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NZ624945B2 - Uracil derivatives as axl and c-met kinase inhibitors - Google Patents

Uracil derivatives as axl and c-met kinase inhibitors Download PDF

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Publication number
NZ624945B2
NZ624945B2 NZ624945A NZ62494512A NZ624945B2 NZ 624945 B2 NZ624945 B2 NZ 624945B2 NZ 624945 A NZ624945 A NZ 624945A NZ 62494512 A NZ62494512 A NZ 62494512A NZ 624945 B2 NZ624945 B2 NZ 624945B2
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New Zealand
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lcms
acid
nmr
dioxo
dmso
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NZ624945A
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NZ624945A (en
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Reddeppareddy Dandu
Robert L Hudkins
Kurt A Josef
Catherine P Prouty
Rabindranath Tripathy
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Ignyta Inc
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Priority to NZ712194A priority Critical patent/NZ712194B2/en
Priority claimed from PCT/US2012/065019 external-priority patent/WO2013074633A1/en
Publication of NZ624945A publication Critical patent/NZ624945A/en
Publication of NZ624945B2 publication Critical patent/NZ624945B2/en

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    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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    • 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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

Provided are uracil derivative compounds of the general formula I, where the variables are as defined in the specification. Examples of the compounds include 1-Ethyl-3-( 4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]amide and 4-(4-Fluoro-phenyl)-2-isopropyl-3,S-dioxo-2,3,4,S-tetrahydro-1,2,4-triazine-6-carboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxy-phenyl]-amide. The compounds are AXL and c-MET inhibitors. The compounds may be useful in the treatment of cancer. d 4-(4-Fluoro-phenyl)-2-isopropyl-3,S-dioxo-2,3,4,S-tetrahydro-1,2,4-triazine-6-carboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-2-methoxy-phenyl]-amide. The compounds are AXL and c-MET inhibitors. The compounds may be useful in the treatment of cancer.

Description

URACIL DERIVATIVES AS AXL AND C-MET KINASE INHIBITORS BACKGROUND OF THE INVENTION The present invention relates to novel compounds that are inhibitors of the receptor ne kinases AXL and c-MET. The compounds are suitable for treatment ofAXL or c- MET-mediated disorders such as cancer, and the development of resistance to cancer therapies.
Receptor tyrosine kinases (RTKs) are transmembrane proteins that transduce signals from the extracellular environment to the cytoplasm and nucleus to regulate normal cellular processes, including survival, growth, differentiation, adhesion, and mobility. Abnormal expression or activation of RTKs has been implicated in the pathogenesis of various human cancers, linked with cell ormation, tumor formation and asis. These ations have led to intense interest in the development of tyrosine kinase inhibitors as cancer therapeutics (Rosti et al, Crit. Rev. Oncol. Hematol. 2011. [Epub ahead of print]; Gorden et al, J. Oncol. Pharm. Pract. 2011. [Epub ahead of print]; Grande et al, Mol. Cancer Ther. 2011, 10, 569).
AXL is a member of the TAM (TYRO3, AXL, MER) receptor ne kinase (RTK) family originally identified as a transforming gene expressed in cells from patients with chronic myelogenous leukemia (O'Bryan et. al Mol. Cell Biol. 1991, 11, 5016) or chronic myeloproliferative disorder en et. al ne, 1991, 6, 2113). AXL activation occurs by g of its cognate protein ligand, growth arrest specific 6 (Gas6), homotypic dimerization through its extracellular domain or cross-talk via the interleukin (IL)-15 receptor or HER2. AXL signaling stimulates cellular ses, including activation phoinositide 3-kinase—Akt, extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase cascades, the NF-KB pathway, and signal transducer and activator of transcription (STAT) signaling (Hafizi et. al Cytokine Growth Factor Rev., 2006, 17, 295). Numerous biological consequences ofAXL signaling, including invasion, migration, survival signaling, angiogenesis, resistance to chemotherapeutic and targeted drugs, cell transformation, and proliferation, represent rable traits associated with cancer (Linger et al. Adv. Cancer Res., 2008, 100, 35; Hafizi et. al Cytokine Growth Factor Rev., 2006, 17, 295; Holland et al, Cancer Res. 2005, 65, 9294).
AXL receptors regulate vascular smooth muscle homeostasis (Korshunov et al, Circ. Res. 2006, 98, 1446) and are implicated in the control of oligodendrocyte cell survival (Shankar et al, J. Neurosci. 2003, 23, 4208). Studies in knockout mice have revealed that TAM ors play pivotal roles in innate immunity by inhibiting inflammation in macrophages and dendritic cells (Sharif et al, J. Exp. Med. 2006, 203, 1891; Rothlin et al, Cell. 2007, 131, 1124), promoting the phagocytosis of apoptotic cells (Lu et al, Nature. 1999, 398, 723; Lu & Lemke, Science. 2001, 293, 306; Prasad et al, Mol. Cell Neurosci. 2006, 3, 96) and stimulating the differentiation of natural killer cells (Park et al, Blood 2009, 113, 2470).
AXL has been found to be constitutively activated due to gene amplification and/or altered protein expression (O’Bryan et al, J. Biol. Chem. 1995, 270, 551; Linger et al, Expert Opin. Ther. Targets. 2010, 14, 1073; Mudduluru et al, Oncogene, 2011, 30, 2888). Altered expression ofAXL has been reported in a variety of human cancers (Crosier et al, Leuk. ma. 1995, 18, 443; Challier et al, ia, 1996, 10, 781; Ito et al, d. 1999, 9, 563; Sun et al, Oncology. 2004, 66, 450; Green et al, Br. J.
Cancer. 2006, 94, 1446; Liu et al, Blood. 2010, 116, 297) and is associated with invasiveness and metastasis in lung cancer (Shieh et al, Neoplasia. 2005, 7, 1058), prostate cancer (Shiozawa et al, Neoplasia. 2010, 12, 116), breast cancer (Zhang et al, Cancer Res. 2008, 68, 1905), geal cancer (Hector et al, Cancer Biol. Ther. 2010, 10, 1009), ovarian cancer (Rankin et al, Cancer Res. 2010, 70, 7570), pancreatic cancer (Koorstra et al, Cancer Biol. Ther. 2009, 8, 618; Song et al, Cancer, 2011, 117, 734), liver cancer (He et al, Mol. Carcinog. 2010, 49, 882), gastric cancer (Wu et al, Anticancer Res. 2002, 22, 1071; Sawabu et al, Mol Carcinog. 2007, 46, 155), thyroid cancer (Avilla et al, Cancer Res. 2011, 71, 1792), renal cell oma (Chung et al, DNA Cell Biol. 2003, 22, 533; Gustafsson et al, Clin. Cancer Res. 2009, 15, 4742) and glioblastoma (Hutterer et al, Clin.
Cancer Res. 2008, 14, 130).
Indeed, AXL overexpression is associated with late stage and poor l survival in many of those human s (Rochlitz et al, Leukemia, 1999, 13, 1352; Vajkoczy et al, Proc Natl. Acad. Sci.. 2006, 103, 5799). AXL contributes to at least three of the six fundamental mechanisms of malignancy in human, by promoting cancer cell migration and invasion, involving in tumor angiogenesis, and facilitating cancer cell survival and tumor growth (Holland et al, Cancer Res. 2005, 65, 9294; Tai et al, Oncogene. 2008, 27, 4044; Li et al, Oncogene, 2009, 28, 3442; Mudduluru et al, Mol. Cancer Res. 2010, 8, 159). AXL is strongly induced by epithelial-to-mesenchymal transitions (EMT) in immortalized mammary epithelial cells and AXL knockdown completely prevented the spread of highly metastatic breast carcinoma cells from the mammary gland to lymph nodes and l major organs and increases overall survival rum et al, Proc. Natl.
Acad. Sci. U S A. 2010, 107, 1124; Vuoriluoto et al, Oncogene. 2011, 30, 1436), indicating AXL represents a critical downstream effector of tumor cell EMT requiring for cancer metastasis.
AXL is also induced during progression of resistance to therapies including imatinib in intestinal stromal tumors (Mahadevan et al, Oncogene. 2007, 26, 3909) and Herceptin and EGFR inhibitor therapy (e.g. lapatinib) in breast cancer (Liu et al, Cancer Res. 2009, 69, 6871) via a “tyrosine kinase switch”, and after chemotherapy in acute myeloid leukemia (Hong et al, Cancer Lett. 2008, 268, 314). AXL knockdown was also reported to lead to a significant increase in chemosensitivity of astrocytoma cells in response to herapy treatment (Keating et al, Mol. Cancer Ther. 2010, 9, 1298).
These data te AXL as an important mediator for tumor resistance to conventional chemotherapy and molecular-based cancer therapeutics.
The c-MET receptor was initially identified as the TPR—MET oncogene in an osteosarcoma cell line treated with a chemical carcinogen. The TPR—Met protein is able to orm and confer invasive and metastatic ties to non-tumorigenic cells (Sattler et. al, Current Oncology Rep., 2007, 9, 102). The oncogenic potential is a result of spontaneous dimerization and constitutive activation of TPR—MET. Aberrant expression ofHGF and c-MET is associated with the development and poor prognosis of a wide range of solid tumors, ing , prostate, thyroid, lung, stomach, colorectal, pancreatic, kidney, ovarian, and e carcinoma, malignant glioma, uveal ma, and osteo-and soft-tissue sarcoma (Jaing et. al Critical Rev. Oncol/Hematol., 2005, 53, ). Gastric tumors with an amplification of the wt-c-MET gene are more susceptible to MET tion, thereby making c-MET an attractive target (Smolen et. al Proc. Natl.
Acad. Sci. USA, 2006, 103, 2316).
In vitro and in vivo s have shown that increased and ulated c-MET activation leads to a wide range of biological responses associated with the malignant phenotype. These responses include increased motility/invasion, increased tumorigenicity, enhanced angiogenesis, protection of carcinoma cells from apoptosis induced by DNA- damaging agents such as adriamycin, iolet light, and ionizing radiation, and enhanced rate of repair ofDNA strand breaks [Comoglio et. al J. Clin. Invest., 2002, 109, 857, Sattler et. al Current gy Rep., 2007, 9, 102; Fan et. al, Mol. Cell Biol., 2001, 21, 4968). Based upon these data, HGF may enhance mutagenicity following DNA damage, ng tumor cells with genetic damage to survive, and thus leading to resistance to chemo- and radiotherapeutic treatment regimens (Fan et. al, Mol. Cell Biol., 2001, 21, 4968; Hiscox et. al Endocrine-Related Cancer, 2004, 13, 1085).
MET amplification plays a unique critical role in mediating resistance of non-small cell lung cancer to EGFR inhibitors (e.g. TarcevaTM, TM the resistance of , TykerbTM) HER2 positive breast cancer to trastuzumab (Sattler et. al, Update Cancer Ther., 2009, 3, 109; Engleman et. al, Science, 2007, 316, 1039, Shattuck et. al Cancer Res., 2008, 68, 1471, Agarwal et. al, Br. J. Cancer, 2009, 100, 941; Kubo et. al, Int. J. Cancer 2009, 124, 1778). Inhibition of c-MET in TarcevaTM or IressaTM resistant cells using shRNA or small molecules alone or in combination with an EGFR inhibitor overcame diated ance to EGFR inhibitors [Agarwal et. al, Br. J. Cancer, 2009, 100, 941; Bachleitner- Hoffman et. al, Mol. Cancer Ther., 2008, 7, 3499, Tang et. al, Br. J. Cancer, 2008, 99, 911; Bean et. al, Proc. Natl. Acad. Sci. USA, 2007, 104, 20932). Due to the pleiotropic, pro-tumorigenic activities of the HGF-c-MET axis, inhibiting this pathway would be predicted to have potent anti-tumor effects in many common cancers through multiple complimentary mechanisms.
A need exists for AXL and c-MET inhibitors for use as pharmaceutical agents.
SUMMARY OF THE INVENTION The present ion provides a compound of Formula I a. T3 x/“YO R1b / \IY NWME Rd o o R161 Rb N Formula I or a pharmaceutically acceptable salt form thereof, wherein Ra, Rb, RC, Rd, D, W, Y, Rla, Rlb, R10, R3, X, G and E are as defined herein.
The compound of Formula I has AXL and c-MET inhibitory activity, and may be used to treat AXL-, or c-MET- ed ers or ions.
The present ion fiarther provides a pharmaceutical composition comprising at least one compound of the present invention together with at least one pharmaceutically able carrier, diluent, or excipient therefor.
In another aspect, the present ion provides a method of treating a subject suffering from an AXL- or c-MET- mediated disorder or condition comprising administering to the subject a therapeutically effective amount the pharmaceutical composition of the t invention.
The present invention fiarther provides a method of treating a proliferative disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention.
DETAILED DESCRIPTION OF THE INVENTION I. Definitions As used herein, the following terms have the meanings ascribed to them unless specified otherwise.
“Alkylamino” or an “alkylamino group” refers to an —NH-alkyl group.
“Alkoxy” or “alkoxy group” refers to an —O-alkyl group. ycarbonyl” refers to an all<yl-O-C(=O)- group.
"Alkyl" or “alkyl group” refers to a branched or unbranched saturated arbon chain. Examples include, but are not limited to, , ethyl, n-propyl, l, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, etc. Alkyl groups typically contain l-lO carbon atoms, such as 1-6 carbon atoms.
“Substituted alkyl” tes that one or more hydrogen atoms on an alkyl group has been replaced with a different atom or group of atoms and the atom or group of atoms replacing the hydrogen atom is a “substituent”. Representative substituents include, but are not limited to, halogen, (C1-C8)alkyl, (Cl-Cg)alkoxy, (Cl-Cg)alkoxy(C1-C4)alkyl, carboxyl, formyl, (C1-C6)acyl, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, hydroxyl, nitro, cyano, amino, trifluoromethyl, mono- or di-(C1-C6)alkylamino, oxo, (C6-C10)aryl, (C5- C9)heteroaryl, (C1-C6)alkoxycarbonyl, (Cg-Clo)cycloalkyl, (Cg-Clo)cycloalkyloxy, (C3- cloalkyl(C1-C6)alkoxy, (C2-C9)heterocyclyl, (C2-C9)heterocyclyloxy, (C2- C9)heterocyclyl(C1-C4)alkoxy, (C1-C6)alkoxycarbonyl(C1-C4)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylsulf1nyl, (C1-C6)alkylsulfonyl, mono- and di-(C1-C6)alkylaminocarbonyl, (C1- C6)acylthio, and (C1-C6)acyloxy.
“Alkenyl” refers to an alkyl group containing the requisite number of carbon atoms as described herein for “alkyl”, and which contains at least one double bond. Representative examples of alkenyl groups include, but are not limited to l, allyl, isopropenyl, and 2- methyl- 1 nyl.
“Substituted l” indicates that one or more hydrogen atoms on an alkenyl group has been replaced with a different atom or group of atoms and the and the atom or group of atoms replacing the hydrogen atom is a “substituent”. Representative substituents include, but are not limited to, halogen, (C1-C8)alkyl, (C1-C8)alkoxy, )alkoxy(C1-C4)alkyl, carboxyl, formyl, (C1-C6)acyl, halo(C1-C4)alkyl, 1-C4)alkoxy, hydroxyl, nitro, cyano, amino, trifluoromethyl, mono- or di-(C1-C6)alkylamino, oxo, (C6-C10)aryl, (C5- C9)heteroaryl, (C1-C6)alkoxycarbonyl, (Cg-C10)cycloalkyl, (Cg-C10)cycloalkyloxy, (C3- C10)cycloalkyl(C1-C6)alkoxy, (C2-C9)heterocyclyl, (C2-C9)heterocyclyloxy, (C2- C9)heterocyclyl(C1-C4)alkoxy, (C1-C6)alkoxycarbonyl(C1-C4)alkyl, (C1-C6)alkoxycarbonyl, )alkylsulf1nyl, (C1-C6)alkylsulfonyl, mono- and di-(C1-C6)alkylaminocarbonyl, (C1- C6)acylthio, and (C1-C6)acyloxy.
“Alkynyl” refers to an alkyl group containing the requisite number of carbon atoms as described herein for “alkyl”, and which ns at least one triple bond. Representative examples of alkenyl groups include, but are not limited to l, propargyl, and l- and 2- “Substituted alkynyl” indicates that one or more hydrogen atoms on an alkynyl group has been replaced with a different atom or group of atoms and the and the atom or group of atoms replacing the hydrogen atom is a “substituent”. Representative tuents include, but are not limited to, halogen, (Cl-Cg)alkyl, (C1-C8)alkoxy, (C1-C8)alkoxy(C1- C4)alkyl, yl, formyl, (C1-C6)acyl, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, hydroxyl, nitro, cyano, amino, trifluoromethyl, mono- or di-(Cl-C6)alkylamino, oxo, (C6-C10)aryl, (C5- C9)heteroaryl, (C1-C6)alkoxycarbonyl, (Cg-C10)cycloalkyl, (Cg-C10)cycloalkyloxy, (C3- C10)cycloalkyl(C1-C6)alkoxy, (C2-C9)heterocyclyl, (C2-C9)heterocyclyloxy, (C2- C9)heterocyclyl(C1-C4)alkoxy, (C1-C6)alkoxycarbonyl(C1-C4)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylsulf1nyl, (C1-C6)alkylsulfonyl, mono- and di-(C1-C6)alkylaminocarbonyl, (C1- C6)acylthio, and (C1-C6)acyloxy.
“Alkanoyl” refers to an C(=O)— group.
The term “CH” indicates the number of carbon atoms in a group. For example, a “C1_6-alkyl” is an alkyl group haVing from one (1) to six (6) carbon atoms.
The term “cyano” refers to a CN group.
“Cycloalkyl” refers to a non-aromatic, saturated carbocyclic ring system, and may be monocyclic, bicyclic or tricyclic, and may be bridged, spiro and/or fiJsed. Preferably the cycloalkyl group contains from 3 to 10 ring atoms. Examples include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and norbomyl.
“Cycloalkoxyalkyl” refers to a cycloalkyl-O-alkyl- group.
“Cycloalkylalkyl” refers to a lkyl-alkyl- group.
“Carbamoyl” refers to a NH2C(=O)- group.
“N-alkylcarbamoyl” or “alkyl carbamoyl” refers to an alkyl-NH-C(=O)— group.
“N,N—dialkylcarbamoyl” or “dialkylcarbamoyl” refers to an (alkyl)(alkyl)N— C(=O)- group. On such a group the alkyl groups may be the same or different.
“Aryl” or “aryl group” refers to phenyl and 7-15 membered monoradical bicyclic or tricyclic hydrocarbon ring systems, ing bridged, spiro, and/or fused ring s, in which at least one of the rings is aromatic. Aryl groups can be substituted or unsubstituted. Examples include, but are not limited to, phenyl, naphthyl, indanyl, l,2,3,4- ydronaphthalenyl, 9-tetrahydro-5H-benzocycloheptenyl, and 6,7,8,9- tetrahydro-5H-benzocycloheptenyl. Preferably, the aryl group contains 6 (i.e., phenyl) or 9 to 15 ring atoms. More preferably, the aryl group contains 6 (i.e., phenyl), 9 or 10 ring atoms.
“Substituted aryl indicates that one or more hydrogen atoms on an aryl group has been replaced with a different atom or group of atoms and the and the atom or group of atoms replacing the hydrogen atom is a ituent”. Representative substituents include, but are not d to, halogen, (C1-C8)alkyl, (C1-C8)alkoxy, (Cl-Cg)alkoxy(C1-C4)alkyl, carboxyl, formyl, (C1-C6)acyl, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, hydroxyl, nitro, cyano, amino, romethyl, mono- or -C6)alkylamino, oxo, (C6-C10)aryl, (C5- C9)heteroaryl, (C1-C6)alkoxycarbonyl, (Cg-C10)cycloalkyl, (Cg-C10)cycloalkyloxy, (C3- C10)cycloalkyl(C1-C6)alkoxy, (C2-C9)heterocyclyl, (C2-C9)heterocyclyloxy, (C2- C9)heterocyclyl(C1-C4)alkoxy, (C1-C6)alkoxycarbonyl(C1-C4)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylsulf1nyl, (C1-C6)alkylsulfonyl, mono- and di-(C1-C6)alkylaminocarbonyl, (C1- C6)acylthio, and (C1-C6)acyloxy.
“Arylalkyl” refers to an lkyl- group.
“Arylalkoxy” refers to an aryl-alkyl-O- group.
“Arylalkoxyalkyl” refers to an aryl-alkyl-O-alkyl- group.
“Aryloxy” refers to an aryl-O- group.
“Heterocyclyl” or “heterocyclyl group” refers to 3-15 membered monocyclic, bicyclic, and lic non-aromatic rings, which may be saturated or unsaturated, can be substituted or unsubstituted, may be d, spiro, and/or fused, and which contain, in addition to carbon ), at least one heteroatom, such as nitrogen, oxygen or sulfilr.
Examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl, ydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, oxazolidinonyl, dihydropyrazolyl, opyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, quinuclidinyl, 2-oxa- -azabicyclo[2.2. l]heptane, 8-oxaaza-bicyclo[3 .2. l ]octane, 3 ,8-diazabicyclo [3.2. l]octane, 2,5-diaza-bicyclo[2.2. l]heptane, 3,8-diaza-bicyclo[3.2.l]octane, 3,9- diaza-bicyclo[4.2. l]nonane and 2,6-diaza-bicyclo[3.2.2]nonane. Preferably, the heterocyclyl group contains from 3 to 10 ring atoms. More preferably, the heterocycyl group contains from 3 to 7 ring atoms. More preferably, the heterocyclyl group contains from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms. Unless otherwise indicated, the ing heterocyclyl groups can be C- attached or N-attached where such is possible and results in the creation of a stable structure. For example, piperidinyl can be piperidin-l-yl (N-attached) or piperidinyl (C-attached). A heterocyclyl group can also include ring systems substituted on ring carbons with one or more —OH functional groups (which may fiarther tautomerize to give a ring C=O group) and/or substituted on a ring sulfur atom by one (1) or two (2) oxygen atoms to give S=O or 802 groups, tively.
“Substituted heterocyclyl” indicates that one or more hydrogen atoms on a heterocyclyl group has been replaced with a different atom or group of atoms and the and the atom or group of atoms replacing the hydrogen atom is a ituent”. entative substituents include, but are not limited to, n, (C1-C8)alkyl, )alkoxy, (C1- oxy(C1-C4)alkyl, carboxyl, formyl, (C1-C6)acyl, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, hydroxyl, nitro, cyano, amino, trifluoromethyl, mono- or di-(Cl-C6)alkylamino, oxo, (C6- yl, (C5-C9)heteroaryl, (C1-C6)alkoxycarbonyl, (C3-C10)cycloalkyl, (C3- C10)cycloalkyloxy, (Cg-C10)cycloalkyl(C1-C6)alkoxy, (C2-C9)heterocyclyl, (C2- C9)heterocyclyloxy, (C2-C9)heterocyclyl(C1-C4)alkoxy, (C1-C6)alkoxycarbonyl(C1-C4)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylsulf1nyl, (C1-C6)alkylsulfonyl, mono- and di-(Cl- ylaminocarbonyl, (C1-C6)acylthio, and )acyloxy. ocyclylalkoxyalkyl" refers to a heterocylylalkyl-O-alkyl- group.
“Heterocyclylcarbonyl” refers to a heterocyclyl-(C=O)- group.
“Heteroaryl” or “heteroaryl group” refers to (a) 5 and 6 membered monocyclic aromatic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) 7-15 membered bicyclic and tricyclic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and in which at least one of the rings is aromatic. Heteroaryl groups can be substituted or unsubstituted, and may be bridged, spiro, and/or fused. Examples include, but are not limited to, 2,3-dihydrobenzofuranyl, l,2-dihydroquinolinyl, 3,4- dihydroisoquinolinyl, l ,2,3 ,4-tetrahydroisoquinolinyl, l ,2,3 ,4-tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl, filranyl, 2-fi1ranyl, 3-furanyl, imidazolyl, isoxazolyl, azolyl, oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, zinyl, 3- or 4-pyridazinyl, zinyl, thienyl, 2-thienyl, 3- thienyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl, lyl, pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, naphthyridinyl, pteridinyl, phthalazinyl, purinyl, alloxazinyl, benzimidazolyl, benzofuranyl, benzofilrazanyl, 2H-l-benzopyranyl, benzothiadiazine, hiazinyl, hiazolyl, hiophenyl, benzoxazolyl, cinnolinyl, furopyridinyl, nyl, zinyl, indolyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 3H-indolyl, quinazolinyl, quinoxalinyl, isoindolyl, isoquinolinyl, lO-aza-tricyclo [6.3 . l .0*2,7*]dodeca-2(7),3 ,5- trienyl, l2-oxa-lO-aza-tricyclo[6.3. l *]dodeca-2(7),3,5-trienyl, l2-azatricyclo [7.2.l.0*2,7*]dodeca-2(7),3,5-trienyl, l0-aza-tricyclo[6.3.2.0*2,7*]trideca- 2(7),3,5-trienyl, 2,3,4,5-tetrahydro-lH-benzo[d]azepinyl, l,3,4,5-tetrahydro- benzo[d]azepinonyl, l ,3 ,4,5-tetrahydro-benzo[b]azepinonyl, 2,3 ,4,5-tetrahydrobenzo [c]azepin-l-onyl, l,2,3,4-tetrahydro-benzo[e][l,4]diazepinonyl, 2,3,4,5- tetrahydro- l H-benzo [e] [l ,4] diazepinyl, 5 ,6, 8 ,9-tetrahydrooxa-benzocycloheptenyl, 2,3 ,4,5 hydro- l H-benzo [b] azepinyl, l,2,4,5 -tetrahydro-benzo [e] [ l ,3 ] diazepin-3 -onyl, 3 ,4-dihydro-2H-benzo [b] [l ,4]dioxepinyl, 3 ,4-dihydro-2H-benzo[f] [ l ,4]oxazepin-5 -onyl, 6,7,8,9-tetrahydro-5 -thiaaza-benzocycloheptenyl, 5,5-dioxo-6,7,8,9-tetrahydrothia aza-benzocycloheptenyl, and 2,3,4,5-tetrahydro-benzo[f][l,4]oxazepinyl. Preferably, the heteroaryl group contains 5, 6, or 8-15 ring atoms. More preferably, the heteroaryl group contains 5 to 10 ring atoms, such as 5, 6, 9, or 10 ring atoms. A heteroaryl group can also include ring systems substituted on ring carbons with one or more —OH or C=O fianctional groups and/or substituted on a ring sulfur atom by one (1) or two (2) oxygen atoms to give S=O or 802 groups, respectively.
“Substituted heteroaryl” indicates that one or more hydrogen atoms on a heteroaryl group has been replaced with a ent atom or group of atoms and the and the atom or group of atoms replacing the hydrogen atom is a “substituent”. Representative substituents include, but are not limited to, halogen, (Cl-Cg)alkyl, (C1-C8)alkoxy, (C1-C8)alkoxy(C1- C4)alkyl, carboxyl, formyl, (C1-C6)acyl, halo(C1-C4)alkyl, 1-C4)alkoxy, hydroxyl, nitro, cyano, amino, trifluoromethyl, mono- or di-(C1-C6)alkylamino, oxo, (C6-C10)aryl, (C5- eroaryl, (C1-C6)alkoxycarbonyl, (Cg-Clo)cycloalkyl, (Cg-Clo)cycloalkyloxy, (C3- C10)cycloalkyl(C1-C6)alkoxy, (C2-C9)heterocyclyl, (C2-C9)heterocyclyloxy, (C2- C9)heterocyclyl(C1-C4)alkoxy, (C1-C6)alkoxycarbonyl(C1-C4)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylsulf1nyl, (C1-C6)alkylsulfonyl, mono- and di-(C1-C6)alkylaminocarbonyl, (C1- C6)acylthio, and (C1-C6)acyloxy. oarylalkyl” refers to a heteroaryl-alkyl- group.
“Halo” and “halogen” include fluoro, chloro, bromo and iodo, and fluorine, chlorine, bromine and iodine atoms.
“Trihalomethyl” refers to a —CH3 group, the hydrogens of which have been substituted with halogen atoms, which may be the same or different. Representative trihalomethyl groups include CF3, CClg, CBrg or C13. A preferred trihalomethyl group is CF3.
“Trihaloalkyl” refers to an alkyl group substituted by three halogen atoms, which may be the same or different.
“Alkoxyalkyl” or “alkoxyalkyl group” refers to an alkyl group containing an alkoxy group substituent.
“Hydroxyl”, “hydroxy”, “hydroxyl group” or “hydroxyl group” refers to an —OH group.
“Amino” or “amino group” refers to an —NH2 group.
“Alkylamino” or “alkylamino group” refers to an alkyl-N(H)- group.
“Dialkylamino” or “dialkylamino” group refers to an (alkyl)(alkyl)N— group. In such a group the alkyl groups substituting the nitrogen may be the same or different.
“Carboxy3, “ , carboxyl”, “carboxy group” or “carboxyl group” refers to a —COOH group.
“Oxo” refers to a =0 group.
“Pseudohalogen” refers to —OCN, —SCN, —CF3, and —CN.
“Chemically stable” or “stable” refers to a compound that is ently robust to be isolated to a useful degree of purity from a reaction mixture. The present invention is directed only to ally stable nds.
“Pharmaceutical composition” refers to a composition suitable for administration in medical or veterinary use.
When lists of ative substituents include members which, owing to valency requirements, chemical stability, or other reasons, cannot be used to substitute a particular group, the list is ed to be read in context to include those members of the list that are suitable for substituting the particular group.
“Pharmaceutically acceptable” refers to physiologically tolerable materials, which do not typically produce an allergic or other untoward reaction, such as gastric upset, dizziness and the like, when administered to a mammal.
“Therapeutically effective amount” refers to an amount of a nd, or a ceutically acceptable salt thereof, sufficient to t, halt, or cause an improvement in a disorder or condition being treated in a particular subject or subject population. For example in a human or other , a therapeutically effective amount can be determined mentally in a laboratory or al setting, or may be the amount 2012/065019 required by the guidelines of the United States Food and Drug Administration, or equivalent foreign , for the particular disease and subject being treated.
It should be appreciated that ination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the ceutical and medical arts, and is described below.
“Subject” refers to a member of the class Mammalia. Examples ofmammals include, without limitation, , primates, chimpanzees, rodents, mice, rats, rabbits, horses, livestock, dogs, cats, sheep, and cows.
“Treatment” refers to the acute or prophylactic diminishment or alleviation of at least one symptom or characteristic associated or caused by a disorder being treated. For example, treatment can include diminishment of several symptoms of a disorder or complete eradication of a disorder.
“Administering” refers to the method of contacting a nd with a subject.
Modes of “administering” include, but are not limited to, methods that involve contacting the compound intravenously, intraperitoneally, intranasally, transdermally, topically, via implantation, aneously, parentally, intramuscularly, orally, systemically, and via adsorption.
II. Compounds The present invention provides a compound of a I or a salt form thereof, | I R1b / | NWBKE Rd \ Y o 0 R3 R13 Rb NJ Formula I wherein: E and G are independently chosen from H, C1_6alkyl optionally substituted by l-6 R19, C2_6alkenyl optionally substituted by l-6 R19, C2_6alkynyl optionally substituted by 1-6 R19, C6_11aryl optionally substituted by 1-6 R19, c3- 11cycloalkyl optionally substituted by 1-6 R19, 3—15 membered heterocyclyl optionally tuted by l-6 R19, 5-15 membered heteroaryl ally substituted by 1-6 R19, —C(=O)R20, —C(=O)OR2°, NR22R23, — S(=O)2R2°, and —S(=O)2NR22R23; X is N or C-R4; Y is N or C-Rld; R3 is H or C1_6alkyl; D is O S SO SOZ C(—O) CHOH CH2 NH or , , , , , , , NC1_6alkyl—; W is CH or N; Ra, Rb, RC, Rd, Rla, Rlb, R10, Rld, and R4 are independently chosen from H, C1- 6alkyl optionally substituted by l-6 R119 tuted by , C2_6alkenyl optionally l-6 R119, C2_6alkynyl optionally substituted by l-6 R , C6_11aryl optionally substituted by l-6 R119, C3_11cycloalkyl optionally substituted by 1-6 R119, 3-15 membered heterocyclyl optionally substituted by 1-6 R119, 5-15 membered heteroaryl optionally substituted by l-6 R119, halogen, —CN, —C(=O)R110, — C(=O)OR110,—C(=O)NR112R113,—NC, —N02, —NR112R113, C(=O)R110, _ NR114C(=O)OR1“, C(=O)NR112R113, S(:O)2R111’ _ NR114S(=O)2NR“2R“3, —0R“°, —OCN, —0C(=0)R“°, —OC(=O)NR“2R“3, — OC(=O)OR“°, —S(=O)nR“0, and —S(=O)2NR“2R“3; or any of Ra and Rb, Ra and Rd, and Rb and RC can, together with the atoms linking them, form a C6_11aryl optionally substituted by l-6 R119, C3- 11cycloalkyl optionally substituted by 1-6 R119, 3—15 membered heterocyclyl optionally substituted by l-6 R119 or a 5-15 membered heteroaryl optionally substituted by 1-6 R119; R19 at each occurrence is independently chosen from kyl optionally substituted by l-6 R39, C2_6alkenyl ally substituted by l-6 R39, C2_ 6alkynyl optionally substituted by l-6 R39, C6_11aryl optionally substituted by 1-6 R39, C3_11cycloalkyl optionally substituted by l-6 R39, 3-15 membered cyclyl optionally substituted by l-6 R39, 5-15 membered heteroaryl optionally substituted by 1-6 R39, halogen, —CN, —C(=O)R3°, —C(=O)OR3°, — C(=O)NR32R33, —N02, —NR32R33, —NR34C(=0)R3°, —NR34C(=O)OR31, — =O)NR32R33, —NR34S(=O)2R31,—NR34S(=O)2NR32R33, —0R3°, =0, — OC(=O)R3°, —OC(=O)NR32R33, —OC(=O)OR30, —S(=O)HR30, and — S(=O)2NR32R33; R20, R30, R31, and R34 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-6 R49, C2_6alkenyl optionally substituted by 1-6 R49, C2_6alkynyl optionally substituted by 1-6 R49, C6_11aryl optionally substituted by 1-6 R49, C3_11cycloalkyl optionally substituted by 1-6 R49, 3-15 ed heterocyclyl optionally substituted by 1-6 R49, and 5-15 ed heteroaryl optionally substituted by 1-6 R49; R22, R23, R32 and R33 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-6 R59, C2_6alkenyl optionally substituted by 1-6 R59, C2_6alkynyl optionally substituted by 1-6 R59, C6_11aryl optionally substituted by 1-6 R59, C3_11cycloalkyl optionally substituted by 1-6 R59, 3-15 membered heterocyclyl optionally tuted by 1-6 R59, and 5-15 membered heteroaryl optionally substituted by 1-6 R59; or any R22 and R23 and/or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 3-15 membered cyclyl optionally substituted by 1-6 R69 or a 5-15 membered heteroaryl ally substituted by 1-6 R69; R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6all<yl optionally substituted by 1-6 R79, C2_6alkenyl optionally substituted by 1-6 R79, C2_6alkynyl optionally substituted by 1-6 R79, C6_11aryl ally substituted by 1-6 R79, C3_11cycloalkyl optionally substituted by 1-6 R79, 3-15 membered heterocyclyl optionally substituted by 1-6 R79, 5-15 membered aryl optionally substituted by 1-6 R79, halogen, —CN, —C(=O)R7°, —C(=O)OR7°, — C(=O)NR72R73, —N02, —NR72R73, —NR74C(=O)R7°, —NR74C(=O)OR71, — =O)NR72R73, —NR74S(=O)2R71,—NR74S(=O)2NR72R73, —0R7°, =o, — R7°, —OC(=O)NR72R73, —S(=O)nR7°, and —S(=O)2NR72R73; R70, R71, R72, R73, and R74 at each ence is independently chosen from H, C1- 6alkyl and aloalkyl; R79 at each occurrence is independently chosen from C1_6alkyl, C1_6-haloalkyl, benzyl, halogen, —CN, —C(=O)(C1_6alkyl), —C(=O)O(C1_6alkyl), —C(=O)N(C1_ 6alkyl)2, —C(=O)OH, —C(=O)NH2, —C(=O)NHC1_6alkyl, —N02, —NH2, —NHC1_ 6alkyl, —N(C1_6alkyl)2, —NHC(=O)C1_6alkyl, —NHS(=O)2C1_6alkyl, —OH, —OC1_ 6alkyl, =0, —OC(=O)C1_6alkyl, —OS(=O)2C1_6alkyl, —S(=O)2C1_6alkyl, and — S(=O)2N(C1_6alkyl)2; R110, R111, and R114 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-6 R129 substituted by 1-6 , C2_6alkenyl optionally R129, kynyl optionally substituted by 1-6 R129, ryl optionally substituted by 1-6 R129, C3_11cycloalkyl optionally substituted by 1-6 R129, 3-15 membered heterocyclyl optionally substituted by 1-6 R129 and 5-15 membered aryl optionally substituted by 1-6 R129; R112 and R113 at each occurrence is independently chosen from H, C1_6alkyl optionally substituted by 1-6 R139 substituted by 1-6 , C2_6alkenyl optionally R139, C2_6alkynyl optionally substituted by 1-6 R139, C6_11aryl optionally substituted by 1-6 R139, ycloalkyl optionally substituted by 1-6 R139, 3-15 membered heterocyclyl optionally substituted by 1-6 R139 and 5-15 membered heteroaryl optionally substituted by 1-6 R139; or any R112 and R113 may form, together with the nitrogen atom to which they are attached, a 3-15 membered heterocyclyl optionally substituted by 1-6 R149 or a 5-15 membered heteroaryl optionally substituted by 1-6 R149; R119 at each ence is ndently chosen from C1_6alkyl optionally substituted by 1-6 R159, C2_6alkenyl optionally tuted by 1-6 R159, C2- 6alkynyl optionally substituted by 1-6 R substituted by , ryl optionally 1-6 R159, C3_11cycloalkyl ally substituted by 1-6 R159, 3-15 membered heterocyclyl optionally substituted by 1-6 R159 5 -15 membered heteroaryl optionally tuted by 1-6 R159, halogen, —CN, —C(=O)R15°, —C(=O)OR150, — C(=O)NR152R153, —NC, —N02, —NR152R153, —NR154C(=O)R150, _ NR154C(:O)OR151, —NR154C(:O)NR152R153, —NR154S(:O)2R151, _ NR154S(=O)2NR152R153, —OR150, :0, —OC(=O)R150, —OC(=O)NR152R153, _ S(=O)nR15°, and —S(=O)2NR152R153; R150, R151, R152, R153 and R154 at each occurrence is independently chosen from H, C1_6alkyl, benzyl, and aloalkyl; R129, R139, R149, and R159 at each occurrence is independently chosen from C1- 6alkyl, C1_6-haloalkyl, benzyl, halogen, —CN, (C1_6alkyl), —C(=O)O(C1_ 6alkyl), —C(=O)N(C1_6alkyl)2, —C(=O)OH, —C(=O)NH2, —C(=O)NHC1_6alkyl, N02, —NH2, —NHC1_6alkyl, —N(C1_6alkyl)2, —NHC(=O)C1_6alkyl, — WO 74633 NHS(=O)2C1_6alkyl, —OH, —OC1_6alkyl, =0, —OC(=O)C1_6alkyl, —OS(=O)2C1_ 6alkyl, —S(=O)2C1_6alkyl, and —S(=O)2N(C1_6alkyl)2; and n at each occurrence is independently chosen from 0, l, and 2.
In one embodiment, E and G are independently chosen from H, C1_6alkyl optionally substituted by 1-6 R19, C2_6alkenyl optionally substituted by 1-6 R19, C2_6alkynyl optionally substituted by 1-6 R19, phenyl optionally tuted by 1-5 R19, C3_6cycloalkyl optionally substituted by 1-6 R19, 3-6 ed heterocyclyl optionally substituted by 1-5 R19, 5-6 membered heteroaryl optionally substituted by 1-3 R19, —C(=O)R20, —C(=O)OR20, —C(=O)NR22R23, —S(=O)2R2°, and —S(=O)2NR22R23.
In one embodiment, E is chosen from H, C1_6alkyl optionally tuted by 1-6 R19, C2_6alkenyl ally substituted by 1-6 R19, C2_6alkynyl optionally substituted by 1-6 R19, C6_11aryl optionally substituted by 1-6 R19, and C3_11cycloalkyl optionally substituted by 1-6 R”.
In one embodiment, E is chosen from H, C1_6alkyl optionally substituted by 1-6 R19, C2_6alkenyl optionally substituted by 1-6 R19, C2_6alkynyl optionally substituted by 1-6 R19, phenyl optionally substituted by 1-6 R19, and C3_6cycloalkyl ally substituted by 1-6 R19.
In one embodiment, E is chosen from H, kyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, phenyl optionally substituted by 1-3 R19, and cloalkyl optionally substituted by 1—3 R19.
In one embodiment, E is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl, C2_6alkynyl optionally substituted by —OH, phenyl optionally substituted by halogen, and C3_6cycloalkyl.
In one embodiment, E is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl, C2_6alkynyl optionally substituted by —OH, phenyl optionally tuted by halogen, and cyclohexyl.
In one embodiment, E is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl, kynyl optionally substituted by —OH, phenyl optionally substituted by fluoro, and cyclohexyl.
In one embodiment, E is chosen from C1_6alkyl ally substituted by R19, phenyl, and ophenyl.
In one embodiment, E is phenyl optionally substituted by 1-5 halogen.
In one embodiment, E is C1_6alkyl optionally substituted by R19. -l6- 2012/065019 In one embodiment, E is p-fluorophenyl.
In one embodiment, G is chosen from H, C1_6alkyl optionally substituted by 1-6 R19, C2_6alkenyl optionally tuted by 1-6 R19, kynyl optionally tuted by 1-6 R19, C6_11aryl optionally substituted by 1-6 R19, C3_11cycloalkyl optionally substituted by l- 6 R19, and 3-15 membered heterocyclyl optionally substituted by 1-6 R19.
In one ment, G is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, kenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19, phenyl optionally substituted by 1-3 R19, cloalkyl optionally substituted by 1-3 R19, and 3-6 membered heterocyclyl optionally substituted by 1-3 R19.
In one embodiment, G is chosen from H, C1_6alkyl ally substituted by 1-3 R19, C2_6alkenyl ally substituted by 1-3 halogen, C2_6alkynyl, phenyl optionally substituted by 1-3 halogen, C3_6cycloalkyl, and 3-6 membered heterocyclyl.
In one embodiment, G is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 halogen, C2_6alkynyl, phenyl optionally substituted by 1-3 halogen, C3_6cycloalkyl, and 6 membered heterocyclyl.
In one embodiment, G is chosen from H, C1_6alkyl ally substituted by 1-3 R19, C3_6alkenyl optionally substituted by 1-3 fluoro, C3_6alkynyl, phenyl optionally substituted by 1-3 fluoro, C3_6cycloalkyl, and 6 membered heterocyclyl.
In one embodiment, G is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C3_6alkenyl optionally substituted by 1-3 fluoro, C3_6alkynyl, phenyl optionally substituted by 1-3 fluoro, C3_6cycloalkyl, and 6 membered heterocyclyl.
In one embodiment, G is chosen from H, C1_6alkyl optionally substituted by R19, C3_6alkenyl optionally substituted by 2 fluoro, C3_6alkynyl, phenyl optionally substituted by fluoro, C3_6cycloalkyl, and tetrahydropyranyl.
In one embodiment, G is H.
In one embodiment, G is C1_6alkyl optionally substituted by R19.
In one embodiment, G is C1_6alkyl.
In one embodiment, G is C3_6alkenyl optionally substituted by 2 .
In one embodiment, G is C3_6alkynyl.
In one embodiment, G is phenyl optionally tuted by fluoro.
In one embodment, G is p-fluorophenyl.
In one embodiment, G is C3_6cycloalkyl.
In one embodiment, G is tetrahydropyranyl.
In one embodiment, X is N.
In one embodiment, X is C-R4.
In one embodiment, Y is N.
In one embodiment, Y is CH.
In one ment, Y is C-Rld.
In one embodiment, R3 is H.
In one embodiment, R3 is C1_6alkyl.
In one embodiment, D is —O—, —S—, —C(=O)—, —CHOH—, —CH2—, —NH— or —NC1_ 6alkyl—.
In one embodiment, D is —O—, —S—, —C(=O)—, , —CH2—, or —NH—.
In one embodiment, D is —O—, —S—, —C(=O)—, —CHOH—, or —CH2—.
In one embodiment, D is —O—, —C(=O)—, , or —CH2—.
In one embodiment, D is —O—, —C(=O)—, —CHOH—, or —CH2—.
In one ment, D is —O—.
In one embodiment, D is —C(=O)—.
In one embodiment, D is .
In one ment, D is —CH2—.
In one embodiment, W is CH.
In one embodiment, W is N.
In one embodiment, Ra, Rb, RC, and Rd are independently chosen from H, C1_6alkyl optionally substituted by l-6 R substituted by l-6 R119, C2- , C2_6alkenyl optionally 6alkynyl optionally substituted by l-6 R119 substituted by l-6 R119, C3- , C6_11aryl optionally llcycloalkyl optionally substituted by l-6 R119, 3-15 ed heterocyclyl optionally substituted by l-6 R119, 5-15 membered heteroaryl optionally substituted by 1-6 R119, halogen, —CN, —C(=0)R“°, —C(=O)NR“2R“3, —N02,—NR112R113, —NR“4C(=0)R“°, — NR114C(=O)OR111, _NR114C(:O)NR1 12R113, —NR114S(=O)2R111, —OR110, —S(=O)2R110, and —S =0 ZNRmRm; or any of Ra and Rb, Ra and Rd, and Rb and RC can, together with the atoms linking them, form a C6_11aryl optionally substituted by l-6 R , C3_1lcycloalkyl optionally substituted by 1-6 R119, 3-15 membered cyclyl optionally substituted by l-6 R119 or a 5-15 membered heteroaryl optionally substituted by l-6 R119.
In one embodiment, Ra, Rb, RC, and Rd are independently chosen from H, C1_6alkyl optionally substituted by l-6 R119, —CN, and —OR110; or Ra and Rb can, together with the atoms linking them, form a 3-6 membered heterocyclyl optionally substituted by l-6 R119.
In one embodiment, Ra, Rb, RC, and Rd are independently chosen from H, C1_6alkyl ally substituted by 1-6 R119, —CN, and —OR110; or Ra and Rb can, er with the atoms linking them, form a 5-6 membered heterocyclyl ally substituted by 1-6 R119.
In one embodiment, Ra, Rb, RC, and Rd are independently chosen from H, C1_6alkyl optionally tuted by 1-6 R119, —CN, and ; or Ra and Rb can, er with the atoms linking them, form a 5-6 ed heterocyclyl.
In one embodiment, Ra is chosen from H, —CN, and —OC1_6alkyl; Rb is chosen from H, C1_6alkyl ally substituted by 1-6 R119, and —OR110; Rc is chosen from H and — OC1_6alkyl; and Rd is chosen from H and —OC1_6alkyl; or Ra and Rb can, together with the atoms g them, form a 5-6 membered heterocyclyl.
In one embodiment, Ra is chosen from H, —CN, and —OC1_6alkyl; Rb is chosen from H, C1_6alkyl optionally substituted by 6-membered heterocyclyl, and —OR110; RC is chosen from H and —OC1_6alkyl; and Rd is chosen from H and —OC1_6alkyl; or Ra and Rb can, together with the atoms linking them, form a 5-6 membered heterocyclyl.
In one embodiment, Ra is chosen from H, —CN, and —OC1_6alkyl; Rb is chosen from H, C1_6alkyl optionally substituted by 6-membered heterocyclyl, —OH, —OC1_6alkyl, — OCnghenyl, —OC1_6alkyl-O-C1_6alkyl; RC is chosen from H and —OC1_6alkyl; and Rd is chosen from H and —OC1_6alkyl; or Ra and Rb can, together with the atoms linking them, form a 5-6 membered heterocyclyl.
In one embodiment, Ra is chosen from H, —CN, and —OC1_6alkyl; Rb is chosen from H, C1_6alkyl optionally substituted by morpholinyl, —OH, —OC1_6alkyl, —OCH2phenyl, — OC1_6alkyl-O-C1_6alkyl; RC is chosen from H and —OC1_6alkyl; and Rd is chosen from H O O < E and —OC1_6alkyl; or Ra and Rb together form 0or O.
