidine-5-carboxylic acid (benzofuran-5-ylmethyl)-amide,
2-Pheny-pyrimidine-5-carboxylic acid 4-methanesulfonylamino-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 4-carbamoyl-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 3-(2-hydroxy-ethylsulfamoyl)-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 4-(morpholin-4-sulfonyl)-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide,
2-Pheny-pyrimidine-5-carboxylic acid [2-(2-amino-4-methyl-thiazol-5-yl)-ethyl]-amide, 2-(3-Fluoro-phenyl)-pyτimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide, {4-{[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-benzyl}-phosphonic acid diethyl ester, {4-[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-bu1yl)-phosphonic acid diethyl ester, {4-[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-ethyl)-phosphonic acid diethyl ester,
{Phenyl-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-methyl)-phosphonic acid diethyl ester, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methanesulfonyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (l-methanesulfonyl-piperidin-3-ylmethyl)-amide, 2-(3 -Fluoro-phenyl)-pyrimidine-5-carboxylic acid ( 1 -dimethanesulfamoyl-piperidin-3 -ylmethyl)- amide,
2-(Phenyl)-pyrimidine-5-carboxylic acid 3-methanesulfonylamino-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-acetylsulfamoyl-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3-oxo-piperiazine-l-sulfonyl)-benzylamide, 2-Pheny-pyrimidine-5-carboxylic acid (2-sulfamoyl-ethyl)-amide, 2-Pheny-pyrimidine-5-carboxylic acid (2-dimethylsulfamoyl-ethyl)-amide,
2-Phenyl-pyrimidine-5-carboxy lie acid (3-phenyl-[l,2,4]thiadiazol-5-yl)-amide, 4-Memyl-2-phenyl-pyrimidine-5-carboxylic acid (3-phenyl-[l ,2,4]thiadiazol-5-yl)-amide 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (3-phenyl-[l,2,4]thiadiazol-5-yl)amide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-yl)-amide, 2-Cyclohexyl-pyrimidine-5-carboxylic acid phenylamide, 2-Phenyl-pyrimidine-5-carboxylic acid 3-amino-benzylamide,
2-(3-Pyridyl)-pyrimidine-5-carboxylic acid-3-methylsulfamoyl-benzylamide, 2-Pyrazol-l-yl-pyrimidine-5-carboxylic acid 4-sulfamoyl-benzylamide, 2-(2-Methyl-thiazol-4-yl)-pyrimidine-5-carboxylic acid (tetrahydro-pyran-4-yl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (thiophen-2-ylmethyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid (4-methyl-oxazol-2-yl)-amide,
Methoxyimino-{2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazol-4-yl}-acetic acid ethyl ester, 2-Phenyl-pyrimidine-5-carboxylic acid (5-methylsulfanyl-[l,3,4]thiadiazol-2-yl)-amide, 2-[(2-Phenyl-pyrimidine-5-carbonyl)-amino]-benzothiazole-5-carboxylic acid ethyl ester, (R)-2-Phenyl-pyrimidine-5-carboxylic acid (l-phenyl-ethyl)-amide, 2-Phenyl-pyrimidine-5-carboxylic acid [3-(lH-tetrazol-5-yl)-phenyl]-amide,
2-Phenyl-pyrimidine-5-carboxylic acid (l-carbamimidoyl-piperidin-4-ylmethyl)-amide, S-^-Phenyl-pyrimidine-S-carbony^-aminoJ-lH-indole-S-carboxylic acid amide, 2-Phenyl-pyrimidine-5-carboxylic acid [3-(2-amino-thiazol-4-yl)-phenyl]-amide, 2-Phenyl-pyrimidine-5-carboxylic acid {4-[2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-ethyl]-thiazol-2- yl} -amide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid [2-(pyrrolidine-l-sulfonyl)-ethyl]-amide, [3-({[2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amJno}-methyl)-benzyl]-carbamic acid tert-butyl ester, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[(pyridin-2-yhnethyl)-sulfamoyl]-benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(3-hydroxy-2,2-dimethyl-propylsulfamoyl)- benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(2-hydroxy-2-methyl-propylsulfamoyl)- benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[(tetrahydro-pyran-4-ylmethyl)-sulfamoyl]- benzylamide,
2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-(4-hydroxy-butylsulfamoyl)-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[2-(2-hydroxy-ethoxy)-ethylsulfamoyl]- benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-[(tetrahydro-furan-2-yhnethyl)-sulfamoyl]- benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid S-isobutylsulfamoyl-benzylamide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-isopropylsulfamoyl-pyridin-3-ylmethyl)-amide, 2-(3 -Fluoro-phenyl)-pyrimidine-5 -carboxylic acid (5 -methylsulfamoyl-pyridin-3 -ylmethyl)-amide, 2-(3-Fluoro-phenyl)-pyrimidine-5-carboxylic acid (2-methylsulfamoyl-pyridin-4-ylmethyl)-amide, 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (2-methylsulfamoyl-pyridin-4-ylmethyl)- amide, or
2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-isopropylsulfamoyl-pyridin-3- ylmethyl)-amide, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
25. A pharmaceutical composition comprising the compound according to claim 1, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
26. A method for treating an allergic or inflammatory disorder in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to claim 1, or a hydrate, solvate or N-oxide thereof, or a pharmaceutically acceptable salt thereof.
