WO2015069287A1 - Composés à utiliser en tant que modulateurs des tyrosine kinases - Google Patents
Composés à utiliser en tant que modulateurs des tyrosine kinases Download PDFInfo
- Publication number
- WO2015069287A1 WO2015069287A1 PCT/US2013/069337 US2013069337W WO2015069287A1 WO 2015069287 A1 WO2015069287 A1 WO 2015069287A1 US 2013069337 W US2013069337 W US 2013069337W WO 2015069287 A1 WO2015069287 A1 WO 2015069287A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amino
- carbonyl
- fluoro
- pyridin
- phenoxy
- Prior art date
Links
- DHSGAYLNDVUUMJ-UHFFFAOYSA-N CC(C)(C)OC(N(c1cccc([N+]([O-])=O)c1)c1cc(Cl)ncc1)=O Chemical compound CC(C)(C)OC(N(c1cccc([N+]([O-])=O)c1)c1cc(Cl)ncc1)=O DHSGAYLNDVUUMJ-UHFFFAOYSA-N 0.000 description 1
- NNYFLKZPDRZXRW-UHFFFAOYSA-N CC(C)(C)OC(NCCNC(c1c[nH]c(-c2nccc(Oc3cc(C(Nc4cc(C)ccc4F)=O)ccc3F)c2)c1)=O)=O Chemical compound CC(C)(C)OC(NCCNC(c1c[nH]c(-c2nccc(Oc3cc(C(Nc4cc(C)ccc4F)=O)ccc3F)c2)c1)=O)=O NNYFLKZPDRZXRW-UHFFFAOYSA-N 0.000 description 1
- HTQOJAFTQFYYBQ-UHFFFAOYSA-N CC(C)(C)OC([n]1c(C(OC)=O)cc(-c2nccc(Oc(cc3)ccc3N)c2)c1)=O Chemical compound CC(C)(C)OC([n]1c(C(OC)=O)cc(-c2nccc(Oc(cc3)ccc3N)c2)c1)=O HTQOJAFTQFYYBQ-UHFFFAOYSA-N 0.000 description 1
- BSVMPMYZRFLSEK-UHFFFAOYSA-N CC1(C)OB(c2cc(C(OC)=O)c[nH]2)OC1(C)C Chemical compound CC1(C)OB(c2cc(C(OC)=O)c[nH]2)OC1(C)C BSVMPMYZRFLSEK-UHFFFAOYSA-N 0.000 description 1
- QIOFBFTYXKZQMV-SANMLTNESA-N CCNC(CC[C@@H](C(NCC)=O)NC(c1c[nH]c(-c2nccc(Oc(cc3)ccc3NC(Nc3cc(C)ccc3F)=O)c2)c1)=O)=O Chemical compound CCNC(CC[C@@H](C(NCC)=O)NC(c1c[nH]c(-c2nccc(Oc(cc3)ccc3NC(Nc3cc(C)ccc3F)=O)c2)c1)=O)=O QIOFBFTYXKZQMV-SANMLTNESA-N 0.000 description 1
- QISWZCWGPSJQSU-UHFFFAOYSA-N CCOC(CCCCNC(c1c[nH]c(-c2nccc(Oc(cc3)ccc3NC(Nc3cc(C)ccc3F)=O)c2)c1)=O)=O Chemical compound CCOC(CCCCNC(c1c[nH]c(-c2nccc(Oc(cc3)ccc3NC(Nc3cc(C)ccc3F)=O)c2)c1)=O)=O QISWZCWGPSJQSU-UHFFFAOYSA-N 0.000 description 1
- MSXKLXDFAGWGGZ-UHFFFAOYSA-N Cc(cc1)cc(NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(NCC(OC)=O)=O)c[nH]3)ncc2)=O)c1F Chemical compound Cc(cc1)cc(NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(NCC(OC)=O)=O)c[nH]3)ncc2)=O)c1F MSXKLXDFAGWGGZ-UHFFFAOYSA-N 0.000 description 1
- RFGSSZOLBKALKW-UHFFFAOYSA-N Cc(cc1)cc(NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(NCCC(O)=O)=O)c[nH]3)ncc2)=O)c1F Chemical compound Cc(cc1)cc(NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(NCCC(O)=O)=O)c[nH]3)ncc2)=O)c1F RFGSSZOLBKALKW-UHFFFAOYSA-N 0.000 description 1
- OLUFVVPKEWDHSY-UHFFFAOYSA-N Cc(cc1)cc(NC(Nc2cc(-c3ccnc(-c4ccc[nH]4)c3)ccc2)=O)c1F Chemical compound Cc(cc1)cc(NC(Nc2cc(-c3ccnc(-c4ccc[nH]4)c3)ccc2)=O)c1F OLUFVVPKEWDHSY-UHFFFAOYSA-N 0.000 description 1
- BZRWMATYFFIEGO-UHFFFAOYSA-N Cc(cc1NC(Nc(cc2)ccc2-c2cc(-c3ccc[nH]3)ncc2)=O)ccc1F Chemical compound Cc(cc1NC(Nc(cc2)ccc2-c2cc(-c3ccc[nH]3)ncc2)=O)ccc1F BZRWMATYFFIEGO-UHFFFAOYSA-N 0.000 description 1
- XZQJQYSDFRPEAO-UHFFFAOYSA-N Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3c[nH]c(C(OC)=O)c3)ncc2)=O)ccc1F Chemical compound Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3c[nH]c(C(OC)=O)c3)ncc2)=O)ccc1F XZQJQYSDFRPEAO-UHFFFAOYSA-N 0.000 description 1
- FOEPVPYTMCCHOH-UHFFFAOYSA-N Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3c[s]c(C(NCCC(OC)=O)=O)c3)ncc2)=O)ccc1F Chemical compound Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3c[s]c(C(NCCC(OC)=O)=O)c3)ncc2)=O)ccc1F FOEPVPYTMCCHOH-UHFFFAOYSA-N 0.000 description 1