In one embodiment, Ra is chosen from H and —OC1_6alkyl; Rb is chosen from H, C1_6alkyl optionally substituted by morpholinyl, —OH, —OC1_6alkyl, —OCH2phenyl, —OC1_ 6alkyl-O-C1_6alkyl; RC is H; and Rd is chosen from H and —OC1_6alkyl; or Ra and Rb O O < E together form 0or O.
In one embodiment, Ra is chosen from H and —OC1_6alkyl; Rb is chosen from C1- 6alkyl optionally substituted by morpholinyl, —OH, —OC1_6alkyl, —OCH2phenyl, —OC1_ 2012/065019 6alkyl-O-C1_6alkyl; RC is H; and Rd is chosen from H and —OC1_6alkyl; or Ra and Rb <0 [0 O O together form or .
In one embodiment, Ra is —OC1_6alkyl; Rb is chosen from H, C1_6alkyl optionally substituted by morpholinyl, —OH, —OC1_6alkyl, henyl, —OC1_6alkyl-O-C1_6alkyl; RC 0 O < E is H; and Rd is chosen from H and —OC1_6alkyl; or Ra and Rb together form 0or O.
In one embodiment, Ra is chosen from H and —OC1_6alkyl; Rb is chosen from H and —OC1_6alkyl; RC is H; and Rd is chosen from H and —OC1_6alkyl; or Ra and Rb together <0 [0 O O form or .
In one embodiment, Ra, Rb, RC, and Rd are independently chosen from H and —OC1_ <0 E0 0 O 6alkyl; or Ra and Rb together form or .
In one embodiment, Ra is chosen from H and —OC1_6alkyl; Rb is chosen from H and <0 [0 O O —OC1_6alkyl; RC is H; and Rd is H; or Ra and Rb together form or .
In one embodiment, Ra is chosen from H and —OC1_6alkyl; Rb is chosen from H and —OC1_6alkyl; RC is H; and Rd is H.
In one ment, Ra is chosen from H and —OC1_3alkyl; Rb is chosen from H and alkyl; Rc is H; and Rd is H. <0 E0 0 O In one embodiment, RC is H; Rd is H; and Ra and Rb together form or .
In one embodiment, R4 is chosen from H. C1_6alkyl, and C1_6haloalkyl.
In one embodiment, R4 is chosen from H and C1_6alkyl.
In one embodiment, R4 is chosen from H and C1_3alkyl.
In one embodiment, R4 is chosen from H and methyl.
In one embodiment, R4 is H.
In one embodiment, R4 is kyl.
In one embodiment, R4 is methyl.
In one ment, Rla, Rlb, R10, and Rld are independently chosen from H, C1- 6alkyl optionally substituted by l-6 R119 substituted by l-6 R119 , C3_6cycloalkyl optionally , 3-6 membered heterocyclyl optionally substituted by 1-6 R119, halogen, —CN, —NR112R113, and —OR110.
In one embodiment, Rla, Rlb, R10, and Rld are independently chosen from H, C1- 6alkyl ally substituted by l-6 R119 substituted by l-6 R119 , C3_6cycloalkyl optionally , halogen, —NR112R113, and —OR110.
In one ment, Rla, Rlb, R10, and Rld are independently chosen from H, C1- 6alkyl, C1_6haloalkyl, C3_6cycloalkyl, halogen, —NH2, —NHC1_6alkylg, —N(C1_6alkyl)2, —OH, and —OC1_6alkyl.
In one embodiment, Rla, Rlb, R10, and Rld are independently chosen from H, C1- 6alkyl, C1_6haloalkyl, C3_6cycloalkyl, halogen, —N(C1_6alkyl)2, —OC1_6alkyl.
In one embodiment, Rla, Rlb, R10, and Rld are independently chosen from H, C1- galkyl, C1_3haloalkyl, C3_6cycloalkyl, halogen, and alkyl.
In one embodiment, Rla, Rlb, R10, and Rld are ndently chosen from H, C1- galkyl, C1_3haloalkyl, cyclopropyl, halogen, and —OC1_3alkyl.
In one embodiment, Rla, Rlb, R10, and Rld are independently chosen from H, halogen, and —OC1_3alkyl.
In one embodiment, Rla, Rlb, R10, and Rld are independently chosen from H, halogen, and methoxy.
In one embodiment, Rla, Rlb, R10, and Rld are independently chosen from H and halogen.
In one embodiment, Rla, Rlb, R10, and Rld are independently chosen from H and fluoro .
In one embodiment, Rla and Rlb are independently chosen from H, C1_6alkyl optionally substituted by l-6 R119 substituted by l-6 R119 , C3_6cycloalkyl optionally , halogen, and —OR110; and R10 and Rld are independently chosen from H, C1_6alkyl optionally substituted by l-6 R119, n, R113, and —OR110.
In one embodiment, Rla and Rlb are independently chosen from H, C1_6alkyl, C1- 6haloalkyl, C3_6cycloalkyl, halogen, and alkyl; and R10 and Rld are ndently chosen from H, C1_6alkyl, halogen, —N(C1_6alkyl)2, and —OC1_6alkyl.
In one embodiment, Rla and Rlb are ndently chosen from H, C1_3alkyl, C1- 3haloalkyl, C3_6cycloalkyl, halogen, and —OC1_3alkyl; and R10 and Rld are independently chosen from H, C1_3alkyl, halogen, 3alkyl)2, and —OC1_3alkyl.
In one embodiment, Rla and Rlb are independently chosen from H, C1_3alkyl, C1_ 3haloalkyl, ropyl, halogen, and —OC1_3alkyl; and R10 and Rld are independently chosen from H, C1_3alkyl, halogen, 3alkyl)2, and —OC1_3alkyl.
In one embodiment, Rla and Rlb are independently chosen from H, C1_3alkyl, C1- 3haloalkyl, cyclopropyl, halogen, and —OC1_3alkyl; and R10 and Rld are independently chosen from H, C1_3alkyl, halogen, and —OC1_3alkyl.
In one embodiment, Rla, R10, and Rld are H and Rlb is chosen from H, C1_3alkyl, C1_3haloalkyl, cyclopropyl, halogen, and —OC1_3alkyl.
In one embodiment, Rla, R10, and Rld are H and Rlb is chosen from H, halogen, and —OC1_3alkyl.
In one embodiment, Rla, R10, and Rld are H and Rlb is chosen from H and halogen.
In one embodiment, Rla, R10, and Rld are H and Rlb is chosen from H and fluoro.
In one ment, Rla, R10, and Rld are H and Rlb is halogen.
In one ment, Rla, R10, and Rld are H and Rlb is fluoro.
In one embodiment, R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-6 R39, C6_11aryl optionally substituted by 1-6 R39, C3- 11cycloalkyl optionally tuted by 1-6 R39, 3-15 membered heterocyclyl optionally substituted by 1-6 R39, 5-15 membered heteroaryl optionally substituted by 1-6 R39, n, —CN, —C(=O)OR3°, —C(=O)NR32R33, —NR32R33, —0R3°, and :0.
In one embodiment, R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-6 R39, phenyl ally substituted by 1-6 R39, C3_6cycloalkyl optionally tuted by 1-6 R39, 3-6 membered heterocyclyl optionally substituted by 1-6 R39, 5-6 membered aryl optionally substituted by 1-6 R39, halogen, —CN, — C(=O)OR30, —C(=O)NR32R33, —NR32R33, —0R3°, and :0.
In one embodiment, R19 at each occurrence is independently chosen from C1_6alkyl, phenyl optionally tuted by 1-3 halogen, cloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl optionally substituted by 1-3 C1_6alkyl, halogen, —CN, — C(=O)OH, —C(=O)OC1_6alkyl, —C(=O)N(C1_6alkyl)2, —N(C1_6alkyl)2, —OH, —OC1_6alkyl, — Obenzyl, and =0.
In one embodiment, R19 at each occurrence is independently chosen from C1_6alkyl, phenyl optionally substituted by 1-3 halogen, C3_6cycloalkyl, 5-6 membered heterocyclyl, -6 membered heteroaryl optionally substituted by 1-3 kyl, halogen, —CN, — C(=O)OH, —C(=O)OC1_6alkyl, N(C1_6alkyl)2, —C(=O)pyrrolidinyl, — C(=O)morpholinyl, —N(C1_6alkyl)2, —OH, alkyl, —Obenzyl, and =0.
In one embodiment, R19 at each occurrence is independently chosen from C3- 6cycloalkyl and —OH.
In one embodiment, R19 at each occurrence is ndently chosen from cyclopropyl and —OH.
In one embodiment, R20, R30, R31, R34, R22, R23, R32 and R33 at each occurrence is independently chosen from H, C1_6alkyl, C1_6halolkyl, phenyl, benzyl, C5_6cycloalkyl, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl; or R32 and R33 may form, together with the nitrogen atom to which they are ed, a 5-6 membered cyclyl or a 5-6 membered heteroaryl.
In one embodiment, R20, R30, R31, R34, R22, R23, R32 and R33 at each occurrence is independently chosen from H, C1_6alkyl, C1_6halolkyl, phenyl, benzyl, C5_6cycloalkyl, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl.
In one ment, R20, R30, R31, R34, R22, R23, R32 and R33 at each ence is independently chosen from H and C1_6alkyl.
In one embodiment, R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl, C1_6haloalkyl, and benzyl.
In one embodiment, R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl and C1_6haloalkyl.
In one embodiment, R39, R49, R59 and R69 at each occurrence is independently chosen from C1_6alkyl.
In one embodiment, R70, R71, R72, R73, and R74 at each occurrence is independently chosen from H and C1_6alkyl.
In one embodiment, R70, R71, R72, R73, and R74 at each occurrence is H.
In one embodiment, R79 at each occurrence is independently chosen from C1_6alkyl, C1_6-haloalkyl, benzyl, and halogen.
In one embodiment, R79 at each occurrence is independently chosen from C1_6alkyl and C1_6-haloalkyl.
In one embodiment, R79 at each occurrence is independently chosen from C1_6alkyl.
In one embodiment, R110, R111, R112, R113, and R114 at each occurrence is independently chosen from H and C1_6alkyl optionally substituted by 1-3 R129. - 110 111 112 113 and R114 In one embod1ment, R R R R - at each occurrence 1s , , , , ndently chosen from H and C1_3alkyl optionally substituted by 1-3 R129.
In one ment, R110, R111, R112, R113, and R114 at each occurrence is independently chosen from H, benzyl, and C1_6alkyl optionally substituted by —OC1_3alkyl.
In one embodiment, R110, R111, R112, R113, and R114 at each occurrence is independently chosen from H and C1_3alkyl optionally substituted by —OC1_3alkyl.
In one ment, R110, R111, R112, R113, and R114 at each ence is independently chosen from H and C1_3alkyl.
In one embodiment, R110, R111, R112, R113, and R114 at each occurrence is H.
In one embodiment, R at each occurrence is independently chosen from C1- 6alkyl optionally substituted by 1-6 R159, 3-15 membered heterocyclyl ally substituted by 1-6 R159, and halogen.
In one embodiment, R at each occurrence is independently chosen from C1- 6alkyl optionally substituted by 1-3 R159 5-6 membered heterocyclyl optionally substituted by 1-3 R159, and halogen.
In one embodiment, R at each occurrence is independently chosen from C1- 6alkyl, loalkyl, 5-6 membered heterocyclyl, and halogen.
In one embodiment, R at each occurrence is independently chosen from 5-6 membered heterocyclyl and halogen.
In one embodiment, R at each occurrence is independently chosen from 6 membered heterocyclyl and halogen.
In one embodiment, R at each occurrence is independently chosen from morpholinyl and halogen.
In one embodiment, R119 at each occurrence is independently chosen from morpholinyl and fluoro.
In one embodiment, R150, R151, R152, R153 and R154 at each occurrence is independently chosen from H and C1_6alkyl.
In one embodiment, R150, R151, R152, R153 and R154 at each occurrence is H.
In one embodiment, R129, R139, R149, and R159 at each occurrence is independently chosen from C1_6alkyl, C1_6-haloalkyl, , and n.
In one embodiment, R129, R139, R149, and R159 at each occurrence is independently chosen from C1_6alkyl and halogen.
In one ment, R129, R139, R149, and R159 at each occurrence is halogen.
In one embodiment, R129, R139, R149, and R159 at each occurrence is C1_6alkyl.
In one embodiment, n at each occurrence is 0 or 2.
In one ment, n at each ence is 0.
In one embodiment, n at each occurrence is 2.
The present invention also provides compounds of Formula II R2 T3 XI/NYO | NWME Rd \ Y o o Ra R1 Rb N/J a II wherein: Ra is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino, dialkylamino Where the alkyl groups of dialkylamino may be the same or different, carbamoyl, N—alkylcarbamoyl, N,N—diall<ylcarbamoyl, Where the alkyl groups of dialkylcarbamoyl may be the same or ent, trihalomethyl, or Ra is OA; Rb is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino, lamino Where the alkyl groups of dialkylamino may be the same or different, carbamoyl, N—alkylcarbamoyl, N,N—diall<ylcarbamoyl, Where the alkyl groups of dialkylcarbamoyl may be the same or different, trihalomethyl, or Rb is OB; RC is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino, dialkylamino Where the alkyl groups of dialkylamino may be the same or different, carbamoyl, N—alkylcarbamoyl, N,N—diall<ylcarbamoyl, Where the alkyl groups of dialkylcarbamoyl may be the same or different, trihalomethyl, or RC is OJ; Rd is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino, dialkylamino Where the alkyl groups of dialkylamino may be the same or different, carbamoyl, N—alkylcarbamoyl, N,N—diall<ylcarbamoyl, Where the alkyl groups of dialkylcarbamoyl may be the same or different, trihalomethyl, or Rd is 0L; where A, B, J and L, are, independently, H, alkyl, alkoxyalkyl, cycloalkyl, cycloalkoxyalkyl, heterocyclylalkyl, heterocyclylalkoxyalkyl, arylalkyl or arylalkoxyalkyl, or A and B together with the oxygen atoms to which they are attached form or D is O, S, SO, SOZ, C=O, C(H)OH, CH2, NH or N-alkyl; E is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or heteroarylalkyl, where the heteroaryl group of heteroarylalkyl may be substituted or unsubstituted; G is H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, alkyl or cycloalkyl, cycloalkylalkyl, alkenyl or alkynyl, where alkyl, alkenyl or cycloalkyl may be substituted by one, two or three groups selected from the group consisting of alkanoyl, cycloalkyl, alkenyl, l, halo, yl, alkoxy, alkoxycarbonyl, heterocyclyl, aryl, tuted aryl, aryloxy, koxy, amino, alkylamino, dialkylamino, where the alkyl groups of dialkylamino may be the same or different, heteroaryl, carboxyl, oxo, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, where the alkyl groups of dialkylcarbamoyl may be the same or different, and cycyclylcarbonyl; W is CH or N; X is C-R4 or N, where R4 is H, OH or alkyl, where the alkyl group may be substituted by hydroxyl, alkoxy, alkylamino, or dialkyl amino, where the alkyl groups of dialkylamino may be the same or different; Y is N, CH or C where C may be substituted with one of the groups R1 or R2; and R1 and R2 are, independently, H, alkyl, cycloalkyl, halo, alkoxy, trihaloalkyl, amino, alkylamino, dialkylamino, where the alkyl groups on dialkylamino may be the same or different, or heterocyclyl; and R3 is H, or alkyl; or a ceutically acceptable salt thereof.
A red embodiment of the t invention provides compounds of a 11 wherein W is CH.
Another preferred embodiment of the present ion provides compounds of Formula 11 wherein W is N.
Another preferred embodiment of the present invention provides compounds of Formula III.
N 0 R2 x/ Y H ' \ Y O O A_O R1 8—0 N Formula 111 n: A and B are, independently, H, alkyl, alkoxyalkyl, cycloalkyl, cycloalkoxyalkyl, heterocyclylalkyl, heterocyclylalkoxyalkyl, arylalkyl or arylalkoxyalkyl, or A and B together with the oxygen atoms to which they are C: [0 attached form or ; D is O, S, NH, or C=O; E is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, tuted aryl, heteroaryl, heterocyclyl, substituted heteroaryl, or heteroarylalkyl, where the heteroaryl group of arylalkyl may be substituted or unsubstituted; G is H, aryl, substituted aryl, heteroaryl, substituted aryl, heterocyclyl, alkyl or cycloalkyl, cycloalkylalkyl, alkenyl or alkynyl, where alkyl, alkenyl or cycloalkyl may be substituted by one, two or three groups selected from the group ting of alkanoyl, cycloalkyl, alkenyl, alkynyl, halo, hydroxyl, alkoxy, carbonyl, heterocyclyl, aryl, substituted aryl, aryloxy, koxy, amino, alkylamino, dialkylamino, where the alkyl groups of dialkylamino may be the same or different, heteroaryl, carboxyl, oxo, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, where the alkyl groups of dialkylcarbamoyl may be the same or different, and heterocycyclylcarbonyl; X is C-R4 or N, where R4 is H or alkyl; Y is N, CH or C where C may be substituted with one of the groups R1 or R2; and R1 and R2 are, ndently, H, alkyl, halo, alkoxy, trihaloalkyl, amino, alkylamino, dialkylamino, where the alkyl groups on dialkylamino may be the same or different; or a pharmaceutically acceptable salt thereof.
Another preferred embodiment of the t invention provides compounds of Formula 111 wherein A and B are, independently, alkyl, cyclylalkyl or heterocyclylalkoxyalkyl.
Another preferred embodiment of the present invention provides compounds of Formula 111 wherein A and B are, independently, alkyl.
Another preferred ment of the present invention provides compounds of Formula 111 wherein D is O, S or NH.
Another preferred embodiment of the present invention provides nds of Formula 111 wherein D is 0.
Another preferred embodiment of the present invention provides nds of Formula 111 wherein R1 and R2 are, independently, halo, alkoxy, alkyl or H.
Another preferred embodiment of the present invention provides compounds of Formula 111 n R1 and R2 are, independently, halo or alkoxy.
Another preferred ment of the present invention provides compounds of Formula 111 wherein R1 and R2 are, independently, methoxy or fluoro.
Another preferred ment of the t invention provides compounds of Formula 111 n X is N or CH.
Another preferred embodiment of the present invention provides compounds of Formula 111 wherein X is CH. r preferred embodiment of the present invention provides compounds of Formula 111 wherein G is alkyl where alkyl may be substituted by one, two or three groups selected from the group consisting of alkanoyl, cycloalkyl, alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl, aryl, substituted aryl, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, where the alkyl groups of lamino may be the same or different, heteroaryl, carboxyl, oxo, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, where the alkyl groups of dialkylcarbamoyl may be the same or different, and cycyclylcarbonyl.
Another preferred embodiment of the present invention provides compounds of Formula 111 wherein E is aryl, substituted aryl or lkyl.
Another preferred embodiment of the present invention provides compounds of Formula 111 wherein E is substituted aryl. r preferred embodiment of the present ion provides nds of Formula 111 wherein A and B are, independently, alkyl; D is O, S or NH; R1 and R2 are, independently, halo, alkoxy, alkyl or H; X is N or CH; G is alkyl where alkyl may be substituted by one, two or three groups selected from the group consisting of alkanoyl, cycloalkyl, alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl, aryl, substituted aryl, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, where the alkyl groups of dialkylamino may be the same or different, heteroaryl, carboxyl, oxo, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, where the alkyl groups of dialkylcarbamoyl may be the same or ent, and heterocycyclylcarbonyl; and E is aryl, substituted aryl or cycloalkyl.
WO 74633 In other preferred embodiments, the present invention provides any of the nds as described in the Examples.
The present invention provides salts of the AXL and c-MET inhibitory compounds described herein. ably, the salts are pharmaceutically acceptable. Pharmaceutically acceptable acid addition salts of the compounds described herein include, but are not limited to, salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, and phosphorus, as well as the salts d from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy ic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Such salts thus include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulf1te, bisulf1te, nitrate, ate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, osphate, chloride, bromide, iodide, acetate, racetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, mandelate, te, chlorobenzoate, methylbenzoate, obenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, ate, pyroglutamate, maleate, tartrate, and methanesulfonate. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge et al., "Pharmaceutical Salts," J. of Pharmaceutical Science, 1977;66:1-19.
The acid addition salts of basic compounds described herein may be prepared by contacting the free base form with a sufficient amount of the d acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the tional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are in general equivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts of compounds described herein are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and m. Examples of suitable amines include, but are not limited to, N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-l,2-diamine), N—methylglucamine, and ne; see, for e, Berge et al., supra., 1977.
WO 74633 The base addition salts of acidic compounds may be prepared by ting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are in general lent to their respective free acid for es of the present invention.
Some of the compounds in the present invention may exist as stereoisomers, including enantiomers, diastereomers, and geometric isomers. Geometric isomers include compounds of the present invention that have alkenyl groups, which may exist as entgegen or zusammen conformations, in which case all geometric forms thereof, both entgegen and zusammen, cis and trans, and mixtures thereof, are within the scope of the present invention. Some compounds of the present invention have carbocyclyl groups, which may be substituted at more than one carbon atom, in which case all geometric forms thereof, both cis and trans, and mixtures f, are within the scope of the present invention. All of these forms, including (R), (S), epimers, diastereomers, cis, trans, syn, anti, (E), (Z), tautomers, and es thereof, are contemplated in the compounds of the present invention.
The compounds to be used in the present ion can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are ed to be encompassed within the scope of the present invention.
III. Pharmaceutical Compositions The present invention r provides pharmaceutical compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. The pharmaceutical composition may n two or more compounds of the present invention (i.e., two or more compounds of the present invention may be used together in the pharmaceutical composition). Preferably, the pharmaceutical ition contains a therapeutically effective amount of at least one compound of the present invention. In another embodiment, these itions are useful in the treatment of an AXL- or c- MET- mediated disorder or condition. The compounds of the invention can also be ed in a pharmaceutical composition that also comprises compounds that are useful for the ent of cancer or another AXL- or c-MET- mediated disorder.
A compound of the present invention can be formulated as a ceutical composition in the form of a syrup, an elixir, a suspension, a powder, a granule, a tablet, a capsule, a lozenge, a troche, an aqueous solution, a cream, an ointment, a lotion, a gel, an on, etc. ably, a compound of the present invention will cause a decrease in symptoms or a disease indicia associated with an AXL or c-MET- mediated er as measured quantitatively or qualitatively.
For preparing a pharmaceutical composition from a compound of the present invention, pharmaceutically able carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as ts, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely d active component (i.e., compound of the present invention). In tablets, the active ent is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size d.
The powders and tablets contain from 1% to 95% (w/w) of the active compound (i.e., compound of the present invention). In another embodiment, the active compound ranges from 5% to 70% (w/w). Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, , dextrin, starch, gelatin, tragacanth, methylcellulose, sodium ymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
Similarly, cachets and es are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed neously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations e solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol on.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous al, such as natural or tic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well- known suspending agents.
Also included are solid form preparations which are intended to be converted, y before use, to liquid form preparations for oral administration. Such liquid forms e solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The pharmaceutical preparation is ably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package ning discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, , or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg, preferably 1.0 mg to 100 mg, or from 1% to 95% (w/w) of a unit dose, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
Pharmaceutically acceptable carriers are determined in part by the ular ition being stered, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g., Remington: The Science and Practice ofPharmacy, 20th ed., Gennaro et al. Eds., cott Williams and Wilkins, 2000).
A compound of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations (i.e., they can be "nebulized") to be administered via inhalation. Aerosol formulations can be placed into pressurized able propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
Formulations suitable for parenteral administration, such as, for example, by intravenous, intramuscular, intradermal, and subcutaneous , include aqueous and non-aqueous, ic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and nonaqueous e suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In the practice of this invention, itions can be administered, for example, by intravenous infusion, orally, topically, intraperitoneally, intravesically or intrathecally. The formulations of compounds can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials. Injection solutions and suspensions can be prepared from sterile powders, es, and tablets of the kind previously described.
The dose stered to a subject, in the context of the present invention, should be sufficient to effect a beneficial therapeutic response in the subject over time. The dose will be determined by the cy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the subject to be treated. The size of the dose also will be determined by the existence, nature, and extent of any e side-effects that accompany the administration of a particular compound in a particular subject. In ining the effective amount of the compound to be administered in the treatment or laxis of the disorder being treated, the physician can evaluate factors such as the circulating plasma levels of the compound, compound toxicities, and/or the progression of the disease, etc. In general, the dose equivalent of a compound is from about 1 ug/kg to 10 mg/kg for a typical subject. Many different administration methods are known to those of skill in the art.
For administration, compounds of the present invention can be administered at a rate determined by factors that can include, but are not limited to, the LD50 of the compound, the pharmacokinetic profile of the compound, contraindicated drugs, and the side-effects of the nd at various concentrations, as applied to the mass and l health of the subject. Administration can be accomplished via single or divided doses.
IV. Methods of Treatment In another aspect, the t invention provides a method of treating a t suffering from an AXL- or c-MET-mediated disorder or condition comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a ceutically acceptable salt form f. In another , the present invention provides a nd of the present invention or a pharmaceutically acceptable salt form thereof for use in treating a subject suffering from an AXL or c-MET- mediated disorder or condition. Preferably, the compound of the present invention or a pharmaceutically acceptable salt form thereof is administered to the subject in a pharmaceutical composition comprising a pharmaceutically acceptable carrier. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a ceutically acceptable salt form thereof for use in treating a subject ing from an AXL- or c-MET- mediated disorder or condition. In another embodiment, the AXL- or c-MET- mediated ion or disorder is cancer. In another embodiment, the AXL- or c-MET-mediated disorder or condition is the development of resistance to cancer ies. In another embodiment, the AXL or c- MET- mediated condition is selected from chronic myelogenous leukemia, chronic myeloproliferative disorder, lung cancer, prostate cancer, geal cancer, ovarian cancer, pancreatic cancer, gastric cancer, liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breast , acute myeloid leukemia, colorectal cancer, uterine cancer, malignant glioma, uveal melanoma, osteosarcoma and soft tissue sarcoma.
The AXL- or c-MET- mediated disorder or condition can be treated prophylactically, acutely, and cally using compounds of the present invention, depending on the nature of the er or ion. Typically, the host or subject in each of these methods is human, although other mammals can also benefit from the administration of a compound of the present invention.
In another embodiment, the present ion es a method of treating a proliferative disorder in a subject in need thereof, sing administering to the subject a therapeutically ive amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof. In another aspect, the present invention provides a compound of the present invention or a ceutically acceptable salt form thereof for use in treating a proliferative disorder in a t in need thereof. Preferably, the compound of the present invention or a pharmaceutically acceptable salt form thereof is administered to the subject in a pharmaceutical ition comprising a pharmaceutically acceptable carrier. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt form thereof for use in treating a proliferative disorder in -3 5 _ a subject. In certain embodiments, the proliferative disorder is AXL- or c-MET- mediated. In certain embodiments, the proliferative disorder is cancer. In certain embodiments, the proliferative disorder is selected from chronic myelogenous leukemia, chronic myeloproliferative disorder, lung cancer, prostate cancer, esophageal cancer, ovarian cancer, pancreatic , gastric cancer, liver , thyroid cancer, renal cell carcinoma, glioblastoma, breast cancer, acute myeloid leukemia, colorectal cancer, uterine cancer, malignant glioma, uveal melanoma, osteosarcoma and soft tissue sarcoma.
The proliferative disorder can be treated prophylactically, acutely, and chronically using compounds of the present ion, depending on the nature of the disorder or condition. Typically, the host or subject in each of these methods is human, although other mammals can also benefit from the administration of a nd of the present invention.
In therapeutic applications, the compounds of the t invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present ion can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by tion, for example, intranasally. Additionally, the compounds of the present invention can be stered transdermally. In another embodiment, the compounds of the present invention are delivered orally. The compounds can also be delivered rectally, bucally or by insufflation.
The compounds utilized in the pharmaceutical method of the invention can be administered at the initial dosage of about 0.001 mg/kg to about 100 mg/kg daily. In another embodiment, the daily dose range is from about 0.1 mg/kg to about 10 mg/kg.
The dosages, however, may be varied depending upon the requirements of the subject, the severity of the ion being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner.
Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the nd. Thereafter, the dosage is increased by small ents until the optimum effect under the circumstances is d. For convenience, the total daily dosage may be divided and administered in ns during the day, if desired.
V. Chemistry Unless ise indicated, all reagents and solvents were obtained from commercial sources and used as received. 1H NMRs were obtained on a Bruker Avance at 400 MHz in the solvent indicated with tetramethylsilane as an internal standard.
Analytical HPLC was run using a Zorbax RX-C8, 5 X 150 mm column eluting with a mixture of acetonitrile and water containing 0.1% trifluoroacetic acid with a gradient of -100%. LCMS results were obtained from a Bruker e 2000 Mass Spec with the Agilent 1100 HPLC equipped with an Agilent Eclipse XDB-C8, 2 X 30 mm 3.5 micron column. The column was at room temperature, with a run time of five (5) minutes, a flow rate of 1.0 mL/min, and a solvent mixture of 10% (0.1% formic acid/water) : 100% (acetonitrile/0.1% formic acid). Automated normal phase column chromatography was performed on a CombiFlash Companion (ISCO, Inc.). Reverse phase preparative HPLC was performed on a Gilson GX-28l equipped with Gilson 333 and 334 pumps using a Phenomenex 00F00-AX Gemini-NX 5 u C18 column. Melting points were taken on a Mel-Temp apparatus and are uncorrected.
Synthesis The compounds of the present ion can be synthesized using the methods described below or by using methods known to one skilled in the art of organic chemistry or variations thereon as appreciated by those skilled in the art. The preferred s include, but are not limited to or by, those described below. Unless otherwise stated, starting compounds are of commercial origin or are readily synthesized by standard methods well known to one d in the art of c synthesis.
The ons are performed in solvents riate to the reagents, and materials ed are suitable for the transformations being effected. Also, in the description of the synthetic methods below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction ature, duration of experiment and workup ures are chosen to be conditions standard for that reaction which should be readily recognized by one skilled in the art of organic synthesis.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light f will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. Specific chemical transformations are listed in the ensuing schemes and one skilled in the art appreciates that a variety of different reagents may be used in place of those listed. Common replacements for such reagents can be found in, but not d to, texts such as “Encyclopedia of Reagents for Organic Synthesis” Leo A. Paquette John Wiley & Son Ltd (1995) or “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” Richard C. Larock. Wiley-VCH and “Strategic Applications ofNamed Reactions in Organic sis” Kurti and Czako, Elsevier, 2005 and references therein.
The examples of the present invention may be produced according to synthesis routes as depicted in Schemes 1 to 6, and by the synthetic procedures described herein and within the examples.
Rb' N Ra .
Scheme 1 In Scheme 1, W and X are as defined herein. T is Br, Cl or I. D’ is OH, SH, NH2, or NH-alkyl. D is O, S, NH, or N-alkyl. Ra’, Rb’, Rc’, Rd’, R1’ and R2’ are Ra, Rb, RC, Rd, R1 and R2, respectively, as defined herein, or are synthetic precursors thereto. Y is N, CH or C, Where C may be tuted by one of the groups R1’ or R2’.
Looking at Scheme 1, substituted 4-chloroquinolines or 4-bromoquinoline derivatives are known and can be synthesized as bed in the literature from properly substituted arylamines and m’s acid in the presence of trimethyl orthoformate (Bioorg. Medchem. Lett., 1997, 7, 789, WO9813350, US20080004273). Alternatively ly substituted quinolines can be sized from substituted acetophenones by methods bed in the literature (for example J. Med. Chem. 2005, 48, 1359; EP1153920; 45084). Quinazolines analogs may be synthesized by literature methods (described in J. Med. Chem. 2005, 48, 1359; J. Med. Chem. 2006, 49, 2186; J.
Med. Chem. 2010, 53, 8089). The synthesizes of N, O, and S linker quinolines and quinazolines intermediates are described in J. Med. Chem. 2005, 48, 1359A 4- (aminophenoxy)quinoline derivative may be produced by ng a henol derivative with the 4-chloroquinoline derivative in a suitable solvent, for example, chlorobenzene, to synthesize a 4-(nitrophenoxy)-quinoline derivative or a corresponding quinazoline derivative and then reacting the 4-(nitrophenoxy)quinoline derivative in a suitable solvent, for example, N,N—dimethyl formamide, ethanol or ethyl e in the presence of a catalyst, for example, palladium hydroxide-carbon or palladium-carbon, under a hydrogen here. The nitro group can also be reduced with zinc or iron. Alternatively, the 4- phenoxy)quinoline derivative can be produced by reacting an aminophenol derivative with the 4-chloroquinoline tive in a suitable t, for example, dimethyl sulfoxide or N,N—dimethyl ide, in the presence of a base, for example, sodium hydride or potassium t-butoxide. The 4-(aminophenoxy)-quinazoline derivative can be produced by dissolving an aminophenol derivative in an aqueous sodium hydroxide solution and subjecting the solution to a two phase reaction with a solution of the 4- chloroquinazoline derivative in a suitable solvent, DMF, THF, or ethyl methyl ketone, in the presence of a phase transfer catalyst, for example, tetra-n-butylammonium chloride.
An example of the synthesis of oxo-l,2,3,4-tetrahydro-pyrimidine carboxylic acids is shown in Scheme 2.
O O o 0 EtO 05‘ F DCE, DIEA, 90° | NaOEt/ EtOH, 0 O 0 EC —> | NH —> ~85°/° J=O 90 /°0 NH LN 2 ONCQ HN N O 2—Aminomethylene—malonate 4-FIuoro-phenyl)-ureidomethy|ene]— malonic acid diethyl ester F F o o o o R-X, DMF, 60 aC, Method A EtO N H0 N | [Tl/KO | 4M HCI, C4H802, water 70 °C N’go Method B LiOH, THF, MeOH Scheme 2 Where, in Scheme 2, DCE is dichloroethane, DIEA is diisopropylethylamine, NaOEt is sodium ethoxide, EtOH is ethanol, DMF is dimethylformamide, C4H802 is dioxane, THF is tetrahydrofuran, MeOH is ethanol, and R—X is an alkyl halide. ng with a 2-aminomethylene malonate and reacting with any appropriate aryl, heteroaryl or alkyl isocyanate produces ureidomethylene-malonic acid . The ureidomethylene-malonic acid esters can be cyclized using a base such as KOH, NaOH or sodium ethoxide in ethanol to produce the Nl-H 2,4-dioxo-l ,2,3,4-tetrahydro-pyrimidine- -carboxylic acid esters. Starting with an N—substituted omethylene malonate produces an Nl substituted 2,4-dioxo-l,2,3,4-tetrahydro-pyrimidinecarboxylic acid ester. Starting with substitution on the methylene malonate, for example 2-(l- aminoethylidene)-malonic acid ester or 2-(1-aminocyclopropyl-ethylidene)-malonic acid ester produces the corresponding C6 substituted 2,4-dioxo-l,2,3,4-tetrahydro- pyrimidinemethylcarboxylic acid ester or 2,4-dioxo-l,2,3,4-tetrahydro-pyrimidine cyclopropylmethyl-S-carboxylic acid ester. The Nl-H intermediate may be alkylated under standard conditions using a base, for example K2C03 in a solvent such as dimethylsulfoxide or dimethylformamide to produce the Nl-substituted-2,4-di0X0-l - tetrahydro-pyrimidine-S-carboxylic acid ester. 2,4-dioxo-l,2,3,4-tetrahydro-pyrimidinecarboxylic acid esters that are N1 and N3 unsubstituted may be mono- or dialkylated using standard conditions as outlined in Scheme 3 or Scheme 4. o 0 0 o o NH —> I HOwN’ 2 ”A, NAG Scheme 3 a. alkyl halide 80 0C. b. lN LiOH, tetrahydrofuran, , K2C03, dimethylformamide, methanol, 65 0C, or 4N HCl in aqueous dioxane, 80 0C.
H 1 Ii] I? EtOZC COZEt a,b (5(ngK Y c, d N o 1/ 2 I T R HO H2N \R2 0 O O 0 Scheme 4 a. RZNCO, DIEA, dichloroethane, 100 0C, 6 hr. b. sodium ethoxide, ethanol, rt, 18 hr. c. thalide, K2C03, dimethylformamide, 80 0C. d. 4N HCl in s dioxane, 80 0C, Where R1 and R2 are alkyl Hydrolysis of the 2,4-dioxo-l,2,3,4-tetrahydro-pyrimidinecarboxylic acid esters may be achieved under standard acid or basic hydrolysis conditions to produce the acids. a. ethyl isocyanate, tetrahydrofuran, 0 0C. b. diethyl ethoxymethylenemalonate, sodium ethoxide, ethanol, rt, 48 hr. c. ethyl acetate / s. D. IN LiOH, ol, tetrahydrofuran, 60 0C, 18hr.
Examples Where 2,4-dioxo-l,2,3,4-tetrahydro-pyrimidinecarboxylic acid amides are N1 aryl or N1 heteroaryl may be synthesized as outlined in Scheme 5. The synthesis of N1 4-fluorophenyl is delineated for Example 91. The sequential reaction of 4-fluoroaniline with ethyl isocyanate then diethyl ethoxymethylenemalonate produces l(4-fluoro- phenyl)-2,4-dioxo-l ,2,3,4-tetrahydro-pyrimidinecarboxylic acid ethyl ester and 3-ethyll- ro-phenyl)-2,4-dioxo- l ,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid ethyl ester.
The uorophenyl) isomer is readily separated by crystallization. 3-Ethyl-l-(4- fluorophenyl)-2,4-dioxo-l,2,3,4-tetrahydro-pyrimidinecarboxylic acid is produced under basic hydrolysis and can also be sized under acid conditions, then coupled to (6,7-dimethoxyquinolinyloxy)fluorophenylamine to produce the N1 aryl amide example 91. 3,5-Dioxo-2,3,4,5-tetrahydro-[l,2,4]triazinecarboxylic acid esters may be synthesized as outlined in Scheme 6. 0" M0F 000 000 O N,an| —> MNAO| H H F F —>ON|/I\L”M HONI/ILM HOINM M M R R Scheme 6 2-Oxo-malonic acid diethyl ester and 4-fluorophenyl thiosemicarbazide condensation produced 4-(4-fluorophenyl)oxothioxo-2,3,4,5-tetrahydro- [1,2,4]triazinecarboxylic acid ethyl ester. Oxidation with, for example hydrogen peroxide and acetic acid produces 4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro- [1,2,4]triazinecarboxylic acid ethyl ester. Alkylation under conditions bed for 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid esters produced N2-substituted 4-(4-fluorophenyl)-3 xo-2,3 ,4,5 -tetrahydro- [1 ,2,4]triazinecarboxylic acid ethyl esters. N1 and or N4 unsubstituted 3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine carboxylic acid ethyl esters may be ted to e the corresponding substituted 3,5- dioxo-2,3,4,5-tetrahydro-[1,2,4]triazinecarboxylic acid ethyl esters. Hydrolysis of the 3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazinecarboxylic acid ethyl esters may be achieved under acidic or basic conditions to produce 3,5-dioxo-2,3,4,5-tetrahydro- [1,2,4]triazinecarboxylic acids. ng aniline ediates with these acids may be achieved using known standard procedures HATU, HOBT or EDCI, in an appropriate solvent such as DMF or THF or by converting the acid to the acid chloride and reacting with the amine in an inert solvent.
Examples l synthesis methods for 2,4-di0x0-1,2,3,4-tetrahydropyrimidine-S-carboxylic acids Method A: 1-cyclopropylmethyl(4-fluorophenyl)-2,4-dioxo-1,2,3 ,4- tetrahydropyrimidine- 5-carboxylic acid a) 2-Aminomethylene-malonic acid diethyl ester (16.7 g, 89.2 mmol) and 4- fluorophenyl isocyanate (10.6 mL, 93.7 mmol) in 1,2-dichloroethane (25 mL, 320 mmol) was added N,N—diisopropylethylamine (17.1 mL, 98.1 mmol) and heated at 100 0C for 6h. The mixture was cooled on an ice bath and the solid collected and washed with ether to give the urea (24.5 g, 85%). mp = 198-200 0C; LCMS m/z = 347 (M + 23);1HNMR(DMSO)8: 10.57 (d, 1H, J = 12.3 Hz), 10.41 (s, 1H), J = 12.45 Hz), 8.45 (d, 1H, J = 12.5 Hz), 7.48-7.53 (m, 2H), 7.16-7.21 (m, 2H), 4.24 (q, 2H, J = 7 Hz), 4.15 (q, 2H, J = 7 Hz), 1.22-1.28 (m, 6H). b) 2-[3-(4-Fluorophenyl)ureidomethylene]malonic acid diethyl ester (24 g; 70 mmol) was suspended in Ethanol (100 mL) and added 21% NaOEt in EtOH (41.7 mL, 112 mmol) drop wise at rt. The mixture was stirred 4h, upon which time the mixture became thick slurry. The mixture was concentrated and the residue partitioned between ethyl acetate (EtOAc) and 1M citric acid. The EtOAc layer was washed with water and brine, dried over MgSO4 and was concentrated. The solid was triturated with ether-hexanes (1/3) to give 3-(4-fluorophenyl)-2,4-dioxo- 1,2,3,4-tetrahydropyrimidinecarboxylic acid ethyl ester as a white solid. mp 206-8 c’C; LCMS m/z = 279 (M + 1);1H NMR (DMSO) 8: 12.0 (s, 1H), 8.25 (s, 1H),7.31 (bs, 2H), 7.29 (d, 2H, J = 3 Hz), 4.17 (q, 2H, J = 7 Hz), 1.23 (t, 3H, J = 7 Hz). luorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid ethyl ester (3.50 g, 11.6 mmol), potassium carbonate (3.22 g, 23.3 mmol) and cyclopropylmethyl e (3.39 mL, 35.0 mmol) in N,N—dimethylformamide (DMF) (10 mL) was heated at 65 0C for 12h. The mixture was cooled to rt, ioned between EtOAc and 1N Na2C03, water and brine and then dried over MgSO4. LCMS m/z = 333 (M + 1); 1H NMR (CDCLg): 8.42 (s, 1H), 7.16-7.19 (m, 4H), 4.35 (q, 2H, J = 7 Hz), 3.74 (d, 2H, J: 7 Hz), 1.35 (t, 3H, J =7 Hz), 1.25 (m, 1H), 0.72 (m, 2H), 0.42 (m, 2H). d) The oil from step c was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL) and 1 M of m hydroxide (10.6 mL) was added. After stirring at rt for 6h the mixture was concentrated and extracted with 1N N32C03 (2x). The basic layer was ed with 1N HCl on an ice bath and the product collected and dried to give 1-cyclopropylmethyl(4-fluorophenyl)-2,4-dioxo- 1 ,2,3 ,4- tetrahydropyrimidine- 5-carboxylic acid as a white solid. LCMS m/z = 305 (M + 1); 1H NMR (DMSO) 8: 12.62 (s, 1H), 8.82 (s, 1H), 7.30-7.39 (m, 4H), 3.79 (d, 2H, J = 7.2 Hz), 1.20 (m, 1H), 0.50-0.55 (m, 2H), 0.38-0.42 (m, 2H).
Method B: 3-(4-Fluorophenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine carboxylic acid a) 3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid ethyl ester (15 g, 54 mmol), potassium carbonate (14.9 g, 108 mmol) and isopropyl iodide (10.8 mL, 108 mmol) in N,N—dimethylformamide (35 mL) was heated at 70 0C for 12 h. The mixture was concentrated, ved in EtOAc and was filtered.
The EtOAc layer was washed with 1N N32C03, water and brine and was concentrated. The product was crystallized from EtOAc-ether—hexanes to give [3- (4-fluorophenyl)isopropyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic WO 74633 acid ethyl ester as a white solid (15.5 g, 90%). mp 142-4 oC; LCMS m/z = 321 (M + 1), 1H NMR(CDC13) 8: 8.35 (s, 1H), 7.14-7.19 (m, 4H), (4.91 (h, 1H, J = 6.8 Hz), 4.35 (q, 2, J = 7.2 Hz), 1.44 (d, 6H, J = 7 Hz), 1.36 (t, 3H, J = 7.2 Hz). b) [3 -(4-Fluorophenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine-5 - carboxylic acid ethyl ester (15 g, 47 mmol) was added 4M HCl in dioxane (18.7 mL, 216 mmol) and water (5 mL) and heated at 70 OC overnight. The product upon cooling itated, additional water (~ 10 mL) was added and the product collected and dried to give 3-(4-fluorophenyl)isopropyl-2,4-dioxo-1,2,3,4- tetrahydropyrimidine- 5-carboxylic acid as a white solid. mp 168-9 C’C; LCMS m/z = 293 (M + 1); 1H NMR (DMSO) 5: 12.67 (s, 1H), 8.58 (s, 1H), 7.29-7.39 (M, 4H), 4.72 (h, 1H, J = 6.8 Hz), 1.38 (d, 6H, J = 6.8 Hz).
Method C. 3-(4-Fluorophenyl)(3-methoxypropyl)-2,4-dioxo-1,2,3 ,4-tetrahydro- pyrimidine- 5-carboxylic acid a) 3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid (0.25 g, 1.0 mmol), and potassium carbonate (0.55 g, 4.0 mmol) in N,N- dimethylformamide (5 mL, 60 mmol) was heated at 65 CC for 12h. The mixture was filtered, concentrated and d with EtOAc. The EtOAc solution was washed with water and brine then dried over MgSO4 and concentrated to give an oil. b) This oil was dissolved in methanol/tetrahydrofuran (MeOH/THF) (1 :1; 5 mL) and added 3 mL 1N LiOH, then heated at 60 0C for 1h. The cooled on was made acidic with concentrated HCl and the white solid collected to give 125 mg (40%) of 3-(4-fluorophenyl)(3-methoxy-propyl)-2,4-dioxo-1,2,3 ,4- tetrahydropyrimidinecarboxylic acid as a white solid. LCMS m/z = 323 (M + 1); 1H NMR (DMSO) 5: 12.6 (s, 1H), 8.7 (s, 1H), 7.30-7.37 (m, 4H), 3.97 (t, 2H, J = 7.2 Hz), 3.39 (t, 2H, J = 6.3Hz), 3.2 (s, 3H), 1.88 (q, 2H, J = 6.2 Hz).
The following 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acids were synthesized using methods A, B or C described above. 3 -(4-Fluorophenyl)-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine-5 xylic acid.