27. The method according to claim 26, wherein the allergic or inflammatory disorder is allergic rhinitis.
28. The method according to claim 26, wherein the allergic or inflammatory disorder is asthma.
29. The method according to claim 26, wherein the allergic or inflammatory disorder is chronic obstructive pulmonary disease
PCT/US2006/038841 2005-10-04 2006-10-04 Pyrimidine amide compounds as pgds inhibitors WO2007041634A1 (en)

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EP06816247.8A EP1937652B1 (en) 2005-10-04 2006-10-04 Pyrimidine amide compounds as pgds inhibitors
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KR1020087008306A KR101457966B1 (en) 2005-10-04 2006-10-04 Pyrimidine amide compounds as PGDS inhibitors
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IL190411A IL190411A (en) 2005-10-04 2008-03-24 Pyrimidine amide compounds as pgds inhibitors
US12/062,641 US8202863B2 (en) 2005-10-04 2008-04-04 Pyrimidine amide compounds as PGDS inhibitors
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Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008104869A1 (en) * 2007-02-26 2008-09-04 Pfizer Products Inc. Nicotinamide derivatives as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases
WO2009064449A1 (en) * 2007-11-13 2009-05-22 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
WO2009049180A3 (en) * 2007-10-11 2009-05-28 Vertex Pharma Heteroaryl amides useful as inhibitors of voltage-gated sodium channels
WO2009099086A1 (en) * 2008-02-06 2009-08-13 Banyu Pharmaceutical Co., Ltd. 3-substituted sulfonyl piperazine derivative
US20090286261A1 (en) * 2008-05-13 2009-11-19 Cayman Chemical Company Method for assaying compounds or agents for ability to displace potent ligands of hematopoietic prostaglandin d synthase
WO2009153721A1 (en) 2008-06-18 2009-12-23 Pfizer Limited Nicotinamide derivatives
WO2009153720A1 (en) 2008-06-18 2009-12-23 Pfizer Limited Nicotinamide derivatives
WO2010056044A2 (en) * 2008-11-11 2010-05-20 (주)아모레퍼시픽 Novel compound acting as a vanilloid receptor antagonist, isomer or pharmaceutically acceptable salt thereof, and pharmaceutical composition containing same
US7759350B2 (en) * 2005-09-15 2010-07-20 Orchid Research Laboratories Ltd. Pyrimidine carboxamides
WO2010104024A1 (en) 2009-03-09 2010-09-16 大鵬薬品工業株式会社 Piperazine compound capable of inhibiting prostaglandin d synthase
US7902373B2 (en) 2006-12-19 2011-03-08 Pfizer Inc Nicotinamide derivatives
WO2011150457A3 (en) * 2010-06-01 2012-01-26 The University Of Queensland Haematopoietic-prostaglandin d2 synthase inhibitors
US8202863B2 (en) 2005-10-04 2012-06-19 Aventis Pharmaceuticals Inc. Pyrimidine amide compounds as PGDS inhibitors
KR20120131164A (en) 2010-01-22 2012-12-04 다이호야쿠힌고교 가부시키가이샤 Piperazine compound having a pgds inhibitory effect
US8389734B2 (en) 2007-10-11 2013-03-05 Vertex Pharmaceuticals Incorporated Amides useful as inhibitors of voltage-gated sodium channels
KR101252335B1 (en) 2009-07-16 2013-04-08 (주)아모레퍼시픽 Composition for Preventing Skin Aging
US8536185B2 (en) 2008-09-22 2013-09-17 Cayman Chemical Company, Incorporated Multiheteroaryl compounds as inhibitors of H-PGDS and their use for treating prostaglandin D2 mediated diseases
KR101367057B1 (en) 2009-03-17 2014-02-25 (주)아모레퍼시픽 Composition for Reducing Skin Irritation