- VCYAFRAXIHPXCU-UHFFFAOYSA-N Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(N4CCC(CC(OC)=O)CC4)=O)c[nH]3)ncc2)=O)ccc1F Chemical compound Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(N4CCC(CC(OC)=O)CC4)=O)c[nH]3)ncc2)=O)ccc1F VCYAFRAXIHPXCU-UHFFFAOYSA-N 0.000 description 1
- GVMOWHZUDCJBPN-UHFFFAOYSA-N Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(N=S(C)(C)=O)=O)c[nH]3)ncc2)=O)ccc1F Chemical compound Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(N=S(C)(C)=O)=O)c[nH]3)ncc2)=O)ccc1F GVMOWHZUDCJBPN-UHFFFAOYSA-N 0.000 description 1
- URFHWIMCQUTTHF-UHFFFAOYSA-N Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(NCCCN4CCOCC4)=O)c[nH]3)ncc2)=O)ccc1F Chemical compound Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(NCCCN4CCOCC4)=O)c[nH]3)ncc2)=O)ccc1F URFHWIMCQUTTHF-UHFFFAOYSA-N 0.000 description 1
- KXBYOBLLYNHTNG-UHFFFAOYSA-N Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(NCCN4CCCC4)=O)c[nH]3)ncc2)=O)ccc1F Chemical compound Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(NCCN4CCCC4)=O)c[nH]3)ncc2)=O)ccc1F KXBYOBLLYNHTNG-UHFFFAOYSA-N 0.000 description 1
- ZTKFPHZIKPFWHX-UHFFFAOYSA-N Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(OCCOCCOC)=O)c[nH]3)ncc2)=O)ccc1F Chemical compound Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(OCCOCCOC)=O)c[nH]3)ncc2)=O)ccc1F ZTKFPHZIKPFWHX-UHFFFAOYSA-N 0.000 description 1
- ZBUMGFFYJJLQLI-UHFFFAOYSA-N Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3ccc[nH]3)nc(N)c2)=O)ccc1F Chemical compound Cc(cc1NC(Nc(cc2)ccc2Oc2cc(-c3ccc[nH]3)nc(N)c2)=O)ccc1F ZBUMGFFYJJLQLI-UHFFFAOYSA-N 0.000 description 1
- CHZWPZBHXLGJPG-UHFFFAOYSA-N Cc(cc1NC(Nc(cc2)ccc2Sc2cc(Cl)ncc2)=O)ccc1F Chemical compound Cc(cc1NC(Nc(cc2)ccc2Sc2cc(Cl)ncc2)=O)ccc1F CHZWPZBHXLGJPG-UHFFFAOYSA-N 0.000 description 1
- FKQKSLCAWBONDU-UHFFFAOYSA-N Cc(cc1NC(Nc(ccc(Oc2cc(-c3cc(C(NCCC(OC)=O)=O)c[nH]3)ncc2)c2)c2F)=O)ccc1F Chemical compound Cc(cc1NC(Nc(ccc(Oc2cc(-c3cc(C(NCCC(OC)=O)=O)c[nH]3)ncc2)c2)c2F)=O)ccc1F FKQKSLCAWBONDU-UHFFFAOYSA-N 0.000 description 1
- KUYVWUAGELSGSE-UHFFFAOYSA-N Cc(cc1NC(c2cccc(Oc3cc(-c4cc(C(NO)=O)c[nH]4)ncc3)c2)=O)ccc1F Chemical compound Cc(cc1NC(c2cccc(Oc3cc(-c4cc(C(NO)=O)c[nH]4)ncc3)c2)=O)ccc1F KUYVWUAGELSGSE-UHFFFAOYSA-N 0.000 description 1
- SRNVOFSFOLWIQH-UHFFFAOYSA-N Cc1c(C(Nc2cc(Oc3cc(-c4cc(C(NCCCN5CCCCC5)=O)c[nH]4)ncc3)ccc2F)=O)[o]cc1 Chemical compound Cc1c(C(Nc2cc(Oc3cc(-c4cc(C(NCCCN5CCCCC5)=O)c[nH]4)ncc3)ccc2F)=O)[o]cc1 SRNVOFSFOLWIQH-UHFFFAOYSA-N 0.000 description 1
- GILGOPYVAPACPK-UHFFFAOYSA-N Cc1c(C(Nc2cc(Oc3cc(-c4cc(C(NCCCN5CCN(C)CC5)=O)c[nH]4)ncc3)ccc2F)=O)[o]cc1 Chemical compound Cc1c(C(Nc2cc(Oc3cc(-c4cc(C(NCCCN5CCN(C)CC5)=O)c[nH]4)ncc3)ccc2F)=O)[o]cc1 GILGOPYVAPACPK-UHFFFAOYSA-N 0.000 description 1
- CBWFTSSODXUPJM-UHFFFAOYSA-N Cc1c(C(Nc2cc(Oc3cc(-c4cc(C(OC)=O)c[nH]4)ncc3)ccc2F)=O)[o]cc1 Chemical compound Cc1c(C(Nc2cc(Oc3cc(-c4cc(C(OC)=O)c[nH]4)ncc3)ccc2F)=O)[o]cc1 CBWFTSSODXUPJM-UHFFFAOYSA-N 0.000 description 1
- FADJGHQDAILALR-UHFFFAOYSA-N Cc1c(C(Nc2cccc(Oc3cc(-c4c[nH]c(C(OC)=O)c4)ncc3)c2)=O)[o]cc1 Chemical compound Cc1c(C(Nc2cccc(Oc3cc(-c4c[nH]c(C(OC)=O)c4)ncc3)c2)=O)[o]cc1 FADJGHQDAILALR-UHFFFAOYSA-N 0.000 description 1