LCMS m/z = 251 (M + 1);1H NMR (DMSO) 8: 12.56 (b, 1H), 12.39 (s, 1H), 8.36 (s, 1H), 7.29-7.38 (M, 4H). 1—3-(4-flu0r0phcny1)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid. mp = 166-8 oC; LCMS m/z = 279 (M + 1); 1H NNR (DMSO) 5: 12.6 (bs, 1H), 8.82 (s, 1H), 7.29-7.38 (m, 4H), 3.94 (q, 2H, J = 7.3 Hz), 1.25 t, 3H, J = 7 Hz). 3 -(4-F1uorophcny1)rncthy1—2,4-di0x0- 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid LCMS m/z = 265 (M + 1); 1HNMR (DMSO) 5: 12.59 (s, 1H), 8.80 (s, 1H), 7.3 (m, 4H), 3.56 (s, 3H). 1—3-(4-flu0r0phcny1)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid. LCMS m/z = 291 (M + 1); 1H NMR (DMSO) 8: 1H NMR (DMSO) 5: 12.66 (s, 1H), 8.72 (s, 1H), 7.27-7.41 (m, 4H), 5.89-5.99 (m, 1H), 5.24-5.35 (m, 2H), 4.53 (m, 2H). 1-(3 ,3 -Diflu0r0a11y1)—3 -(4-flu0r0phcny1)-2,4-di0xo- 1 ,2,3 rahydr0pyrirnidinc-5 - carboxylic acid. LCMS m/z = 327 (M + 1); 1H NMR (DMSO) 5: 12.6 (s, 1H), 8.8 (s, 1H), 7.31-7.34 (m, 4H), 4.90-4.96 (m, 1H), 4.84-4.86 (m, 1H), 4.54 (d, 2H) 4.78 (m, 1H), 4.60-4.68 (M, 1H), 4.56-4.59 (m, 1H), 4.49 (m, 1H), 4.47 (m, 1H). 3 -(4-F1u0r0phcny1)—1-(3 -rncthy1—butcny1)—2,4-diox0- 1 ,2,3 ,4-tctrahydr0- pyrimidinecarboxy1ic acid. LCMS m/z = 342 (M + 23); 1H NMR (DMSO) 5: 12.6 (s, 1H), 8.7 (s, 1H), 7.30-7.38 (m, 4H), 5.3 (m, 1H), 4.49 (m, 2H), 1.7 (s, 6H). 3 -(4-F1uor0phcny1)-2,4-di0x0pr0py1— 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid. LCMS m/z = 293 (M + 1); 1H NMR (DMSO) 5: 12.62 (s, 1H), 8.78 (s, 1H), 7.30-7.37 (m, 4H), 3.87 (t, 2H, J = 7.5 Hz), 1.67 (q, 2H, J = 7.5 Hz), 0.89 (t, 3H, J = 7.5 Hz). 3 -(4-F1uorophcny1)- 1 ty1—2,4-di0xo- 1 ,2,3 ,4-tctrahydr0-pyrirnidinc carboxylic acid. LCMS m/z = 307 (M + 1). 3 -(4-F1uor0phcny1)—2,4-di0x0pcnty1— 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 xy1ic acid. LCMS m/z = 321 (M +1); 1H NMR (DMSO) 8: 12.62 (s, 1H), 8.78 (s, 1H), 7.30-7.38 (m, 4H), 3.89 (m, 2H), 1.65 (m, 2H), 1.28 (m, 4H), 0.87 (t, 3H, J =7.4 Hz). 1-Ethy1—3-(4-fluor0phcny1)rncthy1—2,4-dioxo-1 ,2,3 ,4-tctrahydropyrirnidinc carboxylic acid. LCMS m/z = 293 (M + 1); 1H NMR (DMSO) 5: 13.36 (s, 1H), 7.28-7.33 (m, 4H), 3.96 (q, 2H, J = 7H2), 2.57 (s, 3H), 1.21 (t, 3H, J = 7 Hz). 1-(2-Eth0xycthy1)—3-(4-flu0r0phcny1)-2,4-di0xo- 1 ,2,3 ,4-tctrahydro-pyrirnidinc-5 - carboxylic acid. LCMS m/z = 323 (M + 1); 1H NMR (DMSO) 5: 12.509 (5, 1H), 8.66 (s, 1H), 7.39-7.39 (rn, 4H), 4.09 (t, 2H, J = 5 Hz), 3.61 (t, 2H, J = 5 Hz), 3.47 (q, 2H, J = 7.2 Hz), 1.11 (t, 3H, J = 7.2 Hz). 1 -(2-Benzyloxyethyl)—3-(4-fluorophenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrirnidine- -carboxylic acid. LCMS rn/z = 385 (M + 1); 1H NMR (DMSO) 5: 12.59 (s, 1H), 8.72 (s, 1H), 7.31-7.34 (rn, 9H), 4.52 (s, 2H), 4.15 (t, 2H, J = 5 Hz), 3.68 (t, 2H, J = 5Hz). 3 -(4-Fluorophenyl)—1-(2-isopropoxy-ethyl)-2,4-dioxo-1,2,3 ,4- tetrahydropyrirnidinecarboxylic acid. LCMS rn/z = 337 (M + 1). 1H NMR (DMSO) 5: 12.57 (s, 1H), 8.67 (s, 1H), 7.32-7.36 (rn, 4H), 4.06 (br, 2H), 3.6 (hr, 3H), 1.07 (d, 6H, J = 6 Hz). 1-(3 -Benzyloxypropyl)(4-fluorophenyl)—2,4-dioxo- 1 ,2,3 ,4- ydropyrirnidinecarboxylic acid. LCMS rn/z = 399 (M + 1); 1H NMR (DMSO) 5: 12.59 (s, 1H), 8.75 (s, 1H), 7.24-7.35 (rn, 9H), 4.43 (s, 2H), 4.01 (rn, 2H), 3.53 (rn, 2H), 1.74 (rn, 2H). 3 -(4-Fluorophenyl)— 1 -(2-rnorpholinyl-ethyl)-2,4-dioxo- 1 ,2,3 rahydro- pyrimidinecarboxylic acid; hydrochloride. LCMS rn/z = 400 (M + 1). 1H NMR (DMSO) 8: 11.11 (br, 1H), 10.18 (br, 1H), 7.43 (rn, 2H), 7.35 (rn, 2H), 4.32 (br, 2H), 3.93 (rn, 4H), 3.73-3.79 (rn, 6H). 1-((S)-2,2-Dirnethyl- 1 ,3 -dioxolanylrnethyl)—3 -(4-fluoro-phenyl)-2,4-dioxo- 1,2,3,4-tetrahydropyrirnidinecarboxylic acid. LCMS m/z = 365 (M + 1). 1H NMR (DMSO) 5:12.60 (5, 1H), 8.66 (s, 1H), 7.34 (rn, 4H), 4.34 (br, 1H),4.12 (rn, 1H),4.01 (rn, 2H),3.72 (rn, 1H), 1.30 (s, 3H), 1.27 (s, 3H). 1-(2-Dirnethylarninoethyl)(4-fluoro-phenyl)-2,4-dioxo-1,2,3 ,4- ydropyrirnidinecarboxylic acid; hydrochloride. LCMS rn/z = 358 (M + 1); 1H NMR (DMSO) 8: 12.4 (b, 1H), 10.3 (s, 1H), 8.76 (s, 1H), 7.3-7.42 (rn, 4H), 4.3 (t, 2H, J = 7Hz), 3.4 (rn, 2H), 2.8 (d, 6H), 3 -(4-Fluorophenyl)-2,4-dioxo(2-pyrrolidinyl-ethyl)-1 ,2,3 ,4-tetrahydro- pyrimidinecarboxylic acid; hydrochloride. LCMS rn/z = 384 (M + 1); 1H NMR(DMSO) 5: 12.63 (br s, 1H), 11.01 (s, 1H), 8.82 (s, 1H), 7.45 (rn, 2H), 7.34 (rn, 2H), 4.29 (t, 2H, J = 5.2 Hz), 3.47 (rn, 4H), 3.05 (rn, 2H), 1.89-2.0 (rn, 4H). 3 -(4-Fluorophenyl)-2,4-dioxo(2-piperidinyl-ethyl)-1,2,3 ,4- ydropyrirnidinecarboxylic acid; hydrochloride. LCMS rn/z = 398 (M + 1). 3 -Cyclohexylethyl-2,4-dioxo-1 ,2,3 ,4-tetrahydro-pyrirnidine-5 -carboxylic acid.
LCMS rn/z = 267 (M + 1); 1H NMR (DMSO) 5: 12.87 (s, 1H), 8.70 (s, 1H), 4.67 (rn, 1H), 3.98 (rn, 2H), 2.26 (rn, 2H), 1.78 (rn, 2H),1.60 (rn, 3H), 1.07-1.33 (rn, 6H). 1-(3 -Dirnethy1arninopropy1)(4-fluoro-pheny1)—2,4-dioxo- 1 ,2,3 ,4-tetrahydro- pyrimidinecarboxy1ic acid; hydrochloride. LCMS rn/z = 372 (M -- 1). 3 -(4-F1uoropheny1)—1-(3 -rnorpholiny1—propy1)-2,4-dioxo- 1 ,2,3 ,4-tetrahydro- pyrimidinecarboxy1ic acid; hydrochloride. LCMS rn/z = 414 (M -- 1). 3 -(4-F1uoropheny1)-2,4-dioxo(tetrahydropyrany1)-1 ,2,3 ,4- tetrahydropyrirnidinecarboxy1ic acid. LCMS rn/z = 335 (M + 1); 1H NMR (DMSO) 5: 12.60 (s, 1H), 8.54 (s, 1H), 7.30-7.38 (rn, 4H), 4.58 (rn, 1H), 3.98 (rn, 2H), 3.39 (rn, 2H), 2.10 (rn, 2H), 1.80 (rn, 2H). 1 -(4-Benzyloxybuty1)(4-fluoropheny1)-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrirnidine- -carboxy1ic acid. LCMS m/z = 413 (M + 1); 1H NMR (DMSO) 3 (5, 1H), 8/79 (s, 1H), 7.27-7.40 (rn, 4H), 4.46 (rn, 2H), 3.92 (rn, 2H), 3.40 (rn, 2H),1.60- 1.74 (rn, 2H), .48 (rn, 2H). 1-Cyclobuty1(4-fluoropheny1)-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrirnidine carboxylic acid. LCMS rn/z = 305 (M + 1); 1H NMR(DMSO) 8: 12.64 (s, 1H), 8.82 (s, 0.5H) 8.52 (s, 0.5H), 7.30-7.39 (rn, 4H), 4.74 (rn, 0.5H), 3.78 (rn, 0.5H), .40 (rn, 2H), 1.75 (rn, 1H), 1.22 (rn, 0.5), .54 (rn, 1.5H) NMR shows rotarners. 3 -(4-F1uoropheny1)-2,4-dioxopropyny1— 1 ,2,3 ,4-tetrahydropyrirnidine-5 - carboxylic acid. LCMS m/z = 289 (M + 1). 3 -(4-F1uoropheny1)—1-(2-irnidazoly1—ethy1)-2,4-dioxo-1,2,3 ,4- tetrahydropyrirnidinecarboxy1ic acid. LCMS rn/z = 345 (M + 1). 3 -(4-F1uoropheny1)-2,4-dioxo(2-pyrazoly1-ethy1)-1,2,3 ,4- tetrahydropyrirnidinecarboxy1ic acid. LCMS rn/z = 345 (M + 1). 3 -(4-F1uoropheny1)-2,4-dioxophenethy1— 1 ,2,3 ,4-tetrahydropyrirnidine-5 - carboxylic acid. LCMS m/z = 355 (M + 1). 1-(2-[1,3]Dioxolany1—ethy1)(4-fluoro-pheny1)-2,4-dioxo-1,2,3 ,4-tetrahydropyrimidinecarboxy1ic acid. LCMS m/z = 351 (M + 1). 1-Diethy1carbarnoylrnethy1(4-fluoropheny1)—2,4-dioxo- 1 ,2,3 ,4- tetrahydropyrirnidinecarboxy1ic acid arnide. LCMS rn/z = 364 (M + 1). 3 -(4-F1uoro-pheny1)(2-rnorpholiny1—2-oxo-ethy1)-2,4-dioxo-1,2,3 ,4- ydro-pyrirnidinecarboxy1ic acid arnide. LCMS m/z = 376 (M + 1). 3 -(4-F1u0r0pheny1)-2,4-di0x0[2-(2-0x0-pyrr01idiny1)-ethy1]—1,2,3 ,4- tetrahydro-pyrimidinecarb0xy1ic acid. LCMS m/z = 362 (M + 1). 1-(2-F1uor0ethy1)(4-flu0ro-pheny1)—2,4-di0x0- 1 ,2,3 ,4-tetrahydr0-pyrimidine-5 - carboxylic acid. LCMS m/z = 397 (M + 1). 1 -tert-Butoxycarbonylmethy1(4-flu0r0phenyl)-2,4-diox0- 1 ,2,3 rahydr0- dinecarb0xylic acid. LCMS m/z = 365 (M + 1). 3 -(4-F1uor0-phenyl)oxaz01y1methy1-2,4-di0x0-1 ,2,3 ,4-tetrahydr0-pyrimidine- -carboxylic acid. LCMS m/z = 332 (M + 1). 3 -(4-F1u0r0-phenyl)-2,4-di0x0(tetrahydr0furanylmethyl)- 1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xylic acid. LCMS m/z = 335 (M + 1). 3 -(4-F1u0r0-phenyl)-2,4-di0x0(tetrahydro-pyrany1methy1)- 1 ,2,3 ,4-tetrahydr0- dinecarb0xylic acid. LCMS m/z = 349 (M + 1). 3 -(4-F1u0r0-pheny1)(2-methy1-thiaz01—4-y1methy1)-2,4-di0xo-1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xylic acid. LCMS m/z = 362 (M + 1). 1-Cyc10penty1—3-(4-flu0ro-pheny1)-2,4-di0x0- 1 ,2,3 ,4-tetrahydr0pyrimidine-5 - carboxylic acid. LCMS m/z = 319 (M + 1). 1-Benzy1—3-(4-flu0ro-pheny1)-2,4-di0x0- 1 ,2,3 ,4-tetrahydro-pyrimidine-5 - carboxylic acid amide. LCMS m/z = 340 (M + 1). 3 -(4-F1uor0phenyl)—1-[2-(2-flu0r0pheny1)-ethy1]-2,4-di0x0-1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xylic acid amide. LCMS m/z = 372 (M + 1). 3 -(4-F1uoropheny1)[2-(4-fluor0-pheny1)—ethy1] -2,4-di0x0- 1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xylic acid amide. LCMS m/z = 372 (M + 1). 1 -(2-Cyc10hexy1—ethy1)-3 -(4-flu0r0-pheny1)—2,4-di0x0-1,2,3 ,4-tetrahydr0- pyrimidinecarb0xylic acid. LCMS m/z = 360 (M + 1). 3 -(4-F1uoropheny1)-2,4-di0x0-1 -(3 -pheny1pr0pyl)-1 ,2,3 rahydro-pyrimidine-5 - carboxylic acid. LCMS m/z = 369 (M + 1). 3 -(4-F1uoropheny1)-2,4-di0x0-1 -(2-ox0pyrr01idin-1 -y1—ethy1)- 1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xylic acid. LCMS m/z = 362 (M + 1). 1 -Dimethy1carbamoylmethy1(4-flu0ro-pheny1)-2,4-di0x0- 1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xylic acid. LCMS m/z = 336 (M + 1). 1-(1-Dimethy1carbamoy1—2-0X0-pr0py1)(4-flu0ro-pheny1)-2,4-di0x0- 1 ,2,3 ,4- tetrahydro-pyrimidinecarb0xy1ic acid. LCMS m/z = 378 (M + 1).
Example 1 2012/065019 OD: .. . 1-Ethyl(4-fluorophenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylicacid [4- (6,7-dimethoxyquinolinyloxy)fluorophenyl]amide.
Step a. 4-(6,7-Dimethoxyquinolinyloxy)fluorophenylamine.
Sodium hydride (60% disp. in mineral oil; 1.3 g, 33.5 mmol) was added to 4-amino fluoro-phenol in dry N,N—dimethylformamide (50 mL) and stirred at rt for 30 min under an here of nitrogen. Then solid 4-chloro-6,7-dimethoxyquinoline (5.0 g, 22.4 mmol) was added and the reaction stirred at 100°C for 30 h. The mixture was concentrated, dissolved in EtOAc (100 mL) and washed with 1N Na2C03, water and brine, then dried over MgSO4. The t was chromatographed on silica gel (5% methanol/dichloromethane (MeOH/DCM)) to give a tan solid 4.9 g, 70%. mp = 172-5 0C; LCMS m/z = 315 (M + 1); 1H NMR (DMSO) 8: 8.48 (d, 1H, J = 5.4 Hz), 7.50 (s, 1H), 7.38 (s, 1H), 7.07 (t, 1H, J = 8.6 Hz), 6.53,6.56 (dd, 1H, J = 2.6, 13.4 Hz), 6.45, 6.47 (dd, 1H, J = 2, 8 Hz), 6.38, 6.39 (dd, 1H, J = 1, 5.4 Hz), 5.48 (s, 2H), 3.94 (s, 6H).
Step b. N,N,N',N'-Tetramethyl-O-(7-azabenzotriazolyl)uronium hexafluorophosphate (HATU) (0.072 g, 0.19 mmol) and 1-ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4- tetrahydropyrimidinecarboxylic acid (0.053 g,0. 19 mmol) in N,N—dimethylformamide (2 mL) was added N,N—diisopropylethylamine (0.055 mL, 0.32 mmol). After 15 min stirring at rt, 4-(6,7-dimethoxyquinolinyloxy)fluorophenylamine (0.05 g, 0.2 mmol) was added. The reaction was stirred at rt for 12 h, diluted with EtOAc , then washed with 1N Na2C03, water and brine and then dried over MgSO4. The product was crystallized from MeOH to give 75 mg (68%) as a white solid. mp = 151-4 0C; LCMS m/z = 575 (M + 1); 1H NMR (DMSO) 8: 11.04 (s, 1H), 8.89 (s, 1H), 8.47 (d, 1H, J = 5.4 Hz), 7.98, 8.01 (dd, 1H, J = 2.3, 12.6 Hz), 7.52-7.56 (m, 2H), 7.33-7.46 (m, 6H), 6.47 (d, 1H, J = 5.4Hz), 4.01 (q, 2H, J = 7Hz), 3.98 (d, 6H), 13.0 (t, 3H, J = 7Hz).
The following compounds were synthesized using procedures r to those for Example 1.
Example 2.
OH: .. . 3 -(4-F1uorophcny1)mcthy1—2,4-di0x0- 1 ,2,3 ,4-tctrahydropyrimidinc-5 -carb0xy1ic acid 7-dimcth0xyquin01iny10xy)—3-flu0ro-phcny1]-amidc. mp = 158-60 0C; LCMS m/z = 561 (M + 1); 1H NMR (DMSO) 5:11.03 (5, 1H), 8.9 (s, 1H), 8.48 (d, 1H, J = 6Hz), 7.99. 8.01 (dd, 1H, J = 3, 12 Hz), 7.52 (m, 2H), 7.36-7.43 (m, 6H), 6.46 (d, 1H, J = 6Hz), 3.92 (s, 3H), 3.94 (s, 3H), 3.54 (s, 3H).
Example 3.
/O N\ I I /] GE“NOFO O N’gO \OMe 3 -(4-F1uorophcny1)(2-mcthoxycthy1)-2,4-di0x0- 1 ,2,3 rahydropyrimidinc-5 - carboxylic acid [4-(6,7-dimcthoxyquino1iny10xy)—3-flu0r0phcny1]—amidc. mp = 118-21 0C; LCMS m/z = 605 (M + 1); 1H NMR (DMSO) 5: 11.0 (s, 1H), 8.74 (, s, 1H), 8.47(d, 1H, J = 6 Hz), 7.99, 8.01 (dd, 1H, J = 3, 12 Hz), 7.52-7.55 (m, 2H), 7.33-7.46 (m, 6H), 6.48 (d, 1H, J = 6 Hz), 4.17 (t, 2H, J: 5 Hz), 3.94 (s, 3H),3.95 (s, 3H), 3.16 (t, 2H, J = 5 Hz).
Example 4. /o N\ CaHwNOFO O 1 -(2-Eth0xycthy1)—3-(4-flu0r0phcny1)-2,4-di0xo- 1 ,2,3 ,4-tctrahydropyrimidinc carboxylic acid [4-(6,7-dimcthoxyquino1iny10xy)—3-flu0r0phcny1]—amidc. mp = 128-30 0C; LCMS m/z = 619 (M +1); 1H NMR (DMSO) 5: 11.0 (s, 1H), 8.76 (s, 1H), 8.47 (d, 1H, J = 5.4 Hz), 7.98-8.01 (dd, 1H, J = 2.4, 12 Hz), 7.52—7.55 (m, 2H), 7.40-7.46 (m, 4H), .38 (m, 2H), 6.48 (d, 1H, J = 5 Hz), 4.16 (t, 2H, J = 5 Hz), 3.94, 3.95 (55, 6H), 3.65 (t, 2H, J = 5 Hz), 3.51 (q, 2H, J = 6.6 Hz), 1.13 (t, 3H, J = 6.6 Hz).
Example 5.
/O N\ I I /] OQWHOFO 0 N’KO 3 -(4-F1uor0pheny1)isopr0py1-2,4-diox0-1 ,2,3 ,4-tetrahydropyrimidinecarb0xy1ic acid [4-(6,7-dimeth0xyquin01iny10xy)—3-fluor0pheny1]— amide. mp = 146-48 0C; LCMS m/z = 589 (M +1);1HNMR(DMSO)5: 11.9 (s, 1H), 8.68 (s, 1H), 8.48 (d, 1H, J = 5.2 Hz), 7.99, 8.02 (dd, 1H, J = 2.4, 12.4 Hz), 7.52-7.55 (m, 2H), 7.33-7.46 (m, 6H), 6.47 (d, 1H, J = 5.2 Hz), 4.78 (m, 1H, J = 7Hz), 3.94 (55, 6H), 1.43 (d, 6H, J = 6.7 Hz).
Example 6 @110? 1 -Cyclopr0py1methy1—3-(4-flu0r0pheny1)—2,4-di0xo- 1 ,2,3 ,4-tetrahydr0pyrimidine carboxylic acid [4-(6,7-dimethoxyquino1iny10xy)fluor0pheny1]— amide. mp = 146-9 0C; LCMS (m/z = 601 (M + 1); 1H NM (DMSO) 5: 11.0 (s, 1H), 8.9 (s, 1H), 8.47 (d, 1H, J = 5.2 Hz), 8.0, 8.02 (dd, 1H, J = 2.3, 12 Hz), 7.52-7.55 (m, 2H), 7.34-7.46 (m, 6H), 6.47 (m, 1H, J = 5.2 Hz), (3.94, SS, 6H), 3.86 (d, 1H, J = 7.2 Hz), 1.25 (m, 1H), 0.57 (m, 2H), 0.44 (m, 2H).
Example 7.
/D/Q\ / 3 -(4-F1u0r0phcny1)—1-(3-mcth0xypropy1)-2,4-di0x0-1 ,2,3 ,4-tctrahydropyrimidinc carboxylic acid [4-(6,7-dimcthoxyquino1iny10xy)fluor0phcny1]— amide. mp = 126-7 0C; LCMS m/z = 619 (M + 1); 1H NMR (DMSO) 5: 11.0 (S, 1H), 8.8 (S, 1H), 8.47 (d, 1H, J = 5.6 Hz), 7.99, 8.02 (dd, 1H, J = 3.2, 13 Hz), 7.52-7.55 (m, 2H), .46 (m, 6H), 6.46 (d, 1H, J = 5.2 Hz), 4.40 (t, 2H, J = 7 Hz), 3.94 (SS, 6H), 3.42 (t, 2H, J = 6.6 Hz), 3.24 (S, 3H), 1.191 (m, 2H).
Example 8. ©0000 3 -(4-F1u0r0phcny1)iS0buty1—2,4-di0x0- 1 ,2,3 ,4-tctrahydr0pyrimidinc-5 -carb0xy1ic acid [4-(6,7-dimcthoxyquino1iny10xy)—3-flu0r0phcny1]—amidc. mp = 136-40 0C; LCMS m/z = 603 (M + 1); 1H NMR (DMSO) 5: 11.0 (S, 1H), 8.81 (S, 1H),8.48 (d, 1H, J = 5.2 Hz), 8.0 (dd, 1H, J = 2.2, 12 Hz), 7.52-7.55 (m, 2H), 7.33-7.46 (m, 6H), 6.47 (d, 1H, J = 5.2 Hz), 3.94 (SS, 6H), 3.82 (d, 2H, J = 7 Hz), 2.05 (m, 1H), 0.93 (d, 6H, J = 7Hz).
Example 9. m“; . 06 . o o 1—3-(4-flu0rophcny1)-2,4-di0x0-1 ,2,3,4-tctrahydropyrimidinccarb0xy1ic acid [4- (6,7-dimcthoxyquino1iny10xy)flu0r0phcny1]—amidc. mp 128-30 0C; LCMS m/z = 587 (M +1); 1H NMR (DMSO) 5: 11.0 (S, 1H), 8.80 (S, 1H), 8.48 (d, 1H, = 5.2 Hz), 7.98, 8.02 (dd, 1H, J = 2.5, 13 Hz), 7.53-7.55 (m, 1H), 7.52 (S, 1H), 7.34-7.46 (m, 6H), 6.47 (d, 1H, J = 4.7 Hz), 5.94-6.02 (m, 1H), 5.36, 5.40 (dd, 1H, J = 1.5. 17 Hz), 5.27, 5.30 (dd, 1H, J = 1.5, 10 Hz), 4.62 (d, 2H, J = 5.5 Hz), 3.94, 3.95 (SS, 6H).
Example 10. ”$10Fo o N O \OBn 1 -(2-Bcnzy10xycthy1)—3-(4-flu0r0phcny1)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrimidinc-5 - carboxylic acid [4-(6,7-dimcthoxyquino1iny10xy)flu0r0phcny1]—amidc. mp > 102 0C (dcc); LCMS m/z = 681 (M + 1); 1H NMR (DMSO) 5: 11.0 (s, 1H), 8.83 (s, 1H), 8.48 (d, 1H, J = 5.3 Hz), 7.99, 8.02 (dd, 1H, J = 2.4, 12.8 Hz), 7.54,7.56 (dd, 1H, J = 1.4, 8.8 Hz), 7.52 (s, 1H), 7.44 (t, 1H, J = 8.8 Hz),7.33-7.41 (m, 9H), 7.30 (m, 1H), 6.47 (d, 1H, J = 5 Hz), 4.55 (s,2H), 4.22 (t, 2H, J = 4.7 Hz), 3.94,3.95 (SS, 6H), 3.72 (t, 2H, J = 4.8 Hz).
Example 11. 3 -(4-F1u0r0phcny1)-2,4-di0xopr0py1-1 ,2,3 ,4-tctrahydr0pyrimidinc-5 - ylic acid [4-(6,7-dimcthoxyquino1iny10xy)—3-flu0r0phcny1]—amidc. mp = 134-6 0C; LCMS m/z = 589 (M + 1); 1H NMR (DMSO) 5: 11.0 (s, 1H), 8.86 (s, 1H), 8.47 (d, 1H, J = 5.3 Hz), 7.98,8.02 (dd, 1H, J = 2.2, 12.6 Hz), 7.52-7.55 m, 2H), 7.40-7.46 (m, 4H), 7.34-7.38 (m, 2H), 6.47 (d, 1H, J = 5.2 Hz), 3.92-3.97 (m, 8H), 1.71 (h, 2H, J = 7.2 Hz), 0.93 (t, 3H, J = 7.2 Hz).
Example 12. 9Q?\ / NJLIdLNH | f0 OiPr 3 u0r0phcny1)— 1 -(2-isopr0p0xycthy1)—2,4-di0x0- 1 ,2,3 ,4-tctrahydr0pyrimidinc-5 - carboxylic acid [4-(6,7-dimcthoxyquino1iny10xy)—3-flu0r0phcny1]—amidc. mp = 138-9 0C; LCMS m/z = 633 (M + 1); 1H NMR (DMSO) 5: 11.00 (s, 1H), 8.78 (s, 1H), 8.47 (d, 1H, J = 4.7 Hz), 7.99 (d, 1H, J = 13 Hz), 7.49-7.56 (m, 2H), 7.38-7.46 (m, 6H), 6.47 (d, 1H, J = 4.6 Hz), 4.12 (m, 2H), 3.94 (d, 6H), 3.65 (m, 3H), 1.10 (d, 6H, J = 6 Hz). e 13. /o\OjijiogN\ a”$10FO O N O KLOBn 1-(3 -Benzy10xypr0py1)(4-flu0r0pheny1)-2,4-di0xo- 1 ,2,3 ,4-tetrahydropyrimidine-5 - carboxylic acid [4-(6,7-dimeth0xyquino1iny10xy)—3-fluor0 pheny1]-amide. mp = 94-96 0C; LCMS m/z = 695 (M + 1); 1H NMR (DMSO) 5: 11.00 (s, 1H), 8.83 (s, 1H), 8.47 (d, 1H, J = 5Hz),7.98, 8.01 (dd, J = 2.4, 12.6 Hz), 7.53-7.59 (m, 1H), 7.52 (s, 1H), 7.42-7.46 (m, 1H), 7.40 (s, 1H), .34 (m, 8H), 7.25-7.28 (m, 1H), 6.47 (dd, 1H, J = 1, 5.2 Hz), 4.46 (s, 2H), 4.09 (t, 2H, J = 7 Hz), 3.94 (d, 6H), 3.59 (t, 2H, J = 5.8 Hz), 1.99 (t, 2H, J = 6.4 Hz).
Example 14. /o N\ N O F F 1-(3 ,3 -Difluor0-a11y1)-3 -(4-flu0r0pheny1)—2,4-di0xo- 1 ,2,3 ,4-tetrahydropyrimidine-5 - carboxylic acid [4-(6,7-dimethoxyquino1iny10xy)flu0r0pheny1]—amide. mp = 128-30 0C; LCMS m/z = 623 (M + 1); 1H NMR (DMSO) 5: 11.0 (s, 1H), 8.9 (s, 1H), 8.48 (d, 1H, J = 5.5Hz), 8.0, 7.98 (dd, 1H, J = 2, 12.8 Hz), 7.52-7.56 (m, 2H), 7.34-7.46 (m, 6H), 6.46 (d, 1H, J = 5 Hz), 4.88-4.99 (m, 1H),4.62 (d, 2H, J = 8Hz), 3.94 (s, 6H).
Example 15.
WO 74633 @110? 3 -(4-F1u0r0phcny1)—1-(3 -mcthy1—butcny1)—2,4-diox0- 1 ,2,3 ,4-tctrahydr0pyrimidinc-5 - carboxylic acid [4-(6,7-dimcthoxyquino1iny10xy)—3-flu0r0phcny1]—amidc. mp = 119- 121°C;LCMS m/z = 615 (M + 1); 1H NMR (DMSO) 5: 11.0 (s, 1H), 8.78 9 (s, 1H), 8.47 (d, 1H, J = 5.2 Hz), 8.0 (d, 1H, J = 13 Hz), 7.52-7.54 (m, 2H), 7.33-7.45 (m, 6H), 6.47 (d. 1H. J = 5.2 Hz), 5.34 (m, 1H), 4.56 (d, 1H, J = 6.8 Hz), 3.94 (s, 6H), 1.76 (s, 3H), 1.74 (s, 3H).
Example 16.
\O / HwNOFO O 3 -(4-F1u0r0phcny1)— 1 -(2-m0rph01iny1—cthy1)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrimidinc-5 - carboxylic acid [4-(6,7-dimcth0xyquino1iny10xy)—3-fluor0 phcny1]-amidc. mp = 124-6 0C; LCMS m/z = 660 (M + 1); 1H NMR(CDC13) 5: 10.9 (s, 1H),8.65 (s, 1H), 8.49 (d, 1H, J = 5.3 Hz), 7.87, 7.90 (dd, 1H, J = 2.4, 12.4 Hz), 7.57 (s, 1H),7.42 (s, 1H), 7.18-7.29 (m, 6H), 6.42 (dd, 1H, J = 0.5, 5.2 Hz), 4.05-4.08 (m, 8H), 3.72 (t, 4H, J = 4.7 Hz), 2.73 (t, 2H, J = 5.7 Hz), 2.56 (m, 4H).
Example 17.
/BQ\ / NJKELNH | N’kO 1u0r0phcny1)-2,4-di0x0-1,2,3,4-tctrahydropyrimidinccarb0xy1ic acid [4-(6,7- dimcthoxyquino1iny10xy)—3-fluor0phcny1]—amidc. mp = 276-8 0C; LCMS m/z = 547 (M + 1); 1H NMR (DMSO) 8: 12.4 (bs, 1H), 11.0 (s, 1H), 8.45 (s, 2H), 7.99 (d, 1H, J = 12 Hz), 7.52 (s, 2H), 7.35-7.40 (m, 6H), 6.4 (s, 1H), 3.9 (s, 6H).
Example 18.
Step a. 4-(6,7-Dimethoxyquin01iny10xy)-phenylamine. /o N\ \ / 4-(6,7-Dimethoxyquino1iny10xy)pheny1amine was synthesized using the methods for Example 1 step a. LCMS m/z = 297 (M + 1); 1H NMR (DMSO) 8: 8.42 (d, 1H, J = 5.3 Hz), 7.50 (s, 1H), 7.36 (s, 1H), 7.91 (d, 2H, J = 8 Hz), 6.67 (d, 2H, J = 8 Hz), 6.36 (d, 1H, J = 5.3 Hz), .14 (s, 2H), 3.93 (s, 6H).
Step b. 3 -(4-F1u0r0pheny1)methy1-2,4-di0x0- 1 ,2,3 ,4-tetrahydr0pyrimidine-5 - carboxylic acid [4-(6,7-dimeth0xyquinoliny10xy)-phenyl]-amide. mp = 143-5 0C; LCMS m/z = 543 (M + 1); 1H NMR (DMSO) 5: 10.92 (s, 1H), 8.85 (s, 1H), 8.46 (d, 1H, J = 5.2 Hz), 7.80 (d, 2H, J = 9 Hz), 7.50 (s, 1H), 7.34-7.42 (m, 5H), 7.25 (d, 2H, J = 9Hz), 6.47 (d, 1H, J: 5.2 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 3.53 (s, 3H). e 19. 0Q F o o 1 nzyloxyethy1)(4-flu0ro-pheny1)-2,4-di0x0- 1 ,2,3 ,4-tetrahydr0pyrimidine-5 - carboxylic acid [4-(6,7-dimeth0xyquinoliny10xy)-phenyl]-amide. mp = 163-4 0C; LCMS m/z = 663 (M +1); 1H NMR (DMSO) 5: 10.89 (s, 1H), 8.81 (s, 1H), 8.47 (d, 1H, J: 5.6 Hz), 8.80 (d, 2H, J = 9 Hz), 7.50 (s, 1H), 7.25-7.41 (m, 12H), 6.49 (d, 1H, J = 5.8 Hz), 4.56 (s, 2H), 4.21 (t, 2H, J: 5 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 3.72 (t, 2H, J = 5 Hz).
Example 20. /o: :\O :N\:/ GEHwNOFO O 1 -(2-Dirnethy1arninoethy1)—3 -(4-flu0r0pheny1)—2,4-di0xo- 1 ,2,3 ,4-tetrahydr0pyrirnidine-5 - carboxylic acid 7-dimethoxyquino1iny10xy)—3-flu0r0pheny1]—arnide. mp (HC1 salt): 208-10 0C; LCMS m/z = 618 (M + 1); 1H NMR (DMSO) 5:11.18 (5, 1H), 10.77 (s, 1H), 8.94 (s, 1H), 8.81 (d, 1H, J = 6.6 Hz), 8.11, 8.08 (dd, 1H, J = 2,14 Hz), 7.74 (s, 1H), 7.65 (m, 2H), 7.50-7.60 (m, 3H), 7.37 (m, 2H), 6.95 (d, 1H, J = 6.5Hz), 4.39 (t, 1H, J = 5.8 Hz), 4.04 (s, 3H), 4.03 (s, 3H), (2.82 (d, 6H). e 21.
/O N\ O”$10FO O N O KLOBn 1-(3 -Benzy10xypr0py1)(4-flu0r0pheny1)-2,4-di0xo- 1 ,2,3 ,4-tetrahydr0pyrirnidine-5 - carboxylic acid [4-(6,7-dimethoxyquino1iny10xy)pheny1]-arnide. mp = 100-104 0C; LCMS m/z = 677 (M + 1);1H NMR (DMSO) 5: 10.90 (s, 1H), 8.81 (s, 1H), 8.47 (d, 1H, J = 5 Hz), 7.80 (d, 2H, J = 8.8 Hz), 7.50 (s, 1H), 7.40 (s, 1H), 7.25-7.33 (m, 11H), 6.49 (d, 1H, J = 5.6 Hz), 4.45 (s, 2H), 4.08 (t, 2H, J = 6.4 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 3.56 (t, 2H, J = 5.6Hz), 1.98 (m, 2H).
Example 22. /o N\ \ / 01911310 1-(3 -Bcnzy10xypr0py1)(4-flu0r0phcny1)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrimidinc-5 - carboxylic acid [4-(6,7-dimcthoxyquino1iny10xy)fluorophcny1]-amidc. mp 93-96 0C; LCMS m/z = 695 (M + 1); 1H NMR (DMSO) 8: 11.13 (s, 1H), 8.85 (s, 1H), 7.46-8.51 (m, 2H), 7.47 (s, 1H), .42 (m, 2H), 7.25-7.34 (m, 9H), 7.18 (d, 1H, J = 10 Hz), 6.59 (d, 1H, J = 5.3 Hz), 4.50 (s, 2H), 4.09 (t, 2H, J = 6.5 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 3.56 (t, 2H, J = 6 Hz), 1.99 (q, 2H, J = 6.2 Hz).
Example 23. 0QMOFo o 3 -(4-F1uor0phcny1)isopr0py1-2,4-diox0-1 ,2,3 rahydr0pyrimidinc-5 -carb0xy1ic acid [4-(6,7-dimcthoxyquin01iny10xy)phcny1]-amidc. mp = 253-6 0C; LCMS m/z = 571 (M + 1); 1H NMR (DMSO) 5: 10.93 (s, 1H), 8.67 (s, 1H), 8.47 (d, 1H, J = 5.3 Hz), 7.78-7.82 (m, 2H), 7.49 (s, 1H), 7.33-7.45 (m, 5H),7.23-7.27 (m, 2H), 6.48 (d, 1H, J = 5.3 Hz), 4.77 (q, 1H, J = 7 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 1.42 (d, 6H, J = 7.4 Hz).
Example 24. /o N\ \ / Qo 0 OF NJKELNH | N’ko 3-(4-F1u0r0phcny1)-2,4-di0x0-1,2,3,4-tctrahydropyrimidinccarb0xy1ic acid [4-(6,7- dimcthoxyquino1iny10xy)phcny1]-amidc. mp = 211-3 0C; LCMS m/z = 529 (M + 1); 1H NMR (DMSO) 5: 12.36 (s, 1H), 10.90 (s, 1H), 8.46 (d, 1H, J = 5.3Hz), 8.43 (s, 1H), 7.77- 7.80 (m, 2H), 7.49 (s, 1H), 7.39-7.43 (m, 3H), 7.32-7.37 (m, 2H), 7.22-7.25 (m, 2H), 6.47 (d, 1H, J = 5.3 Hz), 3.94 (s, 3H), 3.92 (s, 3H).
Example 25.
/O N\ OmWHOO 0 3 -Cyc10hexyl- 1 —2,4-diox0- 1 ,2,3 ,4-tetrahydropyrimidine-5 -carb0xylic acid [4-(6,7- dimethoxyquino1iny10xy)—3-fluor0pheny1]—amide. mp 244-6 0C; LCMS m/z = 563 (M + 1); 1H NMR (DMSO) 5: 11.22 (s, 1H), 8.73 (s, 1H), 8.48 (d, 1H, J = 5.2 Hz), .03 (dd, 1H, J = 2.6, 12.6 Hz), 7.53-7.57 (m, 2H), 7.41-7.47 (m, 2H), 6.48 (d, 1H, J = 5.2 Hz), 4.7 (m, 1H), 3.92-3.98 (m, 8H), 2.32 (m, 3H), 1.80 (m, 2H), 1.62 (m,3H), 1.29 (m, 2H), 1.25 (m, 3H).
Example 26. \ / 0 O O NAKELNH | $0 3 -(4-F1uoropheny1)-2,4-di0x0-1 -(2-pyrr01idin-1 -y1—ethy1)- 1 ,2,3 ,4-tetrahydr0pyrimidine-5 - carboxylic acid [4-(6,7-dimeth0xyquinolinyloxy)—3-fluor0 phenyl]—amide. mp = 118- 120 0C; LCMS m/z = 644 (M + 1); 1H NMR (DMSO) 5: 11.00 (s, 1H), 8.79 (s, 1H), 8.47 (d, 1H, J = 5.2 Hz), 8.01, 7.98 (dd, 1H, J = 2.3, 13 Hz), 7.52-7.55 (m, 2H), 7.33-7.45 (m, 6H), 6.46 (dd, 1H, J = 1, 5.3 Hz), 4.08 (t, 2H, J = 6.3 Hz), 3.94 (d, 6H), 2.73 (t, 2H, J =6 Hz), 2.54 (m, 4H), 1.70 (m, 4H).
Example 27. \ / 0 0 O 3 -(4-F1u0rophcny1)-2,4-di0x0(2-pipcridiny1—cthy1)—1 ,2,3 ,4-tctrahydr0pyrimidinc-5 - carboxylic acid [4-(6,7-dimcthoxyquino1iny10xy)—3-flu0r0phcny1]—amidc. mp =137-40 0C; LCMS m/z = 658 (M + 1); 1H NMR (DMSO) 5: 11.00 (s,1H), 8.78 (s, 1H), 8.47 (d, 1H, J = 5.5 Hz), 7.97, 8.01 (dd, 1H, J = 2.3, 13 Hz), 7.50-7.56 (m, 2H), 7.34-7.46 (m, 6H), 6.46 (d, 1H, J = 5.5 Hz), 4.06 (t, 2H, J = 5.5 Hz), 3.94 (s, 6H), 2.55 (m, 2H), 2.44 (b, 4H), 1.49 (m, 4H), 1.39 (m, 2H).
Example 28.
/O N\ QWHOH F 0 O I N/KO 1-Ethy1—3-(4-flu0r0phcny1)-2,4-di0x0-1 ,2,3 ,4-tctrahydr0pyrimidinc-5 xy1ic acid [4- (6,7-dimcthoxyquino1iny10xy)—phcny1]-amidc. mp = 282-4 0C; LCMS m/z = 557 (M + 1); 1H NMR (DMSO) 5: 10.92 (s, 1H), 8.87 (s, 1H), 8.47 (d, 1H, J = 5.4 Hz), 7.80 (m, 2H, J = 8Hz), 7.49 (s, 1H), 7.33-7.44 (m, 5H), 7.24-7.26 (m, 2H), 6.48 (d, 1H, J = 5.2 Hz), 4.01 (q, 2H, J = 7.1 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 1.29 (t, 3H, J = 7.1 Hz).
Example 29. figFO O 1-Cyc10buty1—3-(4-flu0r0phcny1)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrimidinccarb0xy1ic acid 7-dimcthoxyquino1iny10xy)—3-flu0r0phcny1]—amidc. mp 148-50 0C; LCMS m/z = 601 (M + 1); 1H NMR (DMSO) 5: 11.02 (s, 1H), 8.91 (s, 0.4H), 8.64 (s, 0.6H), 8.48 (d, 1H, J = 5.4 Hz), 7.99, 8.03 (dd, 1H, J = 2.2, 13Hz), 7.52-7.55 (m, 2H), 7.33-7.46 (m, 6H), 6.47 (d, 1H, J =5.4Hz), 3.94 (d, 6H), 4.8 (m, 0.6H), 3.8 (m, 0.4H), 2.32-2.46 (m, 3H), .83 (m, 1H), 1.23-1.27, 0.54-0.57 (m, 1H), 0.43-0.46 (m, 1H).
Example 30.
MOF0 o N O 3 -(4-F1uor0pheny1)-2,4-di0x0(tetrahydr0pyrany1)- 1 ,2,3 ,4-tetrahydr0pyrimidine-5 - ylic acid [4-(6,7-dimeth0xyquino1iny10xy)—3-fluor0 pheny1]-amide. mp = 164- 167 0C; LCMS m/z = 631 (M + 1); 1H NMR (DMSO) 5: 11.0 (s, 1H), 8.65 (s, 1H), 8.48 (d, 1H, J = 5.3 Hz), 7.99, 8.02 (dd, 1H, J = 2.5, 13 Hz), 7.52-7.56 (m, 2H), 7.34-7.46 (m, 6H), 6.48 (d, 1H, J = 5 Hz), 4.64 (m, 1H), 3.98-4.02 (m, 2H), 3.94 (d, 6H), 3.45 (m, 2H), 1.99-2.09 (m, 2H), 1.86-1.89 (m, 2H).
Example 31.
/O039N\ QMOFo o 1-Ethy1(4-flu0r0pheny1)-2,4-di0x0-1 ,2,3 rahydr0pyrimidine-5 -carb0xy1ic acid [5 - (6,7-dimeth0xyquino1iny10xy)-pyridiny1]-amide was synthesized starting with 5- (6,7-dimethoxyquino1iny10xy)-pyridiny1amine. mp = 172-4 0C; LCMS m/z = 558 (M + 1); 1H NMR (DMSO) 5: 11.39 (s, 1H), 8.93 (s, 1H), 8.48 (d, 1H, J = 5.2 Hz), 8.35-8.38 (m, 2H), 7.84, 7.88 (dd, 1H, J = 2.3, 9.3 Hz), 7.52 (s, 1H), 7.33-7.44 (m, 5H), 6.54 (d, 1H, J = 5.2 Hz). 4.02 (q, 2H, J = 7.4 Hz), 3.93 (d, 6H), 1.29 (t, 3H, J = 7.2 Hz).
Example 32. /o N\ I I /] GE“figFO 0 1-Ethy1(4-fluor0pheny1)methy1—2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine carboxylic acid [4-(6,7-dimethoxyquino1iny10xy)fluor0pheny1]— amide. mp = 260-4 0C; LCMS m/z = 589 (M + 1); 1H NMR (DMSO) 5: 10.71 (s, 1H), 8.46 (d, 1H), J = .2Hz), 7.90, 7.94 (dd, 1H, J = 2.3, 12.7 Hz), 7.53 (s, 1H), 7.40-7.47 (m, 3H), 7.32-7.36 (m, 4H), 6.46 (d, 1H, J = 5.2 Hz), 3.97 (q, 2H, J = 7 Hz), 3.94 (s, 6H), 2.47 (s, 3H), 1.25 (t, 3H, J = 7.2 Hz).
Example 33. 06200 . 1-Ethy1(4-flu0r0pheny1)-2,4-di0x0-1 ,2,3 ,4-tetrahydr0pyrimidine-5 -carb0xy1ic acid [4- (6,7-diethoxyquino1iny10xy)—3-flu0r0pheny1]—amide. mp = 216-8 0C; LCMS m/z = 603 (M +1);1H NMR (DMSO) 5: 11.03 (s, 1H), 8.89 (s, 1H), 8.45 (d, 1H, J = 5.2 Hz), 7.98,8.02 (dd, 1H, J = 2.2, 13 Hz), 7.50-7.54 , 7.31-7.45 (m, 6H), 6.45 (d, 1H, J = 5.2 Hz), 4.21 (m, 4H), 4.01 (q, 2H, J = 6.4 Hz), 1.42 (m, 6H), 1.29 (t, 3H, J = 7.2 Hz).
Example 34.
/O N\ \ / QfigF0 O 3 -(4-F1uor0pheny1)is0pr0py1-2,4-diox0-1 ,2,3 ,4-tetrahydropyrimidine- 5 xy1ic acid [5-(6,7-dimethoxyquin01iny10xy)-pyridiny1]-amide was synthesized using the method for example 31. mp = 220-4 0C; LCMS m/z = 572 (M + 1); 1H NMR DMSO) 5: 11.40 (s, 1H), 8.72 (s, 1H), 8.49 (d, 1H, J = 5.2 Hz), 8.36 (d, 1H, J = 6.5 Hz), 8.35 (s, 1H), 8.86,7.84 (dd, 1H, J = 3.0, 9.3 Hz), 7.52 (s, 1H), 7.41-7.45 (m, 3H), 7.34-7.39 (m, 2H), 6.55 (d, 1H, J = 5.4 Hz), 4.78 (h, 1H, J = 6.8 Hz), 3.94, 3.93 (d, 6H), 1.43 (d, 6H, J = 6.9 Hz).
Example 35. /o N\ ”1%“0 1 -Cyclopr0pylmethyl(4-flu0r0phenyl)—2,4-di0xo- 1 ,2,3 ,4-tetrahydr0pyrimidine carboxylic acid [5-(6,7-dimethoxyquinolinyloxy)pyridinyl]-amide was synthesized using the method for example 31. LCMS m/z = 584 (M + 1); 1H NMR (DMSO) 5: 11.43 (s, 1H), 8.97 (s, 1H), 8.74 (m, 1H), 8.44 (m, 2H), 7.96 (m, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.42-7.46 (m, 2H), 7.34-7.39 (m, 2H), 6.91 (m, lH),4.0, 4.02 (ss, 6H), 3.88 (m, 2H), 1.21 (m, 1H), 0.55 (m, 2H), 0.45 (m, 2H).
Example 36. $131”? . 06“10.. . 3 uor0phenyl)—2,4-di0x0pentyl- 1 ,2,3 ,4-tetrahydr0pyrimidine-5 - carboxylic acid [4-(6,7-dimeth0xyquin0linyloxy)flu0r0phenyl]—amide. mp = 128-30 0C; LCMS m/z = 617 (M + 1); 1H NMR (DMSO) 5: 11.0 (s, 1H), 8.85 (s, 1H), 8.47 (d, 1H, J = 4.7 Hz), 8.0 (d, 1H, J = 12.6 Hz), 7.52-7.55 (m, 2H), 7.33-7.45 (m, 6H), 6.46 (d, 1H, J = 4.5 Hz), 3.95 (bm, 8H), 1.70 (brm, 2H), 1.32 (bm, 4H), 0.89 (bm, 3H).
Example 37. ”wNOFO O N/KO 3 -(4-Fluor0phenyl)is0pr0pyl-2,4-diox0-1 ,2,3 ,4-tetrahydropyrimidinecarb0xylic acid [4-(6,7-diethoxyquinolinyloxy)fluor0-phenyl]—amide. mp = 128-130 0C; LCMS m/z = 617 (M + 1); 1H NMR (DMSO) 5: 11.0 (s, 1H), 8.68 (s, 1H), 8.45 (d, 1H, J = 5 Hz), 7.99 (d, 1H, J: 13 Hz), 7.50-7.54 (m, 2H), .45 (m, 6H), 6.45 (d, 1H, J = 5 Hz), 4.78 (m, 1H), 4.20 (m, 4H), 1.42 (m, 12H).