US8779197B2 (en) 2007-10-11 2014-07-15 Vertex Pharmaceuticals Incorporated Aryl amides useful as inhibitors of voltage-gated sodium channels
US8841483B2 (en) 2006-04-11 2014-09-23 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of voltage-gated sodium channels
JP2015110666A (en) * 2007-08-27 2015-06-18 ヘリコン・セラピューティクス・インコーポレーテッド Therapeutic isoxazole compounds
US9181183B2 (en) 2010-09-07 2015-11-10 Taiho Pharmaceutical Co., Ltd. Prostaglandin D synthase inhibitory piperidine compounds
US9469627B2 (en) 2009-10-08 2016-10-18 Sanofi Phenyloxadiazole derivatives as PGDS inhibitors
WO2017103851A1 (en) 2015-12-17 2017-06-22 Astex Therapeutics Limited Quinoline-3-carboxamides as h-pgds inhibitors
WO2018069863A1 (en) 2016-10-13 2018-04-19 Glaxosmithkline Intellectual Property Development Limited 1,3 di-substituted cyclobutane or azetidine derivatives as hematopoietic prostaglandin d synthase inhibitors
WO2018229629A1 (en) 2017-06-13 2018-12-20 Glaxosmithkline Intellectual Property Development Limited Chemical compounds as h-pgds inhibitors
WO2019116256A1 (en) 2017-12-13 2019-06-20 Glaxosmithkline Intellectual Property Development Limited Fused pyridines which act as inhibitors of h-pgds
EP3429588A4 (en) * 2016-03-14 2019-11-13 Emory University Amide-sulfamide derivatives, compositions, and uses related to cxcr4 inhibition
WO2020095215A1 (en) 2018-11-08 2020-05-14 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
EP3700521A4 (en) * 2017-10-29 2021-09-08 China Medical University ADAM9 inhibitors and the uses thereof
WO2021231571A1 (en) * 2020-05-13 2021-11-18 Chdi Foundation, Inc. Htt modulators for treating huntington's disease
WO2021256569A1 (en) 2020-06-19 2021-12-23 佐藤製薬株式会社 Condensed ring compounds that inhibit h-pgds
US20230077316A1 (en) * 2020-10-23 2023-03-09 Nimbus Clotho, Inc. Ctps1 inhibitors and uses thereof
WO2023091456A1 (en) * 2021-11-17 2023-05-25 Chdi Foundation, Inc. N-(2h-indazol-5-yl)pyrazine-2-carboxamide derivatives and similar compounds as htt modulators for the treatment of huntington's disease

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03112985A (en) * 1989-09-28 1991-05-14 Morishita Pharmaceut Co Ltd N-(1h-tetrazol-5-yl)-2-phenyl-5-pyrimidinecarboxamides and synthetic intermediate thereof
WO1995025723A1 (en) * 1994-03-18 1995-09-28 Agrevo Uk Limited Anilide derivatives as fungicides
JP2000226372A (en) * 1999-02-01 2000-08-15 Nippon Soda Co Ltd Amide compound, its production and agricultural and horticultural insecticide
WO2001070671A2 (en) * 2000-03-22 2001-09-27 E.I. Du Pont De Nemours And Company Insecticidal anthranilamides
WO2004011430A1 (en) * 2002-07-25 2004-02-05 Yamanouchi Pharmaceutical Co., Ltd. Sodium channel inhibitor
WO2004072069A1 (en) * 2003-02-14 2004-08-26 Glaxo Group Limited Carboxamide derivatives
EP1471057A1 (en) * 2003-04-25 2004-10-27 Bayer HealthCare AG Pyrimidinylacetic acid derivatives useful for the treatment of diseases mediated by CRTH2
WO2005032493A2 (en) * 2003-10-07 2005-04-14 Renovis, Inc. Amide compounds as ion channel ligands and uses thereof
EP1553089A1 (en) * 2002-07-30 2005-07-13 Banyu Pharmaceutical Co., Ltd. Antagonist of melanin-concentrating hormone receptor comprising benzimidazole derivative as active ingredient

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002003370A (en) * 1999-09-20 2002-01-09 Takeda Chem Ind Ltd Melanin coagulating hormone antagonistic agent
