Classifications

• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/422—Oxazoles 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
  • 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
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • 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
  • 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
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • 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
  • C07D417/14—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 three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• Phosphatidylinositol 3-kinase is a family of lipid kinases that phosphorylate phosphatidylinositol at the 3' position of the inositol ring.
• PI3K is comprised of several classes of genes, including Class IA, IB, II and III and some of these classes contain several isoforms (reviewed in Engelman et al., Nature Review Genetics 7:606-619 (2006)). Adding to the complexity of this family is the fact that PI3Ks function as heterodimers, comprising a catalytic domain and a regulatory domain.
• PI3K family is structurally related to a larger group of lipid and serine/threonine protein kinases known as the phosphatidylinositol 3-kinase like kinases (PIKKs), which also includes DNA-PK, ATM, ATR, mTOR, TRRAP and SMG1.
• PIKKs phosphatidylinositol 3-kinase like kinases
• PI3K is activated downstream of various mitogenic signals mediated through receptor tyrosine kinases, and subsequently stimulates a variety of biological outcomes; including increased cell survival, cell cycle progression, cell growth, cell metabolism, cell migration and angiogenesis (reviewed in Cantley, Science 296:1655-57 (2002); Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005); Engelman et al., Nature Review Genetics 7:606-619 (2006)).
• PI3K hyper-activation is associated with a number of hyper-proliferative, inflammatory, or cardiovascular disorders; including cancer, inflammation, and cardiovascular disease.
• the molecules defined within this invention inhibit the activity of PI3K, and therefore may be useful for the treatment of proliferative, inflammatory, or cardiovascular disorders.
• Cases where PI3K pathway mutations have been linked to proliferative disorders where the molecules defined within this invention may have a therapeutic benefit include benign and malignant tumors and cancers from diverse lineage, including but not limited to those derived from colon (Samuels et al., Science 304:554 (2004); reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), liver (reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), intestine (reviewed in Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)), stomach (Samuels et al., Science 304:554 (2004); reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), esophagus (Phillips et al
• Other classes of disorders with aberrant PI3K pathway signaling where the molecules defined within this invention may have a therapeutic benefit include inflammatory and cardiovascular diseases, including but not limited to allergies/anaphylaxis (reviewed in Rommel et al., Nature Reviews Immunology 7:191-201 (2007)), acute and chronic inflammation (reviewed in Ruckle et al., Nature Reviews Drug Discovery 5:903-12 (2006); reviewed in Rommel et al., Nature Reviews Immunology 7:191-201 (2007)), rheumatoid arthritis (reviewed in Rommel et al., Nature Reviews Immunology 7:191- 201 (2007)); autoimmunity disorders (reviewed in Ruckle et al., Nature Reviews Drug Discovery 5:903- 12 (2006)), thrombosis (Jackson et al., Nature Medicine 11:507-14 (2005); reviewed in Ruckle et al., Nature Reviews Drug Discovery 5:903-12 (2006)), hypertension (reviewed in Ruckle et al., Nature Reviews Drug Discovery 5:
• Vacuolar Protein Sorting 34 is the sole Class III PI3K family member. VPS34 functions in the formation and trafficking of multiple intracellular vesicles, including vacuoles, endosomes, multivesicular bodies, lysosomes and autophagosomes (reviewed in Backer Biochem J 2008; Attorney Docket No.: MPI10-014P3RNWOM
• VPS34 carries out these activities by phosphorylating Ptdlns forming PtdIns3P, resulting in the recruitment and localization of a variety of FYVE and PX domain containing effector proteins that facilitate vesicular formation, elongation and movement.
• inhibition of VPS34 results in defects in protein sorting and autophagy.
• autophagy is a regulated process whereby cells catabolize subcellular components targeted for degradation by enclosing them in double-membrane vesicles which then fuse with lysosomes.
• VPS34 may also participate in several signal transduction pathways (reviewed in Backer Biochem J 2008).
• VPS34 plays an important role in many critical cellular processes including autophagy
• inhibitors of VPS34 may have therapeutic application in a number of diseases, including but not limited to cancer, muscular disorders, neurodegeneration, inflammatory disease, infectious disease and other age related illnesses (reviewed in Shintani and Klionshy Science 2004; Kondo et al Nat Rev Cancer 2005; Delgato et al Immunol Rev 2009).
• VPS34 and/or PI3K inhibitors that possess good therapeutic properties, especially for the treatment of proliferative, inflammatory, or cardiovascular disorders.
• This invention provides compounds that are inhibitors of VPS34 and/or PI3K, and accordingly are useful for the treatment of proliferative, inflammatory, or cardiovascular disorders.
• the compounds of this invention are represented by a compound of formula IA or IB:
• G] is N or CR 3 , wherein R 3 is H, -CN, halogen, -Z-R 5 , C]_ 6 aliphatic, or 3-10-membered cycloaliphatic, wherein: Attorney Docket No.: MPI10-014P3RNWOM
• Z is selected from an optionally substituted Q.3 alkylene chain, -0-, -N(R a )-, -S- , -S(O)-, -S(0) 2 -, -C(O)-, -C0 2 -, -C(0)NR 3a -, -N(R 3a )C(0)-, -N(R 3a )C0 2 -, -S(0) 2 NR 3a -, - N(R 3a )S(0) 2 -, -OC(0)N(R 3a )-, -N(R 3a )C(0)NR 3a -, -N(R 3a )S(0) 2 N(R 3a )-, or -OC(O)-;
• R 3a is hydrogen or an optionally substituted Q_ 4 aliphatic
• R 5 is an optionally substituted group selected from Ci -6 aliphatic, 3-10- membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5
• heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6- 10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms
• R 4 is H, -Z 2 -R 6 , optionally substituted Ci_ 6 aliphatic, 6-10-membered aryl, or 5-10- membered heteroaryl having 1 -5 heteroatoms independently selected from nitrogen, oxygen, or sulfur or optionally substituted 3-10-membered cycloaliphatic, wherein:
• Z 2 is selected from an optionally substituted C J-3 alkylene chain, -S(O)-, -S(0) 2 -, - C(O)-, -C0 2 -, -C(0)NR 4 ⁇ S(0) 2 NR 4 ⁇ or -(CH 2 ) q O(CH 2 ) q -;
• R 4a is hydrogen or an optionally substituted C aliphatic
• R 6 is an optionally substituted group selected from Ci_ 6 aliphatic, -OR 4a , 3-10- membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or
• q 0 to 3;
• R 2 is hydrogen, halogen, CN, -N(R 21 ) 2 , or an optionally substituted monocyclic group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R 2 is optionally substituted with 1-4 occurrences of R 2a , wherein each occurrence of R 2a is independently -R 12a , -T 2 -R 12d , -T 2 -R 12a , or -V 2 -T 2 -R 12d , and:
• each occurrence of R 12a is independently halogen, -CN, -N0 2 , -R 12c , -N(R 12b ) 2 , -OR 12b , -SR 12c , - S(0) 2 R 12c , -C(0)R ,2b , -C(0)OR ,2b , -C(0)N(R 12b ) 2 , -S(0) 2 N(R 12b ) 2 , -OC(0)N(R 12b ) 2 , - Attorney Docket No.: MPI10-014P3RNWOM
• each occurrence of R 12b is independently hydrogen or an optionally substituted group selected from Ci_C 6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• R 12b taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;
• each occurrence of R I2c is independently an optionally substituted group selected from .