Example 38.
OX0 —O H MeO o /o N D 0M0 PhOPh W NHZ —> Q“ — >< —» MeO CH(OMe)3 \o o /o o /O N /O \ /O N N\ \ Z/NH CIn POCI3 / 4 / —> / ——.> —> N02 0 O /0 CI Q / O /O 0C OH N02 Step a. Meldrum acid (470 mg, 3.20 mmol) in triethylorthoformate (4 mL) and heated at 100 0C for 1.5 h. 3,5-Dimethoxyaniline (500 mg, 3.2 mmol) was added and heated and heated at 100 0C for 4 h. The reaction mixture was cooled to rt and hexanes added and stirred. The yellow solid was ted and dried to yield a yellow solid. LCMS m/z = 308 (M + 1); 1H NMR(CDC13) 8; 8.61 (d, 1H, J = 14.0 Hz), 6.365 (m, 3H), 3.82 (s, 6H), 1.76 (s, 6H).
Step b. 5-[(3 ,5-Dimethoxyphenylamino)-methylene]-2,2-dimethyl[1 ,3]dioxane-4,6-dione , 1.30mmol) in yl ether (5 mL) and heated at 200 0C for 30 min. The reaction mixture was cooled to rt and hexane was added and stirred for 30 min. The brown solid was filtered and dried to yield 5,7-dimethoxy-1H-quinolinone LCMS m/z = 206 (M + 1).
Step c. 5,7-dimethoxy-1H-quinolinone (300 mg, 1.4 mmol) in POC13 (5 mL) was heated to reflux for 15 h. The reaction mixture was cooled to rt and poured into ice-water.
The mixture was then basified to pH 7 with NaHC03 and stirred overnight. The solid was filtered and washed with water and dried to give 4-chloro-5,7-dimethoxyquinoline. LCMS m/z = 224 (M + 1); 1H NMR(CDC13) 8: 8.56 (d, 1H, J = 4.4 Hz), 7.23 (d, 1H, J = 4.4 Hz), 7.05 (s, 1H), 6.58 (s, 1H), 3.93(s, 6H).
Step d. 4-Chloro-5,7-dimethoxyquinoline (100 mg, 0.40 mmol) and p-nitrophenol (124 mg, 0.89mmol) in chlorobenzene (2mL) was heated at reflux for 14 h. Then the reaction mixture was cooled to rt, filtered, and the residue washed with toluene. The solid was suspended in 10% NaOH solution and stirred for 1 h at rt. The yellow solid was collected and washed with EtOAc to give 5,7-dimethoxy(4-nitrophenoxy)quinoline. LCMS m/z = 327 (M + 1); 1H NMR(CDC13) 5: 8.60 (d, 1H, J = 6.0 Hz), 8.44 (d, 2, J = 8.8 Hz), 7.72 (s, 1H), 7.35 (d, 2H, J = 8.4 Hz) 6.71 (s, 1H), 6.69 (d, 2H, J = 6.4 Hz ), 4.08 (s, 3H) 3.97 (s, 3H).
Step e. A mixture of 5,7-dimethoxy(4-nitrophenoxy)quinoline (50 mg, 0.15 mmol), Zn dust (100 mg, 1.50 mmol) and ammonium chloride (32 mg, 0.60 mmol) in methanol (3 mL) was heated at reflux for 1 h. The mixture was filtered through celite and washed with CHC13. The organic layer was washed with 10% NaOH solution and brine, dried over , and concentrated to afford 4-(5,7-dimethoxyquinolinyloxy)phenylamine as an offwhite solid. LCMS m/z = 298 (M + 1); 1H NMR(CDC13) 8: 8.44 (d, 1H, J = 4.8 Hz), 7.00 (s ,1H), 6.83 (d, 2H, J = 8.8 Hz), .63 (m, 3H) 6.32 (d, 1H, J = 4.8 Hz) 5.11 , , (br s, 2H), 3.89 (s 3.86 (s, 3H). , 3H), 3 -(4-Fluorophenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidinecarboxylic acid [4-(5,7-dimethoxyquinolinyloxy)phenyl]-amide. mp = 122-4 0C; LCMS m/z = 571 (M + 1); 1H NMR (DMSO) 5: 10.87 (s, 1H), 8.65 (s, 1H), 8.53 (d, 1H, J :53 Hz), 7.73 (d, 2H, J = 9Hz), 7.42 (m, 2H), 7.35 (m, 2H), 7.07 (d, 2H, J = 9Hz), 6.99 (d, 1H, J = 2Hz), 6.63 (d, 1H, J = 2Hz), 6.50 (d, 1H, J = 5Hz), 4.78 (q, 1H, J = 7Hz), 3.90 (s, 3H), 3.80 (s, 3H), 1.42 (d, 6H, J = 7Hz).
Example 39.
/O. ; :N\:/ /O OQMwNO O O 1-Ethyl(4-fluorophenyl)-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid [4- (5,7-dimethoxyquinolinyloxy)-phenyl]-amide was synthesized using 4-(5,7- oxyquinolinyloxy)phenylamine and 3-(4-fluorophenyl)ethyl-2,4-dioxo- 1,2,3,4-tetrahydropyrimidine- 5-carboxylic acid by the method for example 38. mp = 128- 9 0C; LCMS m/z = 557 (M + 1); 1H NMR (DMSO) 5: 10.87 (s, 1H), 8.85 (s, 1H), 8.52 (m, 1H), 7.72 (m, 2H), 7.33-7.41 (m, 4H), 7.07 (m, 2H), 6.99 (m, 1H), 6.63 (m, 1H), 6.49 (m, 1H), 4.01 (m, 2H), 3.90 (s, 3H), 3.81 (s, 3H), 1.28 (m, 3H).
Example 40. 0752 . o o Step a. 4-(7-Benzyloxymethoxyquinolinyloxy)fluorophenylamine. Sodium hydride (60% disp. in mineral oil, 0.534 g, 13.3 mmol) was added to 4-amino fluorophenol in dry methylformamide (10.3 mL) at rt and stirred for 30 min under an atmosphere of nitrogen. Then solid 7-benzyloxychloromethoxyquinoline (2.00 g, 6.67 mmol) was added and the reaction stirred at 100 0C for 30 h. The mixture was concentrated, dissolved in EtOAc ( about 75 mL), and washed with 1N Na2C03, water and brine, then dried over MgSO4. The product was chromatographed on silica gel (5% MeOH/DCM) to give a brown solid 1.9 g (73%). LCMS m/z = 391 (M + 1); 1H NMR (DMSO) 5: 8.43 (s, 1H), 7.36-7.52 (m, 7H), 7.07 (m, 1H), 6.38-6.56 (m, 3H), 5.50 (m, 2H), 5.3 (s, 2H), 3.95 (s, 3H).
Step b. 1-Ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3 ,4-tetrahydropyrimidinecarboxylic acid benzyloxymethoxyquinolinyloxy)fluorophenyl]-amide was synthesized using 4-(7-benzyloxymethoxyquinolinyloxy)fluorophenylamine and 3-(4- fluorophenyl)ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- oxylic acid by the method for example 1. mp = 142-4 0C; LCMS m/z = 651 (M + 1); 1H NMR (DMSO) 5: 11.0 (s, 1H), 8.89 (s, 1H), 8.47 (d, 1H, J = 5.3 Hz), 7.98,8.02 (dd, 1H, J = 2.3, 13 Hz), 7.50-7.54 (m, 5H), 7.41-7.46 (m, 5H), 7.33-7.38 (m, 3H), 6.48 (d, 1H, J = 5 Hz), 5.31 (s, 2H), 4.90 (q, 2H, J = 7 Hz), 3.95 (s, 3H), 1.29 (t, 3H, J = 7 Hz).
Example 41. 3 -(4-Fluorophenyl)isopropyl-2,4-dioxo-1 ,2,3 rahydropyrimidinecarboxylic acid [4-(7-benzyloxymethoxyquinolinyloxy)fluorophenyl]-amide was synthesized using the method for example 40 and 3-(4-fluorophenyl)isopropyl-2,4-dioxo-1,2,3,4- tetrahydropyrimidine- 5-carboxylic acid. mp = 184-6 0C; LCMS m/z = 665 (M + 1); 1H NMR (DMSO) 5: 11.0 (s, 1H), 8.6 (s, 1H), 8.46 (d, 1H, J = 5.3 Hz), 8.0, 8.02 (dd, 1H, J = 2.4, 12.6 Hz), 7.48-7.54 (m, 5H), 7.41-7.46 (m, 5H), 7.33-7.38 (m, 3H), 6.47 (d, 1H, J = 5 Hz), 5.31 (s, 2H), 6.78 (m, 1H), 3.95 (s, 3H), 1.43 (d, 6H, J = 5.5 Hz).
Example 42. 015.. . 1-Ethyl(4-fluorophenyl)-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid [3 - fluoro(7-hydroxymethoxyquinolinyloxy)phenyl]-amide. Example 40 (0.50 g, 0.77 mmol) and 20% Pd(OH)2/C, 50% wet :50, palladium hydroxide:carbon black:Water, 0.1 g, 0.07 mmol) in methylformamide (10 mL) was hydrogenated on a Parr apparatus under an atmosphere of hydrogen 40 psi for 12 h. The solvent was removed and the product was triturated with ether to give 42- mg (97%) as a while solid. mp >200 0C dec; LCMS m/z = 561 (M + 1); 1H NMR (DMSO) 8: 11.75 (bs, 1H), 11.11 (s, 1H), 8.89 (s, 1H), 8.73 (d, 1H, J = 6.5 Hz), 8.07, 8.11 (dd, 1H, J = 2.3, 12.5 Hz), 7.72 (s, 1H), 7.54-7.64 (m, 3H), 7.41-7.45 (m, 2H), 7.34-7.39 (m, 2H), 6.90 (d, 1H, J = 6.5 Hz), 40-405 (s, m, 5H), 1.30 (t, 3H, J = 7.2 Hz).
Example 43.
(Nu/womb amigo 1-Ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid {3- fluoro[6-methoxy(3-morpholinyl-propoxy)quinolinyloxy] phenyl} -amide. e 42 (0.100 g, 0.178 mmol), methanesulfonic acid 3-morpholinyl-propyl ester (0.0438 g, 0.196 mmol) and cesium carbonate (0.116 g, 0.357 mmol) in N,N- dimethylformamide (2 le) was heated at 65 CC for 8h. The mixture was diluted with EtOAc and extracted with 1N Na2C03, water and brine solutions then dried over MgSO4.
The solid was ated with ether, then the ether decanted and the product itated with hexanes to give a white solid. mp = 92-5 0C; LCMS m/z = 688 (M + 1 ); 1H NMR (DMSO) 5: 11.04 (s, 1H), 8.89 (s, 1H), 8.46 (d, 1H, J = 5.3Hz), 7.98, 8,02 (dd, 1H, J = 2.4, 13Hz), 7.51-7.55 (m, 2H), 7.33-7.46 (m, 6H), 6.46 (d, 1H, J = 5.4 Hz, 4.20 (t, 2H, J = 6.4 Hz), 4.01 (q, 2H, J = 7.4 Hz), 3.94 (s, 3H), 3.58 (t, 4H, J = 4.8 Hz), 2.45 (m, 2H), 2.39 (b, 4H), 1.98 (m, 2H), 1.29 (t, 3H, J = 7.2 Hz).
Example 44 \ o: : ’Y; F NkalLNH | NKAO 1-Ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid {3- fluoro[6-methoxy(2-methoxyethoxy)quinolinyloxy]-phenyl}-amide. Example 44 was synthesized by the procedure for e 43 using example 42 and 1-bromo methoxyethane. mp = 178-80 0C; LCMS m/z = 619 (M + 1); 1H NMR (DMSO) 5: 11.00 (s, 1H), 8.89 (s, 1H), 8.46 (d, 1H, J = 5H2), 7.98, 8.00 (dd, 1H, J = 2, 13 Hz), 7.52-7.55 (m, 2H), 7.42-7.46 (m, 4H), 7.33-7.38 (m, 2H), 6.47 (d, 1H, J = 5.4 Hz), 4.28 (m, 2H), 4.01 (q, 2H, J = 7.1 Hz), 3.95 (s, 3H), 3.76-(m, 2H), 3.34 (s, 3H), 1.29 (t, 3H, J = 7.1 Hz).
Example 45 OK/Nwom 1-Ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid {3- fluoro[6-methoxy(2-morpholinyl-ethoxy)-quinolinyloxy]phenyl} .
Example 45 was synthesized by the procedure for example 43 using example 42 and 4-(2- chloroethyl)morpholine hydrochloride. mp = 222-224 0C; LCMS m/z = 674 (M + 1); 1H NMR (DMSO) 5: 11.0 (s, 1H), 8.89 (s, 1H), 8.47 (d, 1H, J = 5.4 Hz), 7.98, 8.01 (dd, 1H, J = 2.4, 12.6 Hz), 7.52-7.55 (m, 2H), 7.41-7.46 (m, 4H), 7.33-7.38 (m, 2H), 6.46 (d, 1H, J = .4 Hz), 4.27 (t, 2H, J = 6 Hz), 4.02 (q, 2H, J = 7.4 Hz), 3.94 (s, 3H), 3.59 (t, 4H, J = 4.6 Hz), 2.79 (t, 2H, J = 5.8 Hz), 2.53 (m, 4H), 1.29 (t, 3H, J =7.4 Hz).
Example 46. 015.. 3 -(4-Fluor0phenyl)is0pr0pyl-2,4-diox0-1 ,2,3 ,4-tetrahydropyrimidinecarb0xylic acid [3-fluor0(7-hydr0xymeth0xyquin0linyloxy)-phenyl]-amide. Example 46 was synthesized using example 41 and the procedure for e 42. mp = 205-7 0C; LCMS m/z = 575 (M NMR(DMSO)5: 11.7 (s, 1H), 11.1 (s, 1H), 8.73 (d, 1H, J =7 Hz), 8.68 (s, 1H), 8.07, 8.11 (dd, 1H, J = 2.4, 12.7 Hz), 7.72 (s, 1H), 7.54-7.64 (m, 3H), 7.34- 7.45 (m, 4H), 6.89 (d, 1H, J = 6.5 Hz), 4.78 (m, 1H), 4.0 (s, 3H), 1.42 (d, 6H, J = 7 Hz).
Example 47.
(\NMongNj ©1010? 3 -(4-Fluor0phenyl)is0pr0pyl-2,4-diox0-1 ,2,3 ,4-tetrahydropyrimidinecarb0xylic acid {3-fluoro[6-meth0xy(3-m0rpholinyl-pr0p0xy)- quinolinyloxy]phenyl} -amide.
Example 47 was synthesized by the procedure for example 43 using example 46. mp =160-162 0C; LCMS m/z = 701 (M + 1); 1H NMR (DMSO) 5: 11.0 (s, 1H), 8.68 (s, 1H), 8.47 (d, 1H, 5.3 Hz), 7.99, 8.02 (dd, 1H, J = 2.3, 13 Hz), 7.5‘-7.55 (m, 2H), 7.33-7.45 (m, 6H), 6.46 (d, 1, J = 5.3 Hz), 4.78 (m, 1H), 4.2 (t, 2H, J = 6.8 Hz), 3.94 (s, 3H), 3.58 (m, 4H), 2.45 (m, 2H), 2.38 (m, 4H), 1.97 (m, 2H), 1.42 (d, 6H, J = 7 Hz).
Example 48. 2012/065019 OH: .. . 1-Ethyl(4-fluorophenyl)-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid [4- (6,7-dimethoxyquinolinyloxy)fluoro-phenyl]-methyl-amide. Example 1 (0.050 g, 0.087 mmol) in N,N—dimethylformamide (2 mL) at 5 oC (ice bath) was added sodium hydride, 60% disp. in mineral oil (0.0052 g, 0.13 mmol). The e was stirred 0.5 h, and then methyl iodide (0.0081 mL, 0.13 mmol) was added. After 2h, EtOAc was added, washed with 1N N32C03, water and brine. The product was purified by prep LC/MS. The fractions were combined and concentrated and the solid was crystallized with EtOAc, ether and hexanes to give a white solid as the TFA salt. mp = 112-5 0C; LCMS m/z = 589 (M +1); 1H NMR (DMSO) 8: 8.66 (d, 1H, J = 5.9 Hz), 8.23 (s, 1H), 7.65 (s, 1H), 7.51- 7.60 (m, 3H), 7.25-7.30 (m, 3H), 7.13-7.16 (m, 2H), 6.6 (d, 1H, J = 5.8Hz), 4.01 (d, 6H), 3.8 (q, 2H, J = 7 Hz), 3.35 (s, 3H), 1.22 (t, 3H, J = 7 Hz).
Example 49.
/O\Om);N\ G”$10Fo o N O 3 -(4-Fluorophenyl)(2-hydroxyethyl)-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine carboxylic acid 7-dimethoxyquinolinyloxy)fluorophenyl]-amide. Example 10 (0.06 g, 0.09 mmol) and palladium hydroxide (20%) on carbon (0.016 g, 0.024 mmol) in ethyl e (7 mL) and MeOH (3 mL) was added 2 drops of 5N HCl. The mixture was hydrogenated under an atmosphere of hydrogen on a Parr tus at 40 psi for 2 h. The mixture was diluted with EtOAc and washed with 1N N32C03, and brine, then dried over MgSO4. The solution was concentrated and the product was triturated with ether-hexanes and the solid collected and dried at 60 0C under vacuum. mp = 166-8 0C; LCMS m/z = 591 (M +1); 1H NMR (DMSO) 8: 11.00 (s, 1H), 8.75 (s, 1H), 8.47 (d,1H, J = 5.4 Hz), 7.98, 8.01 (dd, 1H, J = 2.2, 13 Hz), 7.52—7.55 (m, 2H),7.34-7.46 (m, 6H), 6.47 (d, 1H, J = 5 Hz), 5.03 (t, 1H, J = 5.4 Hz), 4.05 (m, 2H), 3.94 (d, 6H), 3.67 (m, 2H).
Example 50.
/O\OJCLOQN\ Q”$10Fo o N O H\OH 3 -(4-Flu0r0phenyl)(3-hydroxypr0pyl)-2,4-di0xo- 1 ,2,3 ,4-tetrahydropyrimidine carboxylic acid 7-dimethoxyquinolinyloxy)flu0r0phenyl]—amide. Example 50 was synthesized using example 13 by the procedure for example 49. mp =124-6 0C; LCMS m/z = 605 (M + 1); 1H NMR (DMSO) 5: 11.00 (s, 1H), 8.82 (s, 1H), 8.47 (d, 1H, J = 5.4 Hz), 7.98, 8.01 (dd, 1H, J = 2.5, 13 Hz), 7.52-7.55 (m, 2H), 7.33-7.46 (m, 6H), 6.47 (d, 1H, J = 6 Hz), 4.63 (t, 1H, J = 5 Hz), 4.05 (t, 2H, J = 7 Hz), 3.94 (s,s, 6H), 3.50 (q, 2H, J = 5 Hz), 1.85 (p, 2H, J = 6.2 Hz).
Example 51 /o N\ \ / 3 u0r0phenyl)(3-hydroxypr0pyl)-2,4-di0xo- 1 ,2,3 ,4-tetrahydropyrimidine carboxylic acid [4-(6,7-dimeth0xy-quinolinyloxy)fluor0-phenyl]- amide. Example 51 was synthesized using example 22 by the procedure for example 49. mp = 220-4 0C; LCMS m/z = 605 (M + 1);1H NMR (DMSO) 5: 11.16 (s, 1H), 8.83 (s, 1H), 8.45-8.50 (m, 2H), 7.47 (s, 1H), 7.33-7.44 (m, 6H), 7.16 (d, 1H, J = 9H2), 6.58 (d, 1H, J =5Hz), 4.63 (t, 1H, J = 4.9 Hz), 4.04 (t, 2H, J = 7 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 3.50 (q, 2H, J = 5.4 Hz), 1.84 (q, 2H, J = 7Hz).
Example 52.
WO 74633 Q“610Fo o N O KLOH 3 -(4-Flu0r0phenyl)(3-hydroxypr0pyl)-2,4-di0xo- 1 ,2,3 ,4-tetrahydropyrimidine carboxylic acid 7-dimethoxyquinolinyloxy)phenyl]-amide. Example 52 was synthesized using example 21 by the procedure for example 49. mp = 123-6 0C; LCMS m/z = 587 (M + 1); 1H NMR (DMSO) 5: 10.93 (s, 1H), 8.79 (s, 1H), 8.47 (d, 1H, J = 5 Hz), 7.8 )d, 2H, J =9 Hz), 7.50 (s, 1H), 7.33-7.44 (m, 5H), 7.25 (d, 2H, J = 9H2), 6.47 (d, 1H,j= 5.6 Hz), 4.63 (t, 1H, J = 5Hz), 4.04 (t, 2H, J = 7 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 3.50 (q, 2H, J = 5Hz).
Example 53 0Q F o o OH 3 -(4-Fluor0phenyl)(2-hydr0xyethyl)-2,4-di0x0-1 ,2,3 ,4-tetrahydr0pyrimidine-5 - carboxylic acid [4-(6,7-dimethoxyquinolinyloxy)phenyl]-amide. Example 53 was synthesized using example 19 by the procedure for example 49. mp = 153-4 0C; LCMS m/z = 573 (M +1); 1H NMR (DMSO) 5: 10.91 (s, 1H), 8.74 (s, 1H), 8.47 (d, 1H, J = 5.8 Hz), 7.80 (d, 2H, J = 9 Hz), 7.49 (s, 1H), 7.34-7.43 (m, 5H), 7.26 (d, 2H, J = 9 Hz), 6.48 (d, 1H, J = 5.4 Hz), 5.02 (t, 1H, J: 5.2 Hz), 4.03 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.67 (m, 2H).
Example 54. /o N\ 0 o QF WO 74633 1-((S)-2,3-Dihydroxypropyl)—3-(4-fluorophenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine- -carboxylic acid [4-(6,7-dimethoxyquinolinyloxy)fluorophenyl]—amide. -2,2- Dimethyl-1,3-dioxolanylmethyl)(4-fluorophenyl)—2,4-dioxo-1,2,3 ,4- tetrahydropyrimidinecarboxylic acid (0.0446 g, 0.122 mmol) and N,N,N',N'- tetramethyl-O-(7-azabenzotriazolyl)uronium hexafluorophosphate (0.0466 g, 0.122 mmol) in N,N—dimethylformamide (2.00 mL) was added N,N—diisopropylethylamine (0.0388 mL, 0.223 mmol) and stirred at rt for 15 min. 4-(6,7-Dimethoxyquinolinyloxy)— 3-fluorophenylamine (0.035 g, 0.11 mmol) was added and d overnight. The solution was d with EtOAc, washed with 1N N32C03, water and brine then dried over MgSO4 and concentrated. MeOH was added (1 mL) and a solid separated. This material was dissolved in 4 M of hydrogen chloride in 1,4-dioxane (2 mL, 8 mmol), stirred for 2h and then concentrated. To this product was added MeOH and the precipitate collected to give a white solid. mp = 165-6 0C; LCMS m/z = 621 (M + 1); 1H NMR (DMSO) 8: 11.0 (s, 1H), 8.72 (s, 1H), 8.48 9d, 1H, J: 5.4 Hz), 8.01, 7.98 (dd, 1H, J = 2.4, 13.5 Hz), 7.52- 7.55 (j, 1H), 7.34-7.46 (m, 6H), 6.47 (d, 1H, J = 5.4 Hz), 6.17 (d, 1H, J = 5 Hz), 4.78 (t, 1H, J = 5.7 Hz), 4.22 (d, 1H, J = 10 Hz), 3.94 (d, 6H), 3.75-3.78 (m, 2H), 3.3 (m, 2H).
Example 55.
/O N\ \o: : /\(\O/ QHwNONAG F o o KNOH 3 -(4-Fluorophenyl)(4-hydroxybutyl)-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine carboxylic acid [4-(6,7-dimethoxyquinolinyloxy)fluorophenyl]—amide. LCMS m/z = 619 (M +1);1HNMR(DMSO)5: 11.04 (s, 1H), 8.86 (s, 1H), 8.47 (d, 1H, J = 5 Hz), 8.00 (d, 1H, J = 12 Hz), 7.52-7.55 (m, 2H), 7.33-7.46 (m, 6H), 6.47 (d, 1H, J = 5 Hz), 4.48 (t, 1H, J = 4.5 Hz), 3.99 (m, 2H), 3.94 (d, 6H), 3.42 (m, 2H), 1.73 (m, 2H), 1.48 (m, 2H).
Example 56. /o N\ N F 4-(2-fluoromethylaminophenoxy)methoxyquinolinecarbonitrile was synthesized by the method described for 4-(5,7-dimethoxyquinolinyloxy)phenylamine example 38 starting with 4-aminomethoxybenzonitrile; LCMS m/z = 309 (M + 1); 1H NMR (DMSO-d6) 5: 8.73 (s, 1H), 8.71 (d, 1H, J = 5.2 Hz ), 7.58 (s, 1H), 6.95 (d, 2H, J = 8.8 Hz), 6.67(d, 2H, J = 8.4 Hz ), 6.48 (d, 1H, J = 5.6 Hz), 5.20 (br s, NH, 2H), 4.06 (s, 3H). 3 -(4-Fluorophenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid [4-(6-cyanomethoxy-quinolinyloxy)-phenyl]-amide. N,N,N',N'-Tetramethyl-O-(7- azabenzotriazol-l-yl)uronium hexafluorophosphate (0.066 g, 0.17 mmol) and 3-(4- fluorophenyl)isopropyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid (0.062 g, 0.21 mmol) in N,N-dimethylformamide (2 mL, 20 mmol) was added N,N— diisopropylethylamine (0.055 mL, 0.32 mmol). After 15 min ng at rt 4-(4- aminophenoxy)methoxyquinolinecarbonitrile (0.05 g, 0.2 mmol) was added. The reaction was stirred at rt overnight, d with EtOAc, washed with 1N N32C03, water and brine solutions then dried over MgSO4. The product was recrystallized from MeOH then dried overnight at 65 0C under vacuum to give a tan solid. mp = 202-3 0C; LCMS m/z = 566 (M + l); 1H NMR (DMSO) 5: 10.96 (s, 1H), 8.77 (s, 1H), 8.74 (d, 1H, J = 5 Hz), 8.67 (s, 1H), 7.83 (d, 2H, J = 7.3 Hz), 7.61 (s, 1H), 7.42-7.45 (m, 2H), 7.30-7.38 (m, 5H), 6.56 (d, 1H, J = 5.5 Hz), 4.78 (q, 1H, J = 7 Hz), 4.07 (s, 3H), 1.43 (d, 6H, J = 7 Hz).
Example 57.
MeO ON\ / MeO F HO 0 Br Step a. (4-Bromofluoro-phenyl)-(6,7-dimethoxy-quinolinyl)-methanol. A solution of o-6,7-dimethoxyquinoline (0.5 g, 1.8 mmol) in tetrahydrofuran (6 mL) was cooled at -78 0C. n-Butyllithium (0.89 mL, 2.23 mmol, 2.5 M on in hexane) was added dropwise under an argon atmosphere and further stirred at -78 0C for 1 h. 4-Bromo fluoro-benzaldehyde (0.45, 2.2 mmol) in 3 mL of tetrahydrofuran was added dropwise.
The reaction mixture was stirred at -78 0C for l h and slowly warmed to 0 0C for 1.5 h.
The reaction was ed with satd. NH4Cl solution and extracted three times with CHzClz and the combined cs were washed with brine, dried (Na2S04), filtered, and evaporated to yield a crude product. The crude product was purified by silica gel column chromatography to e (4-bromofluoro-phenyl)-(6,7-dimethoxy-quinolinyl)- methanol (0.45 g, 62%) as a yellow solid. MS m/z = 393 (M + l).
MeO N O \ / MeO F Step b. (4-Aminofluoro-phenyl)-(6,7-dimethoxy-quinolinyl)-methanol. A mixture of 4-bromofluoro-phenyl)-(6,7-dimethoxy-quinolinyl)-methanol (0.72 g, 1.8 mmol), bis(dibenzylideneacetone)palladium(0) (0.19 g, 0.33 mmol), tri-t-butylphosphine (0.54 mL, 10% solution), lithium hexamethyldisilazide (6.24 mL, 3.46 mmol, 1 M on in THF) and toluene (5 mL) was charged in a pressure reaction vessel with a screw cap. The mixture was heated at 80 0C for 3 h under an argon atmosphere and quenched with MeOH.
The crude product was purified by Gilson prep. HPLC to produce 4-aminofluoro- )-(6,7-dimethoxy-quinolinyl)-methanol (0.4 g, 66%). MS m/z = 329 (M + 1).
MeoO N\ MeO /F HO O o 0 OF [IV 0 Step c. 3 -(4-fluoro-phenyl)- 1 l-2,4-dioxo- 1 ,2,3 ,4-tetrahydro-pyrimidine-5 - carboxylic acid {4-[(6,7-dimethoxy-quinolinyl)-hydroxy-methyl]fluoro-phenyl}- amide . To a well stirred mixture of 3-(4-fluorophenyl)methyl-2,4-dioxo-1,2,3,4- tetrahydropyrimidinecarboxylic acid (0.058 g, 0.252 mmol) and N, N, N’, N’- tetramethyl-O-(7-azabenzotriazolyl)-uronium hexafluorophosphate (0.096 g, 0.25 mmol) in N, N-dimethylformamide (2 mL) was added N, N-diisopropylethylamine (0.26 mL, 1.5 mmol). After ng for 10 min, 4-aminofluoro-phenyl)-(6,7- dimethoxyquinolinyl)-methanol (0.072 g, 0.21 mmol) was added. The reaction mixture was stirred at rt overnight and purified by Gilson prep. HPLC to produce (0.02 g, 17%) as a solid. mp 164-166 0; LCMS m/z = 546 (M + 1). 1H NMR (DMSO-d6) 2 (s, 1H), 8.82 (s, 1H), 8.68 (d, 1H, J = 4.6 Hz), 7.73 (dd, 1H. J = 1.9 Hz, J = 12.8 Hz), 7.52 (d, 1H, J = 4.56 Hz), 7.31-7.39 (m, 6H), 7.25-7.27 (m, 2H), 6.5 (d, 1H, J = 4.5 Hz), 6.28 (d, 1H, J = 4.6 Hz), 3.88 (s, 3H), 3.81 (s, 3H), 3.50 (s, 3H).
Example 58.
MeO ON\ / MeO F o 0 GOPNkaN 3 -(4-fiuoro-phenyl)methyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid [4-(6,7-dimethoxy-quinolinylmethyl)fiuoro-phenyl]-amide. A mixture of example 57 (0.08 g, 0.13 mmol) and zinc (1.4 g, 21.5 mmol) in formic acid (5 mL) was heated at 60 0C for 5 h. The reaction mixture was diluted with CHzClz and filtered over a celite and washed with CHzClz. The filtrate was evaporated and d by Gilson prep. HPLC to give a white solid (33 mg, 42%), mp 5 0C; MS m/z = 559 (M + H). 1H NMR (DMSO-d6) 5:10.92 (s, 1H), 8.84 (s, 1H), 8.55 (d, 1H, J: 4.5 Hz), 7.78 (dd, 1H, J: 1.80 Hz, J: 12.4 Hz), 7.32-7.39 (m, 6H), 7.21-7.29 (m, 2H), 7.01 (d, 1H, J: 4.48 Hz), 4.38 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.51 (s, 3H).
Example 59.
Step a. 4-(2-Bromonitro-phenoxy)-6,7-dimethoxy-quinoline. A e of 4-chloro- 6,7-dimethoxyquinoline (0.82 g, 3.67 mmol), 2-bromonitrophenol (0.80 g, 3.67 mmol) and 4-dimethylaminopyridine (0.067 g, 0.549 mmol) in chlorobenzene (8 mL) was heated at 140 0C for 2 days under an argon atmosphere. The crude product was purified by silica gel column chromatography followed by llization from a mixture of CHzClz, MeOH, ether, and hexane to produce 4-(2-bromonitrophenoxy)-6,7-dimethoxyquinoline (0.74 g, 50%), LCMS m/z = 406 (M + 1).
Step b. 4-(2-Cyclopropylnitro-phenoxy)-6,7-dimethoxy-quinoline. A mixture of 4-(2- bromonitro-phenoxy)-6,7-dimethoxy-quinoline (0.74 g, 1.8 mmol), ium cyclopropyltrifiuoroborate (0.49 g, 3.39 mmol), palladium acetate (0.07 g, 0.31 mmol), butyl-ditricyclo[3.3.1.1(3,7)]decanyl-phosphane (0.12 g, 0.34 mmol), and cesium carbonate (3.07 g, 9.44 mmol) in a mixture of toluene (24 mL) and water (3.4 mL) was heated at 85 CC for overnight. The reaction mixture was diluted with CHzClz and filtered over a pad of celite, washed with . The filtrate was evaporated and purified by Gilson prep. HPLC to produce 4-(2-cyclopropylnitro-phenoxy)-6,7-dimethoxyquinoline (0.44 g, 65%). LCMS m/z = 367 (M + 1).
Step c. 3-Cyclopropyl(6,7-dimethoxy-quinolinyloxy)-phenylamine. A e of 4- (2-cyclopropylnitro-phenoxy)-6,7-dimethoxy-quinoline (0.30 g, 0.82 mmol) and tin(H) chloride dihydrate (0.92 g, 4.09 mmol) in a mixture of ethanol (10 mL) and ethyl acetate (3 mL) was refluxed for 2 h. The reaction mixture was evaporated and partitioned between CHzClz and satd. NaHCOg solution. The heterogeneous mixture was filtered over celite, washed with CHzClz and the filtrate was separated into two . The aqueous phase was extracted two times with CHzClz and the combined organics was washed with brine, dried (Na2S04), filtered, and evaporated to yield a crude product. The crude product was purified by silica gel column chromatography to produce 3-cyclopropyl (6,7-dimethoxy-quinolinyloxy)-phenylamine (0.22 g, 80%), MS m/z = 337 (M + 1). 1H NMR(CDC13) 8: 8.54 (d, 1H, J = 5.2 Hz), 8.1 (dd, 1H, J = 2.73 Hz, J = 8.9 Hz), 7.90 (d, 1H, J = 2.72 Hz), 7.52 (s, 1H), 7.46 (s, 1H), 7.16 (d, 1H, J = 8.85 Hz), 6.43 (d, 1H, J = 5.2 Hz), 4.06 (s, 3H), 4.04 (s, 3H), 2.04-2.14 (m, 1H), 1.59 (brs, 2H), 0.95-1.04 (m, 2H), 0.78- 0.86 (m, 2H).
Step d. 1-Ethyl(4-fiuoro-phenyl)-2,4-dioxo- 1 ,2,3 rahydropyrimidine-5 xylic acid [3-cyclopropyl(6,7-dimethoxy-quinolinyloxy)-phenyl]-amide was synthesized from 3-cyclopropyl(6,7-dimethoxyquinolinyloxy)phenylamine (0.06 g, 0.20 mmol) and 3-(4-fluoro-phenyl)ethyl-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine-5 xylic acid (0.06 g, 0.21 mmol) in an analogous manner to Example 1. mp 183-185 0C; LCMS m/z = 597 (M + 1). 1H NMR (DMSO-d6) 5: 10.84 (s, 1H), 8.86 (s, 1H), 8.44 (d, 1H, J: 5.2 Hz), 7.71 (d d, 1H, J=2.53 Hz, .1: 8.73 Hz), 7.58 (s 1H), 7.31-7.46 (m, 5H), 7.27 (d, 1H, .1: 2.53 Hz), 7.17 (d, 1H, .1: 8.73 Hz), 6.33 (d, 1H, J: 5.2 Hz), 4.00 (q, 2H, .1: 7.04 Hz), 3.94 (s, 6H), 1.77-1.87 (m, 1H), 1.29 (t, 3H, .1: 7.04 Hz), 0.72-0.82 (m, 2H), 0.62-0.71 (m, 2H).
Example 60. 3:136; £1310 )N\ O 3 -(4-Fluoro-phenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydro-pyrimidine- 5 xylic acid [3-cyclopropyl(6,7-dimethoxy-quinolinyloxy)-phenyl]- amide. This compound was synthesized from 3-cyclopropyl(6,7-dimethoxyquinolinyloxy)phenylamine (0.06 g, 0.20 mmol) and 3-(4-fluorophenyl)isopropyl-2,4-dioxo-1,2,3,4- tetrahydropyrimidinecarboxylic acid (0.063 g, 0.21 mmol) in an ous manner to Example 59. mp 172-174 0C; LCMS m/z = 611 (M + 1). 1H NMR (DMSO-d6) 5: 10.86 (s, 1H), 8.67 (s, 1H), 8.44 (d, 1H, J = 5.24 Hz), 7.65 (dd, 1H, J = 2.52 Hz, J = 7.65 Hz), 7.58 (s, 1H), 7.31-7.48 (m, 6H), 7.16 (d, 1H, J = 8.73 Hz), 6.34 (d, 1H, J = 5.20 Hz), 4.70- 4.85 (m, 1H), 3.94 (s, 6H), 1.78-1.88 (m, 1H), 0.73-0.82 (m, 2H), 0.62-0.69 (m, 2H).
The following examples were synthesized using the procedures for Example 1.
Example 61.
/O N\ \O / 3 -(4-Fluoro-phenyl)-2,4-dioxopropynyl-1 ,2,3 rahydro-pyrimidine-5 -carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)fluoro-phenyl]—amide. mp 155-157 0C; LCMS m/z = 585 (M +1);1HNMR(DMSO)5: 10.97 (s, 1H), 8.95 (s, 1H), 8.48 (d, 1H, J = 5.5 Hz), 8.01 (dd, 1H, J = 2.5 Hz, J =13 Hz), 7.56 (bd, 1H, J = 9.0 Hz), 7.53 (s, 1H), 7.47- 7.42 (m, 3H), 7.41 (s, 1H),7.40-7.32 (m, 2H), 6.48 (d, 1H, J = 5.0 Hz), 4.85 (d, 2H, J = 2.5 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 2.69 (s, 1H).
Example 62. :66; 3 -(4-F1u0r0-pheny1)(2-imidaz01y1-ethy1)-2,4-di0x0-1 ,2,3 ,4-tetrahydr0-pyrimidine-5 - carboxylic acid [4-(6,7-dimeth0xy-quino1iny10xy)flu0r0-pheny1]—amide. mp 218-221 0C; LCMS m/z = 641 (M + 1); 1H NMR (DMSO) 5: 11.05 (s, 1H), 9.20 (s, 1H), 8.77 (s, 1H), 8.75 (m, 1H), 8.06 (dd, 1H, J = 2.5 Hz, J =13 Hz), 7.85 (t, 1H, J = 1.7 Hz), 7.71 (t, 1H, J = 1.7 Hz), 7.68 (s, 1H), 7.62 (dd, 1H, J = 1.7 Hz, J = 9.0 Hz), 7.57 (s, 1H), 7.55 (t, 1H, J = 9.0 Hz), 7.39 (s, 2H), 7.27 (s, 2H), 6.84 (m, 1H), 4.59 (t, 2H, J = 6.5 Hz),4.45 (t, 2H, J = 6.5 Hz), 4.02 (s, 3H), 4.01 (s, 3H).
Example 63. 6.15:1? 3 -(4-F1u0ro-pheny1)-2,4-di0x0(2-pyraz01—1-y1-ethy1)-1 ,2,3 ,4-tetrahydro-pyrimidine-5 - carboxylic acid [4-(6,7-dimeth0xy-quino1iny10xy)flu0r0-pheny1]—amide. mp 149- 151°C;LCMS m/z = 641 (M + 1); 1H NMR (DMSO) 5: 10.92 (s, 1H), 8.49 (d, 1H, J = 6.6 Hz), 8.36 (s, 1H), 7.97 (dd, 1H, J = 2.5 Hz, J = 12.5 Hz), 7.81 (d, 1H, J = 2.0 Hz), 7.54- 7.50 (m, 3H), 7.46-7.34 (m, 6H), 6.48 (d, 1H, J = 4.8 Hz), 6.27 (t, 1H, J = 2.0 Hz), 4.48 (t, 2H, J = 5.7 Hz), 4.38 (t, 2H, J = 5.4 Hz), 3.95 (s, 3H), 3.94 (s, 3H).
Example 64. /o N\ F W“; N O 3 -(4-F1u0r0-pheny1)-2,4-di0x0phenethy1— 1 ,2,3 ,4-tetrahydr0-pyrirnidine-5 -carb0xy1ic acid [4-(6,7-dirneth0xy-quinoliny10xy)flu0r0-pheny1]—arnide. mp 168-170 0C; LCMS m/z = 651 (M + 1); 1H NMR (DMSO) 5: 11.00 (s, 1H), 8.79 (s, 1H), 8.48 (d, 1H, J = 4.8 Hz), 7.99 (dd, 1H, J = 2.5 Hz, J = 12.5Hz), 7.56 (bd, 1H, J = 9.0 Hz), 7.52 (s, 1H), 7.47-7.23 (m, 11H), 6.48 (d, 1H, J = 5.6 Hz), 4.20 (t, 2H, J = 6.8 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 3.02 (t, 2H, J = 6.9 Hz). e 65.
/O N\ \O / 1-[2-(1 ,3-Di0x01any1-ethy1)](4-flu0r0-pheny1)—2,4-di0x0- 1 ,2,3 ,4-tetrahydr0- pyrimidinecarboxy1ic acid [4-(6,7-dirneth0xy-quin01iny10xy)—3-fluor0-pheny1]— amide. mp 138-140 0C; LCMS m/z = 647 (M + 1); 1H NMR (DMSO) 8: 11.01 (s, 1H), 8.82 (s, 1H), 8.48 (d, 1H, J :54 Hz), 8.00 (dd, 1H, J = 2.3 Hz, J = 12.5 Hz), 7.55 (bd, 1H, J = 9.7 Hz), 7.54 (s, 1H), 7.49-7.34 (m, 6H), 6.47 (d, 1H, J = 5.3 Hz), 4.93 (t, 1H, J = 4.2 Hz), 4.10 (t, 2H, J = 6.9 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 3.94-3.90 (m, 2H), .77 (m, 2H), 2.05 (q, 2H, J = 4.5 Hz).
Example 66. /o N\ on o 0 OF . 1%: N O \/N\/ 1 -Dicthy1carbamoylmcthy1(4-flu0ro-phcny1)-2,4-di0x0- 1 ,2,3 ,4-tctrahydr0-pyrimidinc- -carb0xy1ic acid [4-(6,7-dimcthoxy-quinolinyloxy)flu0r0-phcny1]-amidc. mp 147- 149 0C ; LCMS m/z = 660 (M + 1); 1H NMR (DMSO) 5: 10.98 (s, 1H), 8.86 (s, 1H), 8.48 (d, 1H, J = 4.5 Hz), 8.00 (dd, 1H, J = 3.1 Hz, J = 12.5 Hz), 7.56 (bd, 1H, J = 9.3 Hz), 7.53 (s, 1H), .34 (m, 6H), 6.48 (d, 1H, J = 4.6 Hz), 4.96 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.39-3.28 (m,4H), 1.18 (t, 3H, J = 7.0 Hz), 1.05 (t, 3H, J = 7.1 Hz).
Example 67. /o N\ F 1%: N O 3 -(4-F1u0ro-phcny1)- 1 rph01iny1—2-oxo-cthy1)-2,4-di0x0- 1 ,2,3 ,4-tctrahydr0- pyrimidinecarboxy1ic acid [4-(6,7-dimcth0xy-quin01iny10xy)—3-fluor0-phcny1]— amide. mp 159-161 0C; LCMS m/z = 674 (M + 1); 1H NMR (DMSO) 5: 10.97 (s, 1H), 8.82 (s, 1H), 8.49 (d, 1H, J = 5.3 Hz), 8.00 (dd, 1H, J = 2.6 Hz, J = 12.6 Hz), 7.56 (bd, 1H, J = 9.5 Hz), 7.53 (s, 1H), 7.48-7.34 (m, 6H), 6.49 (d, 1H, J = 5.0 Hz), 5.00 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.65 (t, 2H, J = 4.4 Hz), 3.60 (t, 2H, J = 4.4 Hz), 3.52-3.46 (m, 4H).
Example 68. /o N\ O91>”ngF O O 9100 3 -(4-F1u0r0-phcny1)-2,4-di0x0[2-(2-0x0-pyrr01idiny1)-cthy1]—1 ,2,3 ,4-tctrahydr0- pyrimidinecarboxy1ic acid [4-(6,7-dimcth0xy-quin01iny10xy)—3-fluor0-phcny1]— amidc. mp 157-159 0C; LCMS m/z = 658 (M + 1); 1H NMR (DMSO) 5: 10.97 (s, 1H), 8.80 (s, 1H), 8.48 (d, 1H, J = 5.3 Hz), 8.00 (dd, 1H, J = 2.6 Hz, J =12.6 Hz), 7.55 (bd, 1H, J = 9.5 Hz), 7.53 (s, 1H), 7.47-7.36 (m, 6H), 6.48 (d, 1H, J = 5.0 Hz), 4.16 (t, 2H, J = 4.6 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 3.54-3.49 (m, 4H), 2.12 (t, 2H, J = 7.8 Hz), 1.93 (p, 2H, J = 8.2 Hz).
Example 69. £236; meifigj 1-(2-F1u0r0-ethy1)(4-flu0ro-pheny1)—2,4-di0x0- 1 ,2,3 ,4-tetrahydro-pyrimidine-5 - carboxylic acid 7-dimeth0xy-quino1iny10xy)flu0r0-pheny1]—amide. mp 138- 140 0C; LCMS m/z = 593 (M + 1); 1H NMR (DMSO) 5: 11.00 (s, 1H), 8.82 (s, 1H), 8.48 (d, 1H, J=5.2 Hz), 8.01 (dd, 1H, J = 2.4 Hz, J = 13 Hz), 7.55 (bd, 1H, J = 8.9 Hz), 7.52 (s, 1H), 7.48-7.33 (m, 6H), 6.48 (d, 1H, J = 5.1 Hz), 4.73 (dt, 2H, J = 4.2 Hz, J = 42 Hz), 4.36 (dt, 2H, J = 4.2 Hz, J = 28 Hz), 3.95 (s, 3H), 3.94 (s, 3H).
Example 70. 53:: 101,9 [5-[4-(6,7-Dimethoxy-quinoliny10xy)fluor0-pheny1carbamoy1](4-flu0r0-pheny1)- 2,4-di0x0-3,4-dihydr0-2H-pyrimidiny1]-acetic acid tert-butyl ester. mp 138-143 0C; LCMS m/z = 661 (M + 1); 1H NMR (DMSO) 5: 10.94 (s, 1H), 8.94 (s, 1H), 8.48 (d, 1H, J = 5.2 Hz), 8.00 (dd, 1H, J = 2.5 Hz, J = 12.8 Hz), 7.56 (bd, 1H, J = 8.9 Hz), 7.52 (s, 1H), 7.48-7.35 (m, 6H), 6.48 (d, 1H, J = 4.9 Hz), 4.76 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 1.44 (s, 9H).
Example 71.
/O N\ \O / WO 74633 [5-[4-(6,7-Dimeth0xyquinolinyloxy)fluorophenylcarbamoyl]—3-(4-flu0rophenyl)- 2,4-di0x0-3,4-dihydr0-2H-pyrimidinyl]-acetic acid. Example 70 was hydrolyzed using trifiaoroacetic acid in dichloromethane at room temperature for 18 to give Example 71 mp 225 0C dec.; LCMS m/z = 605 (M + 1); 1H NMR (DMSO) 8: 13.42 (bs, 1H), 11.00 (s, 1H), 8.95 (s, 1H), 8.72 (d, 1H, J = 6.2 Hz), 8.07 (dd, 1H, J :25 Hz, J = 13 Hz), 7.69 (s, 1H),7.62 (bd, 1H, J = 8.6 Hz), 7.54 (t, 1H, J = 9.1 Hz), 7.50 (s, 1H), 7.44-7.34 (m, 4H), 6.84 (bs, 1H), 4.79 (s, 2H), 4.01 (s, 3H), 4.00 (s, 3H).
Example 72. /o N\ or) 0 0 OF F ”wNNAG 3 -(4-Fluor0-phenyl)0xazolylmethyl-2,4-di0x0-1 ,2,3 ,4-tetrahydr0-pyrimidine-5 - carboxylic acid 7-dimeth0xy-quinolinyloxy)flu0r0-phenyl]—amide. mp 148- 150 0C; LCMS m/z = 628 (M + 1); 1H NMR (DMSO) 5: 10.85 (s, 1H), 9.05 (s, 1H), 8.48 (d, 1H, J = 5.2Hz), 8.17 (s, 1H), 8.01 (dd, 1H, J = 2.3 Hz, J =13 Hz), 7.56 (bd, 1H, J = 8.5 Hz), 7.52 (s, 1H), 7.48-7.33 (m, 6H), 7.25 (s, 1H), 6.48 (d, 1H, J = 5.0 Hz), 5.41 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H).