- QJAIWFQXMXEWND-UHFFFAOYSA-N Cc1cccc(NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(NCC(CO)O)=O)c[nH]3)ncc2)=O)c1 Chemical compound Cc1cccc(NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(NCC(CO)O)=O)c[nH]3)ncc2)=O)c1 QJAIWFQXMXEWND-UHFFFAOYSA-N 0.000 description 1
- ACQMQLIWZDUBIB-UHFFFAOYSA-N Cc1cccc(NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(OCC(CO)(CO)CO)=O)c[nH]3)ncc2)=O)c1 Chemical compound Cc1cccc(NC(Nc(cc2)ccc2Oc2cc(-c3cc(C(OCC(CO)(CO)CO)=O)c[nH]3)ncc2)=O)c1 ACQMQLIWZDUBIB-UHFFFAOYSA-N 0.000 description 1
- ZDWXFWNFQRHKKX-UHFFFAOYSA-N OCCOC(c1c[nH]c(-c2nccc(Oc(cc3)ccc3NC(Nc(cc3)cc(C(F)(F)F)c3Cl)=O)c2)c1)=O Chemical compound OCCOC(c1c[nH]c(-c2nccc(Oc(cc3)ccc3NC(Nc(cc3)cc(C(F)(F)F)c3Cl)=O)c2)c1)=O ZDWXFWNFQRHKKX-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur 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
- 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
Definitions
- PTKs Protein tyrosine kinases
- PTKs can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
- signal transduction mediated by receptor tyrosine kinases (“RTKs”) is initiated by extracellular interaction with a specific growth factor (i.e., a ligand), followed by receptor dimerization, transient stimulation of the intrinsic protein tyrosine kinase activity and phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic homeostasis, and responses to the extracellular microenvironment).
- RTKs receptor tyrosine kinases
- tyrosine phosphorylation sites function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules.
- SH2 serosine phosphorylation sites
- Several intracellular substrate proteins that associate with RTKs have been identified and are divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack a catalytic domain but serve as adapters and associate with catalytically active molecules.
- the specificity of the interactions between receptors or proteins and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue.
- RTKs The intrinsic function of RTKs is activated upon ligand binding, which results in phophorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses. At present, at least nineteen distinct RTK subfamilies have been identified.
- One RTK subfamily designated the HER subfamily, is believed to be comprised of EGFR, HER2, HER3 and HER4.
- Ligands to the HER subfamily of receptors include epithelial growth factor (EGF), TGF- , amphiregulin, HB-EGF, betacellulin and heregulin.
- the second subfamily of RTKs, designated the insulin subfamily is comprised of the INS-R, the IGF-1R and the IR-R.
- the third RTK subfamily includes the PDGF ⁇ and receptors, CSFIR, c- kit and FLK-II.
- Another subfamily of RTKs, identified as the FLK family is believed to be comprised of the kinase insert domain-receptor fetal liver kinase-1 (KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosine kinase 1 (flt-1). Each of these receptors was initially believed to be a receptor for hematopoietic growth factors.
- RTKs Two other subfamilies of RTKs have been designated as the FGF receptor family (FGFR1, FGFR2, FGFR3 and FGFR4) and the Met subfamily (c-met and Ron). Because of the similarities between the PDGF and FLK subfamilies, the two subfamilies are often considered together.