• each occurrence of R 12d is independently hydrogen or an optionally substituted group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5- 10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each occurrence of R 12e is independently hydrogen or an optionally substituted C y . 6 aliphatic group
• each occurrence of V 2 is independently -N(R 12e )-, -0-, -S-, -S(O)-,
• T 2 is an optionally substituted C]_C 6 alkylene chain wherein the alkylene chain optionally is interrupted
• each occurrence of R 21 is independently hydrogen, -S(0) 2 R 2a , -C(0)R 2a , or an optionally substituted Cl-6aliphatic, provided that only one occurrence of R 2 ' is hydrogen; or wherein two Attorney Docket No.: MPI10-014P3RNWOM occurrences of R21, taken together with the atom to which they are bound, form an optionally substituted 5-6-membered heteroaryl ring having 0-3 additional heteroatoms independently selected from nitrogen, oxygen or sulfur;
• HY is an optionally substituted group selected from:
• each occurrence of X 4 , X 5 , X 6 , X 7 , and X 8 is independently -CR 10 or N, provided no more than two occurrences of X 4 , X 5 , X 6 , X 7 , and X 8 are N;
• each occurrence of Qi and Q 2 is independently S, O or -NR 9 ;
• each occurrence of Y Y 2 , Y3, Y 4 , Y5, ⁇ , Y7, and Y g is independently -CR 10 or N, provided no more than two occurrences of Y 6 , Y 7 , and Y 8 are N;
• R 10 is -R 10b , -V R 10c , -T R 10b , or -V 1 -T 1 -R 10b wherein:
• Vj is -NR 11 -, -NR n -C(0)-, -NR n -C(S)-, -NR n -C(NR n )-, -NR n C(O)OR 10a -, - NR n C(0)NR n - ; -NR u C(O)SR 10a -, -NR n C(S)OR 10a -, -NR n C(S)NR n -, -NR n C(S)SR 10a -, -NR ⁇ tNR ⁇ OR 103 -, -NR 11 C(NR 11 )NR 11 -, -NR H S(0) 2 -, -NR n S(0) 2 NR u -, -C(O)-, -C0 2 - , -C(0)NR H -, -C(0)NR n O-, -SO 2 -, or -S0 2 NR n -;
• each occurrence of R 10a is independently hydrogen or an optionally substituted group selected from Ci -6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Attorney Docket No.: MPI10-014P3RNWOM
• T] is an optionally substituted C ⁇ _Ce alkylene chain wherein the alkylene chain optionally is interrupted by -N(R n )-, -0-, -S-, -S(O)-, -S(0) 2 -, -C(O)-, -C(0)0-, -C(0)N(R n )-, -SCO ⁇ R 1 ')-, -O C(0)N(R n )-, -N(R n )C(0)-, -N(R H )S0 2 -, -N(R l la )C(0)0-, -NR 10a C(O)N(R 10a )-, -N(R 10a )S(O) 2 N(R 10a )-, -OC(O)-, or -C(0)N(R n )-0- or wherein Tj forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;
• each occurrence of R 10b is independently hydrogen, halogen, -CN, -N0 2 , - N(R U ) 2 , -OR 10a , -SR 10a , -S(O) 2 R 10a , -C(O)R 10a , -C(O)OR 10a , -C(0)N(R u ) 2 , -S(0) 2 N(R ll ) 2 , -OC(0)N(R n ) 2 , -N(R n )C(O)R 10a , -N(R n )SO 2 R 10a , -N(R !
• each occurrence of R 10c is independently hydrogen or an optionally substituted group selected from Ci_ 6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1 -5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or
• R 10a and R 10c taken together with a nitrogen atom to which they are bound form an optionally substituted 4-7 -membered heterocyclyl ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each occurrence of R 11 is independently hydrogen, -C(0)R Ua , -C0 2 R l la , -C(0)N(R l la ) 2 , - C(0)N(R 1 Ia )-OR l la , -S0 2 R , ]a , -S0 2 N(R Ha ) 2 , or an optionally substituted group selected from C,_ 6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each occurrence of R Ua is independently hydrogen or an optionally substituted group selected from Ci_ 6 aliphatic, 3-10-membered cycloaliphatic, 4-10- membered heterocyclyl having 1 -5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1 -5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each occurrence of R 9 is independently hydrogen, -C(0)R 9a , -C0 2 R 9a , -C(0)N(R 9b ) 2 , -S0 2 R 9a , - S0 2 N(R 9b ) 2 , or an optionally substituted group selected from Ci_ 6 aliphatic, 3-10-membered Attorney Docket No.: MPI10-014P3RNWOM cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each occurrence of R 9a is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each occurrence of R 9b is independently hydrogen or an optionally substituted group selected from C )-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R 9b taken together with the nitrogen atom to which they are bound, form an optionally substituted group selected from 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that:
• R 2 when R 2 is a ring, then R 2 is substituted with at least one R 2a ;
• CY is a 3-7-membered cycloaliphatic or a 5-6-membered aryl group, then the cycloaliphatic or aryl group is substituted with at least one non-hydrogen substituent;
• R 2 is hydrogen, then HY is selected from:
• R 10' is -NHR 11 ;
• HY is a group other than indolyl, 4-pyridinyl, 3-pyridinyl, indazolyl, pyrrolopyridinyl, or pyrazolyl;
• 2-Pyrimidinamine 4-[4-(4-fluorophenyl)-2-(4-pyridinyl)-5-oxazolyl]-N-[( 1 S)-l - phenylethyl]-;
• Pyrimidine 5-[4-chloro-5-[4-(trichloromethyl)phenyl]-2-oxazolyl]-2,4,6trimethoxy-; Pyridine, 3-[4-(4-fluorophenyl)-5-iodo-2-oxazolyl]-4-methyl-;
• 4-Oxazolecarboxylic acid 5-[(ethoxymethylene)amino]-2-(4-pyridinyl)-, ethyl ester
• 2-Pyridinecarboxylic acid 5-[5-bromo-2-(5-chloro-3-pyridinyl)-4-oxazolyl]-, methyl ester;
• compounds of the invention may be optionally substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
• substituents such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
• phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.”
• substituted whether preceded by the term “optionally” or not, means that a hydrogen radical of the designated moiety is replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible compound.
• substituted when used in reference to a designated atom, means that attached to the atom is a hydrogen radical, which hydrogen atom can be replaced with the radical of a suitable substituent.
• an "optionally substituted” group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
• a stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature from about -80°C to about +40°, in the absence of moisture or other chemically reactive conditions, for at least a week, or a compound which maintains its integrity long enough to be useful for therapeutic or prophylactic administration to a patient.
• substituents refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites, provided that the above conditions of stability and chemical feasibility are met.
• a 3-7-membered saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10- membered partially unsaturated, or aromatic bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur includes cycloaliphatic, heterocyclic, aryl and heteroaryl rings.
• aromatic includes aryl and heteroaryl groups as described generally below and herein.
• aliphatic or "aliphatic group”, as used herein, means an optionally substituted straight-chain or branched C n hydrocarbon, or a cyclic CM 2 hydrocarbon which is completely saturated or which contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle”, “cycloaliphatic”, “cycloalkyl”, or “cycloalkenyl”).
• suitable aliphatic groups include optionally substituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids Attorney Docket No.: MPI10-014P3RNWOM thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.
• aliphatic groups have 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms.
• alkyl used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms.
• alkenyl used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one double bond and having 2- 12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms.
• alkynyl used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms.
• cycloaliphatic refers to an optionally substituted saturated or partially unsaturated cyclic aliphatic ring system having from 3 to abovit 14 ring carbon atoms.
• the cycloaliphatic group is an optionally substituted monocyclic hydrocarbon having 3-8 or 3-6 ring carbon atoms.
• Cycloaliphatic groups include, without limitation, optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, or cyclooctadienyl.
• cycloaliphatic also include optionally substituted bridged or fused bicyclic rings having 6-12, 6-10, or 6-8 ring carbon atoms, wherein any individual ring in the bicyclic system has 3-8 ring carbon atoms.
• cycloalkyl refers to an optionally substituted saturated ring system of about 3 to about 10 ring carbon atoms.
• exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
• cycloalkenyl refers to an optionally substituted non-aromatic monocyclic or multi cyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
• exemplary monocyclic cycloalkenyl rings include cyclopentyl, cyclohexenyl, and cycloheptenyl.
• haloaliphatic refers to an aliphatic, alkyl, alkenyl or alkoxy group, as the case may be, which is substituted with one or more halogen atoms.
• halogen or halo means F, CI, Br, or I.
• fluoroaliphatic refers to a haloaliphatic wherein the halogen is fluoro, including perfluorinated aliphatic groups.
• fluoroaliphatic groups include, without limitation, fluoromethyl, difluoromethyl, trifluoromethyl, 2- fluoroethyl, 2,2,2-trifluoroethyl, 1 , 1 ,2-trifluoroethyl, 1 ,2,2-trifluoroethyl, and pentafluoroethyl.