Example 73. /o N\ F 1%: N 0 3 -(4-Flu0r0-phenyl)-2,4-di0x0(tetrahydro-fi.1ranylmethyl)- 1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xylic acid [4-(6,7-dimeth0xy-quinolinyloxy)fluor0-phenyl]— amide. mp 127-130 0C; LCMS m/z = 631 (M + 1); 1H NMR (DMSO) 8: 11.01 (s, 1H), 8.77 (s, 1H), 8.48 (d, 1H, J = 5.2 Hz), 8.01 (dd, 1H, J = 2.3 Hz, J =13 Hz), 7.54 (bd, 1H, J = 9.5 Hz), 7.52 (s, 1H), 7.47-7.33 (m, 6H), 6.48 (d, 1H, J = 5.3 Hz), .09 (m, 2H), 3.99-3.93 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.88-3.81 (m, 1H), 3.74-3.68 (m, 1H), 2.04- 1.77 (m, 3H), 1.65-1.55 (m, 1H). e 74. /o N\ . 1%: N O 3 -(4-F1u0r0-phcny1)-2,4-di0x0(tctrahydro-pyrany1mcthy1)- 1 ,2,3 ,4-tctrahydr0- pyrimidinecarboxy1ic acid [4-(6,7-dimcth0xy-quin01iny10xy)—3-fluor0-phcny1]— amide. mp 185-187 0C; LCMS m/z = 645 (M + 1); 1H NMR (DMSO) 8: 11.05 (s, 1H), 8.83 (s, 1H), 8.48 (d, 1H, J = 5.4 Hz), 8.01 (dd, 1H, J = 2.4 Hz, J =13 Hz), 7.54 (bd, 1H, J = 8.6 Hz), 7.52 (s, 1H), 7.46-7.33 (m, 6H), 6.47 (bd, 1H, J = 5.4 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 3.92-3.85 (m, 4H), 3.26 (bd, 2H, J = 11.1 Hz), 1.60 (bd, 2H, J = 12.2 Hz), 1.32-1.23 (m, 3H).
Example 75. /ommN\ 093%ngN/KO F O O 3 -(4-F1u0ro-phcny1)(2-mcthy1—thiaz01—4-y1mcthy1)-2,4-dioxo- 1 ,2,3 ,4-tctrahydr0- dinecarboxy1ic acid [4-(6,7-dimcth0xy-quin01iny10xy)—3-fluor0-phcny1]— amide. mp 196-198 0C; LCMS m/z = 658 (M + 1); 1H NMR (DMSO) 8: 11.01 (s, 1H), 8.95 (s, 1H), 8.48 (d, 1H, J = 5.3 Hz), 8.01 (dd, 1H, J = 2.3 Hz, J = 12.5 Hz), 7.55 (bd, 1H, J = 9 Hz), 7.54 (s, 1H), 7.52 (s, 1H), 7.47-7.33 (m, 6H), 6.48 (bd, 1H, J = 5.9 Hz), 5.24 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.66 (s, 3H).
Example 76. 9380.0 1-Cyc10pcnty1—3-(4-flu0r0-phcny1)-2,4-di0x0- 1 ,2,3,4-tctrahydr0-pyrimidinccarb0xy1ic acid [4-(6,7-dimcth0xy-quinolinyloxy)flu0r0-phcny1]—amidc. mp 222-224 0C; LCMS m/z = 615 (M + 1);1HNMR(DMSO)8: 11.03 (s, 1H), 8.63 (s, 1H), 8.48 (d, 1H, J = 5.4 Hz), 8.01 (dd, 1H, J = 2.5 Hz, J =13 Hz), 7.54 (bd, 1H, J = 9 Hz), 7.52 (s, 1H), 7.46- 7.33 (m, 6H), 6.48 (bd, 1H, J = 5.4 Hz), 4.90-4.81 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.12-2.04 (m, 2H), 1.93-1.78 (m, 4H), 1.69-1.63 (m, 2H).
Example 77. /o N\ . 1%: N O 1 -Benzy1—3 -(4-flu0ro-phenyl)-2,4-di0x0- 1 ,2,3 rahydro-pyrirnidine-5 -carb0xylic acid [4-(6,7-dirneth0xy-quino1iny10xy)—3-flu0r0-phenyl]—arnide. mp 242-244 0C; LCMS m/z = 637 (M + 1); 1H NMR (DMSO) 5: 11.01 (s, 1H), 8.97 (s, 1H), 8.48 (d, 1H, J = 5.8 Hz), 8.00 (dd, 1H, J = 2.5 HZ, J =13 Hz), 7.54 (bd, 1H, J = 9 Hz), 7.52 (s, 1H), .33 (m, 11H), 6.47 (bd, 1H, J = 5.4 Hz), 5.22 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H).
Example 78. /o N\ . 1%: N 0 3 -(4-F1u0r0-phenyl)[2-(2-fluor0-pheny1)—ethy1]-2,4-diox0-1 ,2,3 ,4-tetrahydr0- pyrimidinecarboxylic acid [4-(6,7-dirneth0xy-quinoliny10xy)—3-fluor0-pheny1]— amide. mp 178-180 0C; LCMS m/Z = 669 (M + 1); 1H NMR (DMSO) 5: 10.98 (s, 1H), 8.72 (s, 1H), 8.48 (d, 1H, J = 5.4 Hz), 7.98 (dd, 1H, J = 2.4 Hz, J =13 Hz), 7.53 (bd, 1H, J = 9 Hz), 7.52 (s, 1H), 7.46-7.28 (m,8H), 7.22-7.16 (m, 2H), 6.47 (bd, 1H, J = 5.3 Hz), 4.23 (t, 2H, J = 7.4 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 3.07 (t, 2H, J = 7.3 Hz).
Example 79. /o N\ F 1%: N O 3 -(4-F1u0r0-pheny1)[2-(4-flu0r0-pheny1)—ethy1]-2,4-di0x0-1,2,3 ,4-tetrahydr0- pyrimidinecarboxy1ic acid 7-dirneth0xy-quin01iny10xy)—3-fluor0-pheny1]— amide. mp 203-205 0C; LCMS m/z = 669 (M + 1); 1H NMR (DMSO): 11.00 (s, 1H), 8.79 (s, 1H), 8.48 (d, 1H, J = 5.4 Hz), 7.99 (dd, 1H, J = 2.4 Hz, J =13 Hz), 7.53 (bd, 1H, J = 9 Hz), 7.52 (s, 1H), 7.47-7.33 (m,8H), 7.20-7.14 (m, 2H), 6.47 (bd, 1H, J = 5.3 Hz), 4.18 (t, 2H, J = 7.4 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 3.01 (t, 2H, J = 7.3 Hz).
Example 80.
/O N\ F 1%: N O 1-(2-Cyclohexy1—ethy1)(4-flu0ro-pheny1)—2,4-di0x0- 1 ,2,3 ,4-tetrahydr0-pyrirnidine-5 - carboxylic acid [4-(6,7-dirneth0xy-quino1iny10xy)flu0r0-pheny1]—arnide. mp 186- 190 0C; LCMS m/z = 657 (M + 1); 1H NMR (DMSO) 8: 11.04 (s, 1H), 8.86 (s, 1H), 8.48 (d, 1H, J = 5.2 Hz), 8.01 (dd, 1H, J =2.3 Hz, J =13 Hz), 7.54 (bd, 1H, J = 9.5 Hz), 7.52 (s, 1H), 7.46-7.27 (m, 6H), 6.48 (d, 1H, J = 5.3 Hz), 4.00 (t, 2H, J = 7.2 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 1.75-1.57 (m, 8H), 1.23-1.15 (m, 3H), 0.99-0.90 (m, 2H).
Example 81. /o N\ \O / F NkfikNH | NAG 3 -(4-F1uor0-phcny1)-2,4-di0x0(3-phcny1—propy1)- 1 ,2,3 ,4-tctrahydr0-pyrimidinc-5 - carboxylic acid [4-(6,7-dimcth0xy-quino1iny10xy)flu0r0-phcny1]—amidc. mp 128- 131 0C; LCMS m/z = 665 (M + 1); 1H NMR (DMSO) 8: 11.02 (s, 1H), 8.84 (s, 1H), 8.48 (d, 1H, J = 5.4 Hz), 8.01 (dd, 1H, J = 2.5 Hz, J =10 Hz), 7.54 (bd, 1H, J = 11 Hz), 7.52 (s, 1H), 7.46-7.16 (m, 11H), 6.48 (d, 1H, J = 4.9 Hz), 4.03 (t, 2H, J = 7.2 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 2.68 (dd, 2H, J = 7.2 Hz, J = 16 Hz), 2.03 (t, 2H, J = 7.2 Hz).
Example 82.
/O N\ F ”*6: N 0 3 -(4-F1u0ro-phcny1)-2,4-di0x0(2-0X0pyrr01idiny1—cthy1)-1 ,2,3 ,4-tctrahydr0- pyrimidinecarb0xy1ic acid [4-(6,7-dimcth0xy-quin01iny10xy)—3-fluor0-phcny1]— amide. mp 2 0C; LCMS m/z = 658 (M + 1); 1H NMR (DMSO) 5: 10.97 (s, 1H), 8.80 (s, 1H), 8.48 (d, 1H, J = 5.3 Hz), 8.00 (dd, 1H, J = 2.4 Hz, J =12 Hz), 7.56 (bd, 1H, J = 8.5 Hz), 7.53 (s, 1H), 7.47-7.35 (m, 6H), 6.48 (d, 1H, J = 5.2 Hz), 4.88 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.48 (t, 2H, J = 6.6 Hz), 3.35 (t, 2H, J = 6.9 Hz), 1.93 (p, 2H, J = 6.7 Hz), 1.80 (p, 2H, J = 6.9 Hz).
Example 83.
O N / \ 1 -Dimcthy1carbamoylmcthy1(4-flu0r0phcny1)—2,4-di0xo- 1 ,2,3 ,4-tctrahydr0-pyrimidinc- -carb0xy1ic acid [4-(6,7-dimcth0xy-quino1iny10xy)—3-fluor0phcny1]—amidc. mp 163- 166 0C; LCMS m/z = 632 (M + 1); 1H NMR (DMSO) 5: 10.96 (s, 1H), 8.79 (s, 1H), 8.48 (d, 1H, J = 5.0 Hz), 8.00 (dd, 1H, J = 2.5 Hz, J = 13 Hz), 7.56 (bd, 1H, J = 9.4 Hz), 7.53 (s, 1H), 7.47-7.35 (m, 6H), 6.48 (d, 1H, J = 5.4 Hz), 4.97 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.03 (s, 3H), 2.89 (s, 3H).
Example 84. /o\0mN\ I N O /N1§J:§/ 1-(1-Dimethylcarbamoyloxo-propyl)(4-fluoro-phenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydro- dinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)fluoro-phenyl]- amide. mp 137-140 0C; LCMS m/z = 674 (M + 1); 1H NMR (DMSO) 5: 10.93 (s, 1H), 8.56 (s, 1H), 8.48 (d, 1H, J = 5.3 Hz), 8.00 (dd, 1H, J = 2.3 Hz, J =13 Hz), 7.55 (bd, 1H, J = 9 Hz), 7.52 (s, 1H), 7.47-7.33 (m, 6H), 6.72 (s, 1H), 6.48 (d, 1H, J = 5.7 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 3.17 (s, 3H), 2.97 (s, 3H), 2.31 (s, 3H).
Example 85.
Step a. 4-(6,7-Dimethoxyquinolinyloxy)fluoro-phenylamine. A mixture of 3-fiuoro- 4-nitrophenol (0.644 g, 4.10 mmol) and 60% sodium hydride (0.215 g, 5.60 mmol) in dimethylformamide (20 mL) was stirred 15 min. 4-Bromo-6,7-dimethoxyquinoline (1.0 g, 3.73 mmol) was added and the mixture stirred at 110 0C for 18 h. After partitioning between water and ethyl acetate, the organics were washed with water and brine. The solvent was removed under vacuum, and the residue was purified by column chromatography (0-5% methanol in romethane).
Step b. The nitro intermediate (0.52 g, 1.51 mmol) from step a in ethanol (20 mL) was hydrogenated on a Parr apparatus at 50 psi with 10% ium on carbon (0.05 g) for 4 h.
The solution was filtered and the product purified by column chromatography (0-5% MeOH in dichloromethane) to give 4-(6,7-dimethoxyquinolinyloxy) fluorophenylamine in 36% yield. 1H NMR (DMSO) 5: 8.80 (d, 1H, J = 6.5 Hz), 7.72 (s, 1H), 7.70 (s, 1H), 7.26 (dd, 1H, J = 2.6 Hz, J = 12 Hz), .96 (m, 2H), 6.90 (d, 1H, J = 6.5 Hz), 4.69 (bs, 2H), 4.04 (s, 3H), 4.03 (s, 3H).
The following examples were synthesized using 4-(6,7-dimethoxy-quinolinyloxy) fluorophenylamine and the method for Example 1. /o N\ I10 00 . 1W1 N O 3-(4-F1uor0-phcnyl)-2,4-di0x0- 1 ,2,3 rahydro-pyrimidinccarb0xylic acid [4-(6,7- dimcthoxy-quino1iny10xy)flu0r0-phcnyl]-amidc. mp 23 8-243 0C; LCMS m/z = 547 (M + 1); 1H NMR (DMSO) 5: 12.44 (bs, 1H), 11.16 (bs, 1H), 8.52-8.46 (m, 3H), 7.47 (s, 1H), 7.44-7.33 (m, 5H) 7.40 (s, 1H), 7.14 (d, 1H, J = 9.0 Hz), 6.59 (d, 1H, J = 5.0 Hz), 3.95 (s, 3H), 3.92 (s, 3H).
Example 86. /o N\ 00 O 0 OF . 1%: III 0 3 -(4-F1u0r0-phcny1)mcthy1—2,4-di0x0-1 ,2,3 ,4-tctrahydr0-pyrimidinc-5 -carb0xylic acid [4-(6,7-dimcth0xy-quino1iny10xy)—2-fluoro-phcnyl]-amidc. mp 208-210 0C; LCMS m/z = 561 (M + 1); 1H NMR (DMSO) 5: 11.17 (bs, 1H), 8.90 (s, 1H), 8.51-8.46 (m, 2H), 7.47 (s, 1H), .34 (m, 6H) 7.40 (s, 1H), 7.16 (d, 1H, J = 9.0 Hz), 6.59 (d, 1H, J = 5.0 Hz), 3.95 (s, 3H), 3.92 (s, 3H), 3.54 (s, 3H).
Example 87. £139”; 9”(EC 1-Ethy1—3-(4-fluor0-phcny1)—2,4-di0xo-1 ,2,3,4-tctrahydr0-pyrimidinccarb0xy1ic acid [4- (6,7-dimcthoxy-quinolinyloxy)flu0ro-phcnyl]-amidc. mp 142-144 0C; LCMS m/z = 575 (M + 1); 1H NMR (DMSO) 5: 11.18 (bs, 1H), 8.91 (s, 1H), 8.50 (d, 1H, J = 5.2 Hz), 8.48 (t, 1H, J = 9.8 Hz), 7.47 (s, 1H), 7.45-7.33 (m, 6H), 7.16 (bd, 1H, J = 8.3 Hz), 6.59 (d, 1H, J = 5.2 Hz), 4.02 (q, 2H, J = 7.0 Hz), 3.95 (s, 3H), 3.92 (s, 3H), 1.30 (t, 3H, J = 7.0 Hz).
Example 88. 1:131”; @1181? 1-Allyl-3 -(4-flu0ro-phenyl)-2,4-di0x0- 1 ,2,3 ,4-tetrahydro-pyrimidine-5 -carb0xylic acid [4- (6,7-dimethoxy-quinolinyloxy)flu0ro-phenyl]-amide. mp 6 0C; LCMS m/z = 587 (M +1);1HNMR(DMSO)5: 11.16 (s, 1H), 8.82 (s, 1H), 8.50 (d, 1H, J = 5.5 Hz), 8.47 (t, 1H, J = 8.0 Hz), 7.47 (s, 1H), 7.46-7.34 (m, 6H), 7.16 (bd, 1H, J = 8.6 Hz), 6.59 (d, 1H, J = 5.4 Hz), .93 (m, 1H), 5.38 (d, 1H, J =17 Hz), 5.29 (d, 1H, J = 10.6 Hz), 4.63 (d, 2H, J = 5.7 Hz), 3.95 (s, 3H), 3.92 (s, 3H).
Example 89. /o N\ 080 . 0 F ”*61 M O lu0r0-phenyl)-2,4-di0xo-1,2,3,4-tetrahydr0pyrimidinecarboxylic acid [4-(6,7- dimethoxy-quinolinyloxy)-3,5-difluor0-phenyl]—amide. Example 89 was synthesized using the 4-(6,7-dimethoxyquinolinyloxy)-3,5-difluor0phenylamine (synthesized using the method for example 85 starting with 2,6-difluor0nitrophenol; LCMS m/z = 333 M+ 1); LCMS m/z = 565 (M + 1); 1H NMR(CDC13) 5: 8.50 (bd, 1H), 8.47 (s, 1H),7.60 (d, 1H, J = 4.0 Hz), 7.46 (bd, 2H, J = 15 Hz), 7.24-7.12 (m, 6H), 6.36 (d, 1H, J = 8.9 Hz), .88 (d, 1H, J = 8.1 Hz), 4.07 (s, 3H), 4.05 (s, 3H).
Example 90. /o\omN\ 01> 0 . 0F . NW1 2N O 1-Ethyl(4-flu0r0-phenyl)—2,4-di0x0-1,2,3,4-tetrahydro-pyrimidinecarb0xylic acid [4- (6,7-dimethoxy-quinolinyloxy)-3,5-difluoro-phenyl]—amide. mp 166-170 0C; LCMS m/z = 593 (M + 1); 1H NMR (DMSO) 5: 11.13 (s, 1H), 8.91 (s, 1H), 8.50 (d, 1H, J = 6.8 Hz), 7.83 (d, 2H, J = 9.8 Hz), 7.54 (s, 1H), 7.45-7.32 (m, 5H), 6.59 (d, 1H, J = 6.5 Hz), 4.02 (q, 2H, J = 6.5 Hz), 3.96 (s, 6H), 2.69 (t, 3H, J = 6.5 Hz).
Example 91. /o N\ on o o . ”W1“ N 0 3 -Ethyl- 1 oro-phenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid [4- (6,7-dimethoxy-quinolinyloxy)fluoro-phenyl]-amide. To a solution of 4- fluoroaniline (1.0 g, 9.01 mmol) in THF (20 mL) at 0 0C, was slowly added ethyl isocyanate (0.70 g, 10.0 mmol). After stirring 30 min. at 0 0C, the solution was warmed to rt and the solvent was d under vacuum. To the residue was added ethanol (30 mL), diethyl ethoxymethylenemalonate (1.95 g, 9.01 mmol) and 21% NaOEt in ethanol (2.92 mL, 9.01 mmol)) and the reaction stirred 48 h at rt. The t was removed under vacuum and cold conc. HCl was added to pH 6. The aqueous layer was removed under vacuum and the solids were crystallized from ethyl acetate and hexanes. 3-Ethyl(4- fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid ethyl ester isomer was isolated in 25% yield. 1H NMR(CDC13) 5: 8.32 (s, 1H), 7.20-7.14 (m, 4H), 4.35 (q, 2H, J = 7.1 Hz), 3.95 (q, 2H, J = 7.2 Hz), 1.42 (t, 3H, J = 7.2 Hz), 1.36 (t, 3H, J = 7.2 Hz). 3 -Ethyl(4-fluorophenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid ethyl ester was hydrolyzed with 1N LiOH in MeOH and THF at 65 0C. The acid was coupled with -Dimethoxyquinolinyloxy)fluorophenylamine using the method for example 1 to give 3-ethyl(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro- pyrimidinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)fluoro-phenyl]- amide mp 140-142 0C; LCMS m/z = 575 (M + 1); 1H NMR (DMSO) 5: 11.18 (s, 1H), 8.49 (d, 1H, J = 2.5 Hz), 8.46 (s, 1H), 8.03 (dd, 1H, J = 3 Hz, J =13 Hz), 7.65-7.39 (m, 6H), 7.55 (s, 1H), 7.41 (s, 1H), 6.49 (d, 1H, J = 5.0 Hz), 4.00 (q, 2H, J =7.4 Hz), 3.95 (s, 6H), 1.23 (t, 3H, J =7.3 Hz).
Example 92.
/O N\ 000 O F ”w“ methyl-2,4-dioxo-1,2,3 ,4-tetrahydropyrimidinecarboxylic acid [4-(6,7- dimethoxy-quinolinyloxy)fluorophenyl]-amide.
Step a. A mixture of 2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid ethyl ester (0.100 g, 0.543 mmol), iodomethane (0.130 mL, 1.63 mmol), and potassium carbonate (0.225 g, 1.63 mmol) was d in N,N—dimethylformamide (5 mL, 60 mmol) at 80 0C 18 h. The mixture was poured into water and extracted with ethyl acetate. The residue was hydrolyzed with 1equivalent of 1N LiOH in THF / MeOH (1 :1; 6 mL) at 60 CC 4h.
The cs were removed under vacuum, and the aqueous was washed with ethyl acetate. The aqueous was then cooled and acidified with conc. HCl. The 1,3-dimethyl- 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid was filtered off in 60% yield. 1H NMR (DMSO) 8: 12.78 (bs, 1H), 8.72 (s, 1H), 3.45 (s, 3H), 3.22 (s, 3H).
This intermediate acid was d with 4-(6,7-dimethoxyquinolinyloxy) fluorophenylamine as described in example 1. mp 25 8-260 0C; LCMS m/z = 481 (M + 1); 1H NMR (DMSO) 8: 11.22 (s, 1H), 8.76 (s, 1H), 8.49 (d, 1H, J = 5.3 Hz), 8.02 (dd, 1H, J = 2.5 Hz,J = 13 Hz), 7.54 (d, 1H, J = 8 Hz), 7.54 (s, 1H), 7.47 (t, 1H, J = 9.0 Hz), 7.41 (s, 1H), 6.49 (d, 1H, J = 9.0 Hz), 3.95 (s, 6H), 3.51 (s, 3H), 3.29 (s, 3H).
Examples 92-98 intermediate acids were synthesized as in Scheme 2 and described in Example 92 and coupled using methods described for Example 1.
Example 93. /o N\ on o o F 1W1“ N O 1,3-Diethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid [4-(6,7-dimethoxyquinolinyloxy )fluoro-phenyl]-amide. mp 178-180 0C; LCMS m/z = 509 (M + 1); 1H NMR (DMSO) 5: 11.22 (s, 1H), 8.76 (s, 1H), 8.49 (d, 1H, J = 5.5 Hz), 8.02 (dd, 1H, J = 2.5 Hz, J = 13 Hz), 7.55 (d, 1H, J = 8 Hz), 7.54 (s, 1H), 7.46 (t, 1H, J = 9.0 Hz), 7.41 (s, 1H), 6.49 (d, 1H, J = 9.0 Hz), 4.02-3.96 (m, 4H), 3.95 (s, 6H), 1.27 (t, 3H, J = 7.4 Hz), 1.18 (t, 3H, J = 7.5 Hz).
Example 94. 121)? .1151ng )N\ O 1,3-Diisopr0py1—2,4-diox0-1,2,3,4-tctrahydr0-pyrimidinccarb0xy1ic acid [4-(6,7- dimcthoxy-quino1iny10xy)flu0r0-phcny1]—amidc. mp 6 0C; LCMS m/z = 537 (M +1); 1H NMR (DMSO) 5: 11.22 (s, 1H), 8.54 (s, 1H), 8.49 (d, 1H, J = 5.0 Hz), 8.02 (dd, 1H, J = 2.5 Hz, J =13 Hz), 7.54 (bd, 1H, J = 9 Hz), 7.53 (s, 1H), 7.46 (t, 1H, J = 8.1 Hz), 7.42 (s, 1H), 6.49 (d, 1H, J = 5.6 Hz), 5.18 (h, 1H, J = 6.7 Hz), 4.78 (h, 1H, J = 6.8 Hz), 3.95 (s, 6H), 1.45 (d, 6H, J = 6.7 Hz), 1.38 (d, 6H, J = 6.4 Hz).
Example 95 Dim” 1,3-Bis-cyc10pr0py1mcthy1—2,4-di0x0-1,2,3,4-tctrahydr0-pyrimidinccarb0xy1ic acid [4- (6,7-dimcthoxy-quinoliny10xy)—3-fluoro-phcny1]—amidc. mp 63-65 0C; LCMS m/z = 561 (M + 1); 1H NMR (DMSO) 5: 11.192 (8, 1H), 8.83 (s, 1H), 8.49 (d, 1H, J = 5.3 Hz), 8.03 (dd, 1H, J = 2.3 Hz, J = 13.5 Hz), 7.55 (bd, 1H, J = 9 Hz), 7.54 (s, 1H), 7.46 (t, 1H, J = 8.9 41 (s, 1H), 6.49 (d, 1H, J = 5.1 Hz), 3.95 (s, 6H), 3.84 (t, 4H, J = 7.1 Hz), 1.16-1.08 (m, 2H), 0.56-0.38 (m, 8H).
Example 96.
/O N\ on O O . NW 1,3-Dia11y1-2,4-di0x0-1,2,3,4-tctrahydr0-pyrimidinccarb0xy1ic acid [4-(6,7-dimcthoxy- quinoliny10xy)flu0r0-phcny1]—amidc. mp 172-174 0C; LCMS m/z = 529 (M + 1); 1H NMR (DMSO) 8: 11.10 (s, 1H), 8.72 (s, 1H), 8.49 (d, 1H, J = 5.2 Hz), 8.02 (dd, 1H, J = 2.5 Hz, J = 13 Hz), 7.56 (bd, 1H, J = 8.9 Hz), 7.53 (s, 1H), 7.46 (t, 1H, J = 8.8 Hz), 6.49 (d, 1H, J = 5.2 Hz), .03 (m, 2H), 5,31-5.27 (m, 1H), 5.27-5.25 (m, 1H), .17 (m, 1H), 5.16-5.14 (m, 1H), 4.60 (d, 2H, J = 5.5 Hz), 4.53 (d, 2H, J = 5.5 Hz), 3.95 (s, 3H), 3.94 (s, 3H).
Example 97.
/O N\ on O O . ”$1“ N O 1 ,3-Bis—(3 -methy1—buteny1)-2,4-diox0- 1 ,2,3 ,4-tetrahydr0-pyrimidinecarb0xy1ic acid [4-(6,7-dimeth0xy-quinoliny10xy)—3-flu0r0-pheny1]—amide. mp 184-186 0C; LCMS m/z = 589 (M + 1); 1H NMR (DMSO) 5: 11.15 (s, 1H), 8.65 (s, 1H), 8.49 (d, 1H, J = 5.7 Hz), 8.02 (dd, 1H, J = 2. Hz, J =13 Hz), 7.54 (bd, 1H, J = 9 Hz), 7.52 (s, 1H), 7.46 (t, 1H, J = 9.5 Hz), 7.71 (s, 1H), 6.49 (bd, 1H, J = 5 Hz), 5.30 (m, 1H), 5.19 (m, 1H), 4.53 (dd, 4H, J = 6.7 Hz, J = 15.3 Hz), 3.95 (s, 6H), 1.78 (bs, 3H), 1.77 (bs, 3H), 1.74 (bs, 3H), 1.69 (bs, 3H).
Example 98. /o N\ \O / F N N H I § N O 2,4-Di0x0-1,3-di-pr0pyny1—1,2,3 ,4-tetrahydro-pyrimidinecarb0xy1ic acid [4-(6,7- dimethoxy-quino1iny10xy)flu0r0-pheny1]—amide. mp 133-138 0C; LCMS m/z = 529 (M +1); 1H NMR (DMSO) 5: 10.94 (s, 1H), 8.88 (s, 1H), 8.49 (d, 1H, J = 6.5 Hz), 8.03 (dd, 1H, J = 2.5 Hz, J =13 Hz), 7.59 (bd, 1H, J = 8.5 Hz), 7.54 (s, 1H), 7.48(t, 6H, J = 9.1 Hz), 6.50 (d, 1H, J = 5.3 Hz), 4.84 (d, 2H, J = 2.4 Hz), 4.42 (d, 2H, J = 2.2 Hz), 3.96 (s, 6H), 3.61 (t, 1H, J = 2.5 Hz), 3.25 (t, 1H, J = 2.5 Hz).
Example 99. 2012/065019 \0m/o N\ 00 o o F 1%“: N O 2,4-Dioxo- 1 ,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid [4-(6,7-dimethoxy-quinolin yloxy)fluoro-phenyl]-amide. A solution of 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine carboxylic acid (0.156 g, 1.00 mmol) in thionyl chloride (2 mL, 30 mmol) was stirred at 100 oC 3h. After the t was removed under vacuum, [ 4-(6,7-dimethoxy-quinolin yloxy)fluoro-phenylamine (0.314 g, 1.00 mmol) and pyridine (2 mL, 20 mmol) were added and stirred at room temperature 18 hr. The solvent was d under vacuum and the residue was purified on HPLC. 0.15 g of the trifluoracetic acid salt was isolated in 27% yield. mp 251-255 0C; LCMS m/z = 453 (M + 1); 1H NMR (DMSO) 8: 11.99 (bs, 1H), 11.93 (s, .18 (s, 1H), 8.74 (d, 1H, J = 4.5 Hz), 8.31 (d, 1H, J = 7.5 Hz), 8.06 (d, 1H, J = 12 Hz), 7.70 (s, 1H), 7.55 (m, 2H), 7.51 (s, 1H), 6.85 (m, 1H), 4.02 (s, 3H), 4.01 (s, 3H).
Example 100. 1:131“; £11305) 1-Ethyl-2,4-dioxophenyl-1,2,3 rahydro-pyrimidine-5 -carboxylic acid [4-(6,7- dimethoxy-quinolinyloxy)fluoro-phenyl]-amide. To a solution of 2- aminomethylene-malonic acid diethyl ester (0.75 g, 4.0 mmol) and phenyl nate (0.57 g, 4.4 mmol) in 1,2-dichloroethane (20 mL) was added N,N—diisopropylethylamine (0.77 mL, 4.4 mmol) and heated at 100 0C 6 h. The mixture was cooled and d. The solids were purified by column chromatography with 0-5% MeOH in methylene chloride.
This intermediate urea was suspended in ethanol (10 mL) and 21% NaOEt in ethanol (1.29 mL, 4.0 mmol ) was added. After 18 h the solvent was removed under vacuum and the residue was slurred in ethyl acetate. The organics were washed with 1M citric acid solution, water and brine. The solvent was removed under vacuum and the residue was purified by chromatography with 0-5% MeOH in dichloromethane to give 0.50 g (40%).
The ester was alkylated and hydrolyzed using methods for example 92 to give 1-ethyl-2,4- dioxophenyl-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid. 1H NMR (DMSO) 5: 12.65 (bs, 1H), 8.82 (s, 1H), 7.54-7.43 (m, 3H), 7.32-7.29 (m, 2H), 4.02 (q, 2H, J = 7.1 Hz), 1.26 (t, 3H, J = 7.1 Hz).
This ediate acid was coupled to 4-(6,7-dimethoxyquinolinyloxy) fluorophenylamine as described in example 1 to give Example 100 . mp 282-285 0C; LCMS m/z = 557 (M + 1); 1H NMR (DMSO) 5: 11.01 (s, 1H), 8.89 (s, 1H), 8.48 (d, 1H, J = 4.6 Hz), 8.00 (dd, 1H, J = 2.3 Hz, J = 13 Hz), .34 (m, 9H), 6.47 (d, 1H, J = 4.6 Hz), 4.02 (q, 2H, J = 6.9 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 1.3 (t, 3H, J = 7.4 Hz).
Example 101. 1:131”; magic )N\ O 1-Isopropyl-2,4-dioxophenyl-1,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid [4-(6,7- dimethoxy-quinolinyloxy)fluoro-phenyl]—amide. mp 235-237 0C; LCMS m/z = 571 (M +1);1H NMR (DMSO) 5: 11.07 (s, 1H), 8.69 (s, 1H), 8.48 (d, 1H, J = 4.6 Hz), 8.01 (dd, 1H, J = 2.3 Hz, J =13 Hz), 7.55-7.35 (m, 9H), 6.48 (d, 1H, J = 4.6 Hz), 4.79 (h, 1H, J = 6.9 Hz), 3.95 (s, 3H), 3.94 (s, 3H), 1.43 (d, 6H, J = 6.8 Hz). e 102.
/OON\\O / O o 0 00 F ”kw NH/go 3 -(4-Fluoro-phenyl)-2,4-dioxopropyl-1 ,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid [4-(6,7-dimethoxy-quinolinecarbonyl)fluoro-phenyl]—amide.
O N /0 O N\ / O \ / \O / /O N\ a, b \O C, d + F \o / O O O O F HO O Br CHO 0 F N N Step a. A solution of 4-bromo-6,7-dimethoxyquinoline (1.0 g, 3.73 mmol) in dry THF (20 mL) was cooled to -78 0C. A solution of 2,5M n-butyllithium in hexanes (1.50 mL, 3.73 mmol) was added and stirred 15 min. A solution of 4-bromofluoro-benzaldehyde WO 74633 (0.757 g, 3.73 mmol) in THF (10 mL) was added dropwise over 5 min. After stirring 30 min. at -78 0C, saturated ammonium de solution (1 mL) was added. The solvent was d under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. After the solvent was removed under vacuum, the residue was purified by chromatography with 0-5% MeOH in dichloromethane to give (4-bromofluoro-phenyl)- (6,7-dimethoxy-quinolinyl)-methanol in 52% yield. 1H NMR(CDC13) 5: 8.63 (d, 1H, J = 4.1 Hz), 7.57 (d, 1H, J = 4.7 Hz), 7.34 (s, 1H), 7.25-7.17 (m, 2H), 7.08 (s, 1H), 6.67 (s, 1H), 4.02-3.96 (m, 1H), 3.94 (s, 3H), 3.88 (s, 3H).
Step b. The intermediate from step a (0.196 g, 0.50 mmol) was dissolved in THF (5 mL) and 1M lithium hexamethyldisilazane in THF (0.55 mL, 0.55 mmol), bis(dibenzylideneacetone)palladium (0.014 g, 5 mol%) and tri-tert-butylphosphine (0.061 mL, 5 mol%) were added. The sealed tube was heated at 65 0C 18 hr. After cooling, concentrated HCl was added to pH 1 and stirred 1 hr. The solvent was removed under vacuum, ethyl acetate and saturated sodium bicarbonate solution was added until slightly basic. The organics were separated, the t d under vacuum and the residue purified by chromatography with 0-5% MeOH in romethane to give (4-amino fluoro-phenyl)-(6,7-dimethoxy-quinolinyl)methanone in 60% yield. 1H NMR(CDC13) 8: 8.78 (d, 1H, J = 4.7 Hz), 7.69 (d, 1H, J = 4.7 Hz), 7.42 (s, 1H), 7.10 (s, 1H), 6.90 (t, 1H, J = 8.3 Hz), 6.65 (s, 1H), 6.41 (dd, 1H, J = 2.2 Hz, J = 12.1 Hz), 6.33 (dd, 1H, J = 2.2 Hz, J = 8.4 Hz), 4.00 (s, 3H), 3.90 (s, 3H), 3.80 (bs, 2H), 2.33 (bs, 1H).
Steps c and d. 3-(4-Fluoro-phenyl)-2,4-dioxopropyl-1,2,3,4-tetrahydro-pyrimidine carboxylic acid [4-(6,7-dimethoxy-quinolinecarbonyl)fluoro-phenyl]-amide. The intermediate from step b was coupled with 3-(4-fluorophenyl)-2,4-dioxopropyl-1,2,3,4- tetrahydro-pyrimidinecarboxylic acid using the methods for Example 1.. The alcohol (0.075 g, 0.12 mmol) product was dissolved in dichloromethane (5 mL) and cooled to 0 0C. Dess-Martin periodinane (0.076 g, 0.18 mmol) was added slowly and the solution warmed to room temperature for 4 h. The organics were washed with saturated sodium bicarbonate and the t removed under vacuum. The residue was purified by column chromatography with 5% MeOH in dichloromethane to give 0.063g (84%) mp 125-127 0C; LCMS m/z = 601 (M + 1); 1H NMR (DMSO) 8: 11.30 (s, 1H), 8.88 (s, 1H), 8.79 (d, 1H, J = 4.0 Hz), 7.87 (dd, 1H, J = 1.9 Hz, J =13 Hz), 7.72 (t, 1H, J = 8.5 Hz), 7.56 (dd, 1H, J = 1.8 Hz, J = 8.7 Hz), 7.49 (s, 1H), .32 (m, 5H), 7.29 (s, 1H), 3.96 (s, 3H), 3.94 (t, 2H, J = 7.4 Hz), 3.77 (s, 3H), 1.71 (q, 2H, J = 7.8 Hz), 0.92 (t, 3H, J = 8.3 Hz).
Synthesis of 3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazinecarboxylic acid Method A.
Step a. uorophenyl)oxothioxo-2,3 ,4,5-tetrahydro-[1,2,4]triazinecarboxylic acid ethyl ester. A mixture of 2-oxo-malonic acid diethyl ester (2.5 mL, 16 mmol) and 4- fluorophenyl thiosemicarbazide (3.0 g, 16 mmol) in ethanol (60 mL, 1000 mmol) was heated at reflux for 3 days. The mixture was cooled to rt and the separated solid was filtered, washed with cold l and dried to give 3.44 g (71%). LCMS m/z = 296 (M + 1); 1H NMR (DMSO) 8: 7.35 (m, 4H), 4.30 (q, 2H, J = 7.1 Hz), 1.27 (t, 3H, J = 7.1 Hz).
Step b. 4-(4-Fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazinecarboxylic acid ethyl ester. To a solution of 4-(4-fluorophenyl)oxothioxo-2,3,4,5-tetrahydro-1,2,4- triazinecarboxylic acid ethyl ester (11 g, 37 mmol) in N,N—dimethylformamide (100 mL) and acetic acid (40 mL, 700 mmol) was added 50% aq. hydrogen peroxide (11 mL, 190 mmol). The mixture was stirred at rt 2 days, the solvent was removed and the product was taken up in ethylacetate and washed successively with water and brine. After drying, the solvent was ated. The solid obtained was triturated with ether, filtered and washed with cold ether to yield 9.85 g (95%). LCMS m/z = 280 (M + 1); 1H NMR (DMSO) 8: 13.1 (s, 1H), 7.42-7.28 (2m, 4H), 4.29 (q, 2H, J = 7.1 Hz), 1.27 (t, 3H, J = 7.1 Hz).
Step c. 4-(4-Fluorophenyl)isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine carboxylic acid ethyl ester. 4-(4-Fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4- necarboxylic acid ethyl ester (1000 mg, 4 mmol), isopropyl iodide (0.72 mL, 7.16 mmol) and potassium carbonate (544 mg, 3.94 mmol) in N,N—dimethylformamide (20 mL) was heated at 65 CC for 60 min. The reaction mixture was cooled to rt and was trated, diluted with EtOAc and was filtered through a pad of celite. The filtrate was concentrated and the product purified by flash chromatography (hexane: EtOAc 3:1) to give a white solid (1.1 g, 96%). LCMS m/z = 322 (M + 1); 1H NMR (DMSO) 5: 7.41-7.31 (m, 4H), 4.86 (m, 1H), 4.31 (q, 2H, J = 7.0 Hz), 1.31-1.26 (overlapping t and d, 9H).
Step d. 4-(4-Fluorophenyl)isopropyl-3 ,5-dioxo-2,3 ,4,5-tetrahydro[1,2,4]triazine carboxylic acid. Sulfuric acid (10 mL, 200 mmol) was carefully added to a mixture of 4- (4-fluorophenyl)isopropyl-3 ,5-dioxo-2,3 ,4,5 -tetrahydro-1 ,2,4-triazinecarboxylic acid ethyl ester (1100 mg, 3.4 mmol) and water (2 mL). The mixture became homogenous after a few minutes. The reaction mixture was d at 40 OC overnight, was cooled to rt and was carefully added to ice. The mixture was saturated with solid NaCl and was extracted repeatedly from EtOAc (3 x). The combined EtOAc layer was washed with brine, dried over ium e, and concentrated to give the product as foam (100%). LCMS m/z = 294 (M + 1); 1H NMR (Methanol d4) 5: 7.35-7.31 (2m, 4H), 4.95 (m, 1H), 4.31 (q, 2H, J = 7.0 Hz), 1.41 (d, 6H, J = 6.6 Hz).
The following 3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazinecarboxylic acids were synthesized using the previous procedure. 2-Ethyl(4-fluorophenyl)-3 ,5-dioxo-2,3 ,4,5 -tetrahydro-[1,2,4]triazinecarboxylic acid.
LCMS m/z = 280 (M + 1); 1H NMR (Methanol-d4) 8: 7.34-7.18 (m, 4H), 4.10 (q, 2H, J = 7.2 Hz), 1.38 (t, 3H, J = 7.2 Hz). 4-(4-Fluorophenyl)(2-hydroxyethyl)-3 xo-2,3 ,4,5 -tetrahydro- [1 ,2,4]triazine carboxylic acid. Synthesized from 2-[2-(t-butyldimethylsilanyloxy)ethyl](4- fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazinecarboxylic acid. LCMS m/z = 296 (M + 1); 1H NMR (DMSO) 5: 7.41-7.36 (m, 4H), 4.09-4.01 (2m, 3H), 3.72 (m, 2H).
Tert(4-Fluorophenyl)-3 ,5 -dioxo(2-oxo-propyl)-2,3 ,4,5 -tetrahydro-[1,2,4]triazine carboxylic acid. (from the ester precursor, 4-(4-fluorophenyl)-3,5-dioxopropynyl- 2,3,4,5-tetrahydro-[1,2,4] triazinecarboxylic acid ethyl ester). LCMS m/z = 308 (M + 1); 1H NMR (DMSO) 8: 7.46-7.32 (m, 4H), 4.95 (s, 2H2.21 (s, 3H). 2-Cyclopropylmethyl(4-fluoro-phenyl)-3 ,5-dioxo-2,3 ,4,5 -tetrahydro- [1 riazine carboxylic acid. LCMS m/z = 306 (M + 1). 4-(4-Fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazinecarboxylic acid. 4-(4- Fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazinecarboxylic acid ethyl ester (300 mg, 1 mmol) in THF (3 mL) and MeOH (7 mL) was added 5M NaOH (2 mL, 2 mmol). The mixture was stirred at rt for 1h and was trated. Water was added and the mixture was extracted with ether. The aq. layer was made acidic with HCl at 0°C and was extracted with EtOAc and trated. LCMS m/z = 274 (M + Na); 1H NMR (DMSO) 5: 13.03 (s, 1H), 7.35-7.30 (m, 4H). 4-(4-F|uoro-pheny|)—2-methyI-3,5-di 3,4,5-tetrahydro-[1,2,4]triazine carboxylic acid Method B Step a. 4-(4-Fluoro-phenyl)methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine carboxylic acid. To a mixture of 2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine WO 74633 carboxylic acid ethyl ester (220 mg, 1.1 mmol) (Yuen, K. J Org. Chem. 1962, 27, 976) 4- Fluorophenyl boronic acid (230 mg, 1.6 mmol) and triethylamine (0.46 mL, 3.3 mmol) in ene chloride (5 mL, 80 mmol) was added copper acetate (150 mg, 1.2 mmol). The mixture was stirred under argon at rt 18h. The solvent was removed and the product was purified by flash chromatography (hexane: EtOAc 60:40) to yield 34 mg (10%). LCMS = 294 (M + 1).
Step b. 4-(4-Fluorophenyl)methyl-3 ,5-dioxo-2,3 ,4,5 -tetrahydro- [1 ,2,4]triazine ylic acid. 4-(4-fiuorophenyl)methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine- 6-carboxylic acid ethyl ester (30 mg, 0.1 mmol) was dissolved in THF-MeOH (1 :1, 2 mL) and 1M of lithium ide (0.102 mL, 0.102 mmol) was added. After stirring at rt overnight, the solution was concentrated, dissolved in 1N N32C03 and washed with EtOAc. The aqueous layer was filtered and made acidic with 5N HCl and extracted with EtOAc. The combined organics were washed with water and brine, dried (MgSO4) and ated to give a white solid (30 mg, 100%). LCMS m/z = 266 (M + 1); 1H NMR (Methanol d4): 7.55-7.52 (m, 2H), 7.07-7.03 (m, 2H), 3.52 (s, 3H).
Example 103. 9G?\ / NJYlLNH | N\ARI/£0 4-(4-Fluoro-phenyl)isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)fiuoro-phenyl]-amide. A mixture of 4-(4- fiuorophenyl)isopropyl-3 ,5-dioxo-2,3 ,4,5 -tetrahydro- 1 ,2,4-triazinecarboxylic acid (500 mg, 2 mmol), 4-(6,7-dimethoxyquinolinyloxy)fluorophenylamine (535 mg, 1.70 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazolyl)uronium hexafiuorophosphate (639 mg, 1.68 mmol) and N,N—diisopropylethylamine (279 uL, 1.60 mmol) in N,N—dimethylformamide (8 mL) was stirred at rt for 3h. The solvent was removed and the e dissolved in EtOAc and washed with saturated NaHC03 on water and brine. After drying over magnesium sulfate, solvent was evaporated and the product was purified by ISCO silica gel chromatography (hexane: EtOAc 1:4) to give 835 mg (83%), which triturated with ether and dried. mp =225-226 C’C; LCMS m/z = 590 (M + 1); 1H NMR DMSO) 5: 10.87 (s, 1H), 8.49 (d, 1H, J = 5.2 Hz), 7.97 (dd, 1H, J = 12.6, 2.2 Hz), 7.59-7.36 (m, 8H), 6.50 (d, 1H, J = 4.9 Hz), 4.90 (m, 1H), 3.95 (s, 6H), 3.32 (s, 3H), 1.38 (d, 6H, J = 6.6 Hz).
The following examples were synthesized using the procedure for Example 103.
Example 104. /o N\ \OI I /] OQ”M10FO 0 N"? O 4-(4-Fluorophenyl)methyl-3 ,5-dioxo-2,3 ,4,5 hydro-[1,2,4]triazinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)fluoro-phenyl]—amide TFA salt. The product was purified by reverse phase HPLC (Gilson) and the fractions showing product were concentrated as the TFA salt to give an off-white solid. LCMS m/z = 562 (M + 1); 1H NMR (DMSO) 5: 10.98 (s, 1H), 8.74 (d, 1H, J = 6.1 Hz), 8.02 (dd, 1H, J = 12.7, 2.3 Hz), 7.70 (s, 1H), 7.67-7.56 (2m, 2H), 7.52 (s, 1H), .37 (m, 4H), 6.88 (d, 1H, J = 5.5 Hz), 4.02 (s, 3H), 4.01 (s, 3H), 3.69 (s, 3H).
Example 105. /o N\ I I /] OQ”JJYILNOFO O N‘N/ko 2-Ethyl(4-fluoro-phenyl)-3 ,5 -dioxo-2,3 ,4,5 -tetrahydro-[1,2,4]triazinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)fluoro-phenyl]-amide TFA salt. ite solid, LCMS m/z = 576 (M + 1); 1H NMR (DMSO) 5: 10.99 (s, 1H), 8.78(d, 1H, J = 6.2 Hz), 8.03 (dd, 1H, J = 12.7, 2.3 Hz), 7.72 (s, 1H), 7.67-7.58 (m, 2H), 7.54 (s, 1H), 7.45-7.32 (2 m, 4H), 6.93 (d, 1H, J = 6.1 Hz), 4.08 (q, 2H, J = 7.1 Hz), 4.03 (s, 3H), 4.02 (s, 3H), 1.35 (t, 3H, J = 7.1 Hz).
Example 106. (21>? .