- the known RTK subfamilies are identified in Plowman et al, 1994, DN&P 7(6): 334-339, which is incorporated herein by reference.
- the non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences.
- non- receptor tyrosine kinases comprising eleven subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK) have been identified.
- the Src subfamily of non- receptor tyrosine kinases is comprised of the largest number of PTKs, and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.
- the Src subfamily of enzymes has been linked to oncogenesis.
- non-receptor tyrosine kinases A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, 1993, Oncogen 8: 2025-2031, which is incorporated herein by reference. Many of the protein tyrosine kinases (PTKs), whether an RTK or non-receptor tyrosine kinase, have been found to be involved in cellular signaling pathways leading to cellular signal cascades and pathogenic conditions such as cancer, psoriasis and hyper immune responses.
- PTKs protein tyrosine kinases
- WO 94/14808 and 1-cyclopropyl-4-pyridyl-quinolones have been described generally as tyrosine kinase inhibitors.
- Styryl compounds U.S. Patent No. 5,217,999
- styryl-substituted pyridyl compounds U.S. Patent No. 5,302,606
- certain quinazoline derivatives EP Application No. 0566 266 A1
- seleoindoles and selenides PCT Application No. WO 94/03427
- tricyclic polyhydroxylic compounds PCT Application No. WO 92/21660
- benzylphosphonic acid compounds PCT Application No.
- WO 91/154905 have been described as compounds for use as tyrosine kinase inhibitors for use in the treatment of cancer.
- other small molecules were studied as tyrosine kinase inhibitors, such as the compounds disclosed in U.S. Pat. Nos. 6,765,012; 6,541,504; 6,747,025; 5,792,783; 5,834,504; 5,883,113; 5,883,116 and 5,886,020, all of which are incorporated by reference in their entireties.
- the identification and use of compounds which specifically inhibit signal transduction by modulating the activity of receptor and non-receptor tyrosine is one aspect of the present invention.
- the present invention is directed to compounds represented by Formula I capable of modulating, regulating and/or inhibiting tyrosine kinase signal transduction, and uses of the compounds and compositions incorporating the compounds for disease treatment and prevention.
- the compounds of the present invention can be found in general Formula I:
- X is selected from the group consisting of NR 1 , O, S(O) n ; n is 0 or an integer of from 1 to 2; R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 and R 3 and may be taken together to form a 5-7 membered heterocyclic ring with N; R I is selected from the group consisting of hydrogen, halogen, C 1 to C 8 alkyl, S(
- each R 4 is independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 8 alkyl, aryl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxyalkyl, (CR 5 R 6 ) d and N(R 4 ) 2 may form a 3-7 membered heterocyclic ring, comprising of aziridine, azetidine, pyrrolidine, 5-fluoropyrrolidine, piperidine, 6-fluoropiperidine, N- methylpiperazine, morpholine, 2,6-
- hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, sulfonate and CR 5 R 6 may represent a carbocyclic or heterocyclic ring of from 5 to 6 carbons or alternatively, (CR 5 R 6 ) d and (CR 5 R 6 ) e may form a 3-7 membered carbocyclic or heterocyclic ring, wherein the ring may be optionally substituted with up to three of hydroxyl, halo, C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and sulfonate; a is 0 or an integer of from 1 to 3; d is 0 or an integer of from 1 to 5; e is an integer of from 1 to
- R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 and R 3 and may be taken together to form a 5-7 membered heterocyclic ring with N; b is 0 or an integer of from 1 to 2; Y is selected from the group consisting of: (1’)—(CH 2 )g—O—(CH 2 )h—;
- R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
- R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl,
- alkylcarbonyl alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
- Ring A is selected from the group consisting of:
- Ring A can be illustrated but not limited to the following:
- R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
- R III represents optionally 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 5 alkoxy, hydroxy, amino, C 1 -C 5 alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
- Z is selected from the group consisting of (1’) (CH 2 ) i N(R 7 )C(O)N(R 8 )(CH 2 ) j; (2’) (CH 8
- Ring B is selected from the group consisting of:
- Ring B can be illustrated but not limited to the following:
- R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
- R IV represents optionally 1-3 substituents, independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and—NR 9 R 10 ; wherein R 9 and R 10 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl.
- a compound according to Formula I including any tautomer, stereoisomer,
- hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, sulfonate and CR 5 R 6 may represent a carbocyclic or heterocyclic ring of from 5 to 6 carbons or alternatively, (CR 5 R 6 ) d and (CR 5 R 6 ) e may form a 3-7 membered carbocyclic or heterocyclic ring, wherein the ring may be optionally substituted with up to three of hydroxyl, halo, C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxyalkyl,
- alkoxycarbonylalkyl alkoxycarbonyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl and sulfonate.