• fluoroaliphatic groups include, without limitation, fluoromethyl, difluoromethyl, trifluoromethyl, 2- fluoroethyl, 2,2,2-trifluoroethyl, 1 , 1 ,2-trifluoroethyl, 1 ,2,2-trifluoroethyl, and pentafluoroethyl.
• heteroatom refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro- 2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
• aryl and “ar-”, used alone or as part of a larger moiety e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refer to an optionally substituted C ⁇ waromatic hydrocarbon moiety comprising one to three aromatic rings.
• the aryl group is a group.
• Aryl groups include, without limitation, optionally substituted phenyl, naphthyl, or anthracenyl.
• aryl and “ar-”, as used herein, also include groups in which an aryl ring is fused to one or more cycloaliphatic rings to form an optionally substituted cyclic structure such as a tetrahydronaphthyl, indenyl, or indanyl ring.
• aryl may be used interchangeably with the terms “aryl group”, “aryl ring”, and “aromatic ring”.
• an "aralkyl” or “arylalkyl” group comprises an aryl group covalently attached to an alkyl group, either of which independently is optionally substituted.
• the aralkyl group is C 6 _io arylC]_ 6 alkyl, including, without limitation, benzyl, phenethyl, and naphthylmethyl.
• heteroaryl and “heteroar-”, used alone or as part of a larger moiety refer to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
• a heteroaryl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.
• heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen.
• a nitrogen atom of a heteroaryl may be a basic nitrogen atom and may also be optionally oxidized to the corresponding N-oxide.
• heteroaryl When a heteroaryl is substituted by a hydroxy group, it also includes its corresponding tautomer.
• heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocycloaliphatic rings.
• heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl
• heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are Attorney Docket No.: MPI10-014P3RNWOM optionally substituted.
• heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
• heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic or 7-10- membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
• nitrogen includes a substituted nitrogen.
• the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl).
• a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
• saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl.
• a heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.
• heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
• a heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings.
• partially unsaturated refers to a ring moiety that includes at least one double or triple bond between ring atoms.
• the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties, as herein defined.
• alkylene refers to a bivalent alkyl group.
• An "alkylene chain” is a polymethylene group, i.e., -(CH 2 ) n -, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
• An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3-7-membered ring. The substituents can be on the same or different atoms.
• An alkylene chain also can be optionally interrupted by a functional group.
• An alkylene chain is "interrupted" by a functional group when an internal methylene unit is interrupted by the functional Attorney Docket No.: MPI10-014P3RNWOM group. Examples of suitable "interrupting functional groups" are described in the specification and claims herein.
• An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents and thus may be "optionally substituted".
• An aliphatic or heteroaliphatic group, or a non-aromatic carbocyclic or heterocyclic ring may contain one or more substituents and thus may be "optionally substituted".
• a ring nitrogen atom of a heteroaryl or non-aromatic heterocyclic ring also may be oxidized to form the corresponding N-hydroxy or N-oxide compound.
• a nonlimiting example of such a heteroaryl having an oxidized ring nitrogen atom is N-oxidopyridyl.
• two independent occurrences of R + are taken together with their intervening atom(s) to form a monocyclic or bicyclic ring selected from 3-13-membered cycloaliphatic, 3-12-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Exemplary rings that are formed when two independent occurrences of R + (or any other variable similarly defined in the specification and claims herein), are taken together with their intervening atom(s) include, but are not limited to the following: a) two independent occurrences of R + (or any other variable similarly defined in the specification or claims herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R + ) 2 , where both occurrences of R + are taken together with the nitrogen atom to form a piperidin-l-yl, piperazin-l-yl, or morpholin-4-yl group; and b) two independent occurrences of R + (or any other variable similarly defined in the specification or claims herein) that are bound to different atoms and are taken together with both of those atoms to form a ring,
• Exemplary rings that are formed when two independent occurrences of X 4 and X 3 ⁇ 4 , or X 6 and X 7 ; are taken together with their intervening atom(s) include, but are not limited to the following: pyrazolopyrimidinyl, purinyl, quinolyl, tetrahydroquinolinyl, quinazolinyl, naphthyridinyl, pyridopyrimidinyl, pyrazolopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, 1H- pyrrolo[2,3-b]pyridinyl-2(3H)-one, 3,4-dihydro-l ,8-naphthyridinyl-2(lH)-one, 1 ,8-naphthyridinyl-2(l H)- one, lH-pyridyl[2,3-d]
• Exemplary rings that are formed when two independent occurrences of Yi and Qi, Y 3 and Q 2 , or Y 4 and Y 5 are taken together with their intervening atom(s) include, but are not limited to the Attorney Docket No.: MPI10-014P3RNWOM following: indolyl, indazolyl, 4H-furo[3,2-b]pyrrolyl, 4H-thieno[3,2-b]pyrrolyl, 5H-furo[2,3-b]pyrrolyl, 5H-thieno[2,3-b]pyrrolyl, pyrrolo[3,4-b]pyrrolyl, pyrrolo[3,2-b]pyrrolyl, pyrrolo[2,3-b]pyrrolyl, dihydropyrrolo[3,2-b]pyrrolyl, dihydropyrrolo[2,3-b]pyrrolyl, 5H-pyrrolo[3,2-d]oxazole, 5H-pyrrolo[3,2-
• structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures where there is a replacement of hydrogen by deuterium or tritium, or a replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
• Such compounds are useful, as a nonlimiting example, as analytical tools or probes in biological assays.
• the present invention encompasses one enantiomer of inhibitor free from the corresponding optical isomer, racemic mixture of the inhibitor and mixtures enriched in one enantiomer relative to its corresponding optical isomer.
• the mixture contains, for example, an enantiomeric excess of at least 50%, 75%, 90%, 95% 99% or 99.5%.
• the enantiomers of the present invention may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
• enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
• the present invention encompasses a diastereomer free of other diastereomers, a pair of diastereomers free from other Attorney Docket No.: MPI10-014P3RNWOM diasteromeric pairs, mixtures of diasteromers, mixtures of diasteromeric pairs, mixtures of diasteromers in which one diastereomer is enriched relative to the other diastereomer(s) and mixtures of diasteromeric pairs in which one diastereomeric pair is enriched relative to the other diastereomeric pair(s).
• the mixture is enriched in one diastereomer or diastereomeric pair(s) relative to the other diastereomers or diastereomeric pair(s), the mixture is enriched with the depicted or referenced diastereomer or diastereomeric pair(s) relative to other diastereomers or diastereomeric pair(s) for the compound, for example, by a molar excess of at least 50%, 75%, 90%, 95%, 99% or 99.5%.
• the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Specific procedures for chromatographically separating diastereomeric pairs of precursors used in the preparation of compounds disclosed herein are provided the examples herein.
• R 1 is CY and CY is:
• X], X 2 , and X 3 are each independently N, O, S, NR 4 , or CR 7 , provided that only
• Y 9 is N or CR 7 ;
• R 4 is independently hydrogen, -Z 2 -R 6 , optionally substituted
• Z 2 is selected from an optionally substituted Q_ 3 alkylene chain, -S(O)-,
• R a is hydrogen or an optionally substituted Q_ 4 aliphatic
• R 6 is an optionally substituted group selected from C ⁇ 6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
• each occurrence of R 7 and R 7 is independently hydrogen, -CN, halogen, -Z 3 -R 8 ,
• Ci_6 aliphatic or 3-10-membered cycloaliphatic, wherein: Attorney Docket No.: MPI10-014P3RNWOM
• Z 3 is selected from an optionally substituted Cy alkylene chain, -0-, -N(R 7a )-, - S-, -S(O)-, -S(0) 2 -, -C(O)-, -CO 2 -, -C(0)NR 7a -, -N(R 7a )C(0)-, -N(R 7a )C0 2 -, -S(0) 2 NR 7a -, -N(R 7a )S(0) 2 -, -OC(0)N(R 7a , -N(R 7a )C(0)NR 7a -, -N(R 7a )S(0) 2 N(R 7a )-, or -OC(O)-;
• R 7 is hydrogen or an optionally substituted CM aliphatic
• R 8 is an optionally substituted group selected from Ci_ 6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• R 1 is CY and CY
• Xi, X 2 , and X 3 are each independently N, O, S, NR 4 , or CR 7 , provided that only one of
• R 4 is independently H, -Z 2 -R 6 , optionally substituted C 1-6 aliphatic, or optionally substituted 3-10-membered cycloaliphatic, wherein:
• Z 2 is selected from an optionally substituted C 1 -3 alkylene chain, -S(O)-, -S(0) 2 -, - C(O)-, -CO 2 -, -C(0)NR 4a -, or -S(0) 2 NR 4a -.