EP1218336A2 (en) * 1999-09-20 2002-07-03 Takeda Chemical Industries, Ltd. Melanin concentrating hormone antagonist
JP2003112985A (en) 2001-10-01 2003-04-18 Nre Happiness Kk Food leftover manure, feed raw material forming system, and crushing and storing treatment unit and drying and cooling treatment unit used for the same
US20050165028A1 (en) * 2004-01-23 2005-07-28 Norman Mark H. Vanilloid receptor ligands and their use in treatments
PE20110118A1 (en) 2005-10-04 2011-03-08 Aventis Pharma Inc PYRIMIDINE AMIDE COMPOUNDS AS INHIBITORS OF PGDS

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03112985A (en) * 1989-09-28 1991-05-14 Morishita Pharmaceut Co Ltd N-(1h-tetrazol-5-yl)-2-phenyl-5-pyrimidinecarboxamides and synthetic intermediate thereof
WO1995025723A1 (en) * 1994-03-18 1995-09-28 Agrevo Uk Limited Anilide derivatives as fungicides
JP2000226372A (en) * 1999-02-01 2000-08-15 Nippon Soda Co Ltd Amide compound, its production and agricultural and horticultural insecticide
WO2001070671A2 (en) * 2000-03-22 2001-09-27 E.I. Du Pont De Nemours And Company Insecticidal anthranilamides
WO2004011430A1 (en) * 2002-07-25 2004-02-05 Yamanouchi Pharmaceutical Co., Ltd. Sodium channel inhibitor
EP1553089A1 (en) * 2002-07-30 2005-07-13 Banyu Pharmaceutical Co., Ltd. Antagonist of melanin-concentrating hormone receptor comprising benzimidazole derivative as active ingredient
WO2004072069A1 (en) * 2003-02-14 2004-08-26 Glaxo Group Limited Carboxamide derivatives
EP1471057A1 (en) * 2003-04-25 2004-10-27 Bayer HealthCare AG Pyrimidinylacetic acid derivatives useful for the treatment of diseases mediated by CRTH2
WO2005032493A2 (en) * 2003-10-07 2005-04-14 Renovis, Inc. Amide compounds as ion channel ligands and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PALANKI M S S ET AL: "INHIBITORS OF NF-KAPPABETA AND AP-1 GENE EXPRESSION: SAR STUDIES ONTHE PYRIMIDINE PORTION OF 2-CHLORO-4-TRIFLUOROMETHYLPYRIMIDINE-5- N-(3',5'-BIS(TRIFLUOROMETHYL)-PHENYL)CARBOXAMIDEL", 2000, JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, PAGE(S) 3995-4004, ISSN: 0022-2623, XP000986229 *

Cited By (60)

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Publication number Priority date Publication date Assignee Title
US7759350B2 (en) * 2005-09-15 2010-07-20 Orchid Research Laboratories Ltd. Pyrimidine carboxamides
US8202863B2 (en) 2005-10-04 2012-06-19 Aventis Pharmaceuticals Inc. Pyrimidine amide compounds as PGDS inhibitors
US8841483B2 (en) 2006-04-11 2014-09-23 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of voltage-gated sodium channels
US7902373B2 (en) 2006-12-19 2011-03-08 Pfizer Inc Nicotinamide derivatives
US8067589B2 (en) 2007-02-26 2011-11-29 Pfizer Inc Heterocyclic compounds useful in treating diseases and conditions
WO2008104869A1 (en) * 2007-02-26 2008-09-04 Pfizer Products Inc. Nicotinamide derivatives as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases
US7582643B2 (en) 2007-02-26 2009-09-01 Pfizer Inc Heterocyclic compounds useful in treating diseases and conditions
JP2015110666A (en) * 2007-08-27 2015-06-18 ヘリコン・セラピューティクス・インコーポレーテッド Therapeutic isoxazole compounds
US9650349B2 (en) 2007-08-27 2017-05-16 Dart Neuroscience (Cayman) Ltd. Therapeutic isoxazole compounds