- W is C or N
- X is selected from the group consisting of NR 1 , O, and S(O) n ;
- n is 0 or an integer of from 1 to 2;
- R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
- R 2 and R 3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
- R 5 and R 6 are independently selected from the group consisting of hydrogen, halo, hydroxyl, C 1 - C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, sulfonate;
- R II is independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR 2 R 3 )alkoxy, (NR 2 R 3 )alkenyl
- g is 0 or an integer of from 1 to 3;
- h is 0 or an integer of from 1 to 3;
- R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 and R 3 and may be taken together to form a 5-7 membered heterocyclic ring with N; R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,
- Ring A can be illustrated but not limited to the following:
- R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,
- R III represents optionally 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 5 alkoxy, hydroxy, amino, C 1 -C 5 alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
- Z is selected from the group consisting of (1’) (CH 2 ) i N(R 7 )C(O)N(R 8 )(CH 2 ) j;
- i 0 or 1
- Ring B is selected from the group consisting of:
- Ring B An 8 to 10 membered bicyclic heteroaryl group which have 1-3 heteroatoms independently selected from the group consisting of O, N and S; Ring B can be illustrated but not limited to the following:
- R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
- R IV represents optionally 1-3 substituents, independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and—NR 9 R 10 ; wherein R 9 and R 10 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and any pharmaceutical acceptable salt or prodrug.
- Z is selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxy
- the diseases or conditions are selected from the group consisting of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast cancer, diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal neovascularization, laser-induced choroidal neovascularization, neovascularization associated with keratoplasty, glaucoma and ocular tumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases and immune disorders.
- the diseases or conditions are selected from the group consisting of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast
- a pharmaceutical composition comprising a therapeutic effective amount of a
- composition of paragraph 26 which are in the form selected from the group comprising of tablets, capsules, intravenous injections, intramuscular injections, local injections, topical creams, gels and ointments, eye drops, ophthalmic solutions, ophthalmic suspensions, ophthalmic emulsions, intravitreal injections, subtenon injections, ophthalmic biodrodible implant, and non-bioeordible ophthalmic inserts or depots.
- Fig. 1 shows a powder X-Ray Diffraction (XRPD) of Example 78;
- Fig 2 shows a powder X-Ray Diffraction (XRPD) of Example 69;
- Fig 3 shows a fluorescein angiography (blood-retinal barrier breakdown) of Example 121, Example 84 Sodium, Example 83, Example 78, Example 75 Sodium, Example 69, and Example 66;
- Fig 4 shows a fundus photography (retinal vasodilation and vessel tortuosity) of Example 121, Example 84 Sodium, Example 83, Example 78, Example 75 Sodium, Example 69, and Example 66.
- the present invention is directed to a series of compounds with multiple aromatic components useful as protein tyrosine kinase inhibitors.
- the compounds of the present invention are useful for treating diseases related to unregulated tyrosine kinase signal transduction, for example, cancer, blood vessel proliferative disorders, fibrotic disorders, and neurodegenerative diseases.
- compounds of the present invention are useful for the treatment of colorectal cancer, lung cancer, hematological cancer, renal cancer, liver cancer, breast cancer, diabetic retinopathy, macular degeneration, age-related macular degeneration, retinopathy of prematurity, ocular angiogenesis, retinal edema, retinal ischemia, diabetic macular edema, cystoid macular edema, retinal vein occlusion, branch vein occlusion, preretinal
- neovascularization laser-induced choroidal neovascularization, neovascularization associated with keratoplasty, glaucoma and ocular tumors, arthritis, restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetes mellitus, wound healing, transplant rejection, inflammation, neurodegenerative diseases and immune disorders.