• R 4a is hydrogen or an optionally substituted C aliphatic
• R 6 is an optionally substituted group selected from Ci_ 6 aliphatic, 3-10- membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms
• each occurrence of R 7 or R 7 is independently hydrogen, -CN, halogen, -Z3-R 8 , Ci_ 6 aliphatic, or 3-10-membered cycloaliphatic, wherein:
• Z 3 is selected from an optionally substituted Ci_ 3 alkylene chain, -0-, -N(R 7a )-, - S-, -S(O)-, -S(0) 2 -, -C(O)-, -C0 2 -, -C(0)NR 7 ⁇ -N(R 7a )C(0)-, -N(R 7a )C0 2 -, -S(0) 2 NR 7a -, -N(R 7a )S(0) 2 -, -OC(0)N(R 7a )-, -N(R 7a )C(0)NR 7a -, -N(R 7a )S(0) 2 N(R 7a )-, or -OC(O)-.
• R 7a is hydrogen or an optionally substituted CM aliphatic, and Attorney Docket No.: MPI10-014P3RNWOM
• R is an optionally substituted group selected from Ci_ 6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• R 1 is CY and CY is
• R 1 is CY and CY is:
• Xj is N
• G 2 is N(R 4' )
• X 2 and X 3 are CH.
• Xi and X 2 are N, G 2 is N(R 4 ' ), and X 3 is CH.
• X 3 is N
• G 2 is N(R 4' )
• Xi and X 2 are CH.
• Xi is N(R 4 ), G 2 is N, and X 2 and X 3 are CH.
• X, and G 2 are N, X 3 is N(R 4' ), and X 2 is CH.
• X x and X 2 are CH, G 2 is N, and X 3 is N(R 4' ).
• X 2 and G 2 are CH, X] is N, and X 3 is N(R 4 ).
• G 2 is N
• X 3 is CH 2
• X 2 is N(R 4' )
• X is N.
• R 1 is an optionally substituted 6-membered aryl or heteroaryl ring.
• R 1 is selected from:
• R is optionally further substituted with one or more occurrences of R 7 or R 4
• R 1 is selected from:
• R 1 is COOR 4 .
• R 1 is COOR 4 or CY and CY is 1
• R 1 is CON(R 4 ) 2 .
• each occurrence of R 4 is independently hydrogen, -Z 2 -R 6 , optionally substituted C]. 6 aliphatic, optionally substituted C 3 . 7 cycloaliphatic, optionally substituted C 3-7 heterocyclyl, or optionally substituted 5-6-membered aryl or heteroaryl ring.
• each occurrence of R 4 is independently hydrogen, -Z 2 -R 6 , or optionally substituted Ci_ 6 aliphatic.
• Z 2 is Ci_ 3 aliphatic and R 6 is -OR 4a or an optionally substituted C 3 . 7 cycloaliphatic, optionally substituted C 3 _ 7heterocyclyl, or optionally substituted 5-6-membered aryl or heteroaryl ring.
• HY is an optionally
• each occurrence of X 5 , X 6 , and X 7 is independently -CR 10 or N, provided no more than two occurrences of X 5 , X 6 , and X 7 are N;
• each occurrence of Qi and Q 2 is independently S, O or -NR 9 ;
• each occurrence of Yi , Y 7 , and Y 8 is independently -CR 10 or N;
• each occurrence of X 5 , X 6 , and X 7 is independently -CR or N, provided no more than two occurrences of X 5 , X 6 , and X 7 are N;
• each occurrence of Qj and Q 2 is independently S, O or -NR 9 ;
• each occurrence of Yi , Y 7 , and Y 8 is independently -CR 10 or N; Attorney Docket No.: MPI10-014P3RNWOM or wherein two adjacent occurrences of X 6 , and X 7 involve Yj and Qi,or two adjacent occurrences of R 10 , taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl, or 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• HY is selected from:
• each HY group is optionally additionally substituted with one or more occurrences of R 10 , and the dashed line in xviii represents a single bond or a double bond.
• HY is selected from:
• each HY group is optionally additionally substituted with one or more occurrences of R 10 , and the dashed line in xviii represents a single bond or a double bond.
• HY is selected from:
• HY is additionally optionally substituted at one or more carbon atoms with one or more occurrences of R 10 .
• HY is selected from (v), wherein HY is additionally optionally substituted with one or more occurrences of R 10 .
• R 1U is NHCOR luc and wherein R , R z and R ,u are as defined generally and in subsets herein.
• HY is , wherein R 10 is hydrogen, methyl, chloro, bromo, fluoro, CN, CF 3 , OR 10c , COR 10c , and R !0 is NHCOR 10c or -NHCOOR 10c .
• Gi is C(R 3 ).
• Gi is CH.
• Gi is N.
• R 2 is a 6-10-membered aryl or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; optionally substituted with 1-3 occurrences of R 2a .
• R 2 is a phenyl group; optionally substituted with one or more independent occurrences of halogen, alkyl, C 3 . 6 cycloalkyl, C3_ 6 heterocyclyl, -CN, d -3 haloalkyl, -(CH 2 ) p N(R 12b ) 2 , -OR 12b , -NHC(0)R 12b , -NHC(0)NHR 12b , -NHS(0) 2 R 12b , C(0)OR 12b , - C(0)N(R 12b ) 2 , or -C(0)R 12b .
• R 2 is a phenyl group; optionally substituted with one or more independent occurrences of halogen, C 1-3 alkyl, -CN, Q_ 3 haloalkyl, -CH 2 N(R 12b ) 2 , -OC,. 3 alkyl, - OC 1-3 haloalkyl, -NHC(0)C,_ 3 alkyl, -NHC(0)NHC 1-3 alkyl, -NHS(0) 2 C,_ 3 alkyl, or -C(0)H.
• R 2 is a phenyl group; optionally substituted with one or more independent occurrences of halogen, Q_ 3 alkyl, -CN, Ci_ 3 haloalkyl, -CH 2 N(CH 3 ) 2 , -OCi_ 3 alkyl, - OQ.3 haloalkyl, -NHC(0)C]_ 3 alkyl, -NHC(0)NHC,. 3 alkyl, -NHS(0) 2 d_ 3 alkyl, or -C(0)H.
• R 2 is a phenyl group substituted with 1 or 2 occurrences of halogen.
• R 2 is a phenyl group substituted with 1 occurrence of halogen.
• the halogen is CI.
• R 2 is a phenyl group substituted with 1 occurrence of halogen in the meta position.
• the halogen is CI.
• R 2 is a phenyl group substituted with 1 occurrence of halogen in the meta position and is further substituted with 1 occurrence of R 2a .
• the halogen is CI and R 2a is -CH 2 N(R 12b ) 2
• R 2 is a 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1 -5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• R 2 is an optionally substituted N-linked 3-, 4-, 5-, 6-, or 7- membered heterocyclyl ring.
• the wherein the N-linked 3-, 4-, 5-, 6-, or 7- membered heterocyclyl ring is optionally substituted with one or more occurrences of R 2a .
• R 2 is an optionally substituted N-linked 5- or 6-membered ring optionally substituted with one or more occurrences of R 2a .
• the ring is optionally substituted with one or more C ⁇ alkyl groups.
• R 1 is CON(R 4 ) 2 or CY;
• R 2 is phenyl substituted with one or more occurrences of R 2 ;
• HY is > vw , wherein HY is additionally optionally substituted with one or more occurrences of R 10
• R 1 is CON(R 4 ) 2 or CY;
• R 2 is phenyl substituted with one or more occurrences of R 2a ;
• HY is T 1 wv , wherein HY is additionally optionally substituted with one or more occurrences of R 10
• the compounds of the present invention can be prepared by methods known to one of ordinary skill in the art and / or by reference to the schemes shown below and the synthetic examples that follow. Exemplary synthetic routes are set forth in the Schemes below, and in the Examples.