QMEJF ‘AN 0 4-(4-Fluorophenyl)isopropyl-3 ,5 -dioxo-2,3 ,4,5 -tetrahydro-[1,2,4]triazinecarboxylic acid [4-(2,3-dihydro-[1,4]dioxino[2,3-g]quinolinyloxy)fluorophenyl]-amide TFA salt. This compound was sized from 4-(2,3-dihydro[1,4]dioxino[2,3-g]quinolin yloxy)fluorophenylamine; hydrochloride (synthesized using the ure for example 111 step a; LCMS m/z = 313 (M + 1); 1H NMR (DMSO) 5: 8.85 (d, 1H, J = 6.5 Hz), 7.87 (s, 1H), 7.76 (s, 1H), 7.26 (t, 1H, J = 8.9 Hz), 6.88 (dd, 1H, J = 6.6, 0.8 Hz), 6.78 (dd, 1H, J = 8.6, 1.9 Hz), 6.67 (br d, 1H, J = 8.6 Hz), 4.52 (m, 4H)) and 4-(4-fluorophenyl) isopropyl-3 ,5 -dioxo-2,3 ,4,5 -tetrahydro- 1 ,2,4-triazinecarboxylic acid using the procedure for example 103 to give an off-white solid, LCMS m/z = 588 (M + 1); 1H NMR (DMSO) 5: 10.94 (s, 1H), 8.74 (d, 1H, J = 6.0 Hz), 8.02 (dd, 1H, J = 12.6, 2.3 Hz), 7.80 (s, 1H), 7.63-7.53 (2m & s, 3H), 7.54 (s, 1H), 7.45-7.36 (m, 4H), 6.81 (d, 1H, J = 5.9 Hz), 4.90 (q, 1H, J = 6.6 Hz), 4.48 (m, 4H), 1.38 (d, 6H, J = 6.6 Hz).
Example 107. /m\ / NJJYlLNH | N\N’ko H 4-(4-Fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazinecarboxylic acid [4-(6,7- dimethoxy-quinolinyloxy)fluoro-phenyl]-amide TFA salt. Off-White solid, LCMS m/z = 548 (M + 1); 1H NMR DMSO) 5: 13.30 (s, 1H), 10.97 (s, 1H), 8.71(d, 1H, J = 6.0 Hz), 8.02 (dd, 1H, J = 12.7, 2.3 Hz), 7.68 (s, 1H), 7.65 (m, 1H), 7.65 , 7.56 (m, 1H), 7.5 (s, 1H), 7.46-7.31 (2 m, 4H), 6.83 (d, 1H, J = 6.3 Hz),4.01 (s, 6H).
Example 108. a” o oN/Q/F N.NA 4-(4-Fluorophcnyl)(2-hydroxycthyl)-3 ,5-dioxo-2,3 ,4,5 -tctrahydro- [1 ,2,4]triazinc carboxylic acid 7-dimcthoxyquinolinyloxy)—3-fluorophcnyl]—arnidc. TFA salt Off-white solid; LCMS m/z = 592 (M + 1); 1H NMR DMSO) 5: 10.96 (s, 1H), 8.75 (d, 1H, J = 6.2 Hz), 8.02 (dd 1H, J = 12.6, 2.4 Hz), 7.70 (s, 1H), 7.66-7.57 (m, 2H), 7.51 (s, 1H), .39 (m and s, 4H), 6.89 (d, 1H, J = 5.4 Hz), 4.11 (m, 2H), 4.02 (2s, 6H), 3.77 (m, 2H).
Example 109.
V0 N\ 0 O 0 “MNH | 2-Ethyl(4-fluorophcnyl)-3 ,5-dioxo-2,3 ,4,5 -tctrahydro [1 ,2,4]triazinccarboxylic acid [4-(6,7-dicthoxy-quinolinyloxy)—3-fluoro-phcnyl]—arnidc. TFA salt Off-White solid; LCMS m/z = 604 (M + 1); 1H NMR (DMSO) 5: 10.98 (s, 1H), 8.74 (d, 1H, J = 6.2 Hz), 8.03 (dd 1H, J = 12.6, 2.2 Hz), 7.69 (s, 1H), 7.66-7.54 (m, 2H), 7.51 (s, 1H), 7.46-7.34 (m, 4H), 6.89 (d, 1H, J = 5.0 Hz), 4.29 (m, 4H), 4.09 (q, 2H, J = 7.1 Hz) 1.45 (overlapping triplets, 6H), 1.35 (t, 3H, J = 7.1 Hz).
Example 110. /o N\ NHJKNIHLN 4-(4-Fluoro-phcnyl)isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazinccarboxylic acid [5-(6,7-dimcthoxy-quinolinyloxy)-pyridinyl]-arnidc di-TFA salt. Off-White solid, LCMS m/z = 573 (M + 1); 1H NMR DMSO) 5: 11.29 (s, 1H), 8.75 (d, 1 H, J = 6.2 Hz), 8.50 (d, 1H, J = 2.8 Hz), 8.42 (m, 1H), 7.99 (dd, 1H, J = 9, 2.9 Hz), 7.70 (s, 1H), 7.51 -104— (s, 1H), .37 (m, 4H), 6.93 (d, 1H, J = 6.1 Hz), 4.91 (m, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 1.38 (d, J = 6.6 Hz).
Example 111.
Qfififlg 3-Fluoro(7-methoxy-quinolinyloxy)-phenylamine; hydrochloride.
Step a. A e of 4-chloromethoxyquinoline (1.0 g mg, 5 mmol), ro hydroxyphenyl)-carbamic acid t-butyl ester (1.88 mg, 8.26 mmol) and 4- dimethylaminopyridine (1010 mg, 8.26 mmol) in N,N—dimethylformamide (25 mL) was stirred at 145 0C for 5h. The mixture was cooled to rt, the solvent was removed and the residue was taken in DCM and washed with water and brine. After drying, the solvent was evaporated. The crude product was purified by flash chromatography (hexanes:EtOAc 1:1) to give a white solid; LCMS = 385 (M + 1).
Step b. The intermediate from step-a was treated with 4M HCl in dioxane (4 mL, 50 mmol) and the mixture was stirred at rt overnight. The solvent was removed and the mixture was triturated with ether and dried to 368 mg (20%, two steps) of o(7- methoxy-quinolinyloxy)-phenylamine; hydrochloride. LCMS m/z = 285 (M + 1); 1H NMR (DMSO) 5: 8.98 (d, 1H, J = 6.6 Hz), 8.50 (d, 1H, J = 9.3 Hz), 7.78 (d, 1H, J = 2.4 Hz), 7.42 (t, 1H), 7.61 (m, 1H), 7.04-6.84 (m, 4H), 4.03 (s, 3H), 3.72 (s, 3H).
Step c. 4-(4-Fluorophenyl)isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine carboxylic acid [3-fluoro(7-methoxyquinolinyloxy)-phenyl]-amide TFA salt. This compound was synthesized from 3-fluoro(7-methoxy-quinolinyloxy)-phenylamine hydrochloride and 4-(4-fluorophenyl)isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4- necarboxylic acid using the procedure for example 103 to give a white solid, LCMS m/z = 560 (M + 1); 1H NMR (DMSO) 5: 10.98 (s, 1H), 8.88 (d, 1H, J = 6.1 Hz), 8.43 (d, 1H, J = 9.8 Hz), 8.04 (dd, 1H, J = 12.6, 2.2 Hz), 7.63-7.34 (m, 8H), 6.88 (d, 1H, J = 6.0 Hz), 4.90 (m, 1H), 1.38 (d, 6H, J = 6.6 Hz).
Example 112. 2012/065019 Ca F O O H I A N\N O 4-(4-Fluorophenyl)-3 ,5 -dioxo(2-oxo-propyl)-2,3 ,4,5 -tetrahydro-[1,2,4]triazine carboxylic acid [4-(6,7-dimethoxyquinolinyloxy)fluorophenyl]—amide. TFA salt off- white solid, LCMS m/z = 604 (M + 1); 1H NMR (DMSO) 5: 11.04 (s, 1H), 8.78 (d, 1H, J = 6.3 Hz), 8.02 (dd 1H, J = 11.5, 2.1 Hz), 7.73 (s, 1H), 7.62 (m, 2H), 7.55 (s, 1H), 7.39- 7.34 (m, 4H), 6.94 (d, 1H, J = 6.2 Hz), 4.02 (2s, 6H), 2.25 (s, 3H). e 113. /ohmN\ Cafilm/[LNGFO O N\N O 4-(4-Fluoro-phenyl)-3 ,5-dioxopropynyl-2,3 ,4,5 -tetrahydro-[1,2,4] triazine carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)fluoro-phenyl]—amide TFA salt. A mixture of example 107 (25 mg, 0.046 mmol), propargyl bromide (10 uL, 0.1 mmol), and ium carbonate (10 mg, 0.07 mmol) in N,N—dimethylformamide (1 mL) was stirred at rt 18h. The mixture was filtered, solvent was removed and the product was purified by reverse phase HPLC to give an off-white solid (7 mg, 30%). LCMS m/z = 586 (M + 1); 1H NMR (DMSO) 5: 10.99 (s, 1H), 8.71 (d, 1H, J = 6.1 Hz), 8.0 (dd, 1H, J = 2.3, 12.7 Hz), 7.68 (s, 1H), 7.65-7.58 (m, 2H), 7.4 (s, 1H), 7.37-7.35 (m, 4H), 6.84 (d, 1H, J = 5.8 Hz), 4.88 (d, 2H, J = 2.3 Hz), 4.01 (2s, 6H), 3.53 (s, 3H).
Example 114. \ / 2-Methyl-3 ,5 -dioxo-2,3 ,4,5 -tetrahydro-[1,2,4]triazinecarboxylic acid 7- dimethoxy-quinolinyloxy)fluoro-phenyl]—amide. TFA salt. A mixture of 2-methyl- 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazinecarboxylic acid (500 mg, 3 mmol) (Yuen, K.
J Org. Chem. 1962, 27, 976), 4-(6,7-dimethoxyquinolinyloxy)fluorophenylamine (0.80 g, 2.54 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazolyl)uronium hexafluorophosphate (1.06 g, 2.80 mmol) and N,N—diisopropylethylamine (1.33 mL, 7.64 mmol) in N,N—dimethylformamide (8 mL) was stirred at rt 18h. The solvent was removed and the residue was triturated with DCM collected and dried. Yield-quantitative, LCMS m/z = 468 (M + 1); 1H NMR (DMSO) 5: 12.69 (br s, 1H), 11.01 (s, 1H), 8.77 (d, 1H, J = 6.2Hz), 8.01 (dd, 1H, J = 2.2, 11.4 Hz), 7.72 (s, 1H), 7.64-7.57 (m, 2H), 7.56 (s, 1H), 6.92 (d, 1H, J = 5.6Hz), 4.03 (2s, 6H), 3.58 (s, 3H).
Example 115. 0319\ / o o f NJIYtkNH N‘nll’go| 2-Methyl-3,5-dioxopropynyl-2,3,4,5-tetrahydro-[1,2,4]triazinecarboxylic acid [4- (6,7-dimethoxy-uinolinyloxy)fluoro-phenyl]—amide. TFA salt A e of example 114 (100 mg, 0.2 mmol), propargyl bromide (60 uL, 0.7 mmol), and ium ate (44.4 mg, 0.321 mmol) in N,N—dimethylformamide (3 mL) was stirred at rt 18h.
The mixture was filtered and the solvent was removed. The product was purified by reverse phase HPLC to give an off-white solid (36 mg, 30%). LCMS m/z = 506 (M + 1); 1H NMR (DMSO) 8: 10.98 (s, 1H), 8.79 (d, 1H, J = 6.2 Hz), 8.00 (dd, 1H, J = 2.3, 12.5 Hz), 7.72 (s, 1H), 7.66-7.58 (m, 2H), 7.53 (s, 1H), 6.92 (d, 1H, J = 6.1 Hz), 4.61 (d, 2H, J = 2.4 Hz), 4.03 (2s, 6H), 3.65 (s, 3H), 3.29 (t, 1H, J = 2.4 Hz).
The following examples were synthesized from Example 114 using the procedure for Example 115.
Example 116. ”m\ / o /9 o o yl(5-rncthyl-isoxazolylrncthyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazinc- 6-carboxylic acid [4-(6,7-dimcthoxy-quinolinyloxy) fluoro-phcnyl]—arnidc. TFA salt.
Off-white solid; LCMS m/z = 563 (M + 1); 1H NMR (DMSO) 5: 10.99 (s, 1H), 8.76(d, J = 6.2 Hz, 1H), 8.0 (dd, 1H, J = 2.2, 12.6 Hz), 7.71 (s, 1H), 7.66-7.53 (m, 2H), 7.71 (s, 1H), 6.80 (d, 1H, J = 6.0 Hz), 6.27 (s, 1H), 5.05 (s, 2H), 4.02 (2xs, 6H), 3.66 (s, 3H), 2.38 (s, 3H). e 117. 2-Mcthyl-3,5-dioxopcntynyl-2, 3,4,5-tctrahydro-[1,2,4]triazinccarboxylic acid [4- (6,7-dirncthoxy-uinolinyloxy)fluoro-phcnyl]—arnidc. TFA salt. yellowish solid.
LCMS m/z = 534 (M + 1); 1H NMR (DMSO) 5: 10.98 (s, 1H), 8.75 (d, 1H, J = 6.2 Hz), 8.00 (dd, 1H, J = 2.3, 12.5 Hz), 7.71 (s, 1H), 7.66-7.57 (m, 2H), 7.53 (s, 1H), 6.89 (d, 1H, J = 6.0 Hz), 4.56 (s, 2H), 4.02 (2s, 6H), 3.65 (s, 3H), 2.18 (m, 2H), 1.04 (t, 3H, J = 7.5 Hz).
Example 118.
\ / O O III 0 4-(4-Hydroxy-but—2-ynyl)—2-rncthyl-3 ,5 -dioxo-2,3 ,4,5 -tctrahydro-[1 ,2,4] triazinc carboxylic acid [4-(6,7-dimcthoxy-quinolinyloxy)—3-fluoro-phcnyl]—arnidc. TFA salt Off-white solid; LCMS m/z = 536 (M + 1); 1H NMR (DMSO) 5: 10.98 (s, 1H), 8.74 (d, J = 6.1Hz, 1H), 7.99 (dd, 1H, J = 2.1, 12.7Hz), 7.70 (s, 1H), 7.65-7.54 (m, 2H), 7.51 (s, 1H), 6.87 (d, 1H, J = 5.9Hz), 4.65 (s, 2H), 4.07 (s, 2H), 4.02 (2xs, 6H), 3.65 (s, 2H).
Example 119.
WO 74633 4-(1 ,5 -Dimcthyl-1H-pyrazol-3 -ylmcthyl)—2-mcthyl-3 ,5 -dioxo-2,3 ,4,5 hydro- [1,2,4]triazinccarboxylic acid [4-(6,7-dimcthoxyquinolinyloxy)—3-fluorophcnyl]— amide. TFA salt Off-White solid; LCMS m/z = 576 (M + 1); 1H NMR (DMSO) 5: 11.00 (s, 1H), 8.81 (d, 1H, J = 6.3 Hz), 8.01 (d, 1H, 11.2 Hz), 7.74 (s, 1H), 7.65-7.59 (s, m, 3H), 6.96 (d, 1H, J = 5.9 Hz), 6.02 (s,1H), 5.01 (s, 2H), 4.04 (s, 6H), 3.84 (s, 3H), 3.65 (s, 3H), 2.07 (s, 3H).13.30 (s, 1H), 10.97 (s, 1H), 8.71(d, 1H, J = 6.0 Hz), 8.02 (dd, 1H, J = 12.7, 2.3 Hz), 7.68 (s, 1H), 7.65 (m, 1H), 7.65 (m,1H), 7.56 (m, 1H), 7.5 (s, 1H), 7.46-7.31 (2 m, 4H), 6.83 (d, 1H, J = 6.3 Hz),4.01 (s, 6H) Example 120.
/I:Q\ / o 0 IN/“3 NJJYtkNH lel/koI 2-Mcthyl-3 ,5 -dioxo(2-pyrazolyl-cthyl)-2,3 ,4,5 -tctrahydro- [1 ,2,4] triazinc carboxylic acid [4-(6,7-dimcthoxyquinolinyloxy)fluorophcnyl]—amidc. TFA salt Off- Whitc solid. LCMS m/z = 562 (M + 1); 1H NMR (DMSO) 5: 10.98 (s, 1H), 8.77 (d, 1H, J = 6.0 Hz), 8.01 (dd, 1H, J = 2.2, 12.6 Hz), 7.77 (d, 1H, J = 2.0 Hz), 7.72 (s, 2H), .57 (m, 2H), 7.55 (s, 1H), 7.42 (d, 1H, J = 1.4 Hz), 6.90 (d,1H, J = 6.0 Hz)), 6.22 (d, 1H, J :19 Hz), 4.39 (m, 2H), 4.22 (m, 2H),4.03 (2s, 6H), 3.61 (s, 3H).
Example 121.
UCQ\ / F / //\N N I o o NMNH )7“ N\ (ll/k0 2-Mcthyl(1-mcthyl-1H-[1,2,4]triazolylmcthyl)-3 ,5-dioxo-2,3 ,4,5-tetrahydro- [1,2,4]triazinccarboxylic acid [4-(6,7-dimcthoxy-quinolinyloxy)fluoro-phcnyl]— amidc TFA salt Off-White solid; LCMS m/z = 563 (M + 1); 1H NMR( DMSO) 5: 11.06 (s,1H), 8.78 (d, 1H, J = 6.3 Hz), 8.39 (s, 1H), 7.99 (dd, 1H, J = 2.3, 12.5 Hz), 7.93 (s, 1H), 7.68-7.58 (m, 2H), 7.73 (s, 1H), 6.93 (d, 1H, J = 6.2 Hz), 5.06 (s, 2H), 4.03 (s, 3H), 4.02 (s, 3H), 3.81 (s, 3H), 3.66 (s, 3H).
Example 122.
/I:Q\ / o 0 NMNH j“ N‘lil’goI orncthylrncthyl-3 ,5 -diox0-2, 3 ,4,5 -tctrahydro-[1 ,2,4]triazinccarb0xylic acid [4-(6,7-dirncth0xy-quinolinyloxy)flu0r0-phcnyl]—arnidc. TFA salt; LCMS m/z = 507 (M + 1); 1H NMR (DMSO) 5: 10.95 (s, 1H), 8.76 (d, 1H, J = 6.2 Hz), 7.81 (dd, 1H, J = 2.2, 12.6 Hz), 7.72 (s, 1H), 7.68-7.58 (m, 2H), 7.56 (s, 1H), 4.92 (s, 2H), 4.03 (s, 3H), 4.02 (s, 3H), 3.66 (s, 3H).
Example 123.
UCQ\ / O O J NJKHLNH I N\”1&0 4-Ethylrncthyl-3,5-di0X0-2,3,4,5-tetrahydr0-[1,2,4]triazinccarboxylic acid [4-(6,7- dirncthoxyquinolinyloxy)fluor0-phcnyl]-arnidc TFA salt. LCMS m/z = 496 (M + 1); 1H NMR (DMSO) 5: 11.03 ((s, 1H), 8.78 (d, 1H, J = 6.2 Hz), 8.04 (dd, 1H, J = 2.2, 12.6 Hz), 7.72 (s, 1H), .58 (m, 2H), 7.55 (s, 1H), 6.92 (d, 1H, J = 6.2 Hz), 4.03 (s, 6H), 3.89 (q, 2H, J = 7.1 Hz), 3.64 (s, 3H), 1.18 (t, 3H, J = 7.1Hz).
Example 124. 0319\ / o o f/ NJIYtkNH WACI 4-Allylmcthyl-3,5-di0X0-2,3,4,5-tetrahydro-[1,2,4]triazinccarb0xylic acid [4-(6,7- dimcthoxy-quinolinyloxy)flu0r0-phcnyl]—arnidc TFA salt. LCMS m/z = 508 (M + 1); 1H NMR DMSO) 5: 11.00 (s, 1H), 8.76 (d, 1H, J = 6.2 Hz), 8.02 (dd, 1H, J = 2.0, 12.6 -1 10- Hz), 7.72 (s, 1H), 7.67-7.57 (m, 2H), 7.53 (s, 1H), 6.90 (d, 1H, J = 6.0 Hz), 5.84 (m, 1H), .23 (ddd, 2H, J = 25.8, 7.2 and 1.4 Hz), 4.46 (d, 1H, J = 4.3 Hz), 4.03 (25, 6H), 3.65 (s, 3H).
Example 125. 03K}\ / 4-Cyclopropylmethylrnethyl-3 ,5-di0X0-2,3 ,4,5 -tetrahydro-[1 riazinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)flu0r0-phenyl]—arnide TFA salt. LCMS m/z = 522 (M + 1); 1H NMR (DMSO) 5: 11.01 (s, 1H), 8.74 (d, 1H, J = 6.1 Hz), 8.01 (m, 1H), 7.70(s, 1H), 7.65-7.59 (m, 2H), 7.53 (s, 1H), 6.87 (d, 1H, J = 6.0 Hz), 4.02 (25, 6H), 3.92 (m, 1H), 3.75 (d, 1H, J = 7.0 Hz), 3.64 (s, 3H), 2.36 (m, 2H), 1.18 (m, 1H), 0.49 (m, 1H), 0.38 (m, 1H).
Example 126. /o N\ \ / F O o 0 “MNH | N\N’kO 2-Methyl-3 ,5 -di0x0(tetrahydr0-pyranylrnethyl)-2,3 ,4,5 -tetrahydro-[1 ,2,4]triazine carboxylic acid [4-(6,7-dirneth0xy-quinolinyloxy)- 0-phenyl]—amide TFA salt .
LCMS m/z = 566 (M + 1); 1H NMR (DMSO) 5: 10.99 (s, 1H), 8.75 (d, 1H, J = 6.1 Hz), 8.01 (dd, 1H, J = 12.6, 2.3 Hz), 7.71 (s, 1H), 7.65-7.57 (m, 2H), 7.52 (s, 1H), 6.88 (d, 1H, J = 6.1 Hz), 4.02 (25, 6H), 3.84 (m, 2H), 3.76 (d, 2H, J = 7.0 Hz), 3.64 (s, 3H), 3.24 (m, 3H), 2.02 (m, 1H), 1.57 (m, 2H), 1.27 (m, 2H).
Example 127. /o N\ \ / O O f NijNH | N\TAO 4-Isobutylmcthyl-3,5-di0X0-2,3,4,5-tetrahydr0-[1,2,4]triazinccarboxylic acid [4-(6,7- dimcthoxy-quinolinyloxy)flu0r0-phcnyl]—arnidc TFA salt. LCMS m/z = 524 (M + 1); 1H NMR (DMSO) 8: 11.02 (s, 1H), 8.76 (d, 1H, J = 6.2 Hz), 8.01 (dd, 1H, J = 2.3, 12.6 Hz), 7.71 (s, 1H), 7.66-7.57 (m, 2H), 7.53 (s, 1H), 6.90 (d, 1H, J = 5.9 Hz), 4.03 (25, 6H), 3.70 (d, 2H, J = 7.3 Hz), 3.64 (s, 3H), 2.07 (m, 1H), 0.90 (d, 6H, J = 6.7 Hz).
Example 128. /o N\ \ / 4-Cyclobutylrncthylrncthyl-3 ,5 -di0X0-2,3 ,4,5 -tctrahydr0- [1 ,2,4]triazinccarb0xylic acid 7-dirncth0xy-quinolinyloxy)flu0r0-phcnyl]—arnidc. TFA salt. LCMS m/z = 536 (M + 1); 1H NMR (DMSO) 5: 11.02 (s, 1H), 8.79 (d, 1H, J = 6.3 Hz), 8.01 (dd, 1H, J = 2.2, 12.4 Hz), 7.74 (s, 1H), 7.69-7.58 (m, 2H), 7.55 (s, 1H), 6.95 (d, 1H, J = 6.2 Hz), 4.03 (s, 6H), 3.92 (d, 2H, J = 7.0 Hz), 3.63 (s, 3H), 2.66 (m, 1H), 1.99 (m, 2H), 1.81 (m, 4H).
Example 129. 0319\ / o o f NMNH | 4-(2,2-Dirncthylpropyl)rncthyl-3 , 5 -di0X0-2,3 ,4,5 -tctrahydro-[1 ,2,4]triazinc ylic acid [4-(6,7-dimcthoxyquinolinyloxy)—3-flu0r0phcnyl]—arnidc TFA salt.
LCMS m/z = 538 (M + 1); 1H NMR (DMSO) 5: 11.0 (s, 1H), 8.72 (d, 1H, J = 6.0 Hz), 7.99 (dd, 1H, J = 2.2, 12.5 Hz), 7.69 (s, 1H), 7.63-7.55 (m, 2H), 7.50 (s, 1H), 6.83 (d, 1H, J = 5.8 Hz), 4.01 (25, 6H), 3.63 (s, 3H), 0.94 (s, 9H).
Example 130.
”Di:\ / 0 O 3) “MNH I N\ "1&0 ::2-Methyl(2-methyl-butyl)-3 ,5 -dioxo-2,3 ,4,5 -tetrahydro-[1,2,4]triazinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)fluoro-phenyl]-amide TFA salt. LCMS m/z = 538 (M + 1); 1H NMR (DMSO) 5: 11.01 (s, 1H), 8.76 (d, 1H, J = 6.2 Hz), 8.01 (dd, 1H, J = 2.2, 12.6 Hz), 7.71 (s, 1H), 7.66-7.57 (m, 2H), 7.53 (s, 1H), 6.89 (d, 1H, J = 6.1 Hz), 4.03 (2s, 6H), 3.76 (m, 2H), 3.64 (s, 3H), 1.87 (m, 1H), 1.40 (m, 1H), 1.17 (m, 1H), 0.87 (m, 6H).
Example 131. o N\ Ca:”MNOFO O N‘N’go 3 -(4-Fluoro-phenyl)methyl-2,4-dioxo-1 ,2,3 ,4-tetrahydro-pyrimidine-5 xylic acid [4-([1,3]dioxolo[4,5-g]quinolinyloxy)fluoro-phenyl]-amide, TFA salt. This compound was synthesized from uorophenyl)methyl-2,4-dioxo-1,2,3,4- tetrahydro-pyrimidinecarboxylic acid and -dioxolo[4,5-g]quinolinyloxy) fluoro-phenylamine hydrochloride (LCMS m/z = 299 (M + 1); 1H NMR (DMSO) 5: 8.80 (d, 1H, J = 6.6 Hz), 7.85 (s, 1H), 7.74 (s, 1H), 7.31 (t, 1H, J = 8.9 Hz), 6.94 (dd, 1H, J = 6.6, 0.8 Hz), 6.87 (dd, 1H, J = 12.6, 2.2 Hz), 6.76 (d, 1H, J = 12.6, 2.1 Hz), 6.43 (s, 2H); synthesized using the procedure for example 111 steps a-b)) using the procedure for examples 103. LCMS m/z = 545 (M + 1); 1H NMR (DMSO) 5: 11.08 (s, 1H), 8.89 (s, 1H), 8.69 (d, 1H, J = 6.0 Hz), 8.43 (d, 1H, J = 9.8 Hz), 8.05 (dd, 1H, J = 12.8, 2.4 Hz), 7.76 (s, 1H), 7.68-7.52 (2 m and a s, 3H), 7.48-7.31 (m, 4H), 6.84 (d, 1H, J = 5.9 Hz), 6.36 (s, 2H), 3.54 (s, 3H).
Example 132. cm“; . 1-Ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid [4- (2,3-dihydro-[1, 4]dioxino[2,3-g]quinolinyloxy)fluoro-phenyl]-amide TFA salt. This compound was synthesized from 1-ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4- tetrahydropyrimidinecarboxylic acid and 4-(2,3-dihydro-[1,4]dioxino[2,3-g]quinolin fluorophenylamine using the procedure for examples 103. LCMS m/z = 545 (M + 1); 1H NMR (DMSO) 5: 11.09 (s, 1H), 8.89 (s, 1H), 8.78 (d, 1H, J = 6.2 Hz), 8.43 (d, 1H, J = 9.8 Hz), 8.07 (dd, 1H, J = 12.8, 2.2 Hz), 7.83 (s, 1H), 7.62-7.50 (2 m and a s, 3H), 7.44-7.32 (2m, 4H), 6.85 (d, 1H, J = 6.1 Hz), 4.49 (m, 4H), 4.02 (q, 2H, J = 7.0 Hz), 1.30 (t, 3H, J = 7.0 Hz).
Example 133.
/I>Q\ / 0 00 NHJJYlLN 2-Cyclopropylmethyl(4-fluorophenyl)-3 xo-2,3 ,4,5 -tetrahydro-[1 ,2,4]triazine carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)fluoro-phenyl]-amide TFA salt.
This compound was synthesized from 1-cyclopropylmethyl(4-fluorophenyl)-2,4-dioxo- 1,2,3,4-tetrahydropyrimidinecarboxylic acid and 4-(6,7-dimethoxyquinolinyloxy) fluorophenylamine using the procedure for example 103. LCMS m/z = 602 (M + 1); 1H NMR (DMSO) 5: 10.98 (s, 1H), 8.72 (d, 1H, J = 5.9 Hz), 8.02 (dd 1H, J = 12.6, 2.2 Hz), 7.69 (s, 1H), 7.66-7.56 (m, 2H), 7.50 (s, 1H), .36 (m and s, 4H), 7.27 (m, 1H), 6.85 (d, 1H, J = 5.1 Hz), 5.12 (m, 1H), 4.02 (m and 2s, 7H), 2.49 (m, 1 H), 2.32 (m, 2H), 1.80 (m, 2H).
Example 134.
HNCZ F O O Step a. 4-Chloro-6,7-dimethoxyquinoline (0.40 g, 1.79 mmol, p-nitroaniline (0.414 g, 2.68 mmol) and p-toluenesulfonic acid (0.154 g, 0.894 mmol) in 1-methoxypropanol (5 mL) were heated to 120 0C for 8h. The mixture was cooled to rt, triturated with ether and filtered to yield (6,7-dimethoxyquinolinyl)-(4-nitrophenyl)amine (0.43 g, 73%). LCMS m/z = 326 (M + 1); 1H NMR (DMSO) 5: 14.37 (s, 1H), 10.72 (s,1H), 8.54 (d, 1H, J = 6.80 Hz), 8.39 (d, 2H, J = 9.08 Hz), 8.05 (s, 1H), 7.74 (d, 2H, J =9.09 Hz), 7.47 (d, 1H, 8.13 -114— 2012/065019 Hz), 7.43 (s, 1H), 7.19 (d, 1H, J = 6.85), 7.10 (d, 1H, J = 7.84),4.02 (d, 7H, J = 5.48), 2.28, (s, 1H).
Step b. N-(6,7-Dimethoxyquinolinyl)-benzene-1,4-diamine. imethoxyquinolin yl)-(4-nitrophenyl)amine (0.425 g, 1.31 mmol), palladium hydroxide 4 g, 0.601 mmol) and potassium carbonate (0.542 g, 3.92 mmol) in ol (106 mL) were hydrogenation on a Parr apparatus at 40 psi overnight. The mixture was filtered through Celite and concentrated to yield a crude product which was purified by prep. HPLC to yield N—(6,7-dimethoxyquinolinyl)-benzene-1,4-diamine (0.13 g, 33%). LCMS m/z = 296 (M + 1).
Step c. 1-Ethyl(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid [4-(6,7-dimethoxy-quinolinylamino)-phenyl]-amide 1 -Ethyl(4-fluorophenyl)- 2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid (0.104 g, 0.372 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazolyl)uranium hexafluorophosphate (0.154 g, 0.406 mmol) in N,N—dimethylformamide (5 mL) was added N,N—diisopropylethylamine (0.425 mL, 2.44 mmol). After 15 min N—(6,7-dimethoxyquinolinyl)-benzene-1,4- diamine (0.10 g, 0.34 mmol) was added and stirred at rt for18 h. The reaction mixture was evaporated under vacuum, quenched with saturated NaHC03 solution and extracted with CHzClz. The combined organics were washed with brine, dried (Na2S04), filtered and concentrated to obtain a crude product which was purified by prep. HPLC to give a brown solid (0.58 g, 31%). mp = 178-181 0C (CHCl2, MeOH, ether and hexane); LCMS m/z = 556 (M + H); 1H NMR (DMSO-d6) 5: 10.85 (s, 1H), 8.85 (s, 1H), 8.65 (s, 1H), 8.25 (d, 1H, J = 6.3Hz), 7.70 (d, 2H, J = , 7.65 (s, 2H), 7.45-7.29 (m, 7H),7.23 (s, 1H), 6.74 (d, 1H, J = 5.3Hz), 4.01 (d, 2H, J = 7.1Hz), 3.91 (d, 7H, J = 10.6), 1.30 (t, 3H, J = 7.1).
Example 135.
HNOMOF0 O 3 -(4-Fluorophenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine-5 xylic acid [4-(6,7-dimethoxyquinolinylamino)-phenyl]-amide. This compound was synthesized using N—(6,7-dimethoxyquinolinyl)-benzene-1,4-diamine and 3-(4-fluorophenyl) isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-carboxylic acid the method for WO 74633 example 134. mp = 190-193 0C; LCMS m/z = 570 (M + 1); 1H NMR (DMSO- d6) 5: 10.85 (s, 1H), 8.65 (brs, 2H), 8.26 (d, 1H, J = 5.3 Hz), 7.71 (d, 2H, J = 8.8 Hz), 7.65 (s, 1H), 7.27-7.47 (m, 7H), 7.23 (s, 1H), 6.75 (d, 1H, J = 5.3 Hz), 4.72-4.84 (m, 1H), 3.92 (s, 3H), 3.90 ( s, 3H), 1.42 (d, 7H, J = 6.8 Hz).
Example 136.
Q F 0 O 4-(4-Fluoro-phenyl)isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazinecarboxylic acid [4-(6,7-dimethoxy-quinolinylamino)-phenyl]-amide. This compound was synthesized using N—(6,7-dimethoxyquinolinyl)-benzene-1,4-diamine and 4-(4- fluorophenyl)isopropyl-3 ,5-dioxo-2,3 ,4,5-tetrahydro[1,2,4]triazinecarboxylic acid by the method for example 134. mp = 152-155 0C; LCMS m/z = 571 (M + 1); 1H NMR (DMSO- d6) 5: 8.67 (s, 1H), 7.68 (d, 2H, J = 8.87 Hz), 7.54 (d, 2H, J = 8.68 Hz), 7.20-7.34 (m, 12H), 7.10 (brs, 1H), 6.99 (s,1H), 6.60 (d, 2H, J = 8.6 Hz), 4.04 (d, 7H, J = 2.2 Hz), 3.79 (brs, 2H), 1.21 (t, 1H, J = 7.0 Hz), .91 (m, 1H).
Example 137.
Step a. 4-[(6,7-dimethoxyquinolyl)sulfanyl]aniline. 4-Chloro-6,7-dimethoxyquinoline (0.40 g, 1.79 mmol) and othiophenol (0.379 g,2.68 mmol) in N,N— dimethylformamide (5 mL) was d at rt for 8 h. The product was extracted with calcium carbonate, washed with brine, dried with sodium sulfate, filtered and concentrated. The crude product was dissolved in CHzClz and was recrystallized with ether and hexanes, and was filtered to yield 4-[(6,7-dimethoxyquinolyl)sulfanyl]aniline (0.49 g, 88%) as a yellow solid. mp = 235-238 0C LCMS m/z = 313 (M + 1); 1H NMR (CDC13)52 8 8.58 (d, 1H, J = 6.41Hz), 7.51 (s, 1H), 7.46 (s, 1H), 7.31 (d, 2H, J = 8.7 Hz), 6.81(d, 1H, J = 6.1Hz), 6.77 (d, 2H, J = 8.6Hz), 4.03 (d, 7H, J = 5.6 Hz). /0 N\ \ / 2012/065019 Step b. 1-Ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid [4-(6,7-dimethoxy-quinolinylsulfanyl)-phenyl]-amide. l(4- fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid and 4-(6,7- dimethoxyquinolinylsulfanyl)phenylamine were coupled using the procedure for example 134 to produce 1-ethyl(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro- pyrimidinecarboxylic acid [4-(6,7-dimethoxy-quinolinylsulfanyl)-phenyl]-amide as a white solid, mp = 241-244 0C; LCMS m/z = 573 (M + 1); 1H NMR (DMSO-dg) 5:11.04 (s, 1H), 8.88 (s, 1H), 8.43 (d, 1H, J = 4.8 Hz), 7.84 (d, 2H, J = 8.72 Hz), 7.58 (d, 2H, J = 8.7 Hz),7.30-7.44 (m, 6H), 6.64 (d, 1H, J = 4.9 Hz), 4.01 (q, 2H, J = 7.05 Hz), 3.96 (q, 7H, J = 6.4 Hz), 1.29 (t, 3H, J = 7.1 Hz).
Example 138.
SQ F o o 3 -(4-Fluoro-phenyl)isopropyl-2,4-dioxo-1,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid [4-(6,7-dimethoxy-quinolinylsulfanyl)-phenyl]-amide. This compound was sized using the procedure for example 134 to give a light tan solid. mp = 236-239 0C; LCMS m/z = 587 (M + 1); 1H NMR (DMSO- d6) 5: 11.04 (s, 1H), 8.67 (s, 1H), 8.44 (d, 1H, J = 4.8 Hz), 7.84 (d, 2H, J = 8.78 Hz), 7.58 (d, 2H, J = 8.7 Hz), 7.30-7.47 (m, 7H), 6.71 (d, 2H, J = 4.9 Hz), .81 (m, 1H), 3.92 (d, 7H, J = 7.1 Hz), 1.42 (d, 7H, J = 6.8).
Example 139.
”QMOFo o Step a. 4-Chloro-6,7-dimethoxyquinoline (0.50 g, 2.24 mmol), N-methyl(4- nitrophenyl)amine; (0.564 g, 3.35 mmol) and p-toluenesulfonic acid (0.192 g, 1.12 mmol) in 1-methoxypropanol (6.56 mL, 67.1 mmol) were heated tol20 0C for 8h. The reaction was cooled to rt, triturated with ether and filtered to yield (6,7- dimethoxyquinolinyl)methyl(4-nitrophenyl)amine (0.40 g, 40%). LCMS m/z = 340 (M WO 74633 + 1); 1H NMR (CDCl3) 5: 8.80 (d, 1H, J = 4.8 Hz), 8.10 (d, 2H, J = 9.4 Hz),7.5 (brs, 1H), 7.16 (d, 1H, J = 4.8), 6.84 (s, 1H), 6.64 (d, 2H, J = 9.4 Hz), 4.05 (s, 3H), 3.81 (s, 3H), 3.52 (s, 3H).
Step b. (6,7-Dimethoxyquinolinyl)-methyl-(4-nitrophenyl)amine (0.30 g, 0.88 mmol), potassium carbonate (1.3 g, 9.4 mmol) and ium hydroxide (1.00 g, 7.12 mmol) was hydrogenated in a e of l (32 mL, 540 mmol), N,N-dimethylformamide (5 mL, 60 mmol) and methylene chloride (19 mL, 290 mmol) at 40 psi overnight. The mixture was filtered through Celite, and washed with calcium carbonate solution and brine then dried over sodium sulfate and concentrated to yield a crude product. This material was purified by prep. HPLC to yield [N-(6,7-Dimethoxy-quinolinyl)-N-methyl-benzene- 1,4-diamine (0.180 g, 66%). LCMS m/z = 310 (M + 1).
Step c. 3 -(4-Fluorophenyl)isopropyl-2,4-dioxo-1 ,2,3 rahydropyrimidine-5 - carboxylic acid {4-[(6,7-dimethoxy-quinolinyl)-methyl-amino]-phenyl}-amide. This compound was synthesized using 3-(4-fluorophenyl)isopropyl-2,4-dioxo-1,2,3,4- tetrahydro-pyrimidinecarboxylic acid and N—(6,7-dimethoxyquinolinyl)-N-methyl- benzene-1,4-diamine by the method described for example 134. mp = 224-227 0C; LCMS m/z = 584 (M + 1); 1HNMR(CDC13) 5: 10.66 (s, 1H), 8.65 (s, 1H), 8.64 (d, 1H, J = 5.0 Hz), 7.51 (d, 2H, J = 9.0 Hz), 7.38 (s, 1H), 7.00 (d, 1H, J = 5.8 Hz), 6.90 (s, 1H), 6.86 (d, 2H, J = 9.0 Hz), 4.90-5.00 (m, 1H), 4.00 (t, 3H), 3.63 (t, 3H), 3.44 (t, 3H).
Example 140. /o N\ \ / 1-Ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid {4- [(6,7-dimethoxy-quinolinyl)-methylamino]-phenyl}-amide. This compound was synthesized using 1-ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3 ,4-tetrahydropyrimidine carboxylic acid and N—(6,7-dimethoxyquinolinyl)-N-methyl-benzene-1,4-diamine by the method described for example 134. mp = 199-202 0C; LCMS m/z = 570 (M + 1); 1H NMR(CDC13)5: 10.62 (s, 1H), 8.64 (d, 1H, J = 5.0 Hz), 8.60 (s, 1H), 7.50 (d, 2H, J = 9.0 Hz), 7.38 (s, 1H), 7.31 (s, 1H), 7.00 (d, 1H, J = 5.3 Hz), 6.90 (s, 1H), 6.86 (d, 2H J = 8.9 Hz), 4.01 (s, 1H), 4.00 (s, 3H), 3.63 (s, 3H), 3.44 (s, 3H).
Example 141. 0QV10Fo o Step a. 4-(6,7-Dimethoxy-quinazolinyloxy)-phenylamine. 4-Chloro-6,7-dimethoxy- quinazoline (0.500 g, 2.22 mmol), 4-aminophenol (0.291 g, 2.67 mmol), 2-butanone (4.01 mL, 44.5 mmol), 2N sodium hydroxide solution (1.00 mL, 0.213 mmol), and tetra-N- butylammonium bromide (0.308 g, 0.957 mmol) were combined and heated to reflux (80 0C) for 15 min. The reaction was cooled to rt. DCM was added and washed with calcium carbonate solution and brine, then dried over sodium sulfate and concentrated to yield a crude product. The solid was ated with diethyl ether and hexanes to yield 4-(6,7- dimethoxyquinazolinyloxy)-phenylamine (0.52 g, 78%). LCMS m/z = 298 (M + 1).
Step b. 3 -(4-Fluoro-phenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydro-pyrimidine-5 - carboxylic acid [4-(6,7-dimethoxy-quinazolinyloxy)-phenyl]-amide. This compound was synthesized using -dimethoxyquinazolinyloxy)-phenylamine and 3-(4- fluorophenyl)isopropyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid by the procedure for e 134. mp = 1 0C; LCMS m/z = 572 (M + 1); 1H NMR (CDC13)83 10.86 (s, 1H), 8.70 (s, 1H), 8.62 (s, 1H), 7.76 (d, 2H, J = 9.0 Hz), 7.54 (s, 1H), 7.32 (s, 1H), 4.90-5.03 (m, 1H), 4.06 (t, 7H, J = 20 Hz).
Example 142. 0Q F o o 1-Ethyl(4-fluorophenyl)-2,4-dioxo-1 ,2,3 ,4-tetrahydro-pyrimidine-5 xylic acid [4- (6,7-dimethoxy-quinazolinyloxy)-phenyl]-amide. This compound was synthesized using 1-ethyl(4-fluorophenyl)-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid and 4-(6,7-dimethoxy-quinazolinyloxy)-phenylamine by the procedure for example 134. mp = 1 0C; LCMS m/z = 558 (M+H); 1H NMR (CDCl3): 5 10.82 (s, 1H), 8.63 (d, 2H J = 6.5 Hz), 7.76 (d, 2H, J = 9.0 Hz), 7.55 (s, 1H), 7.32 (s, 1H), 7.23 (d, 2H, J = 8.9 Hz), 4.07 (s, 7H), 4.03 (q, 3H, J = 7.2 Hz), 1.59 (s, 1H), 1.49 (s, 1H), 1.46 (t, 3H, 7.2 Hz), 1.20 (t, 1H, J = 7.0 Hz), 1.03 (t, 1H, J = 7.3 Hz).
Example 143. /o N\ \ / Q 0 00N MeO Hkfii NK 0 Step a. A solution of 4-chloro-6,7-dimethoxyquinoline (0.4 g, 2 mmol) , 3-methoxy henol (0.30 g, 1.8 mmol) and 4-dimethylaminopyridine (0.011 g, 0.089 mmol) in chlorobenzene (5 mL) was stirred at 140 OC overnight. After cooling to rt the solid that formed was filtered and dried to yield pure product 0.48 g (75%), MS: 357 (M+H).
Step b. 6,7-Dimethoxy(3-methoxynitrophenoxy)quinoline was hydrogenated in EtOH/DMF using 10% Pd/C at 40 psi to yield 4-(6,7-dimethoxyquinolinyloxy) methoxy-phenylamine. LCMS m/z = 327 (M + 1); 1H NMR (DMSO) 5: 8.43 (d, 1H, J = 6 Hz), 7.5 (s, 1H), 7.37 (s, 1H), 6.76 (d, 1H, J = 2.6 Hz), 6.72 (d, 1H, J = 9 Hz), 6.60 (dd, 1H, J = 2.5, 8.5 Hz), 6.41 (d, 1H, J = 5.6 Hz), 3.75 (s, 3H), 3.31 (s, 6H). 1-Ethyl(4-fluorophenyl)-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid [4- (6,7-dimethoxy-quinolinyloxy)methoxyphenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxyquinolinyloxy)methoxy-phenylamine and 1- ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid using the procedure for e 1. LCMS m/z = 587 (M + 1); 1H NMR(CDC13) 5: 11 (s, 1H), 8.63 (s, 1H), 8.54 (d, 1H, J = 9 Hz), 8.49 (d, 1H, J = 5 Hz), 7.55 (s, 1H), 7.42 (s, 1H), 7.26-7.23 (m, 3H), 6.82 (dd, 1H, J = 3, 9 Hz), 6.74 (d, 1H, J = 3 Hz), 6.52 (d, 1H, J = 6 Hz), 4.05 (d, 6H), 4.01 (q, 2H, J = 8 Hz), 3.85 (s, 3H), 1.45 (t, 3H, J = 8 Hz).
Example 144. /o N\ \ / Q 0 00N MeO Hwi )1 o WO 74633 1-Methyl(4-fluoro-phenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)methoxy-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxyquinolinyloxy)methoxy-phenylamine and 3-(4- fluorophenyl)methyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid using the procedure for example 1. LCMS m/z = 573 (M + 1); 1H NMR(CDC13) 5: 11 (s, 1H), 8.61 (s, 1H), 8.54 (d, 1H, J = 9 Hz), 8.49 (d, 1H, J = 5 Hz), 7.55 (s, 1H), 7.42 (s, 1H), 7.26-7.23 (m, 4H), 6.81 (dd, 1H, J = 3, 9 Hz), 6.74 (d, 1H, J = 3 Hz), 6.5 (d, 1H, J = 5 Hz), 4.05 (s, 6H), 3.84 (s, 3H), 3.61 (s, 3H).
Example 145.
/O N\ \ / Q 0 00F 1-Isopropyl(4-fluoro-phenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)methoxy-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxyquinolinyloxy)methoxy-phenylamine and 3-(4- fluorophenyl)isopropyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid using the procedure for example 1. LCMS m/z = 601 (M + 1); 1H NMR(CDC13) 5: 11.0 (s, 1H), 8.68 (s, 1H), 8.54 (d, 1H J = 9 Hz), 8.5 (d, 1H, J = 6 Hz), 7.55 (s, 1H), 7.42 (s, 1H), 7.25- 7.23 (m, 3H), 6.81 (dd, 1H, J = 3.9 Hz), 6.74 (d, 1H, J = 3 Hz), 6.52 (d, 1H, J = 6 Hz), 4.96 (p, 1H, J = 7 Hz), 4.05 (d, 6H), 3.83 (s, 3H), 1.47 (d, 6H, J = 6 Hz).
Example 146.
/O N\ 1 W50FO O F F H l A Ii] 0 Step a. Potassium utoxide (0.13 g, 1.12 mmol) was added to 4-aminofluorophenol in dry N—methylpyrrolidinone (5 mL, 50 mmol) at rt and stirred for 30 min under an atmosphere of nitrogen . Then solid 4-bromo-6,7-dimethoxyquinoline (0.30 g, 1.1 mmol) was added and the reaction d at 100 0C for 30 h. The mixture was concentrated, ved in EtOAc (~75 mL), and washed 1x with 1N Na2C03, water and NaCl solution, then dried over MgSO4. The t was chromatographed on silica gel (5% MeOH/DCM) to give -dimethoxyquinolinyloxy)-2,3-difluoro-phenylamine 0.066 g (18%). LCMS m/z = 333 (M + 1). 1H NMR(CDC13) 5: 8.5 (d, 1H, J = 8 Hz), 7.58 (s, 1H), 7.44 (s, 1H), 6.89-6.83 (m, 1H), 6.64-6.58 (m, 1H), 6.42 (d, 1H, J = 5 Hz), 4.05 (d, 6H, J = 5 Hz).