- X is selected from the group consisting of NR 1 , O, and S(O) n ; n is 0 or an integer of from 1 to 2; R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,
- R I is selected from the group consisting of hydrogen, halogen, C 1 to C 8 alkyl, S(O) f R 4 , (CR 5 R 6 ) d C(O)OR 4 , S(O) f (CR 5 R 6 ) d C(O)OR 4 , (CR 5 R 6 ) d Ar, NR 4 (CR 5 R 6 ) d Ar, O(CR 5 R 6 ) d Ar, S(O) f (CR 5 R 6 ) d Ar, (CR 5 R 6 ) d S(O) f R 4 , NR 4 (CR 5 R 6 ) d S(O) f R 4 , O(CR 5 R 6 ) d S(O) f R 4 ,
- each R 4 is independently selected from the group consisting of hydrogen, hydroxyl, C 1 -C 8 alkyl, aryl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxyalkyl, (CR 5 R 6 ) d and N(R 4 ) 2 may form a 3-7 membered heterocyclic ring, comprising of aziridine, azetidine, pyrrolidine, 5-fluoropyrrolidine, piperidine, 6-fluoropiperidine, N-methylpiperazine, morpholine, 2,6-dimethylmorpholine, thiomorpholine, and wherein said heterocyclic ring may be optionally substituted with up to three of R 5 ; wherein R 5 and R 6 are independently selected from the group consisting of
- R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl,
- R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 and R 3 and may be taken together to form a 5-7 membered cyclic ring;
- Ring A is selected from the group consisting of: (i) Phenyl; (ii) Naphthyl; (iii) A 5 or 6 membered monocyclic heteroaryl group which have 1-5 heteroatoms independently selected from the group consisting of O, N and S; and (iv) An 8 to 10 membered bicyclic heteroaryl group which have 1-6 heteroatom
- R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
- R III represents optionally 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 5 alkoxy, hydroxy, amino, C 1 -C 5 alkylamino, C1-C6 dialkylamino, halogen, cyano, and nitro;
- Z is selected from the group consisting of (1’) (CH 2 ) i N(R 7 )C(O)N(R 8 )(CH 2 ) j; (2’) (CH 2 ) i N(R 7 )C(S)N(R 8 )(CH 2 ) j; (3’) (CH 2 ) i N(R 7 )C(O) ; (4’) C(O)N(R 8 )(CH
- Ring B is selected from the group consisting of:
- Ring B can be illustrated but not limited to the following:
- R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
- R IV represents optionally 1-3 substituents, independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and—NR 9 R 10 ; wherein R 9 and R 10 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
- the compounds of the present invention can be represented by the general formula II:
- W is C or N
- X is selected from the group consisting of NR 1 , O, and S(O) n ;
- n is 0 or an integer of from 1 to 2;
- R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and
- R 2 and R 3 and may be taken together to form a 5-7 membered heterocyclic ring with N;
- R 5 and R 6 are independently selected from the group consisting of hydrogen, halo, hydroxyl, C 1 - C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 alkoxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, amide, alkylamide, amidoalkyl, and sulfonate;
- R II is independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR 2 R 3 )alkoxy, (NR 2 R 3 )alkeny
- g is 0 or an integer of from 1 to 3;
- h is 0 or an integer of from 1 to 3;
- R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 and R 3 and may be taken together to form a 5-7 membered heterocyclic ring with N; R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl,
- a 5 or 6 membered monocyclic heteroaryl group which have 1-5 heteroatoms independently selected from the group consisting of O, N and S;
- Ring A An 8 to 10 membered bicyclic heteroaryl group which have 1-6 heteroatoms independently selected from the group consisting of O, N and S; Ring A can be illustrated but not limited to the following:
- R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 and R 3 and may be taken together to form a 5-7 membered heterocyclic ring with N; R III represents optionally 1-3 substituents independently selected from the group consisting of C 1 -C 5 linear or branched alkyl, C 1 -C 5 linear or branched haloalkyl, C 1 -C 5 alkoxy, hydroxy, amino, C
- i 0 or 1
- j 0 or 1
- R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl.
- Ring B is selected from the group consisting of:
- Ring B An 8 to 10 membered bicyclic heteroaryl group which have 1-3 heteroatoms independently selected from the group consisting of O, N and S; Ring B can be illustrated but not limited to the following:
- R 1 is independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, CF 3 , alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, heterocycloalkyl, hydroxyalkyl, and alkyl(N R 2 R 3 ), wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; alternatively R 2 and R 3 and may be taken together to form a 5-7 membered heterocyclic ring with N; R IV represents optionally 1-3 substituents, independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, hal
- a pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human.
- a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
- a salt comprises one or more ionic forms of the compound, such as a conjugate acid or base, associated with one or more corresponding counter-ions. Salts can form from or incorporate one or more deprotonated acidic groups (e.g. carboxylic acids), one or more protonated basic groups (e.g. amines), or both (e.g. zwitterions).
- a "prodrug” is a compound, which when administered to the body of a subject (such as a mammal), breaks down in the subject's metabolic pathway to provide an active compound of Formula I.
- a prodrug is an active or inactive "masked" compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject or patient.
- a prodrug is a masked carboxylic acid group.
- Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
- Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, Apr.
- Methyl 5-(4-(tert-butoxycarbonyl(3-nitrophenyl)amino)pyridine-2-yl)-1H-pyrrole-3-carboxylate (0.40 g, 0.91 mmol) was taken up in toluene (38 mL) and SiO 2 (9.0 g) was added. The mixture stirred at reflux for 20 h. The mixture was cooled to rt and filtered over celite, washing with EtOAc. The filtrate was concentrated to a bright orange color. The solid was taken up in hexanes and filtered.
- Methyl 5-(4-((3-nitrophenyl)amino)pyridin-2-yl)-1H-pyrrole-3-carboxylate (1.32 g, 3.9 mmol) was taken up in EtOAc/EtOH (1:1; 90 mL) and purged with N 2 . Pd/C (10%, 0.145 g) was added and the mixture was stirred under an atmosphere of H 2 at rt for 18 h. The mixture was filtered over celite, washing with EtOAc/EtOH. The filtrate was concentrated, taken back up in EtOAc and filtered over celite again to remove any residual catalyst. The filtrate was concentrated again and taken back up in EtOAc.
- the reaction vessel was sealed and the mixture stirred at 95°C for 16 h.