• Examples of the solvent for the below-mentioned reactions include, but are not limited to halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1 ,2-dichloroethane and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, alcohols such as methanol, ethanol, isopropanol, ieri-butanol, phenol and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, DME and the like, acetone, acetonitrile, ethyl acetate, NN-dimethylformamide, NN-dimethylacetamide, 1 -methyl -2 -pyrrolidone, dimethyl sulfoxide, hexamethylphosphoramide, water or a mixed solvent thereof and the like.
• halogenated hydrocarbons such as dichloromethane, chloroform
• reaction conditions including variations in solvent, reagents, catalysts, reaction temperatures and times are possible for each of the reactions described. Variation of order of synthetic steps and alternative synthetic routes are also possible.
• synthesis can be started from commercially available furan/oxazole analogs to prepare target compounds.
• specially functionalized furan/oxazole analogs can be prepared by the procedures described in the Schemes below.
• the compounds of the present invention can be prepared by methods known to one of ordinary skill in the art and / or by reference to the schemes shown below and the synthetic examples that follow.
• Scheme 1 describes a method of preparing substituted oxazoles vi.
• Treatment of ethyl 1,3- oxazole-5-carboxylate with lithium hexamethyldisilazane and iodine in DMPU gives ii as reported in the literature (Vedejs, E., Luchetta, L. M. J. Org. Chem. 1999, 64, 1011).
• Compounds iii can then be prepared from compounds ii by Method A.
• Method A is the coupling reaction of an aryl or heteroaryl bromide with an appropriate aryl or heteroaryl stannane under suitable conditions, for example Pd(PPh 3 ) 4 , Cul, LiCl in an appropriate solvent, such as dioxane, at elevated temperature.
• Method A can refer to the coupling reaction of an aryl or heteroaryl bromide with an appropriate boronic acid or boronic ester under suitable conditions, for example Pd(PPh 3 ) 4 , Cs 2 C0 3 , in an appropriate solvent, such as dioxane, at elevated temperature or under microwave irradiation.
• Method A can subsequently be used to prepare compounds iv from iii when R 2 is an aromatic or heteroaromatic group.
• Method B is the coupling of an aryl or heteroaryl bromide with an amine under suitable conditions, for example Pd 2 (dba) 3 , xantphos, Cs 2 C0 3 , in an appropriate solvent, such as dioxane, at elevated temperature or under microwave irradiation.
• suitable conditions for example Pd 2 (dba) 3 , xantphos, Cs 2 C0 3 , in an appropriate solvent, such as dioxane, at elevated temperature or under microwave irradiation.
• Method B can refer to the direct displacement of a halogen by an amine under suitable conditions, for example reaction in an appropriate solvent, such as DMSO, at an elevated temperature or under microwave irradiation.
• Compounds vi can be prepared via the intermediate acids v (obtained by hydrolysis of the ester of compounds iv under standard conditions) or by transformation of the esters iv directly to a variety of groups using standard methods.
• Scheme 2 describes an alternative method of preparing substituted oxazoles vi.
• Compounds vi can be prepared via the intermediate acids vii (obtained by hydrolysis of the ester of compounds iii under standard conditions) or by transformation of the esters iii directly to a variety of groups using standard methods.
• Oxazoles vi can be prepared from viii by reaction according to Method A or Method B.
• Scheme 3 General method for the synthesis of oxazoles xv
• Scheme 3 describes a method of preparing substituted oxazoles xv.
• Acid chlorides ix can be reacted with methyl isocyanoacetate (x) according to procedures described in the literature (e.g., Hirashima, S. et al. J. Med. Chem. 2006, 49, 4721).
• the resulting oxazoles xi can be iodinated under standard conditions, for example treatment with lithium hexamethyldisilazine and iodine in a solvent such as THF to give iodides xii.
• the oxazoles xiii can be prepared from xii using Method A.
• Compounds xiii can be elaborated to oxazoles xv through a series of standard transformations as described for the preparation of compounds vi from iv in Scheme 1.
• Scheme 4 describes an alternative method of preparing substituted oxazoles xv.
• Compounds xvi can be prepared from esters xii through a series of standard transformations as described for the preparation of compounds vi from iv in Scheme 1.
• Compounds xvi can be elaborated to oxazoles xv using Method A.
• Scheme 5 describes a general method for preparation of furans of formula xxi.
• Ethyl 5-[2- (acetylamino)pyridin-4-yl]-2-bromo-3-furoate xvii can be transformed according to Method A to furan xviii.
• Reaction again according to Method A or Method B can be used as a method to prepare compounds xix.
• Compounds xxi can be prepared from esters xix through a series of standard transformations as described for the preparation of compounds vi from iv in Scheme 1.
• Scheme 6 describes an alternative a general method for preparation of furans of formula xxi.
• Furan xxii can be halogenated under standard conditions, for example treatment with bromine in a suitable solvent, such as chloroform, at an appropriate temperature.
• the bromides xxiii can then be transformed according to Method A to furans xxiv.
• Compounds xxiv can also undergo bromination under standard conditions, for example treatment with NBS in a suitable solvent, such as DMF, at an Attorney Docket No.: MPI10-014P3RNWOM appropriate temperature, such as 80 °C, to give bromides xxv.
• Compounds xxvi can be prepared from esters xxv through a series of standard transformations as described for the preparation of compounds vi from iv in Scheme 1.
• Compounds xxxvi can be transformed to furans xxi by either Method A or Method B.
• the present invention provides compounds that are useful as inhibitors of VPS34 and/or PI3K, and thus the present compounds are useful for treating proliferative, inflammatory, or cardiovascular disorders such as tumor and/or cancerous cell growth mediated by VPS34 and/or PI3K.
• the compounds are useful in the treatment of cancers in a subject, including, but not limited to, lung and bronchus, prostate, breast, pancreas, colon and recum, thyroid, liver and intrahepatic bile duct, hepatocellular, gastric, glioma/glioblastoma, endometrial, melanoma, kidney, and renal pelvis, urinary bladder, uterine corpus, uterine cervix, ovary, multiple myeloma, esophagus, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, brain, oral cavity, and pharynx, small intestine, non-Hodgkin lymphoma, and villous colon adenoma.
• compounds of the invention are suitable for the treatment of breast cancer, bladder cancer, colon cancer, glioma, glioblastoma, lung cancer, hepatocellular cancer, gastric cancer, melanoma, thyroid cancer, endometrial cancer, renal cancer, cervical cancer, pancreatic cancer, esophageal cancer, prostate cancer, brain cancer, or ovarian cancer.
• compounds of the invention are suitable for the treatment of inflammatory and cardiovascular disorders including, but not limited to, allergies/anaphylaxis, acute and chronic inflammation, rheumatoid arthritis; autoimmunity disorders, thrombosis, hypertension, cardiac hypertrophy, and heart failure.
• compositions comprising any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
• these compositions optionally further comprise one or more additional therapeutic agents.
• a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
• the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• a “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
• the term “inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of VPS34 and/or PI3K.
• compositions of this invention include those derived from suitable inorganic and organic acids and bases.
• Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
• organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
• Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci_ 4 alkyl) 4 salts.
• This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization.
• Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
• Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
• the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface Attorney Docket No.: MPI10-014P3RNWOM active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
• Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof.
• any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
• materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc
• safflower oil sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;
• Ringer's solution ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
• a method for treating a proliferative, inflammatory, or cardiovascular disorder comprising administering an effective amount of a compound, or a pharmaceutical composition to a subject in need thereof.
• an "effective amount" of the compound or pharmaceutical composition is that amount effective for treating a proliferative, inflammatory, or cardiovascular disorder, or is that amount effective for treating cancer.
• an "effective amount" of a compound is an amount which inhibits binding of PI3K and thereby blocks the resulting signaling cascades that lead to the abnormal activity of growth factors, receptor tyrosine kinases, protein serine/threonine kinases, G protein coupled receptors and phospholipid kinases and phosphatases.
• the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for treating the disease.
• the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
• the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
• dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
• the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disease being treated and the severity of the disease; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
• patient means an animal, preferably a mammal, and most preferably a human.
• compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated
• Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• the oral compositions can also include adj
• Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. Attorney Docket No.: MPI10-014P3RNWOM and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid are used in the preparation of injectables.