Step b. yl(4-fluorophenyl)-2,4-dioxo-1,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)-2,3-difluoro-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxyquinolinyloxy)-2,3-difluoro-phenylamine and 3 -(4-fluorophenyl)methyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid using the procedure for example 1. mp = 226-267 0C; LCMS m/z = 579 (M + 1); 1H NMR )52 11.07 (s, 1H), 8.62 (s, 1H), 8.51 (d, 1H, J = 6 Hz), 8.25 (m, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.25-7.23 (m, 4H), 7.05 (m, 1H), 6.46 (d, 1H, J = 5 Hz), 4.05 (d, 6H), 3.65 (s, 3H).
Example 147. /o N\ F/Q F o o O F #1 )N o 1-Ethyl(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid [4- (6,7-dimethoxy-quinolinyloxy)-2,3-difluoro-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxyquinolinyloxy)-2,3-difluoro-phenylamine and 1- ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid using the procedure for example 1. mp = 270-272 0C; LCMS m/z = 593 (M + 1); 1H NMR (CDC13)52 11.08 (s, 1H), 8.63 (s, 1H), 5.51 (d, 1H, J = 6 Hz), 8.28-8.22 (m, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.25-7.23 (m, 4H), 7.09-7.03 (m, 1H), 6.46 (d, 1H, J = 5 Hz), 4.05 (d, 6H), 4.04-3.99 (m, 2H), 1.47 (t, 3H, J = 8 Hz).
Example 148.
:QMOF0 O Step a. 4-(6,7-Dimethoxy-quinolinyloxy)methylphenylamine was synthesized using the procedure for example 143 steps a/b. LCMS m/z = 311 (M + 1).
Step b. 1-Ethyl(4-fluoro-phenyl)-2,4-dioxo-1,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)methyl-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxy-quinolinyloxy)methylphenylamine and 1-ethyl- 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid using the procedure for example 1. mp = 265-267 0C; LCMS m/z = 571 (M + 1); 1H NMR (DMSO- d6) 5: 10.93 (s, 1H), 8.85 (s, 1H), 8.44 (d, 1H, J = 5 Hz), 7.73 (dd, 1H, J = 2, 8 Hz), 7.66 (d, 1H, J = 3 Hz), 7.55 (s, 1H), 7.46-7.33 (m, 5H), 7.18 (d, 1H, J = 8 Hz), 6.31 (d, 1H, J = 5 Hz), 4.02 (q, 2H, J = 8 Hz), 3.32 (s, 6H), 2.09 (s, 3H), 1.30 (t, 3H, J = 8 Hz).
Example 149. 3-(4-Fluoro-phenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid [4-(6,7- oxy-quinolinyloxy)methyl-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxy-quinolinyloxy)methylphenylamine and 3-(4-fluorophenyl)- 2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid using the procedure for example 1. mp = 2 0C; LCMS m/z = 543 (M + 1); 1H C13) 5: 10.74 (s, 1H), 8.61 (s, 1H), 8.45 (d, 1H, J = 5 Hz), 7.63-7.61 (m, 1H), 7.60 (s, 1H), 7.58-7.53 (m, 1H), 7.44 (s, 1H), 7.29-7.26 (m, 3H), 7.08 (d, 1H, J = 10 Hz), 6.30 (d, 1H, J = 5 Hz), 5.30 (s, 1H), 4.05 (d, 6H, J = 5 Hz), 2.05 (s, 3H).
Example 150.
MeO/Z: F O O 0/ NJKELNH | VITO 3-(4-Fluoro-phenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid 7- dimethoxy-quinolinyloxy)methoxy-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxy-quinolinyloxy)methoxy-phenylamine (LCMS m/z = 327 (M + 1)) and 3-(4-fluorophenyl)-2,4-dioxo-l,2,3,4-tetrahydropyrimidinecarboxylic acid using the procedure for example 1. LCMS m/z = 559 (M + l); 1H NMR (CDClg) 8: 10.94 (s, 1H), 8.69 (s, 1H), 8.45 (d, 1H, J = 6 Hz), 8.2 (d, 1H, J = 5 Hz), 7.61 (s, 1H), 7.42 (s, 1H), .26 (m, 3H), 7.2 (s, 1H), 6.57 (d, 1H, J = 7 Hz), 6.33 (d, 1H, J = 7 Hz), 5.30 (s, 1H), 4.05 (s, 6H), 3.76 (s, 3H).
Example 151.
MeOO/Q F O O l(4-fluoro-phenyl)-2,4-dioxo- l ,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)methoxy-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxy-quinolinyloxy)methoxy-phenylamine and lethyl (4-fluorophenyl)-2,4-dioxo-l ,2,3,4-tetrahydropyrimidinecarboxylic acid using the ure for example 1. mp = 245-247 0C; LCMS m/z = 587 (M + l); 1H NMR (DMSO-d6) 5: 10.98 (s, 1H), 8.89 (s, 1H), 8.46 (d, 1H, J: 6 Hz), 7.56 (d,lH, J = 2 Hz), 7.53 (s, 1H), 7.49 (dd, 1H, J = 3, 9 Hz), 7.45-7.41 (m, 2H), 7.39-7.34 (m, 3H), 7.25 (d, 1H, J = 9 Hz), 6.36 (d, 1H, J = 6 Hz), 4.01 (q, 2H, J =8 Hz), 3.95 (d, 6H), 3.71 (s, 3H), 1.3 (t, 3H, J =8 Hz).
Example 152. 0|:CZ F O O 3-Chloro(6,7-dimethoxy-quinolinyloxy)-phenylamine was synthesized using the procedure for example 146 step a, LCMS = 331 (M + l). l-Ethyl(4-fluoro-phenyl)-2,4-dioxo- l ,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid [3-chloro(6,7-dimethoxy-quinolinyloxy)methoxy-phenyl]-amide. This compound was synthesized using 3-chloro(6,7-dimethoxy-quinolin yloxy)phenylamine and l-ethyl(4-fluorophenyl)-2,4-dioxo- 1 ,2,3,4- tetrahydropyrimidinecarboxylic acid using the procedure for example 1. mp = 257-259 —124— 0C; LCMS m/z = 591 (M + 1); 1H NMR (DMSO-d6) 8: 11.0 (s, 1H), 8.88 (s, 1H), 8.47 (d, 1H, J = 6 Hz), 8.18 (d, 1H, J = 3 Hz), 7.71 (dd, 1H, J = 3, 9 Hz), 7.52 (s, 1H), 7.45-7.33 (m, 6H), 6.37 (d, 1H, J = 6 Hz), 4.0 (q, 2H, J = 7 Hz), 3.95 (d, 6H), 1.30 (t, 3H, J = 7 Hz).
Example 153. [5-(6,7-Dimethoxy-quinolinyloxy)methyl-phenyl]-dimethyl-amine was synthesized using the procedure for example 143 step a. LCMS m/z = 340 (M + 1). 1H NMR(CDC13) : 8.48 (d, 1H, J = 9 Hz), 7.89 (s, 1H), 7.63(s, 1H), 6.83 (d, 1H, J = 3 Hz), 6.80 (d, 1H, J = 8 Hz), 6.74 (dd, 1H, J = 3, 8.6 Hz), 6.66 (d, 1H, J = 5 Hz), 4.10 (d, 6H), 2.69 (s, 6H). 1-Ethyl(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid [4- (6,7-dimethoxy-quinolinyloxy)dimethylamino-phenyl]-amide. This compound was synthesized using [5-(6,7-dimethoxyquinolinyloxy)methylphenyl]dimethylamine and 1-ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid using the procedure for example 1. mp = 144-145 0C; LCMS m/z = 600 (M + 1); 1H NMR (DMSO-d6) 5: 11.18 (s, 1H), 8.87 (s, 1H), 8.51 (d, 1H, J = 9 Hz), 8.47 (d, 1H, J = 5 Hz), 7.51 (s, 1H), 7.45-7.33 (m, 5H), 7.10 (d, 1H, J = 3 Hz), 6.98 (dd, 1H, J = 3, 9 Hz), 6.49 (d, 1H, J = 5 Hz), 4.01 (q, 2H, J = 7 Hz), 3.94 (d, 6H), 2.58 (s, 6H), 1.29 (t, 3H, J = 7 Hz).
Example 154. gm“; 8919 3 -(4-Fluoro-phenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)dimethylamino- ]-amide. This nd was synthesized using [5-(6,7-dimethoxyquinolinyloxy) methylphenyl]dimethylamine and 3-(4-fluorophenyl)isopropyl-2,4-dioxo-1,2,3,4- tetrahydropyrimidinecarboxylic acid using the procedure for example 1. mp = 231-233 0C; LCMS m/z = 614 (M + 1); 1H NMR (DMSO-d6) 5: 11.19 (s, 1H), 8.67 (s, 1H), 8.52- 8.46 (m, 2H), 7.50 (s, 1H), 7.45-7.33 (m, 5H), 7.11 (d, 1H, J = 3 Hz), 6.97 (dd, 1H, J =3, 9 Hz), 6.50 (d, 1H, J = 5 Hz), 4.78 (p, 1H, J = 6 Hz), 3.94 (d, 6H), 2.58 (s, 6H), 1.42 (d, 6H, J: 6 Hz).
Example 155. /o N\ \ / Q o 00F NAKELNH | N/KO 4-(6,7-Dimethoxy-quinolinyloxy)isopropyl-phenylamine was synthesized using the ure for example 143 step a. LCMS m/z = 338 (M + 1); 1H NMR (CDC13) 8: 8.45 (d, 1H, J = 7 Hz), 7.63 (s, 1H), 7.27 (s, 1H), 6.88 (d, 1H, J = 8.5 Hz), 6.73-6.71 (m, 1H), 6.63-6.58 (m, 1H), 6.44 (d, 1H, J = 6 Hz), 4.07 (s, 6H), 2.98-2.90 (m, 1H0, 1.16 (d, 6H, J = 6 Hz). 1-Ethyl(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid [4- (6,7-dimethoxy-quinolinyloxy)isopropyl-phenyl]-amide. This nd was synthesized using 4-(6,7-dimethoxy-quinolinyloxy)isopropyl-phenylamine and 1- ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid using the procedure for example 1. mp = 173-175 S m/z = 599 (M + 1); 1H NMR (DMSO-d6) 5: 10.93 (s, 1H), 8.80 (s, 1H), 8.45 (d, 1H, J = 6 Hz), 7.76 (dd, 1H, J = 2, 8 Hz), 7.68 (d, 1H, J = 2 Hz), 7.55 (s, 1H), 7.46-7.33 (m, 5H), 7.16 (d, 1H, J = 8 Hz), 6.36 (d,1H, J =5 Hz), 4.01 (q, 2H, J = 8 Hz), 3.94 (d, 6H), 2.99 (m, 1H), 1.3 (t, 3H, J = 7 Hz), 1.14 (d, 6H, J = 7 Hz).
Example 156. /o N\ \ / NJKELNH | NAG 3 -(4-Fluoro-phenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)isopropyl-phenyl]- amide. This compound was synthesized using 4-(6,7-dimethoxy-quinolinyloxy)isopropyl-phenylamine and 3 -(4-fluorophenyl)isopropyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid using the procedure for example 1. mp = 165-167 S m/z = 613 (M + 1); 1H NMR )52 10.86 (s, 1H), 8.72 (s, 1H), 8.46 (d, 1H, J = 5.5 Hz), 7.66 (dd, 1H, J = 2.5, 8 Hz), 7.63 (d, 1H, J = 2 Hz), 7.60 (s, 1H), 7.44 (s, 1H), 7.27-7.25 (m, 3H), 7.05 (d, 1H, J = 9 Hz), 6.37 (d, 1H, J = 5.5 Hz), 4.98 (p, 1H, J = 8 Hz), 4.06 (s, 6H), 3.09 (p, 1H, J = 8 Hz), 1.5 (d, 6H, J = 7 Hz), 1.18 (d, 6H, J = 7 Hz).
Example 157.
@HiSE/[Ej/ 4-(6,7-Dimethoxy-quinolinyloxy)-2,3-dimethyl-phenylamine was synthesized using the procedure for example 143 step a. LCMS m/z = 325 (M + 1).; 1H NMR(CDC13) 5: 8.42 (d, 1H, J = 7 Hz), 7.64 (s, 1H), 7.42 (s, 1H), 6.83 (d, 1H, J = 8 Hz), 6.65 (d, 1H, J = 8 Hz), 6.26 (d, 1H, J = 8 Hz), 4.06 (d, 6H, J = 4.5 Hz), 2.15 (s, 3H), 2.06 (s, 3H). 1-Ethyl(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid [4- (6,7-dimethoxy-quinolinyloxy)-2,3-dimethyl-phenyl]-amide. This compound was synthesized using 4-(6,7-Dimethoxy-quinolinyloxy)-2,3-dimethyl-phenylamine and 1- ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid using the procedure for example 1. mp = 283-285 0C; LCMS m/z = 585 (M + 1); 1H NMR (DMSO-d6) 5: 10.81 (s, 1H), 8.88 (s, 1H), 8.43 (d, 1H, J = 5.5 Hz), 8.07 (d, 1H, J = 8.5 Hz), 7.56 (s, 1H), .42 (m, 2H), 7.40 (s, 1H), 7.39-7.33 (m, 2H), 7.10 (d, 1H, J = 9 Hz), 6.26 (d, 1H, J = 6 Hz), 4.02 (q, 2H, J = 7 Hz), 3.95 (s, 6H), 2.21 (s, 3H), 2.07 (s, 3H), 1.3 (t, 3H, J = 7 Hz).
Example 158. @110? 3 -(4-Fluoro-phenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)-2,3-dimethyl-phenyl]-amide. This compound was synthesized using 4-(6,7-Dimethoxy-quinolinyloxy)-2,3-dimethyl-phenylamine and 3-(4-fluorophenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid using the procedure for example 1. mp = 238-240 0C; LCMS m/z = 599 (M + 1); 1H NMR (DMSO-d6) 8: 10.82 (s, 1H), 8.68 (s, 1H), 8.43 (d, 1H, J = 5.5 Hz), 8.06 (d, 1H, J = 9 Hz),7.56 (s, 1H), 7.47-7.42 (m, 2H), 7.39-7.34 (m, 2H), 7.09 (d, 1H, J = 9 Hz), 6.27 (d, 1H, J = 5.5 Hz), 4.78 (p, 1H, J = 8 Hz), 3.95 (s, 6H), 2.21 (s, 3H), 2.07 (s, 3H), 1.43 (d, 6H, J = 6 Hz).
Example 159. 3-(1,1-Difluoro-ethyl)(6,7-dimethoxy-quinolinyloxy)-phenylamine was sized using the procedure for example 143 step a. LCMS m/z = 365 (M + 1). 1H NMR(CDC13) : 8.48 (d, 1H, J = 6 Hz), 7.56 (s, 1H), 7.42 (s, 1H), 7.06-7.01(m, 2H) 6.90-6.86 (m, 1H), 6.41 (d, 1H, J = 6 Hz), 4.05 (s, 6H). 1-Ethyl(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid [4- (6,7-dimethoxy-quinolinyloxy)trifluoromethyl-phenyl]-amide. This nd was synthesized using 3-(1,1-difluoroethyl)(6,7-dimethoxy-quinolinyloxy)-phenylamine and 1-ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid using the procedure for example 1. mp = 260-262 0C; LCMS m/z = 625 (M + 1); 1H NMR (DMSO-d6) 5: 11.08 (s, 1H), 8.89 (s, 1H), 8.51 (d, 1H, J = 5 Hz), 8.37 (d, 1H, J = 2.5 Hz), 7.45-7.41 (m, 5H), 7.36 (t, 2H, J = 8.5 Hz), 6.58 (d, 1H, J = 6 Hz), 4.02 (q, 2H, J = 7.5 Hz), 3.90 (d, 6H), 1.30 (t, 3H, J = 8 Hz).
Example 160. ”318100F F O O 3 -(4-Fluoro-phenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)trifluoromethyl- phenyl]-amide. This nd was sized using 3-(1,1-difluoroethyl)(6,7-dimethoxy-quinolin yloxy)-phenylamine and 3-(4-fluorophenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4- tetrahydropyrimidinecarboxylic acid using the procedure for example 1. mp = 228-230 0C; LCMS m/z = 639 (M + 1); 1H NMR (DMSO-d6) 5: 11.08 (s, 1H), 8.89 (s, 1H), 8.51 (d, 1H, J = 5 Hz), 8.37 (d, 1H, J = 2.5 Hz), 7.45-7.41 (m, 5H), 7.36 (t, 2H, J = 8.5 Hz), 6.58 (d, 1H, J = 6 Hz), 4.02 (q, 2H, J = 7.5 Hz), 3.90 (d, 6H), 1.30 (t, 6H, J = 8 Hz).
Example 161. /o N\ \ / N N 4-(6,7-Dimethoxy-quinolinyloxy)-3,5-dimethyl-phenylamine was synthesized using the procedure for example 143 step a. LCMS m/z = 325 (M + 1). 1H NMR(CDC13) 8: 8.43 (d, 1H, J = 8 Hz), 7.65 (s, 1H), 7.48 (s, 1H), 6.48 (s, 2H), 6.26 (d, 1H, J = 6 Hz), 4.07 (s, 6H), 2.03 (s, 6H). 1-Ethyl(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid [4- (6,7-dimethoxy-quinolinyloxy)-3,5-dimethyl-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxy-quinolinyloxy)-3,5-dimethyl-phenylamine and 1- ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid using the ure for e 1. mp = 240-242 0C; LCMS m/z = 585 (M + 1); 1H NMR (DMSO-d6) 5: 10.90 (s, 1H), 8.84 (s, 1H), 8.41 (d, 1H, J = 5 Hz), 7.61 (s, 1H), 7.55 (s, 1H), 7.45-7.33 (m, 6H), 6.19 (d, 1H, J = 6 Hz), 4.01 (q, 2H, J = 8 Hz), 3.95 (d, 6H, J = 5 Hz), 2.07 (s, 6H), 1.30 (t, 3H, J = 7 Hz).
Example 162. @110? 3 -(4-Fluoro-phenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid 7-dimethoxy-quinolinyloxy)-3,5-dimethyl-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxy-quinolinyloxy)-3,5-dimethyl-phenylamine and 3 -(4-fluorophenyl)- 1 opyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid WO 74633 using the ure for example 1. mp = 180-182 0C; LCMS m/z = 599 (M + 1); 1H NMR (DMSO-d6) 8: 10.89 (s, 1H), 8.65 (s,1H), 8.41 (d, 1H, J = 5 Hz), 7.60 (s, 1H), 7.58 (s, 2H), 7.45-7.33 (m, 5H), 6.19 (d, 1H, J = 7 Hz), 4.18 (p, 1H, J = 7 Hz), 3.95 (d, 6H, J = 6 Hz), 2.05 (s, 6H), 1.45 (d, 6H, J = 7 Hz).
Example 163. filiflofij 4-(6,7-Dimethoxy-quinolinyloxy)methyl-phenylamine was synthesized using the procedure for example 143 step a. LCMS m/z = 311(M + 1). 3 -(4-Fluoro-phenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)methyl-phenyl]-amide. This compound was synthesized using 4-(6,7-Dimethoxy-quinolinyloxy)methyl-phenylamine and 3-(4- fluorophenyl)isopropyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid using the procedure for example 1. mp = 238-240 0C;LCMS m/z = 585 (M + 1); 1H NMR d6) 5: 10.92 (s, 1H), 8.65 (s, 1H), 8.44 (d, 1H, J = 6 Hz), .67 (m, 2H), 7.55 (s, 1H), 7.45-7.41 (m, 2H), 7.39-7.34 (m, 3H), 7.17 (d, 1H, J = 8 Hz), 6.31 (d, 1H, J = 4.5 Hz), 4.78 (p, 1H, J = 6 Hz), 3.95 (s, 6H), 2.09 (s, 3H), 1.43 (d, 6H, J = 7 Hz).
Example 164.
Q F 0 O 2-Ethyl(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine- 6-carboxylic acid [5-(6,7-dimethoxy-quinolinyloxy)-pyridinyl]-amide This compound was synthesized using 5-(6,7-dimethoxyquinolinyloxy)-pyridinylamine and 2-ethyl(4- fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazinecarboxylic acid using the procedure for example 1. mp = 200-202 0C; LCMS m/z = 585 (M + 1); 1H NMR(CDC13) : 11.13 (s, 1H), 8.52 (d, 1H, J = 5 Hz), 8.48 (d, 1H, J = 8.5 Hz), 8.27 (d, 1H, J = 2.6 Hz), 7.60 (dd, 1H, J = 2, 9 Hz), 7.52 (s, 1H), 7.43 (s, 1H), 7.28-7.26 (m, 3H), 6.47 (d, 1H, J = 4.3 Hz), 4.33 (q, 2H, J = 8.5 Hz), 4.05 (d, 6H), 1.51 (t, 3H, J = 8 Hz).
Example 165. /o N\ \ / NJJYlLNH | N\JAG 2-Ethyl(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine- 6-carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)isopropyl-phenyl]-amide. This nd was sized using 4-(6,7-dimethoxy-quinolinyloxy)isopropyl-phenylamine and 2- ethyl(4-fluorophenyl)-3 ,5 -dioxo-2,3 ,4,5 -tetrahydro-[1 ,2,4]triazinecarboxylic acid using the procedure for example 1. mp = 155-156 0C; LCMS m/z = 600 (M + 1); 1H NMR (CDC13)52 10.78 (s, 1H), 8.47 (d, 1H, J = 5.5 Hz). 7.72 (s, 1H), 7.66 (d, 1H, J = 8 Hz), 7.59 (s, 1H), 7.43 (s, 1H), 7.31-7.24 (m, 3H), 7.07 (d, 1H, J = 9 Hz), 6.35 (d, 1H, J = 6 Hz), 4.34 (q, 2H, J = 7.3 Hz), 4.05 (s, 6H), 3.11 (m, 1H), 1.58 (t, 3H, J = 6 Hz), 1.19 (d, 6H, J = 7 Hz).
Example 166. /o N\ \ / Q F 0 0 O MeO HM“ 4-(4-Fluoro-phenyl)isopropyl-3 ,5 -2,3 ,4,5 -tetrahydro-1,2,4-triazine- 6-carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)methoxy-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxyquinolinyloxy)methoxy-phenylamine and 4-(4- Fluorophenyl)isopropyl-3 ,5 -dioxo-2,3 ,4,5 -tetrahydro[1,2,4]triazinecarboxylic acid using the procedure for examplel. mp = 216-218 0C; LCMS m/z = 602 (M + 1); 1H NMR (CDC13)82 11.02 (s, 1H), 8.66 (d, 1H, J = 8.5 Hz), 8.50 (d, 1H, J = 5 Hz), 7.54 (s, 1H), 7.43 (s, 1H), 7.30-7.27 (m, 3H), 6.83 (dd, 1H, J = 3.5, 10 Hz), 6.75 (d, 1H, J = 2.5 Hz), 6.53 (d, 1H, J = 5 Hz), 5.09 (m, 1H), 4.05 (s, 6H), 3.86 (s, 3H), 1.53 (d, 6H, J = 6.5 Hz) Example 167. \or» O O W0F0 O 1-Ethyl(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid [4- (5,6-dimethoxy-quinolinyloxy)-phenyl]-amide. This compound was synthesized using 4-(5,6-dimethoxy-quinolinyloxy)-phenylamine and 1-ethyl(4-fluorophenyl)-2,4- 1,2,3,4-tetrahydropyrimidinecarboxylic acid using the procedure for example 1. mp > 250 0C; LCMS m/z = 557 (M +1); 1H NMR (DMSO) 5: 10.92 (s, 1H), 8.86 (s, 1H), 8.48 (m, 1H), 7.79 (m, 2H), 7.49 (s, 1H), 7.35-7.42 (m, 5H), 7.24-7.27 (m, 2H), 6.49 (m, 1H), 4.00 (m, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 1.29 (m, 3H).
Example 168. 0Q F o o 1-Ethyl(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid [4- (6,8-dimethoxy-quinolinyloxy)-phenyl]-amide. This compound was synthesized using 4-(6,8-dimethoxy-quinolinyloxy)-phenylamine and 1-ethyl(4-fluorophenyl)-2,4- dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid using the procedure for example 1. mp = 127-9 0C; LCMS m/z = 557 (M + 1); 1H NMR (DMSO) 5: 10.93 (s, 1H), 8.87 (s, 1H), 8.45 (d, 1H, J = 5Hz), 7.79 (d, 2H, J = 8.8 Hz), 7.41-7.45 (m, 2H), .37 (m, 2H), 7.24- (d, 2H, J = 8.8 Hz), 7.10 (d, 1H, J = 2.3 Hz), 6.86 (d, 1H, J = 2.3 Hz), 6.61 (d, 1H, J =5 Hz), 4.01 (q, 2H, J = 7 Hz), 3.94 (s, 3H), 3.89 (s, 3H), 1.29 (t, 3H, J = 7 Hz).
Example 169.
WO 74633 2-Ethyl(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine- oxylic acid [4-(6,7-dimethoxy-quinolinyloxy)trifluoromethyl-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxy-quinolin- y)trifluoromethyl- phenylamine and 2-ethyl(4-fluoro-phenyl)- 3,5-dioxo-2,3,4,5-tetrahydro- 1,2,4-triazine- 6-carboxylic acid using the procedure for example 1. mp = 148-50 0C; LCMS m/z = 626 (M + 1); 1H NMR (DMSO): 10.95 (s, 1H), 8.52 (d, 1H), 8.32 (s, 1H), 8.04 (m, 1H), 7.35- 7.49 (m, 8H), 6.60 (m, 1H), 4.08 (q, 2H, J = 7Hz), 3.97 (s, 3H), 3.89 (s, 3H), 1.35 (t, 3H, J = 7Hz).
Example 170.
/O N\ \ / P888“ 2-Ethyl(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine- 6-carboxylic acid 7-dimethoxy-quinolinyloxy)methoxy-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxy-quinolin- 4-yloxy)methoxy-phenylamineand 2- ethyl(4-fluoro-phenyl)- 3,5-dioxo-2,3,4,5-tetrahydro- 1,2,4-triazinecarboxylic acid using the procedure for example 1. mp = 264-6 0C; LCMS m/z = 588 (M + 1); ); 1H NMR (DMSO): 11.00 (s, 1H), 8.47-8.52 (m, 2H), 7.51 (s, 1H), 7.38-7.46 (m, 5H), 7.10 (m, 1H), 6.88 (m, 1H), 6.53 (d, 1H, J = 5Hz), 4.10 (q, 2H, J = 7Hz), 3.94 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 1.35 (t, 3H, J = 7Hz).
Example 171.
QVLOF 2-Ethyl(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine- 6-carboxylic acid [3-fluoro(7-methoxy-quinolinyloxy)-phenyl]-amide. This compound was synthesized using 3-fluoro(7-methoxy-quinolinyloxy)-phenylamine and 2-ethyl (4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro- 1,2,4-triazinecarboxylic acid. LCMS m/z = 546 (M + 1); ); 1H NMR (DMSO): 11.00 (s, 1H), 8.88 (m, 1H), 8.01-8.05 (m, 1H), -133— 2012/065019 7.58-7.67 (m, 2H), 7.52—7.55 (m, 2H), 7.36-7.45 (m, 4H), 6.88 (m, 1H), 4.08 (q, 2H, J = 7Hz), 4.01 (s, 3H), 1.35 (t, 3H, J = 7Hz).
VI. Biology AXL Kinase Assay The ability of compounds to inhibit the kinase activity of recombinant human baculovirus-expressed AXL was measured by homogeneous TRF (HTRF) using Cisbio’s KinEASETM assay system in white 384-well Optiplates. Assay buffer contained 1 mM DTT, 2 mM MnClz, 2% DMSO, 50 nM ment enzymatic , and 1x enzymatic buffer. A 2x concentration of tyrosine kinase (TK) substrate-biotin/ATP mixture made in assay buffer was added to plates at 10 uL/well using the Multidrop Combi (Thermo Fisher ific, Waltham, MA). The final concentrations were 0.3 uM TK substrate-biotin, and 1.3 uM ATP. Compounds (100 nL), diluted in 100% DMSO on the Biomek FX, (Beckman Coulter, lnc., Brea, CA), were transferred to the assay plates using the Biomek FX pintool (2.5% final DMSO in assay). A 2x concentration (final = 12 ng/mL) of GST- AXL (diluted in assay buffer) was added to plates at 10 uL/well using the Multidrop Combi. Plates were sealed, briefly shaken and incubated at 25°C for 30 minutes. A 4x stock of Streptavidin-XL665 (final = 18.8 nM) and a 1:100 d stock of TK antibody- cryptate were made in HTRF detection buffer and mixed together just prior to adding 20 uL/well 0n the Multidrop Combi. Plates were sealed, briefly shaken and incubated at °C for 1 hour. The fluorescence of the resulting solution was measured using the PerkinElmer EnVisionTM 2102 multi-label plate reader (PerkinElmer, Waltham, MA) with an excitation wavelength of 337 nm (laser) and emission wavelengths of 590 and 665 nm.
Raw data was expressed as the ratio of 665/590 x 10,000.
C-MET Kinase Assay The cMET kinase assay was med in 384-well FluotracTM 200 HiBase microplates using the HTRF KinEASETM assay described above for AXL except that the assay volume was d to half. Enzyme concentration was 8 ng/mL of recombinant human virus-expressed cMET while the substrate concentrations were 0.1 uM and 0.02 uM for the biotinylated peptide and ATP, tively. Instead of the Multidrop Combi, the —134— BioRAPTR® FRD microfiuidic workstation (Beckman Coulter, Brea, CA) was ed for reagent additions.
Data Analysis Inhibition curves for compounds were generated by plotting percent control ty versus log10 of the concentration of compound. IC50 values were calculated by nonlinear regression using the sigmoidal dose-response (variable slope) on in GraphPad Prism as follows: y = bottom + (top - bottom)/(l + 10 (log IC50-x)*Hill Slope) where y is the % kinase activity at a given concentration of compound, x is the logarithm of the concentration of compound, bottom is the % of control kinase activity at the highest compound concentration tested, and top is the % of control kinase activity at the lowest compound concentration examined. The values for bottom and top were fixed at 0 and 100, tively.
Results Biological data for Example compounds is presented in the following Table 1.
Unless otherwise specified in Table l, IC50 nanomolar value ranges ated as A, B, or C indicate the following ranges: IC50 < 10 nM A; IC50 10 nM to 100 nM B; and IC50 101 nM to 1,000 nM C;.
“NT” s not .
Unless otherwise specified, all values are an average of two or more determinations.
Table 1. AXL and c-MET Inhibition c-MET IC50 Example AXL IC50 nM l A A 2 A A 3 A B 4 A B -l35- 2012/065019 C-MET IC50 Example AXL IC50 nM ©00\]O\ 37 ODS0303{73>ijUJ>UJUJO>>UJUJUJUJUJ>>UJ>UJUJUJUJ>UJUJ>UJ 38 Z.4 39 Z.4 48 owwwwwwow>wwoow>>>>>>>>>w>>>>>w>>>w>ww>00>>>>> OUJD>UJUJUJUJOUJ C-MET IC50 e AXL IC50 11M 50 AAAA 52 AAAA 54 AAAA 56 Anhb 58 AnAA 60 puhb 62 AAAA 64 AAAA 66 AAAA 68 AAAA 70 Anhb 72 AAAA 74 AAAA 76 AAAA 78 AAAA 80 Anhb 82 puAA 84 Anhb 86 AAAA 88 AAAA 90 RUAA 91 A 92 by MAAABABBBCBBCAAABBABAABABBBMMBBBCBBBBABBBCBBM 2012/065019 C-MET IC50 Example AXL IC50 nM 98 03003030303 118 nowww>wwww>>ww>w>ww§ 121 5005 122 Z.4 136 wcoww>>>>>>>>wwooonoww>w>>>>w>>>>>>>>>o>w>www OOOUJUJUJUJUJUJUJOUJUJO C-MET IC50 Example AXL IC50 nM 140 550W 152 www>w>>ww>ww 153 Za 166 OUJUJUJUJUJOUJOOUJUJO 167 Za 168 >>ww>03w>wwww>wwwwwo>>>>w>>>>>>wooww Za 171 >UJD> In one embodiment, the invention es a compound of Formula I or a salt thereof having an AXL IC50 of less than 1 uM. In one embodiment, the invention provides a compound of Formula I or a salt thereof having an AXL IC50 of less than 100 nM. In one embodiment, the invention provides a nd of a I or a salt thereof having an AXL IC50 of less than 10 nM. In one embodiment, the invention provides the exemplified compounds of Formula I or salts thereof having AXL IC50s of less than 1 uM. 2012/065019 In one embodiment, the invention provides the exemplified compounds of Formula I or salts thereof having AXL IC50s of less than 100 nM. In one ment, the invention provides the exemplified compounds of Formula I or salts thereof having AXL IC50s of less than 10 nM.
In one embodiment, the invention provides a compound of Formula I or a salt thereof having a c-Met IC50 of less than 1 uM. In one embodiment, the invention provides a compound of a I or a salt f having a c-Met IC50 of less than 100 nM. In one embodiment, the invention provides a compound of Formula I or a salt thereof having a c- Met IC50 of less than 10 nM. In one embodiment, the invention es the exemplified compounds of Formula I or salts thereof having c-Met IC50s of less than 1 uM. In one embodiment, the invention provides the exemplified compounds of Formula I or salts thereof having c-Met IC50s of less than 100 nM. In one embodiment, the invention provides the exemplified compounds of Formula I or salts f having c-Met IC50s of less than 10 nM.
In one embodiment, the invention provides a compound of Formula I or a salt thereof having AXL and c-Met IC50s of less than 1 uM. In one embodiment, the invention provides a compound of Formula I or a salt thereof having AXL and c-Met IC50s of less than 100 nM. In one ment, the invention provides a compound of Formula I or a salt f having AXL and c-Met IC50s of less than 10 nM. In one embodiment, the invention provides the exemplified nds of Formula I or salts thereof having AXL and c-Met IC50s of less than 1 uM. In one embodiment, the invention provides the exemplified compounds of Formula I or salts thereof having AXL and c-Met IC50s of less than 100 nM. In one embodiment, the invention provides the exemplified compounds of Formula I or salts thereof having AXL and c-Met IC50s of less than 10 nM. —140— WO 74633 Additional preferred Embodiments of the present invention include: 1. A compound of the a T3 NY0 R2 XI/ I ”WE Rd \ Y O O Ra 1 Rb N/J wherein: Ra is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino, dialkylamino Where the alkyl groups of dialkylamino may be the same or different, carbamoyl, N—alkylcarbamoyl, N,N—diall<ylcarbamoyl, Where the alkyl groups of dialkylcarbamoyl may be the same or different, trihalomethyl, or Ra is OA; Rb is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino, dialkylamino Where the alkyl groups of dialkylamino may be the same or different, carbamoyl, lcarbamoyl, N,N—diall<ylcarbamoyl, Where the alkyl groups of dialkylcarbamoyl may be the same or different, trihalomethyl, or Rb is OB; Rc is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino, lamino Where the alkyl groups of dialkylamino may be the same or different, carbamoyl, N—alkylcarbamoyl, all<ylcarbamoyl, Where the alkyl groups of dialkylcarbamoyl may be the same or different, trihalomethyl, or RC is OJ; Rd is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino, dialkylamino Where the alkyl groups of dialkylamino may be the same or different, carbamoyl, N—alkylcarbamoyl, N,N—diall<ylcarbamoyl, Where the alkyl groups of dialkylcarbamoyl may be the same or different, trihalomethyl, or Rd is OL; Where A, B, J and L, are, independently, H, alkyl, alkoxyalkyl, cycloalkyl, cycloalkoxyalkyl, heterocyclylalkyl, heterocyclylalkoxyalkyl, arylalkyl or arylalkoxyalkyl, - l 4 l - or A and B together with the oxygen atoms to which they are attached form or D is O, S, SO, SOZ, C=O, C(H)OH, CH2, NH or N-alkyl; E is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl or heteroarylalkyl, where the heteroaryl group of heteroarylalkyl may be substituted or unsubstituted; G is H, aryl, tuted aryl, aryl, substituted heteroaryl, heterocyclyl, alkyl or lkyl, lkylalkyl, alkenyl or alkynyl, where alkyl, alkenyl or cycloalkyl may be substituted by one, two or three groups selected from the group ting of alkanoyl, cycloalkyl, alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl, aryl, substituted aryl, aryloxy, arylalkoxy, amino, mino, dialkylamino, where the alkyl groups of dialkylamino may be the same or different, heteroaryl, carboxyl, oxo, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, where the alkyl groups of lcarbamoyl may be the same or different, and heterocycyclylcarbonyl; W is CH or N; X is C-R4 or N, where R4 is H, OH or alkyl, where the alkyl group may be substituted by hydroxyl, alkoxy, alkylamino, or dialkyl amino, where the alkyl groups of dialkylamino may be the same or different; Y is N, CH or C where C may be substituted with one of the groups R1 or R2; and R1 and R2 are, independently, H, alkyl, cycloalkyl, halo, alkoxy, trihaloalkyl, amino, mino, dialkylamino, where the alkyl groups on dialkylamino may be the same or different, or heterocyclyl; and R3 is H, or alkyl; or a ceutically acceptable salt thereof. 2. A compound according to preferred Embodiment 1 wherein W is CH. 3. A compound according to preferred Embodiment 1 wherein W is N. —142— A compound according to red Embodiment l of the formula A_O R1 8—0 N wherein: A and B are, independently, H, alkyl, alkoxyalkyl, cycloalkyl, cycloalkoxyalkyl, heterocyclylalkyl, heterocyclylalkoxyalkyl, arylalkyl or arylalkoxyalkyl, or A and B together with the oxygen atoms to which they are C: [0 ed form or ; D is O, S, NH, or C=O; E is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted l, cycloalkyl, aryl, substituted aryl, heteroaryl, heterocyclyl, tuted aryl, or heteroarylalkyl, where the heteroaryl group of heteroarylalkyl may be substituted or unsubstituted; G is H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, alkyl or cycloalkyl, lkylalkyl, alkenyl or alkynyl, where alkyl, alkenyl or cycloalkyl may be substituted by one, two or three groups selected from the group consisting of alkanoyl, cycloalkyl, alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl, aryl, substituted aryl, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, where the alkyl groups of dialkylamino may be the same or different, heteroaryl, carboxyl, oxo, oyl, alkylcarbamoyl, dialkylcarbamoyl, where the alkyl groups of dialkylcarbamoyl may be the same or different, and heterocycyclylcarbonyl; X is C-R4 or N, where R4 is H or alkyl; —143— Y is N, CH or C where C may be substituted with one of the groups R1 or R2; and R1 and R2 are, independently, H, alkyl, halo, alkoxy, trihaloalkyl, amino, alkylamino, dialkylamino, where the alkyl groups on dialkylamino may be the same or different; or a pharmaceutically acceptable salt thereof.
. A compound according to preferred Embodiment 4 wherein A and B are, independently, alkyl, heterocyclylalkyl or heterocyclylalkoxyalkyl. 6. A compound according to preferred Embodiment 4 wherein A and B are, independently, alkyl. 7. A compound according to preferred Embodiment 4 wherein D is O, S or NH. 8. A compound according to red Embodiment 4 wherein D is O. 9. A compound according to preferred Embodiment 4 wherein R1 and R2 are, ndently, halo, alkoxy, alkyl or H.
. A compound according to red Embodiment 4 wherein R1 and R2 are, independently, halo or alkoxy. 11. A compound ing to preferred Embodiment 4 wherein R1 and R2 are, independently, methoxy or fluoro. 12. A compound according to preferred Embodiment 4 wherein X is N or CH. 13. A compound according to preferred Embodiment 4 wherein X is CH. 14. A compound according to red Embodiment 4 wherein G is alkyl where alkyl may be substituted by one, two or three groups selected from the group consisting of alkanoyl, cycloalkyl, l, alkynyl, halo, hydroxyl, alkoxy, carbonyl, heterocyclyl, aryl, substituted aryl, aryloxy, arylalkoxy, amino, mino, dialkylamino, -l44- where the alkyl groups of dialkylamino may be the same or different, heteroaryl, carboxyl, oxo, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, where the alkyl groups of dialkylcarbamoyl may be the same or different, and heterocycyclylcarbonyl.