- the reaction vessel was cooled to room temperature and the mixture was poured into 100ml of water.
- the precipitates were filtered, washed with water and dried to give the crude, which was purified via column chromatography eluting with 30-40% EtOAc/hexanes to afford 5- ⁇ 4-[3-(2-Fluoro-5- methyl-phenylcarbamoyl)-phenoxy]-pyridin-2-yl ⁇ -1H-pyrrole-3-carboxylic acid methyl ester (150mg, 58% yield).
- the reaction vessel was sealed and the mixture stirred at 95°C for 16 h.
- the reaction vessel was cooled to room temperature and the mixture was poured into 100ml of water.
- the precipitates were filtered, washed with water and dried to give the crude, which was purified via silica gel chromatography eluting with 2-5% MeOH/CHCl 3 to afford methyl 5-(4- ⁇ [4-( ⁇ [(2-fluoro-5-methylphenyl)amino]carbonyl ⁇ amino)phenyl]thio ⁇ pyridin-2-yl)- 1H-pyrrole-3-carboxylate as off-white solid. Yield: 100mg, 20% yield.
Abstract
La présente invention concerne de nouveaux composés de formule I. Les composés de la présente invention sont de puissants modulateurs des tyrosine kinases, et sont appropriés pour le traitement et la prévention de maladies et d'états associés à des activités anormales des récepteurs des tyrosine kinases.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2013/069337 WO2015069287A1 (fr) | 2013-11-08 | 2013-11-08 | Composés à utiliser en tant que modulateurs des tyrosine kinases |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2013/069337 WO2015069287A1 (fr) | 2013-11-08 | 2013-11-08 | Composés à utiliser en tant que modulateurs des tyrosine kinases |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015069287A1 true WO2015069287A1 (fr) | 2015-05-14 |
Family
ID=53041895
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2013/069337 WO2015069287A1 (fr) | 2013-11-08 | 2013-11-08 | Composés à utiliser en tant que modulateurs des tyrosine kinases |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2015069287A1 (fr) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9708272B2 (en) | 2014-08-29 | 2017-07-18 | Tes Pharma S.R.L. | Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase |
US9782408B2 (en) | 2014-10-06 | 2017-10-10 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
US10570115B2 (en) | 2016-09-30 | 2020-02-25 | Vertex Pharmaceuticals Incorporated | Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator |
US10597387B2 (en) | 2013-12-13 | 2020-03-24 | Dana-Farber Cancer Institute, Inc. | Methods to treat lymphoplasmacytic lymphoma |
US10633348B2 (en) | 2013-12-13 | 2020-04-28 | Dana-Farber Cancer Institute, Inc. | Methods to treat lymphoplasmacytic lymphoma |
US10654829B2 (en) | 2017-10-19 | 2020-05-19 | Vertex Pharmaceuticals Incorporated | Crystalline forms and compositions of CFTR modulators |
US10738030B2 (en) | 2016-03-31 | 2020-08-11 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
US10793547B2 (en) | 2016-12-09 | 2020-10-06 | Vertex Pharmaceuticals Incorporated | Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator |
US10844077B2 (en) | 2014-10-22 | 2020-11-24 | Dana-Farber Cancer Institute, Inc. | Thiazolyl-containing compounds for treating proliferative diseases |
US11034669B2 (en) | 2018-11-30 | 2021-06-15 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
US11179367B2 (en) | 2018-02-05 | 2021-11-23 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions for treating cystic fibrosis |
US11253509B2 (en) | 2017-06-08 | 2022-02-22 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
US11414439B2 (en) | 2018-04-13 | 2022-08-16 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator |
US11434201B2 (en) | 2017-08-02 | 2022-09-06 | Vertex Pharmaceuticals Incorporated | Processes for preparing pyrrolidine compounds |
US11465985B2 (en) | 2017-12-08 | 2022-10-11 | Vertex Pharmaceuticals Incorporated | Processes for making modulators of cystic fibrosis transmembrane conductance regulator |
US11517564B2 (en) | 2017-07-17 | 2022-12-06 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011028995A1 (fr) * | 2009-09-03 | 2011-03-10 | Allergan, Inc. | Composés en tant que modulateurs de la tyrosine kinase |
-
2013
- 2013-11-08 WO PCT/US2013/069337 patent/WO2015069287A1/fr active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011028995A1 (fr) * | 2009-09-03 | 2011-03-10 | Allergan, Inc. | Composés en tant que modulateurs de la tyrosine kinase |
Cited By (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10597387B2 (en) | 2013-12-13 | 2020-03-24 | Dana-Farber Cancer Institute, Inc. | Methods to treat lymphoplasmacytic lymphoma |