• the injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
• a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide.
• the rate of compound release can be controlled.
• biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or
• microemulsions that are compatible with body tissues.
• compositions for rectal or vaginal administration are preferably suppositories which 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 ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
• the active compound is mixed with at least one inert,
• excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stea
• Solid compositions of a similar type 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 solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type 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 polethylene glycols and the like.
• the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
• the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
• the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
• Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding
• compositions that can be used include polymeric substances and waxes.
• Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
• the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
• Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
• the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
• Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
• Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
• monotherapy to treat a disorder, disease or symptom they also may be used in combination therapy, in which the use of an inventive compound or composition (therapeutic agent) is combined with the use of one or more other therapeutic agents for treating the same and/or other types of disorders, symptoms and diseases.
• Combination therapy includes administration of the therapeutic agents concurrently or sequentially.
• the therapeutic agents can be combined into one composition which is administered to the patient.
• the compounds of this invention are used in combination with other therapeutic agents, such as other inhibitors of VPS34 and/or PI3K.
• a compound of the invention is administered in conjunction with a therapeutic agent selected from the group consisting of cytotoxic agents, radiotherapy, and immunotherapy. It is understood that other combinations may be undertaken while remaining within the scope of the invention.
• Another aspect of the invention relates to inhibiting VPS34 and /or PI3K, activity in a biological sample or a patient, which method comprises administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising said compound.
• biological sample generally includes in vivo, in vitro, and ex vivo materials, and also includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
• Still another aspect of this invention is to provide a kit comprising separate containers in a single package, wherein the inventive pharmaceutical compounds, compositions and/or salts thereof are used in combination with pharmaceutically acceptable carriers to treat disorders, symptoms and diseases where VPS34 and/or PI3K kinase plays a role.
• Table 1 below depicts certain compounds represented by compounds of general formula IA and IB. Attorney Docket No.: MPI10-014P3RNWOM
• Table 2 depicts the IUPAC names of certain compounds represented by compounds of general formula I A and IB.
• LCMS spectra were recorded on a Hewlett-Packard HP1100 or Agilent 1100 Series LC system connected to a Micromass mass spectrometer using reverse phase CI 8 columns. Various gradients and run times were selected in order to best characterize the compounds. Mobile phases were based on ACN/water gradients and contained either 0.1% formic acid (methods indicated FA) or 10 mM ammonium acetate (methods indicated AA).
• Step 1 A r -(4-bromopyridin-2-yl)acetamide
• Step 2 iV-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]acetamide
• Step 2 iV-(2,4-dimethoxybenzyl)-5-methyl-4-nitropyridin-2-amine 1-oxide
• Step 3 iV-(5-methyl-4-nitro-l-oxidopyridin-2-yl)acetamide
• Step 4 iV-(4-amino-5-methylpyridin-2-yl)acetamide
• Step 5 iV-(4-bromo-5-methylpyridin-2-yI)acetamide
• Step 6 iV-[5-methyl-4-(trimethylstannyl)pyridin-2-yl]acetamide
• the reaction Attorney Docket No.: MPI10-014P3RNWOM mixture was allowed to stir at -78 for 2 h and then diluted with water (875 mL). The mixture was allowed to warm to rt and was then extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by column chromatography to give 2-fluoro-3-iodo-5-methylpyridine (80 g, 50%).
• Step 2 2-fluora-4-iodo-5-methylpyridine
• Step 3 V-(2,4-dimethoxybenzyl)-4-iodo-5-methylpyridin-2-amine
• Step 4 7Y-(2,4-dimethoxybenzyl)- V-(4-iodo-5-methylpyridin-2- yl)cyclopropanecarboxamide
• Step 2 dimethyl (4-iodo-5-methylpyridin-2-yl)imidodicarbonate
• Step 3 methyl (4-iodo-5-methylpyridin-2-yl)carbamate
• Step 4 methyl [5-methyl-4-(trimethyIstannyl)pyridin-2-yl]carbamate
• Step 1 ethyl 5-[2-(acetylamino)pyridin-4-yl]-2-bromo-3-furoate
• reaction mixture was subjected to microwave irradiation at 95 °C for 1 min.
• the reaction mixture was diluted with water (10 mL) and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by column chromatography to give ethyl 5-[2-(acetylamino)pyridin-4-yl]-2-bromo-3-furoate (0.035 g, 14%) as a white solid.
• LCMS (FA): m/z 339.1 (M+H).
• Step 2 5-[2-(acetylamino)pyridin-4-yl]-2-(2-chlorophenyl)-3-furoic acid Compound 1-2)
• Step 3 5-[2-(acetylamino)pyridin-4-yl]-2-(2-chlorophenyl)-3-furamide
• Step 1 methyl 5-(2-chlorophenyl)-2-iodo-l,3-oxazole-4-carboxylate
• Step 2 methyl 2-[2-(acetylamino)-5-methylpyridin-4-yl]-5-(2-chlorophenyl)-l,3-oxazole-
• Step 3 2-[2-(acetylamino)-5-methylpyridin-4-yl]-5-(2-chlorophenyl)-l,3-oxazole-4- carboxylic acid (Compound I-6)To a round bottom flask was added methyl 2-[2-(acetylamino)-5- methylpyridin-4-yl]-5-(2-chlorophenyl)-l,3-oxazole-4-carboxylate (2.30 g, 6.0 mmol), THF (20 mL), MeOH (30 mL) , and 1M aqueous NaOH (25 mL). The reaction mixture was allowed to stir at rt overnight. The mixture was concentrated and 1M aqueous HC1 was added until the solution became acidic. The mixture was filtered and the solid was dried to give 2-[2-(acetylamino)-5-methylpyridin-4-yl]-
• Step 5 Af- ⁇ 4-[5-(2-chlorophenyl)-4-(4H-l,2,4-triazol-3-yl)-l,3-oxazol-2-yl]-5- rnethylpyridin-2-yl ⁇ acetamide
• Step 1 ethyl 2,4-diiodo-l,3-oxazole-5-carboxylate
• Step 2 ethyl 2-[2-(acetylamino)-5-methylpyridin-4-yl]-4-iodo-l,3-oxazole-5-carboxylate
• Step 3 2-[2-(acetylamino)-5-methylpyridin-4-yl]-4-(2-chlorophenyl)-l,3-oxazole-5- carboxylic acid
• Step 4 2-[2-(acetylamino)-5-methylpyridin-4-yl]-4-(2-chlorophenyI)-l,3-oxazole-5- carboxamide
• Step 1 5-(2-chlorophenyl)-2-iodo-l,3-oxazole-4-carboxylic acid
• Step 2 5-(2-chIorophenyl)-2-iodo-l,3-oxazole-4-carboxamide
• Step 3 3-[5-(2-chlorophenyl)-2-iodo-l,3-oxazol-4-yI]-lH-l,2,4-triazole
• Step 4 3-[5-(2-chlorophenyl)-2-iodo-l,3-oxazol-4-yI]-4- ⁇ [2-(trimethylsUyl)- ethoxy]methyl ⁇ -4H-l,2,4-triazole
• Step 5 A r - ⁇ 4-[5-(2-chlorophenyI)-4-(4- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -4H-l,2,4- triazol-3-yl)- 1 ,3-oxazol-2-yl] phenyl ⁇ acetamide
• Step 6 iV- ⁇ 4-[5-(2-chlorophenyl)-4-(lH-l,2,4-triazol-3-yl)-l,3-oxazol-2- yl]phenyl ⁇ acetamide (Compound 1-8)
• Step 1 2-(2-acetamido-5-methylpyridin-4-yl)-5-(2-chlorophenyl)- V-methoxy-iV-methyl- l,3-oxazole-4-carboxamide
• Step 2 A f - ⁇ 4-[4-acetyl-5-(2-chlorophenyl)-l,3-oxazol-2-yl]-5-methylpyridin-2- yl ⁇ acetamide
• the reaction mixture was Attorney Docket No.: MPI10-014P3RNWOM allowed to warm to rt and stir overnight and then additional methylmagnesium bromide (3.0 M in diethyl ether, 0.30 mL, 0.90 mmol) was added. The reaction mixture was then allowed to stir for 24 hr. Aqueous HC1 was added and then the mixture was basified with NaHC0 3 and washed with EtOAc. The organic solutions were combined, dried over MgS0 4 , filtered and concentrated.