US10053467B2 (en) 2007-08-27 2018-08-21 Dart Neuroscience (Cayman) Ltd. Therapeutic isoxazole compounds
JP2011500598A (en) * 2007-10-11 2011-01-06 バーテックス ファーマシューティカルズ インコーポレイテッド Heteroarylamides useful as inhibitors of voltage-gated sodium channels
US8389734B2 (en) 2007-10-11 2013-03-05 Vertex Pharmaceuticals Incorporated Amides useful as inhibitors of voltage-gated sodium channels
US8865771B2 (en) 2007-10-11 2014-10-21 Vertex Pharamaceuticals Incorporated Amides useful as inhibitors of voltage-gated sodium channels
US8779197B2 (en) 2007-10-11 2014-07-15 Vertex Pharmaceuticals Incorporated Aryl amides useful as inhibitors of voltage-gated sodium channels
US8519137B2 (en) 2007-10-11 2013-08-27 Vertex Pharmaceuticals Incorporated Heteroaryl amides useful as inhibitors of voltage-gated sodium channels
WO2009049180A3 (en) * 2007-10-11 2009-05-28 Vertex Pharma Heteroaryl amides useful as inhibitors of voltage-gated sodium channels
WO2009064449A1 (en) * 2007-11-13 2009-05-22 Renovis, Inc. Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same
US20100331360A1 (en) * 2008-02-06 2010-12-30 Tsuyoshi Nagase 3-substituted sulfonyl piperidine derivative
WO2009099086A1 (en) * 2008-02-06 2009-08-13 Banyu Pharmaceutical Co., Ltd. 3-substituted sulfonyl piperazine derivative
JP5537159B2 (en) * 2008-02-06 2014-07-02 Ｍｓｄ株式会社 3-substituted sulfonylpiperidine derivatives
AU2009211724B2 (en) * 2008-02-06 2013-05-16 Msd K.K. 3-substituted sulfonyl piperazine derivative
US8188280B2 (en) 2008-02-06 2012-05-29 Msd K.K. 3-substituted sulfonyl piperidine derivative
JP2011522524A (en) * 2008-05-13 2011-08-04 ケイマン ケミカル カンパニー Method for assaying the ability of a hematopoietic prostaglandin D synthase to displace a potent ligand in a compound or formulation
EP2286221A4 (en) * 2008-05-13 2011-07-06 Cayman Chem Co Methods for assaying compounds or agents for ability to displace potent ligands of hematopoietic prostaglandin d synthase
US8440417B2 (en) 2008-05-13 2013-05-14 Cayman Chemical Company, Incorporated Method for assaying compounds or agents for ability to displace potent ligands of hematopoietic prostaglandin D synthase
US20090286261A1 (en) * 2008-05-13 2009-11-19 Cayman Chemical Company Method for assaying compounds or agents for ability to displace potent ligands of hematopoietic prostaglandin d synthase
AU2009246446B2 (en) * 2008-05-13 2014-06-26 Cayman Chemical Company, Incorporated Methods for assaying compounds or agents for ability to displace potent ligands of hematopoietic prostaglandin D synthase
EP2286221A2 (en) * 2008-05-13 2011-02-23 Cayman Chemical Company Methods for assaying compounds or agents for ability to displace potent ligands of hematopoietic prostaglandin d synthase
WO2009153720A1 (en) 2008-06-18 2009-12-23 Pfizer Limited Nicotinamide derivatives
WO2009153721A1 (en) 2008-06-18 2009-12-23 Pfizer Limited Nicotinamide derivatives
US9126973B2 (en) 2008-09-22 2015-09-08 Cayman Chemical Company, Incorporated Multiheteroaryl compounds as inhibitors of H-PGDS and their use for treating prostaglandin D2 mediated diseases
US8536185B2 (en) 2008-09-22 2013-09-17 Cayman Chemical Company, Incorporated Multiheteroaryl compounds as inhibitors of H-PGDS and their use for treating prostaglandin D2 mediated diseases