US10633348B2 (en) | 2013-12-13 | 2020-04-28 | Dana-Farber Cancer Institute, Inc. | Methods to treat lymphoplasmacytic lymphoma |
AU2014361798B2 (en) * | 2013-12-13 | 2020-06-11 | Dana-Farber Cancer Institute, Inc. | Methods to treat lymphoplasmacytic lymphoma |
US10513499B2 (en) | 2014-08-29 | 2019-12-24 | Tes Pharma S.R.L. | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase |
US11254644B2 (en) | 2014-08-29 | 2022-02-22 | Tes Pharma S.R.L. | Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase |
US9708272B2 (en) | 2014-08-29 | 2017-07-18 | Tes Pharma S.R.L. | Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase |
US10758534B2 (en) | 2014-10-06 | 2020-09-01 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
US9782408B2 (en) | 2014-10-06 | 2017-10-10 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
US10258624B2 (en) | 2014-10-06 | 2019-04-16 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
US11426407B2 (en) | 2014-10-06 | 2022-08-30 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
US10844077B2 (en) | 2014-10-22 | 2020-11-24 | Dana-Farber Cancer Institute, Inc. | Thiazolyl-containing compounds for treating proliferative diseases |
US10738030B2 (en) | 2016-03-31 | 2020-08-11 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator |
US10570115B2 (en) | 2016-09-30 | 2020-02-25 | Vertex Pharmaceuticals Incorporated | Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator |
US11186566B2 (en) | 2016-09-30 | 2021-11-30 | Vertex Pharmaceuticals Incorporated | Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator |
US10793547B2 (en) | 2016-12-09 | 2020-10-06 | Vertex Pharmaceuticals Incorporated | Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator |
US11453655B2 (en) | 2016-12-09 | 2022-09-27 | Vertex Pharmaceuticals Incorporated | Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator |
US11253509B2 (en) | 2017-06-08 | 2022-02-22 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
US11517564B2 (en) | 2017-07-17 | 2022-12-06 | Vertex Pharmaceuticals Incorporated | Methods of treatment for cystic fibrosis |
US11434201B2 (en) | 2017-08-02 | 2022-09-06 | Vertex Pharmaceuticals Incorporated | Processes for preparing pyrrolidine compounds |
US11155533B2 (en) | 2017-10-19 | 2021-10-26 | Vertex Pharmaceuticals Incorporated | Crystalline forms and compositions of CFTR modulators |
US10654829B2 (en) | 2017-10-19 | 2020-05-19 | Vertex Pharmaceuticals Incorporated | Crystalline forms and compositions of CFTR modulators |
US11465985B2 (en) | 2017-12-08 | 2022-10-11 | Vertex Pharmaceuticals Incorporated | Processes for making modulators of cystic fibrosis transmembrane conductance regulator |
US11179367B2 (en) | 2018-02-05 | 2021-11-23 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions for treating cystic fibrosis |
US11414439B2 (en) | 2018-04-13 | 2022-08-16 | Vertex Pharmaceuticals Incorporated | Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator |
US11034669B2 (en) | 2018-11-30 | 2021-06-15 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2010289353B2 (en) | Compounds as tyrosine kinase modulators | |
WO2015069287A1 (fr) | Composés à utiliser en tant que modulateurs des tyrosine kinases | |
CN101111483B (zh) | Igf-1r抑制剂 | |
RU2571100C2 (ru) | Спироиндолинонпирролидины, полезные при лечении злокачественных новообразований | |
CN101511796B (zh) | 咪唑衍生物 | |
KR20080014046A (ko) | 대사성 글루타메이트 수용체의 양성 알로스테릭 조절자로서페닐-3-{(3-(1h-피롤-2-일)-[1,2,4]옥사디아졸-5-일)피페리딘-1-일}-메탄온 유도체 및 관련 화합물 | |
JP2010510242A (ja) | キナーゼ阻害剤としてのスルホキシミン | |
KR20100095582A (ko) | 야누스 키나제 억제제로서의 4-피라졸릴-n-아릴피리미딘-2-아민 및 4-피라졸릴-n-헤테로아릴피리미딘-2-아민 | |
US10221192B2 (en) | Compounds as tyrosine kinase modulators | |
WO2014027053A1 (fr) | Benzimidazoles pour le traitement d'un cancer | |
US20060004084A1 (en) | (3Z)-3-(2,3-dihydro-1H-inden-1-ylidene)-1,3-dihydro-2H-indol-2-ones as kinase inhibitors | |
US8906944B2 (en) | Compounds as tyrosine kinase modulators | |
MX2010013311A (es) | Derivados de pirrolidina como antagonistas del receptor de nk2. | |
WO2007087419A2 (fr) | Hétérocyclyl-1,3-dihydro-indol-2-ones insaturées et substituées à 3-5 éléments et leurs dérivés en tant qu'inhibiteurs de kinase | |
WO2020103817A1 (fr) | INHIBITEUR DE TGF-βR1 ET SON UTILISATION | |
AU2003295658A1 (en) | Indol derivatives and their use as kinase inhibitors | |
CN115448882A (zh) | 用于治疗ep2、ep4受体介导的疾病的苯并杂环化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13818860 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 13818860 Country of ref document: EP Kind code of ref document: A1 |