• Step 1 2-(2-acetamido-5-methylpyridin-4-yl)-5-(2-chlorophenyl)-/V-(2,2- dimethoxyethyl)-l,3-oxazole-4-carboxamide
• Step 2 A r - ⁇ 4-[5'-(2-chlorophenyl)-2,4'-bi-l,3-oxazol-2'-yl]-5-methylpyridin-2- yl ⁇ acetaniide (Compound 1-10)
• Step 1 iV- ⁇ 4-[4-(2-chlorophenyl)-5-(pyridine-2-yl)-l,3-oxazol-2-yl]-5-methyIpyridin-2- yl ⁇ acetamide (Compound 1-78)
• Step 1 ⁇ - ⁇ 4-[5-(2-chlorophenyl)-4-(4- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -4H-l,2,4- triazol-3-yl)-l,3-oxazol-2-yl]-5-methylpyridin-2-yl ⁇ acetamide
• Step 2 4-[5-(2-chlorophenyl)-4-(4- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -4H-l,2,4-triazol-3- yl)-l,3-oxazol-2-yl]-5-methylpyridin-2-amine
• Step 3 7V- ⁇ 4-[5-(2-chlorophenyl)-4-(4H-l,2,4-triazol-3-yl)-l,3-oxazol-2-yl]-5- methylpyridin-2-yl ⁇ cyclopropanecarboxaniide (Compound 1-77)
• Step 1 ethyl 5-bromo-3-furoate
• Step 2 ethyl 5-(2-acetamido-5-methylpyridin-4-yl)-3-furoate
• Step 3 ethyl 5-(2-acetamido-5-methylpyridin-4-yl)-2-bromo-3-furoate
• Step 4 5-(2-acetamido-5-methylpyridin-4-yl)-2-bromo-3-furoic acid
• Step 6 V- ⁇ 4-[5-bromo-4-(lH-l,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl ⁇ acetamide
• Step 7 A r - ⁇ 4-[5-bromo-4-(l- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -lH-l,2,4-triazol-3-yl)-2- furyl]-5-methylpyridin-2-yl ⁇ acetamide
• Step 8 V-(4- ⁇ 5-[3-(dimethylamino)piperidin-l-yl]-4-(l- ⁇ [2-
• Step 9 V-(4- ⁇ 5-[3-(dimethylamino)piperidin-l-yl]-4-(4H-l,2,4-triazol-3-yl)-2-furyl ⁇ -5- methylpyridin-2-yl)acetamide (Compound 1-26)
• Step 1 A r - ⁇ 4-[5-(2-chloro-5-formyIphenyl)-4-(l- ⁇ [2-(trimethyIsilyl)ethoxy]methyl ⁇ -lH- l,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl ⁇ acetamide
• Step 2 ⁇ -(4- ⁇ 5-[2-chloro-5-(pyrrolidin-l-ylmethyl)phenyl]-4-(l- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ -lH-l,2,4-triazol-3-yl)-2-furyl ⁇ -5-methylpyridin-2-yl)acetamide
• Step 3 ⁇ -(4- ⁇ 5-[2-chloro-5-(pyrrolidin-l-ylmethyl)phenyl]-4-(4H-l,2,4-triazol-3-yl)-2- furyl ⁇ -5-methyIpyridin-2-yl)acetamide (Compound 1-36)
• Step 1 2-(2-acetamido-5-methylpyridin-4-yl)-4-iodo-l,3-oxazole-5-carboxylic acid
• Step 2 2-(2-acetamido-5-methylpyridin-4-yl)-4-iodo-l,3-oxazole-5-carboxamide
• Step 3 ⁇ - ⁇ 4 4-iodo-5-(lH-l,2,4-triazol-3-yl)-l,3-oxazol-2-yl]-5-methylpyridin-2- yl ⁇ acetamide
• Step 4 iV- ⁇ 4-[4-iodo-5-(l- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -lH-l,2,4-triazol-3-yl)-l,3- oxazol-2-yI]-5-methylpyridin-2-yl ⁇ acetaraide
• Step 5 ⁇ - ⁇ 4-[4-(2-chlorophenyl)-5-(4H-l,2,4-triazol-3-yl)-l,3-oxazol-2-yl]-5- methylpyridin-2-yl ⁇ acetamide (Compound 1-39)
• the reaction mixture was allowed to stir and was subjected to microwave irradiation at 150 °C for 20 min.
• the mixture was diluted with water and extracted with EtOAc.
• the organic solutions were combined, dried over MgS0 4 , filtered and concentrated.
• the residue was dissolved in DCM (5 mL) and to this solution was added TFA (2 mL).
• the reaction mixture was allowed to stir at rt overnight and was then concentrated.
• Step 1 ⁇ - ⁇ 4-[4-(l,l-dioxidoisothiazolidin-2-yl)-5-(l- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ - lH-l,2,4-triazol-3-yl)-l,3-oxazol-2-yl]-5-methylpyridin-2-yl ⁇ acetamide
• Step 2 V- ⁇ 4-[4-(l,l-dioxidoisothiazoUdin-2-yl)-5-(4H-l,2,4-triazol-3-yl)-l,3-oxazol-2-yl]- 5-methylpyridin-2-yl ⁇ acetamide (Compound 1-50)
• BIOLOGICAL DATA
• VPS34 (accession number GB:BC033004) was cloned into pDEST20-Thombin as N-terminal GST tagged fusion proteins using the Gateway system (Invitrogen, catalog# 11804-013). The sequences were verified before recombinant protein expression using the Baculovirus Expression System with Gateway® Technology.
• VPS34 was infected at 1MOI in SF9 cells and harvested 72 hours post infection.
• VPS34 is purified by Glutathione Sepharose 4 Fast Flow (GE Healthcare).
• lOOnL compounds in DMSO are added to wells of a 384 well microtitre plate (Greiner 780076).
• 5ul VPS34 reaction buffer Invitrogen Assay Buffer Q (diluted 1 in 5 with nanopure water) plus 2mM DTT and 2mM MnCl 2 ) containing ATP (20uM, Promega) and 200uM PI-PS substrate (Invitrogen PV5122) is added followed immediately by 5ul VPS34 reaction buffer (as above) containing VPS34 (5nM, Millennium Protein Sciences Group) and the mixture is incubated with shaking at room temperature for 1 hour.
• VPS34 stop-detect mix (as per Invitrogen Adapta Assay kit (PV5009) instructions (contains kinase quench buffer, TR-FRET buffer, Adapta Eu anti-ADP antibody and Alexa Fluor 647 ADP tracer)) is added to quench the reaction. The plates are then incubated for 30 minutes at room temperature with shaking and then read on a BMG PheraStar Plus reader.
• the FYVE domain redistribution assay monitors translocation of EGFP-2XFYVE from its initial location bound to (PtdIns(3)P) in early endosomes to the cytoplasm in response to test compounds.
• Recombinant U20S cells stable expressing the FYVE finger from the human homologue of the hepatocyte growth factor-regulated tyrosine kinase substrate Hrs, duplicated in tanden (GenBank Acc. NM 004712) and fused to the C-terminus of enhanced green fluorescent protein (EGFP).
• U20S cells are adherent epithelial cells derived from human osteosarcoma.
• EGFP-2X-FYVE Expression of EGFP-2X-FYVE is controlled by a standard CMV promoter and continous expression is maintained by addition of geneticin to the culture medium. Localization of the fusion protein within the cells is imaged on the Evotec Technologies OPERA Confocal Imager and Integrated Spot Signal Per Cellular Signal is quantified using Acapella software. Using this information, IC50 values for inhibitors can be determined.
• U20S EGFP-2XFYVE cells are propagated in Dulbecco ' s Modified Eagle Media High glucose(D-MEM) (Invitrogen cat. 11995) containing 10% Fetal Bovine Serum (HyClone cat.
• test compounds in DMSO are diluted 1 : 100 in media.
• the diluted test compounds are added to the cells (25 ⁇ per well) in 3-fold dilutions with a final concentration range of 0.0015 to 10 uM.
• the cells are incubated for 30 minutes in a humidified chamber at 37°C with 5% C0 2 .