WO2010056044A2 (en) * 2008-11-11 2010-05-20 (주)아모레퍼시픽 Novel compound acting as a vanilloid receptor antagonist, isomer or pharmaceutically acceptable salt thereof, and pharmaceutical composition containing same
WO2010056044A3 (en) * 2008-11-11 2010-10-21 (주)아모레퍼시픽 Novel compound acting as a vanilloid receptor antagonist, isomer or pharmaceutically acceptable salt thereof, and pharmaceutical composition containing same
US9062035B2 (en) 2009-03-09 2015-06-23 Taiho Pharmaceutical Co., Ltd. Piperazine compound capable of inhibiting prostaglandin D synthase
US8865714B2 (en) 2009-03-09 2014-10-21 Taiho Pharmaceutical Co., Ltd. Piperazine compound capable of inhibiting prostaglandin D synthase
WO2010104024A1 (en) 2009-03-09 2010-09-16 大鵬薬品工業株式会社 Piperazine compound capable of inhibiting prostaglandin d synthase
KR101367057B1 (en) 2009-03-17 2014-02-25 (주)아모레퍼시픽 Composition for Reducing Skin Irritation
KR101252335B1 (en) 2009-07-16 2013-04-08 (주)아모레퍼시픽 Composition for Preventing Skin Aging
US9469627B2 (en) 2009-10-08 2016-10-18 Sanofi Phenyloxadiazole derivatives as PGDS inhibitors
US9937175B2 (en) 2009-10-08 2018-04-10 Sanofi Phenyloxadiazole derivatives as PGDS inhibitors
KR20120131164A (en) 2010-01-22 2012-12-04 다이호야쿠힌고교 가부시키가이샤 Piperazine compound having a pgds inhibitory effect
US8765750B2 (en) 2010-01-22 2014-07-01 Taiho Pharmaceutical Co., Ltd. Piperazine compound having a PGDS inhibitory effect
US9199976B2 (en) 2010-06-01 2015-12-01 The University Of Queensland Haematopoietic-prostaglandin D2 synthase inhibitors
WO2011150457A3 (en) * 2010-06-01 2012-01-26 The University Of Queensland Haematopoietic-prostaglandin d2 synthase inhibitors
US9181183B2 (en) 2010-09-07 2015-11-10 Taiho Pharmaceutical Co., Ltd. Prostaglandin D synthase inhibitory piperidine compounds
WO2017103851A1 (en) 2015-12-17 2017-06-22 Astex Therapeutics Limited Quinoline-3-carboxamides as h-pgds inhibitors
EP3429588A4 (en) * 2016-03-14 2019-11-13 Emory University Amide-sulfamide derivatives, compositions, and uses related to cxcr4 inhibition
WO2018069863A1 (en) 2016-10-13 2018-04-19 Glaxosmithkline Intellectual Property Development Limited 1,3 di-substituted cyclobutane or azetidine derivatives as hematopoietic prostaglandin d synthase inhibitors
WO2018229629A1 (en) 2017-06-13 2018-12-20 Glaxosmithkline Intellectual Property Development Limited Chemical compounds as h-pgds inhibitors
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US11357759B2 (en) 2017-10-29 2022-06-14 China Medical University Composition including ADAM9 inhibitor and the use thereof
WO2019116256A1 (en) 2017-12-13 2019-06-20 Glaxosmithkline Intellectual Property Development Limited Fused pyridines which act as inhibitors of h-pgds
WO2020095215A1 (en) 2018-11-08 2020-05-14 Glaxosmithkline Intellectual Property Development Limited Chemical compounds
WO2021231571A1 (en) * 2020-05-13 2021-11-18 Chdi Foundation, Inc. Htt modulators for treating huntington's disease
US11806346B2 (en) 2020-05-13 2023-11-07 Chdi Foundation, Inc. HTT modulators for treating Huntington's disease
WO2021256569A1 (en) 2020-06-19 2021-12-23 佐藤製薬株式会社 Condensed ring compounds that inhibit h-pgds
KR20230027059A (en) 2020-06-19 2023-02-27 사토 세이야쿠 가부시키가이샤 Condensed ring compounds that inhibit H-PGDS
US20230077316A1 (en) * 2020-10-23 2023-03-09 Nimbus Clotho, Inc. Ctps1 inhibitors and uses thereof
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