• all liquid is removed from the wells and cells are fixed with 4% paraformaldehyde in PBS (75 ⁇ per well) for 15 minutes at room temperature.
• the paraformaldehyde solution is removed from wells and washed once with PBS (100 ⁇ per well).
• the PBS is removed and cells are incubated with DRAQ5 Nucleur Dye (Alexis/Biostatus) (85 ⁇ per well).
• the plates are covered with Flash Plate plastic adhesive foil and imaged on the Evotec Technologies OPERA Confocal Imager Opera after at least a 30 minute incubation. Concentration curves are generated by caluculating the Integrated Spot Intensity Per Cellular Signal decrease in test-compound treated samples relative to DMSO-treated controls and a 100% control inhibitor.
• pDEST10 (pl lObeta, pi lOdelta, and pi lOgamma) as N-terminal His tagged fusion proteins using the Gateway system (Invitrogen, catalog# 11804-010 for pDEST8 and 11806-015 for pDESTIO). The sequences are verified before recombinant protein expression using the Baculovirus Expression System with Gateway® Technology. The accession numbers for the subunits are as follows: Attorney Docket No.: MPI10-014P3RNWOM pi 10 alpha (GB:U79143)
• pl lOdelta (GB: U86453)
• pl lOgamma (GB: X83368)
• the regulatory subunits of PI3Ks are cloned into pDEST8 as un-tagged protein using the Gateway system (Catalog#l 1804-010). The sequences are verified before recombinant protein expression using the Baculovirus Expression System with Gateway® Technology.
• the accession numbers for the subunits are as following:
• VPS34 is cloned into pDEST20-Thombin as N-terminal GST tagged fusion proteins using the Gateway system (Invitrogen, catalog# 11804-013). The sequences are verified before recombinant protein expression using the Baculovirus Expression System with Gateway® Technology.
• the p85 (MOI of 4) is co-infected with pi 10 alpha, beta, and delta respectively (IMOI) in SF9 cells and harvested at 60 hours post co-infection.
• PI 10 gamma was infected at 1 MOI and harvested at 60 hours post infection.
• PI3Ks are purified by Ni-NTA Agarose (Qiagen #30250) followed by Mono
• VPS34 is purified by Glutathione Sepharose 4 Fast Flow
• 0.5uL compounds in DMSO are added to wells of a 384 well microtitre plate (Corning 3575).
• lOul PI3K reaction buffer 50 mM Hepes, 5mM DTT, 150mM NaCl, lOmM beta- glycerophosphate, lOmM MgC12, 0.25mM sodium cholate and 0.001% CHAPS, pH 7.00
• ATP 25uM, Promega
• lOul PI3K reaction buffer containing di-C8 PI(4,5)P2 3.5uM, CellSignals
• PBKalpha 0.4875nM, Millennium Protein Sciences Group
• 5ul PI3K stop mix 50mM Hepes, 5mM DTT, 150 mM NaCl, 0.01% Tween-20, 15 mM EDTA and 25nM biotin-PI(3,4,5)P3 (Echelon) is added to quench the reaction followed immediately by addition of 5ul HTRF detection mix (50mM Hepes, 5mM DTT, 150 mM NaCl, 0.01% Tween-20, 40mM KF, ⁇ GST:GRP-1 PH domain (Millennium Protein Sciences Group), 15nM Streptavidin-XL (CisBio) and 0.375nM anti-GST Eu++ antibody (CisBio) at pH 7.00). The plates are then incubated for 1 hour at room temperature with shaking and then read on a BMG PheraStar Plus reader. Attorney Docket No.: MPI10-014P3RNWOM
• VPS34 is assayed using AdaptaTM Universal Kinase Assay Kit (Invitrogen).
• the pSer473 AKT LI-COR In-Cell Western Assay is a quantitative immunofluorescent assay that measures phosphorylation of serine 473 AKT (pSer473 AKT) in WM266.4 and SKOV3 tumor cell lines grown in cell culture.
• WM266.4 cells are propagated in Minimum Essential Media (MEM) (Invitrogen) containing L-glutamine, 10% Fetal Bovine Serum, 1 mM MEM Sodium Pyruvate, and 0.1 mM MEM Non-Essential Amino Acids and SKOV3 cells are propagated in McCoy's 5 A Media (modified) (Invitrogen) containing L-Glutamine and 10% Fetal Bovine Serum. Both cell lines are kept in a humidified chamber at 37°C with 5% C0 2 .
• MEM Minimum Essential Media
• 1.5 x 10 4 WM266.4 and 1.5 x 10 4 SKOV3 cells are cultured in 100 ⁇ of media per well in tissue culture-treated black-walled, clear bottom Optilux 96-well plates (BD Biosciences) for 16-20 hours. Prior to addition of compounds, cell media is removed and replaced with 75 ⁇ of fresh media. Test compounds in DMSO are diluted 1 : 100 in media. The diluted test compounds are added to the cells (25 ⁇ per well) in 3 -fold dilutions with a final concentration range of 0.0015 to 10 ⁇ . The cells are incubated for 2 hours in a humidified chamber at 37°C with 5% C0 2 .
• Blocking buffer is removed from the wells and primary antibodies (Phospho-AKT (Ser473) (D9E) XPTM Rabbit mAb and AKT (pan) (40D4) Mouse mAb, Cell Signaling Technology) diluted in Odyssey blocking buffer are added (50 ⁇ per well). Plates are incubated at 4°C overnight. The cells are washed for 20 min x 3 with PBS + 0.1% Tween-20 (200 ⁇ per well).
• the ATPLiteTM Assay measures cellular adenosine-triphosphate (ATP) through the generation of a luminescent signal formed from the ATP-dependent enzyme firefly luciferase.
• the luminescent signal intensity can be used as a measure of cellular proliferation, and can be used to assess the anti-proliferative effects of PI3K inhibitors.
• WM266.4 cells propagated in Minimum Essential Media (MEM) (Invitrogen) containing L- Glutamine, 10% Fetal Bovine Serum, 1 mM MEM Sodium Pyruvate, and 0.1 mM MEM Non-Essential Amino Acids are cultured in 384-well tissue culture-treated Black/Clear plates (Falcon) at 1 x 10 3 cells per well in a volume of 75 ⁇ in a humidified chamber at 37°C with 5% C0 2 for 24 h.
• Test compounds (2 ⁇ in 100% DMSO) are diluted in 95 ⁇ of cell culture media. The diluted test compounds are added (8 ⁇ per well) to 384-well plates.
• Final concentration range of 3-fold serial dilution of compounds is 0.001 to 20 ⁇ . Plates are incubated for 72 h in a humidified chamber at 37°C with 5% C0 2 . One control plate without compound addition is processed at the start of the 72 h incubation as a "Time Zero" reading for quantitative evaluation of cell viability at start of assay. After 72 h, all but 25 ⁇ of cell culture media is removed from each well, followed by the addition of 25 ⁇ of ATPlite lstep reagent (Perkin Elmer) to each well. Luminescence is measured on a LEADSeeker Luminescence Counter (GE Healthcare Life Sciences). Concentration response curves are generated by calculating the luminescence decrease in test compound-treated samples relative to DMSO-treated controls, and growth inhibition (IC5 0 ) values are determined from the curves.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Immunology (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Epidemiology (AREA)
• Pulmonology (AREA)
• Hematology (AREA)
• Hospice & Palliative Care (AREA)
• Transplantation (AREA)
• Diabetes (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

Priority Applications (2)

Applications Claiming Priority (6)

Publications (1)

Family

ID=45567934

Family Applications (1)

Country Status (6)

Cited By (5)

Families Citing this family (10)

Citations (3)

Family Cites Families (91)

• 2011
  • 2011-08-10 US US13/206,671 patent/US8859768B2/en active Active
  • 2011-08-10 JP JP2013524201A patent/JP2013533318A/ja active Pending
  • 2011-08-10 EP EP11816983.8A patent/EP2603216A4/en not_active Withdrawn
  • 2011-08-10 WO PCT/US2011/047245 patent/WO2012021615A1/en not_active Ceased
  • 2011-08-11 AR ARP110102930A patent/AR082666A1/es unknown
  • 2011-08-11 TW TW100128763A patent/TW201217362A/zh unknown

Patent Citations (3)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events