. A compound according to preferred Embodiment 4 wherein E is aryl, substituted aryl or cycloalkyl. 16. A nd according to preferred Embodiment 4 wherein E is substituted aryl. 17. A compound according to preferred Embodiment 4 wherein A and B are, independently, alkyl; D is O, S or NH; R1 and R2 are, independently, halo, alkoxy, alkyl or H; X is N or CH; G is alkyl where alkyl may be tuted by one, two or three groups selected from the group consisting of alkanoyl, cycloalkyl, alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl, aryl, substituted aryl, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, where the alkyl groups of dialkylamino may be the same or different, heteroaryl, carboxyl, oxo, carbamoyl, alkylcarbamoyl, lcarbamoyl, where the alkyl groups of dialkylcarbamoyl may be the same or different, and heterocycyclylcarbonyl; and E is aryl, substituted aryl or cycloalkyl. l 8. A compound which is l-Ethyl(4-fluorophenyl)-2,4-dioxo- l ,2,3 ,4-tetrahydropyrimidine-5 - carboxylicacid [4-(6,7-dimethoxyquinolinyloxy)fluorophenyl]amide; 3 uorophenyl)- l l-2,4-dioxo- l ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid [4-(6,7-dimethoxyquinolinyloxy)fluoro-phenyl]-amide; 3 -(4-Fluorophenyl)- l -(2-methoxyethyl)-2,4-dioxo- l ,2,3 rahydropyrimidine-5 - carboxylic acid [4-(6,7-dimethoxyquinolinyloxy)fluorophenyl]-amide; l-(2-Ethoxyethyl)(4-fluorophenyl)-2,4-dioxo- l ,2,3 ,4-tetrahydropyrimidine carboxylic acid [4-(6,7-dimethoxyquinolinyloxy)fluorophenyl]-amide; 3 -(4-Fluorophenyl)- l -isopropyl-2,4-dioxo- l ,2,3 ,4-tetrahydropyrimidine ylic acid [4-(6,7-dimethoxyquinolinyloxy)fluorophenyl]-amide; l -Cyclopropylmethyl(4-fluorophenyl)-2,4-dioxo- l ,2,3 ,4-tetrahydropyrimidinecarboxylic acid [4-(6,7-dimethoxyquinolinyloxy)fluorophenyl]-amide; 3 -(4-Fluorophenyl)- l -(3 -methoxypropyl)-2,4-dioxo-l ,2,3 ,4-tetrahydropyrimidine- oxylic acid [4-(6,7-dimethoxyquinolinyloxy)fluorophenyl]-amide; -l45- 2012/065019 3 -(4-F1u0r0phcnyl)—1-isobuty1—2,4-di0xo-1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 - carboxylic acid 7-dimcthoxyquino1iny10xy)fluor0phcny1]—arnidc; 1-A11y1—3-(4-fluor0phcnyl)-2,4-di0xo-1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid [4-(6,7-dirncthoxyquino1iny10xy)fluor0phcny1]—arnidc; 1 -(2-Bcnzyloxycthyl)(4-flu0r0phcnyl)-2,4-di0xo-1 ,2,3 ,4-tctrahydropyrirnidinccarb0xy1ic acid [4-(6,7-dirncthoxyquinolinyloxy)fluor0phcny1]—arnidc; 3 -(4-F1uorophcny1)-2,4-di0x0-1 -pr0py1—1 ,2,3 ,4-tctrahydr0pyrimidinc-5 - carboxylic acid [4-(6,7-dirncthoxyquino1iny10xy)fluor0phcny1]—arnidc; 3 uorophcnyl)(2-isopr0p0xycthyl)—2,4-dioxo-1 ,2,3 ,4-tctrahydr0pyrimidinc- 5 -carb0xy1ic acid [4-(6,7-dirncthoxyquinolinyloxy)fluor0phcny1]—arnidc; 1-(3 -Bcnzy10xypr0pyl)(4-fluor0phcnyl)-2,4-dioxo-1,2,3 ,4- ydropyrimidinc-S-carb0xylic acid [4-(6,7-dirncth0xyquinoliny10xy)—3-fluor0 phenyl] -arnidc; 1-(3 ,3 -Difluor0-allyl)-3 -(4-fluor0phcny1)—2,4-di0xo-1 ,2,3 ,4-tctrahydropyrimidinccarb0xy1ic acid [4-(6,7-dirncthoxyquinolinyloxy)fluor0phcny1]—arnidc; 3 -(4-F1u0r0phcnyl)—1-(3 -rncthy1—butcnyl)-2,4-diox0- 1 ,2,3 ,4- tctrahydropyrimidinc-S-carb0xy1ic acid [4-(6,7-dimcthoxyquino1iny10xy) fluorophcnyl]—arnidc; 3 -(4-F1u0r0phcnyl)—1-(2-rn0rph01iny1—cthy1)—2,4-dioxo-1 ,2,3 ,4- tctrahydropyrimidinc-S-carb0xylic acid [4-(6,7-dirncth0xyquinoliny10xy)—3-fluor0 phenyl] -arnidc; 3 -(4-F1uorophcny1)-2,4-di0x0-1 ,2,3 rahydr0pyrirnidinc-5 -carb0xy1ic acid [4- (6,7-dimcthoxyquinolinyloxy)flu0r0phcny1]—arnidc; 3 -(4-F1uorophcnyl)rncthy1—2,4-di0x0-1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 - carboxylic acid [4-(6,7-dimcthoxyquino1iny10xy)—phcnyl]-arnidc; 1 -(2-Bcnzyloxycthyl)(4-flu0ro-phcnyl)-2,4-di0x0- 1 ,2,3 rahydropyrimidinc- -carboxy1ic acid [4-(6,7-dimcthoxyquinolinyloxy)-phcnyl]-arnidc; 1-(2-Dirncthy1arninocthyl)(4-flu0r0phcny1)-2,4-diox0-1 ,2,3 ,4- tctrahydropyrimidinc-S-carb0xy1ic acid [4-(6,7-dimcthoxyquino1iny10xy) fluorophcnyl]—arnidc; 1-(3 -Bcnzy10xypr0pyl)(4-fluor0phcnyl)-2,4-dioxo-1,2,3 ,4- tctrahydropyrimidinc-S-carb0xylic acid [4-(6,7-dimcthoxyquino1iny10xy)phcnyl]- amide; 1-(3 -Bcnzy10xypr0pyl)(4-fluor0phcnyl)-2,4-dioxo-1,2,3 ,4- tctrahydropyrirnidinc-S xy1ic acid [4-(6,7-dimcthoxyquino1iny10xy) fluorophcnyl]—arnidc; 3 -(4-F1uor0phcnyl)—1-is0pr0py1—2,4-diox0-1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 - carboxylic acid [4-(6,7-dimcthoxyquinoliny10xy)phcnyl]-arnidc; 3 -(4-F1uorophcny1)-2,4-di0x0-1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid [4- (6,7-dirncth0xyquino1iny10xy)phcnyl]-arnidc; 3 -Cyclohcxylcthy1—2,4-dioxo-1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xylic acid [4-(6,7-dirncthoxyquin01iny10xy)—3-fluor0phcny1]—arnidc; 3 -(4-F1uor0phcny1)-2,4-di0x0(2-pyrr01idiny1—cthy1)-1,2,3 ,4- tctrahydropyrirnidinc-S-carb0xylic acid [4-(6,7-dirncth0xyquinoliny10xy)—3-fluor0 phenyl] -arnidc; 3 -(4-F1u0rophcny1)-2,4-di0x0(2-pipcridiny1-cthy1)—1,2,3 ,4- ydropyrirnidinc-S-carb0xy1ic acid [4-(6,7-dimcthoxyquino1iny10xy) fluorophcnyl]—arnidc; 1-Ethy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid [4-(6,7-dimcthoxyquino1iny10xy)—phcnyl]-arnidc; 1 -Cyc10buty1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrimidinc carboxylic acid [4-(6,7-dirncthoxyquinoliny10xy)fluor0phcny1]—arnidc; 3 -(4-F1u0r0phcnyl)-2,4-dioxo(tctrahydr0pyranyl)-1 ,2,3 ,4- tctrahydropyrirnidinc-S-carb0xylic acid [4-(6,7-dirncth0xyquinoliny10xy)—3-fluor0 phenyl] -arnidc; 1-Ethy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid [5 -(6,7-dimcthoxyquinoliny10xy)-pyridin-2—yl] -arnidc was synthesized ng With 5-(6,7-dirncth0xyquino1iny10xy)—pyridiny1arninc; 1-Ethy1—3-(4-fluor0phcnyl)rncthyl-2,4-dioxo-1 ,2,3 ,4-tctrahydropyrirnidinc carboxylic acid [4-(6,7-dimcthoxyquino1iny10xy)fluor0phcny1]—arnidc; 1-Ethy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 rahydr0pyrirnidinc-5 -carb0xy1ic acid [4-(6,7-dicthoxyquino1iny10xy)—3-flu0r0phcny1]—arnidc; 3 -(4-F1uorophcny1)is0pr0py1—2,4-dioxo- 1 ,2,3 ,4-tctrahydropyrirnidinc carboxylic acid [5 -(6,7-dirncth0xyquino1inyloxy)-pyridinyl]-arnidc; 1 -Cyclopr0pylmcthyl(4-flu0r0phcny1)—2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrimidinccarboxylic acid [5 -(6,7-dimcthoxyquinolinyloxy)pyridiny1] -arnidc; —147— 3 -(4-F1uor0phcny1)-2,4-di0x0pcnty1— 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 - carboxylic acid [4-(6,7-dirncthoxyquino1iny10xy)fluor0phcny1]—arnidc; 3 -(4-F1uorophcny1)isopr0py1—2,4-dioxo- 1 ,2,3 ,4-tctrahydropyrirnidinc carboxylic acid [4-(6,7-dicthoxyquino1iny10xy)flu0r0-phcny1] -arnidc; 3 -(4-F1uorophcny1)isopr0py1—2,4-dioxo- 1 ,2,3 rahydropyrirnidinc carboxylic acid [4-(5,7-dimcthoxyquinoliny10xy)phcnyl]-arnidc; 1-Ethy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid [4-(5,7-dimcthoxyquino1iny10xy)—phcnyl]-arnidc; 1-Ethy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid [4-(7-bcnzyloxyrncth0xyquino1iny10xy)—3-fluor0phcny1]—arnidc; 3 -(4-F1uorophcny1)- 1 0py1—2,4-dioxo- 1 ,2,3 ,4-tctrahydropyrirnidinc carboxylic acid [4-(7-bcnzyloxymcthoxyquino1inyloxy)flu0r0phcny1]—arnidc; 1-Ethy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 rahydr0pyrirnidinc-5 -carb0xy1ic acid [3-fluoro(7-hydr0xyrncthoxyquino1iny10xy)phcny1]-arnidc; 1-Ethy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid {3-flu0ro[6-rncthoxy(3-rnorpho1iny1—pr0poxy)quino1iny10xy] phcny1}- amide; 1-Ethy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid {3-fluor0[6-rncthoxy(2-rncthoxycthoxy)quinolinyloxy]-phcny1} -arnidc; 1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid {3-flu0r0[6-mcthoxy(2-rnorpho1iny1—cthoxy)-quin01inyloxy]phcnyl} - amide; 3 -(4-F1uorophcny1)isopr0py1—2,4-dioxo- 1 ,2,3 ,4-tctrahydropyrirnidinc carboxylic acid [3-fluoro(7-hydr0xyrncthoxyquino1iny10xy)-phcnyl]-arnidc; 3 -(4-F1uorophcny1)isopr0py1—2,4-dioxo- 1 ,2,3 ,4-tctrahydropyrirnidinc ylic acid {3-flu0r0[6-mcth0xy(3-rn0rpholiny1—propoxy)- quinolin yloxy]phcny1}-arnidc; 3 -(4-F1uor0phcnyl)(2-hydr0xycthyl)-2,4-di0x0-1 ,2,3 ,4-tctrahydropyrirnidinc carboxylic acid [4-(6,7-dimcthoxyquino1iny10xy)fluor0phcny1]—arnidc; 3 -(4-F1uorophcnyl)(3 -hydroxypr0pyl)-2,4-di0xo- 1 ,2,3 rahydropyrirnidinccarb0xy1ic acid [4-(6,7-dirncthoxyquinolinyloxy)fluor0phcny1]—arnidc; 3 -(4-F1uorophcnyl)(3 -hydroxypr0pyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydropyrimidinc- -carb0xy1ic acid [4-(6,7-dirncthoxy-quinoliny10xy)—2-fluor0-phcnyl]-arnidc; 3 -(4-F1uorophenyl)(3 -hydroxypr0pyl)-2,4-di0xo- 1 ,2,3 ,4-tetrahydropyrimidine- -carboxy1ic acid [4-(6,7-dimethoxyquinoliny10xy)phenyl]-amide; 3 -(4-F1uor0phenyl)—1-(2-hydr0xyethy1)-2,4-di0x0-1 ,2,3 rahydr0pyrimidine-5 - carboxylic acid [4-(6,7-dimethoxyquinoliny10xy)phenyl]-amide; 1-((S)-2,3-Dihydr0xypropyl)(4-fluor0phenyl)-2,4-dioxo-1,2,3 ,4- tetrahydropyrimidine-S-carb0xy1ic acid [4-(6,7-dimethoxyquino1iny10xy) fluorophenyl]—amide; 3 -(4-F1uorophenyl)(4-hydr0xybuty1)-2,4-di0x0-1 ,2,3 rahydropyrimidine carboxylic acid [4-(6,7-dimethoxyquino1iny10xy)fluor0pheny1]—amide; 3 -(4-F1uor0phenyl)—1-isopr0py1—2,4-diox0-1 ,2,3 ,4-tetrahydr0pyrimidine-5 - ylic acid [4-(6-cyanometh0xy-quino1inyloxy)-phenyl]-amide; 3 -(4-flu0ro-pheny1)-1 -methy1-2,4-di0X0-1 ,2,3 ,4-tetrahydr0-pyrimidine-5 - carboxylic acid {4-[(6,7-dimeth0xy-quinoliny1)-hydroxy-methyl] flu0r0-pheny1} - amide; 3 -(4-flu0ro-pheny1)-1 -methy1-2,4-di0X0-1 ,2,3 ,4-tetrahydr0-pyrimidine-5 - carboxylic acid [4-(6,7-dimeth0xy-quinolinylmethy1)flu0r0-phenyl]-amide; 1-Ethy1—3-(4-flu0ro-pheny1)—2,4-di0x0- 1 ,2,3 ,4-tetrahydr0pyrimidine-5 -carb0xy1ic acid [3-cyc10propy1—4-(6,7-dimethoxy-quinolinyloxy)-phenyl]-amide; 3 u0r0-pheny1)isopr0py1—2,4-di0xo-1 ,2,3 ,4-tetrahydr0-pyrimidine ylic acid [3-cyclopr0pyl(6,7-dimethoxy-quino1iny10xy)-phenyl]-amide; 3 -(4-F1u0r0-phenyl)-2,4-di0xopr0pyny1—1 ,2,3 ,4-tetrahydr0-pyrimidine-5 - carboxylic acid [4-(6,7-dimeth0xy-quinolinyloxy)fluoro-phenyl]-amide; 3 -(4-F1uor0-phenyl)(2-imidaz01—1-y1—ethy1)-2,4-dioxo-1,2,3 ,4-tetrahydr0- pyrimidinecarb0xy1ic acid [4-(6,7-dimethoxy-quinolinyloxy)flu0r0-pheny1]— amide; 3 -(4-F1u0ro-phenyl)-2,4-di0x0(2-pyraz01—1-y1-ethy1)-1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xy1ic acid [4-(6,7-dimethoxy-quinolinyloxy)flu0r0-pheny1]— amide; 3 -(4-F1u0r0-phenyl)-2,4-di0xophenethyl-1 ,2,3 ,4-tetrahydr0-pyrimidine-5 - carboxylic acid [4-(6,7-dimeth0xy-quinolinyloxy)fluoro-phenyl]-amide; 1-[2-(1,3 -Dioxolany1—ethyl)]—3 0ro-pheny1)—2,4-di0x0- 1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xy1ic acid [4-(6,7-dimethoxy-quinolinyloxy)flu0r0-pheny1]— amide; —149— 1-Diethy1carbamoylmethy1(4-flu0r0-phenyl)-2,4-di0x0-1,2,3 ,4-tetrahydr0- pyrimidinecarb0xy1ic acid [4-(6,7-dimethoxy-quinolinyloxy)flu0r0-pheny1]— amide; 3 -(4-F1u0ro-pheny1)(2-m0rph01iny1—2-0X0-ethy1)-2,4-di0x0-1,2,3 ,4- tetrahydro-pyrimidine-S-carb0xy1ic acid [4-(6,7-dimeth0xy-quinoliny10xy)flu0ro- pheny1]-amide; 3 -(4-F1u0r0-phenyl)-2,4-di0x0[2-(2-0x0-pyrr01idiny1)-ethy1]—1 ,2,3 ,4- tetrahydro-pyrimidine-S-carb0xy1ic acid [4-(6,7-dimeth0xy-quinoliny10xy)flu0ropheny1 ]-amide; 1 -(2-F1u0r0-ethy1)-3 -(4-flu0r0-pheny1)-2,4-diox0-1 ,2,3 ,4-tetrahydro-pyrimidine-5 - carboxylic acid [4-(6,7-dimeth0xy-quinolinyloxy)fluoro-phenyl]-amide; [5 -[4-(6,7-Dimeth0xy-quinolinyloxy)fluor0-pheny1carbamoyl](4-flu0r0- phenyl)-2,4-di0X0-3 ydr0-2H-pyrimidiny1]-acetic acid tert-butyl ester; [5 -[4-(6,7-Dimethoxyquinoliny10xy)flu0r0phenylcarbamoy1]—3 -(4- henyl)-2,4-dioxo-3 ,4-dihydr0-2H-pyrimidiny1]-acetic acid; 3 -(4-F1uor0-phenyl)oxaz01ylmethy1-2,4-di0x0-1 ,2,3 ,4-tetrahydr0-pyrimidinecarb0xy1ic acid [4-(6,7-dimethoxy-quinolinyloxy)flu0r0-phenyl]-amide; 3 -(4-F1u0r0-phenyl)-2,4-di0x0(tetrahydro-fi1rany1methyl)- 1 ,2,3 rahydr0- pyrimidinecarb0xy1ic acid [4-(6,7-dimethoxy-quinolinyloxy)flu0r0-pheny1]— amide; 3 -(4-F1u0r0-phenyl)-2,4-di0x0(tetrahydro-pyrany1methy1)- 1 ,2,3 ,4-tetrahydr0- dinecarb0xy1ic acid [4-(6,7-dimethoxy-quinolinyloxy)flu0r0-pheny1]— amide; 3 -(4-F1u0r0-pheny1)(2-methy1—thiaz01—4-y1methy1)-2,4-di0xo-1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xy1ic acid [4-(6,7-dimethoxy-quinolinyloxy)flu0r0-pheny1]— amide; 1-Cyc10penty1—3-(4-flu0ro-phenyl)-2,4-di0x0- 1 ,2,3 ,4-tetrahydro-pyrimidine-5 - carboxylic acid [4-(6,7-dimeth0xy-quinolinyloxy)fluoro-phenyl]-amide; 1-Benzy1—3-(4-flu0ro-phenyl)-2,4-di0x0- 1 ,2,3 ,4-tetrahydro-pyrimidine-5 - ylic acid [4-(6,7-dimeth0xy-quinolinyloxy)fluoro-phenyl]-amide; 3 -(4-F1u0r0-phenyl)[2-(2-fluor0-pheny1)—ethy1]-2,4-diox0-1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xy1ic acid [4-(6,7-dimethoxy-quinolinyloxy)flu0r0-pheny1]— amide; 3 -(4-F1u0r0-phenyl)[2-(4-fluor0-pheny1)—ethy1]-2,4-diox0-1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xy1ic acid [4-(6,7-dimethoxy-quinolinyloxy)flu0r0-pheny1]— amide; 1-(2-Cyc10hexy1—ethyl)(4-flu0r0-pheny1)—2,4-di0x0-1,2,3 ,4-tetrahydr0- pyrimidinecarb0xy1ic acid [4-(6,7-dimethoxy-quinolinyloxy)flu0r0-pheny1]— amide; 3 -(4-F1uor0-phenyl)-2,4-di0x0(3-pheny1—propy1)-1 ,2,3 ,4-tetrahydr0-pyrimidinecarb0xy1ic acid [4-(6,7-dimeth0xy-quinolinyloxy)flu0r0-phenyl]-amide; 3 -(4-F1u0r0-phenyl)-2,4-di0xo(2-oxopyrrolidiny1—ethy1)-1,2,3 ,4- tetrahydro-pyrimidine-S-carb0xy1ic acid [4-(6,7-dimeth0xy-quinoliny10xy)flu0rophenyl ]-amide; 1 -Dimethy1carbamoylmethy1-3 0rophenyl)-2,4-di0xo- 1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xy1ic acid [4-(6,7-dimethoxy-quinolinyloxy)fluor0pheny1]— amide; 1-(1-Dimethy1carbamoy1—2-0X0-pr0py1)(4-flu0ro-phenyl)-2,4-di0x0-1,2,3 ,4- tetrahydro-pyrimidine-S-carb0xy1ic acid [4-(6,7-dimeth0xy-quinoliny10xy)flu0rophenyl ]-amide; 3 -(4-F1uor0-phenyl)-2,4-di0x0-1 ,2,3 ,4-tetrahydro-pyrimidine-5 -carb0xy1ic acid [4- (6,7-dimethoxy-quinolinyloxy)fluoro-pheny1]-amide; 3 -(4-F1uor0-phenyl)methy1-2,4-di0x0-1 ,2,3 ,4-tetrahydr0-pyrimidine-5 - carboxylic acid 7-dimethoxy-quino1iny10xy)fluoro-phenyl]-amide; 1—3-(4-flu0ro-pheny1)—2,4-di0x0- 1 ,2,3 ,4-tetrahydr0-pyrimidine-5 -carb0xy1ic acid [4-(6,7-dimethoxy-quinoliny10xy)fluor0-phenyl]-amide; 1-A11y1—3 -(4-flu0r0-phenyl)-2,4-diox0-1 ,2,3 ,4-tetrahydro-pyrimidine-5 -carb0xylic acid [4-(6,7-dimethoxy-quinoliny10xy)fluor0-phenyl]-amide; 3 uor0-phenyl)-2,4-di0x0-1 ,2,3 rahydr0pyrimidine-5 -carb0xylic acid [4- imethoxy-quinolinyloxy)-3 ,5-difluor0-pheny1]—amide; 1-Ethy1—3-(4-flu0ro-pheny1)—2,4-di0x0- 1 ,2,3 ,4-tetrahydr0-pyrimidine-5 -carb0xy1ic acid [4-(6,7-dimeth0xy-quino1inyloxy)-3,5-diflu0ro-pheny1]—amide; 3 -Ethy1— 1 -(4-flu0ro-pheny1)—2,4-di0x0- 1 ,2,3 ,4-tetrahydr0-pyrimidine-5 -carb0xy1ic acid [4-(6,7-dimethoxy-quinoliny10xy)fluor0-pheny1]-amide; 1,3 -Dimethy1—2,4-dioxo-1,2,3 ,4-tetrahydr0pyrimidine-5 -carb0xy1ic acid [4-(6,7- dimethoxy-quino1iny10xy)fluoropheny1]—amide; 1,3-Dicthyl-2,4-di0X0-1,2,3,4-tctrahydro-pyrirnidinccarb0xylic acid [4-(6,7- dimcthoxy-quino1iny10xy)fluor0-phcny1]—arnidc; 1,3-Diisopr0pyl-2,4-dioxo-1,2,3,4-tctrahydr0-pyrirnidinccarb0xylic acid [4- (6,7-dimcthoxy-quinolinyloxy)fluoro-phcny1]—arnidc; 1 ,3 -Bis-cyc10propy1rncthy1—2,4-di0x0- 1 ,2,3 ,4-tctrahydr0-pyrirnidinc-5 -carb0xylic acid [4-(6,7-dimcthoxy-quinoliny10xy)fluor0-phcnyl]-arnidc; 1,3-Dia11y1—2,4-di0X0-1,2,3,4-tctrahydr0-pyrimidinccarb0xylic acid [4-(6,7- dimcthoxy-quino1iny10xy)fluor0-phcny1]—arnidc; 1 ,3 -Bis-(3 -rncthy1—butcnyl)-2,4-di0xo-1 ,2,3 ,4-tctrahydr0-pyrirnidinc-5 - carboxylic acid [4-(6,7-dimcthoxy-quino1iny10xy)fluor0-phcnyl]-arnidc; 2,4-Di0X0-1,3-di-prop-2—yny1-1,2,3 ,4-tctrahydro-pyrimidinccarb0xy1ic acid [4- (6,7-dimcthoxy-quinolinyloxy)fluoro-phcny1]—arnidc; 2,4-Di0X0-1 ,2,3 ,4-tctrahydro-pyrirnidinccarb0xy1ic acid [4-(6,7-dirncthoxy- quinolinyloxy)flu0ro-phcnyl]-arnidc; 1—2,4-di0X0phcny1—1,2,3 ,4-tctrahydr0-pyrirnidinc-5 -carb0xy1ic acid [4- imcthoxy-quinolinyloxy)fluoro-phcny1]—arnidc; l-Isopropyl-2,4-dioxophcny1-1 ,2,3 ,4-tctrahydro-pyrimidinc-5 -carb0xy1ic acid [4-(6,7-dirncthoxy-quino1iny10xy)—3-fluor0-phcny1]—arnidc; 3 -(4-F1u0ro-phcnyl)-2,4-diox0pr0py1—1 ,2,3 ,4-tctrahydro-pyrirnidinc-5 - carboxylic acid 7-dimcthoxy-quino1inccarb0nyl)flu0ro-phcny1]—arnidc; luoro-phcnyl)isopropyl-3 ,5 -2,3 ,4,5 -tctrahydr0-[1,2,4]triazinc carboxylic acid [4-(6,7-dirncthoxy-quinolinyloxy)flu0r0-phcny1]—arnidc; 4-(4-Fluorophcnyl)rncthyl-3 ,5 -di0X0-2,3 ,4,5 -tctrahydr0-[1 ,2,4]triazinc carboxylic acid [4-(6,7-dimcthoxy-quino1iny10xy)fluor0-phcnyl]-arnidc; 2-Ethy1—4-(4-fluor0-phcnyl)-3 ,5 -di0X0-2,3 ,4,5 -tctrahydr0-[1,2,4]triazinc carboxylic acid [4-(6,7-dimcthoxy-quino1iny10xy)fluor0-phcnyl]-arnidc; 4-(4-Fluorophcnyl)isopr0py1—3,5-di0xo-2,3,4,5-tetrahydr0-[1,2,4]triazinc carboxylic acid [4-(2,3-dihydr0-[1,4]di0xin0[2,3-g]quinoliny10xy)—3-flu0r0phcny1]— amide; 4-(4-F1u0ro-phcny1)-3,5-diox0-2,3,4,5-tetrahydro-[1 ,2,4]triazinccarboxylic acid [4-(6,7-dirncthoxy-quino1iny10xy)—3-fluor0-phcny1]—arnidc; 4-(4-F1u0r0phcny1)(2-hydr0xycthy1)—3,5-di0X0-2,3,4,5-tetrahydro- [1,2,4]triazinccarboxylic acid [4-(6,7-dirncth0xyquinoliny10xy)—3-fluor0phcny1]— amide; WO 74633 2-Ethy1(4-fluor0pheny1)-3 ,5-di0X0-2,3 ,4,5 -tetrahydr0 [1 ,2,4]triazine carboxylic acid [4-(6,7-diethoxy-quino1iny10xy)fluor0-pheny1]—amide; 4-(4-Fluoro-pheny1)isopropy1-3 ,5 -di0X0-2,3 ,4,5 -tetrahydr0-[1,2,4]triazine ylic acid [5-(6,7-dimethoxy-quino1iny10xy)-pyridiny1]-amide; 4-(4-Fluorophenyl)isopr0py1-3,5-di0xo-2,3,4,5-tetrahydr0-[1,2,4]triazine carboxylic acid [3-flu0r0(7-meth0xyquin01iny10xy)-pheny1]-amide; 4-(4-F1uoropheny1)-3 ,5 -di0X0(2-0X0-pr0py1)-2,3 ,4,5 -tetrahydr0-[1,2,4]triazine- 6-carb0xy1ic acid [4-(6,7-dimethoxyquino1iny10xy)flu0r0pheny1]—amide; 4-(4-F1uoro-pheny1)-3 ,5-dioxopr0pyny1-2,3 ,4,5 -tetrahydr0-[1,2,4] triazine carboxylic acid [4-(6,7-dimethoxy-quino1iny10xy)fluor0-pheny1]-amide; 2-Methy1-3,5-di0X0-2,3,4,5-tetrahydr0-[1,2,4]triazinecarb0xy1ic acid [4-(6,7- oxy-quino1iny10xy)—3-fluor0-pheny1]—amide; 2-Methy1-3 ,5-diox0pr0pyny1-2,3 ,4,5 -tetrahydr0-[1,2,4]triazinecarb0xy1ic acid [4-(6,7-dimethoxy-uino1iny10xy)fluor0-pheny1]—amide; 2-Methy1(5-methy1-isoxaz01y1methy1)-3,5-di0X0-2,3,4,5-tetrahydro- [1,2,4]triazinecarboxy1ic acid [4-(6,7-dimeth0xy-quin01iny10xy) fluor0-pheny1]— amide; 2-Methy1-3 ,5 -di0xopentyny1-2, 3 ,4,5 -tetrahydr0-[1,2,4]triazinecarb0xy1ic acid [4-(6,7-dimethoxy-uino1iny10xy)fluor0-pheny1]—amide; 4-(4-Hydr0xy-but—2-yny1)—2-methy1-3 ,5-di0X0-2,3 ,4,5 -tetrahydro-[1 ,2,4] triazine- 0xy1ic acid [4-(6,7-dimethoxy-quino1iny10xy)—3-fluor0-pheny1]—amide; 4-(1 ,5 hy1-1H-pyraz01y1methy1)—2-methy1-3 ,5 -di0X0-2,3 ,4,5 -tetrahydr0- [1,2,4]triazinecarb0xy1ic acid [4-(6,7-dimeth0xyquin01iny10xy)—3-fluor0pheny1]— amide; 2-Methy1-3 ,5 -di0xo(2—pyraz01y1-ethy1)-2,3 ,4,5 -tetrahydr0- [1 ,2,4] triazine carboxylic acid [4-(6,7-dimethoxyquino1iny10xy)fluor0pheny1]—amide; 2-Methy1(1-methy1-1H-[1,2,4]triaz01y1methy1)-3 ,5-di0X0-2,3 ,4,5 -tetrahydr0- [1,2,4]triazinecarboxy1ic acid [4-(6,7-dimeth0xy-quin01iny10xy)fluor0-pheny1]- amide; omethy1methy1-3 ,5-dioxo-2, 3 ,4,5 -tetrahydr0- [1 ,2,4]triazine carboxylic acid [4-(6,7-dimethoxy-quino1iny10xy)fluor0-pheny1]-amide; 4-Ethy1methy1-3 x0-2,3 ,4,5-tetrahydr0-[1,2,4]triazinecarb0xy1ic acid [4- (6,7-dimeth0xyquino1iny10xy)—3-fluor0-pheny1]—amide; 4-A11y1—2-mcthy1—3,5-di0X0-2,3,4,5-tetrahydro-[ 1 ,2,4]triazinccarboxylic acid [4- (6,7-dimcthoxy-quinolinyloxy)fluoro-phcny1]—arnidc; opropylmcthyl-Z-rncthy1—3 ,5-di0X0-2,3 ,4,5 -tctrahydro-[1 ,2,4]triazinc carboxylic acid [4-(6,7-dirncthoxy-quinolinyloxy)flu0r0-phcny1]—arnidc; y1—3,5-dioxo(tctrahydr0-pyrany1rncthyl)-2,3,4,5-tetrahydr0- [1,2,4]triazinccarboxy1ic acid [4-(6,7-dirncth0xy-quinoliny10xy)- 3-flu0ro-phcnyl]— amide; 4-Isobuty1rncthyl-3,5-diox0-2,3,4,5-tetrahydro-[1 ,2,4]triazinccarboxylic acid 7-dirncthoxy-quino1iny10xy)—3-fluor0-phcny1]—arnidc; 4-Cyc10buty1rncthy1—2-rncthyl-3 ,5 -di0X0-2,3 ,4,5 -tctrahydr0- [1 ,2,4]triazinc carboxylic acid [4-(6,7-dimcthoxy-quino1iny10xy)fluor0-phcnyl]-arnidc; 4-(2,2-Dirncthy1propy1)rncthy1—3 , 5 -di0X0-2,3 ,4,5 -tctrahydr0-[1 ,2,4]triazinc carboxylic acid [4-(6,7-dirncthoxyquino1iny10xy)fluor0phcny1]—arnidc; :2-Methyl(2-rncthy1—butyl)-3 ,5 -di0X0-2,3 ,4,5 hydr0-[1,2,4]triazinc carboxylic acid [4-(6,7-dirncth0xy-quinolinyloxy)fluoro-phcnyl] -arnidc; 3 -(4-F1u0r0-phcnyl)-1 -rncthy1—2,4-di0x0- 1 ,2,3 ,4-tctrahydr0-pyrirnidinc-5 - carboxylic acid [4-([1,3]di0x010[4,5 -g]quin01iny10xy)fluoro-phcnyl] -arnidc; 1-Ethy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydro-pyrirnidinc-5 -carb0xy1ic acid [4-(2,3 -dihydro-[1 dioxino [2,3 n01iny10xy)-3 -flu0r0-phcny1]—arnidc; , 4] 2-Cyclopr0pylmcthyl(4-fluorophcnyl)—3 ,5-di0X0-2,3 ,4,5 -tctrahydr0- [1 ,2,4]triazinccarboxylic acid [4-(6,7-dirncth0xy-quino1inyloxy)flu0r0-phcny1]— amide; 1-Ethy1—3-(4-flu0ro-phcny1)—2,4-di0x0- 1 ,2,3 ,4-tctrahydr0-pyrirnidinc-5 -carb0xy1ic acid [4-(6,7-dirncthoxy-quinolinylamino)-phcnyl]-arnidc; 3 -(4-F1uor0phcnyl)—1-isopr0py1—2,4-diox0-1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 - carboxylic acid [4-(6,7-dimcthoxyquino1iny1amino)-phcny1]-arnidc; 4-(4-Fluoro-phcnyl)isopropyl-3 ,5 -di0X0-2,3 ,4,5 hydr0-[1,2,4]triazinc carboxylic acid [4-(6,7-dimcthoxy-quino1inylamin0)-phcnyl]-arnidc; 1-cthy1—3 -(4-flu0r0-phcnyl)-2,4-di0x0-1 ,2,3 ,4-tctrahydr0-pyrirnidinc-5 -carb0xylic acid [4-(6,7-dirncth0xy-quinolinylsu1fany1)-phcnyl]-arnidc; 3 u0r0-phcny1)isopr0py1—2,4-di0xo-1 ,2,3 ,4-tctrahydr0-pyrirnidinc-5 - ylic acid [4-(6,7-dirncthoxy-quinolinylsu1fanyl)-phcnyl]-arnidc; 3 -(4-F1uor0phcnyl)—1-isopr0py1—2,4-diox0-1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 - carboxylic acid {4-[(6,7-dirncth0xy-quino1iny1)-rncthy1—arnino]-phcny1} -arnidc; - 1 5 4- 1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydro-pyrirnidinc-5 -carb0xy1ic acid {4-[(6,7-dimcthoxy-quinoliny1)-rncthylarnin0]-phcny1}-arnidc; 3 -(4-F1u0r0-phcny1)isopr0py1—2,4-di0xo-1 ,2,3 ,4-tctrahydr0-pyrirnidinc-5 - carboxylic acid [4-(6,7-dimcthoxy-quinazo1iny10xy)—phcnyl]-arnidc; 1-Ethy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydro-pyrirnidinc-5 -carb0xy1ic acid [4-(6,7-dimcthoxy-quinazo1iny10xy)—phcnyl]-arnidc; 1-Ethy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid [4-(6,7-dirncth0xy-quinoliny10xy)rncthoxyphcny1]-arnidc; 1-Mcthy1—3-(4-flu0r0-phcnyl)-2,4-di0X0-1 ,2,3 ,4-tctrahydro-pyrirnidinc-5 - carboxylic acid [4-(6,7-dimcth0xy-quinoliny10xy)mcthoxy-phcnyl]-arnidc; 1 -Isopr0py1—3 -(4-flu0ro-phcny1)—2,4-di0x0- 1 ,2,3 ,4-tctrahydr0-pyrimidinc-5 - carboxylic acid [4-(6,7-dimcth0xy-quinoliny10xy)mcthoxy-phcnyl]-arnidc; 1-Mcthy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0-pyrimidinc-5 -carb0xy1ic acid [4-(6,7-dirncthoxy-quino1inyloxy)-2,3-diflu0ro-phcny1]—arnidc; 1-Ethy1—3-(4-flu0ro-phcny1)—2,4-di0x0- 1 ,2,3 ,4-tctrahydr0-pyrimidinc-5 -carb0xy1ic acid [4-(6,7-dirncthoxy-quino1inyloxy)-2,3-diflu0ro-phcny1]—arnidc; 1—3-(4-flu0ro-phcny1)—2,4-di0x0- 1 ,2,3 ,4-tctrahydr0-pyrimidinc-5 -carb0xy1ic acid 7-dirncth0xy-quinolinyloxy)rncthy1—phcnyl]—arnidc; 3 -(4-F1uor0-phcnyl)-2,4-di0x0-1 ,2,3 ,4-tctrahydro-pyrirnidinc-5 -carb0xy1ic acid [4- (6,7-dirncthoxy-quinolinyloxy)-3 -rncthy1—phcny1]—arnidc; 3 -(4-F1uor0-phcnyl)-2,4-di0x0-1 ,2,3 ,4-tctrahydro-pyrirnidinc-5 -carb0xy1ic acid [4- irncthoxy-quino1iny10xy)rncth0xy-phcny1] -arnidc; 1-Ethy1—3-(4-flu0ro-phcny1)—2,4-di0x0- 1 ,2,3 ,4-tctrahydr0-pyrimidinc-5 -carb0xy1ic acid [4-(6,7-dimcthoxy-quinolinyloxy)mcthoxy-phcnyl]-amidc; 1-Ethy1—3-(4-flu0ro-phcny1)—2,4-di0x0- 1 ,2,3 ,4-tctrahydr0-pyrimidinc-5 -carb0xy1ic acid [3 -ch10r0(6,7-dirncth0xy-quinolinyloxy)mcth0xy-phcny1] -arnidc; 1—3-(4-flu0ro-phcny1)—2,4-di0x0- 1 ,2,3 ,4-tctrahydr0-pyrimidinc-5 -carb0xy1ic acid [4-(6,7-dimcthoxy-quinolinyloxy)dimcthylarnino-phcnyl]-arnidc; 3 -(4-F1u0r0-phcny1)isopr0py1—2,4-di0xo-1 ,2,3 ,4-tctrahydr0-pyrirnidinc-5 - carboxylic acid 7-dimcth0xy-quinoliny10xy)dirncthy1arnino-phcnyl]-arnidc; 1-Ethy1—3-(4-flu0ro-phcny1)—2,4-di0x0- 1 ,2,3 ,4-tctrahydr0-pyrimidinc-5 -carb0xy1ic acid [4-(6,7-dimcthoxy-quinolinyloxy)isopropy1—phcnyl]-arnidc; 3 -(4-F1u0r0-phcny1)isopr0py1—2,4-di0xo-1 ,2,3 ,4-tctrahydr0-pyrirnidinc ylic acid [4-(6,7-dimcth0xy-quinoliny10xy)isopropy1—phcnyl]-arnidc; - 1 5 5 - 2012/065019 l-Ethyl(4-fluoro-phenyl)—2,4-dioxo- l ,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)-2,3-dimethyl-phenyl]-amide; 3 -(4-Fluoro-phenyl)- l opyl-2,4-dioxo-l ,2,3 ,4-tetrahydro-pyrimidine carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)-2,3-dimethyl-phenyl]-amide; l-Ethyl(4-fluoro-phenyl)—2,4-dioxo- l ,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)trifluoromethyl-phenyl]-amide; 3 -(4-Fluoro-phenyl)- l -isopropyl-2,4-dioxo-l ,2,3 ,4-tetrahydro-pyrimidine carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)trifluoromethyl- phenyl]-amide; l-Ethyl(4-fluoro-phenyl)—2,4-dioxo- l ,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)-3,5-dimethyl-phenyl]-amide; 3 -(4-Fluoro-phenyl)- l opyl-2,4-dioxo-l ,2,3 ,4-tetrahydro-pyrimidine carboxylic acid 7-dimethoxy-quinolinyloxy)-3,5-dimethyl-phenyl]-amide; 3 -(4-Fluoro-phenyl)- l -isopropyl-2,4-dioxo-l ,2,3 ,4-tetrahydro-pyrimidine carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)methyl-phenyl]-amide; 2-Ethyl(4-fluoro-phenyl)—3 ,5-dioxo-2,3 ,4,5-tetrahydro- l ,2,4-triazine- 6- carboxylic acid [5-(6,7-dimethoxy-quinolinyloxy)-pyridinyl]-amide; 2-Ethyl(4-fluoro-phenyl)—3 xo-2,3 ,4,5-tetrahydro- l riazine- 6- carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)isopropyl-phenyl]-amide; or 4-(4-Fluoro-phenyl)isopropyl-3 ,5 -dioxo-2,3 ,4,5 -tetrahydro-l ,2,4-triazine- 6- ylic acid [4-(6,7-dimethoxy-quinolinyloxy)methoxy-phenyl]-amide; or a pharmaceutically acceptable salt thereof. 19. A method of treating a subject suffering from an AXL- or c-MET-mediated disorder or condition comprising administering to the t a eutically effective amount of a compound according to any one of preferred Embodiments l to 18.
. A method according to preferred Embodiment 19 wherein the AXL- or c-MET- mediated disorder or condition is the development of resistance to cancer therapies. 21. A compound according to any one of preferred Embodiments l to 18 for use in the treatment of a subject suffering from an AXL- or c-MET-mediated disorder or condition. 22. The method of preferred Embodiment 19 wherein the AXL- or c-MET-mediated disorder or condition is cancer. - 1 5 6- 23. A compound according to preferred Embodiment 21 wherein the AXL- or c-MET- mediated disorder or condition is cancer. 24. The method of preferred Embodiment 19 wherein the AXL- or c-MET-mediated disorder is ed from chronic myelogenous leukemia, chronic myeloproliferative disorder, lung cancer, prostate cancer, esophageal cancer, ovarian cancer, pancreatic , gastric cancer, liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breast cancer, acute myeloid ia, colorectal cancer, uterine cancer, malignant glioma, uveal melanoma, osteosarcoma and soft tissue sarcoma.
. A compound according to preferred Embodiment 21 wherein the AXL- or c-MET- mediated disorder is selected from chronic myelogenous leukemia, chronic myeloproliferative disorder, lung cancer, prostate cancer, esophageal cancer, ovarian cancer, pancreatic cancer, c cancer, liver cancer, thyroid , renal cell carcinoma, glioblastoma, breast cancer, acute d leukemia, colorectal cancer, uterine cancer, malignant glioma, uveal melanoma, osteosarcoma and soft tissue sarcoma. 26. A method of treating a proliferative disorder in a t in need thereof, comprising administering to the subject a therapeutically effective amount of a compound ing to any one of preferred Embodiments l to 18. 27. A compound according to any one of preferred Embodiments l to 18 for use in the treatment of a subject suffering from a proliferative disorder. 28. A method according to red Embodiment 26 wherein the proliferative disorder is . 29. A nd according to preferred Embodiment 27 wherein the erative disorder is cancer.
. A method according to preferred Embodiment 26 wherein the proliferative disorder is ed from chronic myelogenous leukemia, chronic roliferative disorder, lung cancer, prostate , esophageal cancer, ovarian cancer, pancreatic - l 5 7- WO 74633 cancer, gastric cancer, liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breast cancer, acute myeloid leukemia, ctal cancer, uterine cancer, malignant glioma, uveal melanoma, osteosarcoma and soft tissue sarcoma. 3 l. A compound according to preferred ment 29 wherein the proliferative disorder is selected from chronic myelogenous leukemia, chronic myeloproliferative disorder, lung , prostate cancer, esophageal cancer, ovarian cancer, pancreatic cancer, gastric cancer, liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breast cancer, acute myeloid leukemia, colorectal , uterine cancer, malignant glioma, uveal melanoma, osteosarcoma and soft tissue sarcoma. 32. A pharmaceutical composition comprising a compound according to any one of preferred Embodiments l to 18 and a pharmaceutically able carrier, diluents or excipient therefor. 33. A compound of Formula I or a salt therof, R3 X/N O R l I T Rd \ Y O O Ra R13 Rb N) wherein: E is chosen from H, C1_6alkyl ally substituted by 1-6 R19, C2_6alkenyl optionally substituted by 1-6 R19, C2_6alkynyl optionally substituted by 1-6 R19, phenyl optionally substituted by 1-6 R19, and C3_6cycloalkyl optionally substituted by 1-6 R19; G is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 R19, C2_6alkynyl optionally substituted by 1-3 R19 u phenyl optionally substituted by 1-3 R19, C3_6cycloalkyl optionally substituted by 1-3 R19, and 3-6 membered heterocyclyl optionally substituted by 1-3 R19; X is N or C-R4; Y is N or C-Rld; R3 is H or C1_6alkyl; D is O S CHOH NH or , , C(—O) , , CH2 , NC1_6alkyl—; W is CH or N; Ra, Rb, RC, and Rd are independently chosen from H, kyl optionally substituted by 1-6 R119, —CN, and —OR110; or Ra and Rb can, together with the atoms linking them, form a 3-6 membered heterocyclyl optionally substituted by 1-6 R119; Rla, Rlb, R10, and Rld are ndently chosen from H, C1_6alkyl optionally substituted by 1-6 R119, C3_6cycloalkyl optionally substituted by 1-6 R119, 3-6 membered heterocyclyl optionally substituted by 1-6 R119, halogen, —CN, — NRmRm, and —OR110; R4 is chosen from H and C1_6alkyl; R19 at each occurrence is independently chosen from C1_6alkyl ally tuted by 1-6 R39, phenyl optionally substituted by 1-6 R39, C3_6cycloalkyl optionally substituted by 1-6 R39, 3-6 membered heterocyclyl optionally substituted by 1-6 R39, 5-6 membered heteroaryl ally substituted by 1-6 R39, halogen, —CN, —C(=O)OR3°, —C(=O)NR32R33, —NR32R33, —0R3°, and =0; R30, R32 and R33 at each occurrence is ndently chosen from H, C1_6alkyl, C1- 6halolkyl, phenyl, benzyl, C5_6cycloalkyl, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl; or R32 and R33 may form, together with the nitrogen atom to which they are ed, a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl; R39 at each occurrence is independently chosen from kyl, C1_6haloalkyl, and benzyl; R110, R112, and R113 at each occurrence is independently chosen from H and C1- 6alkyl ally substituted by 1-3 R129; -lS9- R119 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-3 R159 5-6 membered heterocyclyl optionally substituted by l-3 R159, and n; R129 and R159 at each occurrence is independently chosen from C1_6alkyl, C1_6- haloalkyl, benzyl, and halogen; and n at each occurrence is independently chosen from 0, l, and 2. 34. A compound according to preferred Embodiment 33, wherein E is chosen from H, C1_6alkyl ally substituted by 1-3 R19, C2_6alkenyl, C2_6alkynyl optionally tuted by —OH, phenyl optionally substituted by halogen, and C3_6cycloalkyl. 34. A compound according to preferred Embodiment 33, wherein E is chosen from H, kyl optionally substituted by 1-3 R19, C2_6alkenyl, C2_6alkynyl optionally substituted by —OH, phenyl optionally substituted by halogen, and cyclohexyl.
. A compound according to preferred Embodiment 33, wherein E is chosen from C1_ 6alkyl ally substituted by R19, , and p-fluorophenyl. 36. A compound according to preferred Embodiment 33, wherein E is p-fluorophenyl. 37. A compound ing to any of preferred Embodiments 33-36, wherein G is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 n, kynyl, phenyl optionally substituted by 1-3 halogen, C3- 6cycloalkyl, and 3-6 membered heterocyclyl. 38. A compound according to any of preferred Embodiments 33-36, wherein G is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C3_6alkenyl optionally substituted by 1-3 fluoro, C3_6alkynyl, phenyl optionally substituted by 1-3 fluoro, C3- 6cycloalkyl, and 6 ed heterocyclyl. 39. A compound according to any of preferred Embodiments 33-36, wherein G is chosen from H, C1_6alkyl optionally substituted by R19, C3_6alkenyl optionally substituted by 2 fluoro, C3_6alkynyl, phenyl optionally tuted by fluoro, C3_6cycloalkyl, and tetrahydropyranyl. - l 60- 40. A compound according to any of preferred Embodiments 33-36, wherein G is C1- 6alkyl optionally substituted by cyclopropyl or —OH. 41. A compound according to any of preferred Embodiments 33-40, wherein X is N. 42. A compound according to any of preferred Embodiments 33-40, wherein X is C- 43. A compound according to any of preferred Embodiments 33-42, wherein Y is N. 44. A compound according to any of preferred Embodiments 33-42, wherein Y is CH. 45. A compound according to any of red Embodiments 33-42, wherein Y is C- Rld. 46. A compound according to any of red ments 33-45, wherein R3 is H. 47. A compound according to any of preferred Embodiments 33-46, wherein D is —O—, —S—, —C(=O)—, —CHOH—, or —CH2—. 48. A compound according to any of preferred Embodiments 33-46, wherein D is —O—, —, —CHOH—, or —CH2—. 49. A compound according to any of preferred Embodiments 33-46, wherein D is —O—. 50. A compound according to any of preferred Embodiments 33-49, wherein W is CH. 51. A nd according to any of red Embodiments 33-50, wherein Ra, Rb, RC, and Rd are independently chosen from H, C1_6alkyl optionally substituted by 1-6 R119, —CN, and —OR110; or Ra and Rb can, er with the atoms linking them, form a 5-6 membered heterocyclyl. -l6l- 52. A compound according to any of preferred Embodiments 33-50, wherein Ra is chosen from H, —CN, and —OC1_6alkyl; Rb is chosen from H, C1_6alkyl optionally substituted by 1-6 R119, and ; RC is chosen from H and —OC1_6alkyl; and Rd is chosen from H and alkyl; or Ra and Rb can, together with the atoms linking them, form a 5-6 membered heterocyclyl. 53. A nd according to any of preferred Embodiments 33-50, wherein Ra is chosen from H, —CN, and alkyl; Rb is chosen from H, C1_6alkyl optionally substituted by 6-membered heterocyclyl, —OH, —OC1_6alkyl, —OCH2phenyl, —OC1_6alkyl- O-C1_6alkyl; RC is chosen from H and —OC1_6alkyl; and Rd is chosen from H and —OC1_ ; or Ra and Rb can, er with the atoms g them, form a 5-6 membered heterocyclyl. 54. A compound according to any of preferred Embodiments 33-50, wherein Ra is chosen from H, —CN, and —OC1_6alkyl; Rb is chosen from H, C1_6alkyl optionally substituted by morpholinyl, —OH, —OC1_6alkyl, —OCH2phenyl, —OC1_6alkyl-O-C1_6alkyl; RC is chosen from H and —OC1_6alkyl; and Rd is chosen from H and —OC1_6alkyl; or Ra and Rb O O < E together form 0or O. 55. A compound according to any of preferred Embodiments 33-50, wherein Ra is chosen from H and —OC1_6alkyl; Rb is chosen from H and —OC1_6alkyl; Rc is H; and Rd is <0 E0 0 O chosen from H and —OC1_6alkyl; or Ra and Rb together form or . 56. A compound according to any of preferred Embodiments 33-50, wherein Ra is chosen from H and —OC1_6alkyl; Rb is chosen from H and —OC1_6alkyl; RC is H; and Rd is O O < E H; or Ra and Rb together form 0or 0. -l62- 2012/065019 57. A compound according to any of preferred ments 33-50, wherein RC and Rd <0 [0 O O are H, and Ra and Rb are —OC1_6alkyl; or Ra and Rb together form or . 58. A compound according to any of preferred Embodiments 33-50, wherein Ra is — OC1_6alkyl; Rb is —OC1_6alkyl; Rc is H; and Rd is H. 59. A compound according to any of preferred Embodiments 33-40 or 42-58, wherein R4 is H. 60. A compound according to any of preferred Embodiments 33-59, wherein Rla, Rlb, R10, and Rld are independently chosen from H, C1_6alkyl, C1_6haloalkyl, cloalkyl, halogen, —NH2, —NHC1_6alkylz, 6alkyl)2, —OH, and —OC1_6alkyl. 61. A compound according to any of preferred Embodiments 33-59, wherein Rla, Rlb, R10, and Rld are independently chosen from H, C1_3alkyl, C1_3haloalkyl, ropyl, halogen, and —OC1_3alkyl. 62. A compound according to any of preferred Embodiments 33-59, wherein Rla, Rlb, R10, and Rld are independently chosen from H, halogen, and —OC1_3alkyl. 63. A compound according to any of preferred Embodiments 33-59, wherein Rla, Rlb, R10, and Rld are independently chosen from H and halogen. 64. A compound according to any of preferred Embodiments 33-59, wherein Rla, R10, and Rld are H and Rlb is chosen from H, C1_3alkyl, C1_3haloalkyl, cyclopropyl, halogen, and —OC1_3alkyl. 65. A compound according to any of red Embodiments 33-59, wherein Rla, R10, and Rld are H and Rlb is chosen from H, halogen, and —OC1_3alkyl. 66. A compound according to any of red Embodiments 33-59, wherein Rla, R10, and Rld are H and Rlb is fluoro. 67. A compound according to any of preferred ments 33-66, wherein R19 at each occurrence is independently chosen from kyl, phenyl optionally substituted by l-3 halogen, C3_6cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl optionally substituted by l-3 C1_6alkyl, halogen, —CN, —C(=O)OH, —C(=O)OC1_6alkyl, — C(=O)N(C1_6alkyl)2, —C(=O)pyrrolidinyl, —C(=O)morpholinyl, 6alkyl)2, —OH, — OC1_6alkyl, —Obenzyl, and =0. 68. A compound according to any of preferred ments 33-67, wherein R30, R32 and R33 at each occurrence is independently chosen from H and C1_6alkyl. 69. A compound according to any of preferred Embodiments 33-68, wherein R39 at each occurrence is C1_6alkyl. 70. A nd according to any of preferred Embodiments 33-69, wherein R110, R112, and R113 at each occurrence is independently chosen from H and C1_6alkyl. 71. A compound according to any of preferred Embodiments 33-70, wherein R at each occurrence is independently chosen from 6 membered heterocyclyl and halogen. 72. A compound according to any of preferred Embodiments 33-70, wherein R119 at each occurrence is independently chosen from morpholinyl and fluoro. 73. A compound ing to any of preferred Embodiments 33-72, wherein R129 and R159 at each occurrence is ndently chosen from C1_6alkyl and halogen. 74. A compound according to any of preferred Embodiments 33-73, wherein n at each occurrence is 2. 75. A compound according to red Embodiment 33, wherein E is p-fluorophenyl; G is C1_4alkyl optionally substituted by cyclopropyl, —OH, or -OC1_3alkyl; X, Y, and W are WO 74633 CH; R3, R0, Rd, Rlb and R10 are H; D is —O—; Ra and Rb are —OCH3 or together form [:f3 or ; and Rla is fluoro.

Claims (1)

WHAT IS CLAIMED IS:
1. A compound of Formula I or a salt form thereof, Ric T3 Xl/NYO R1b NWN / \ Rd \ IY O 0 R3 \ W Rla Rb N/J 5 Re Formula I wherein: E and G are independently chosen from H, C1_6alkyl optionally substituted by 1-6 10 R19, C2_6alkenyl optionally substituted by 1-6 R19, C2_6alkynyl optionally substituted by 1-6 R19, €6-11an optionally substituted by 1-6 R19, c3- 11cycloalkyl optionally substituted by 1-6 R19, 3—15 membered heterocyclyl optionally substituted by 1-6 R19, 5-15 ed heteroaryl optionally substituted by 1-6 R19, —C(=O)R20, —C(=O)OR2°, —C(=O)NR22R23, — 15 R2°, and —S(=O)2NR22RZ3; X is N or C-R4; Y is N or C-Rld; R3 is H or C1_6alkyl; D is O S SO CHOH , , , SOZ , C(—O) , , CH2 NH or , NC1_6alkyl—; 20 W is CH or N; Ra, Rb, RC, Rd, Rla, Rlb, R10, Rld, and R4 are independently chosen from H, C1- 6alkyl optionally substituted by 1-6 R119 substituted by , kenyl optionally 1-6 R119, kynyl optionally substituted by 1-6 R119, C6_11aryl optionally substituted by 1-6 R119, C3_11cycloalkyl optionally substituted by 1-6 R119, 3-15 25 membered heterocyclyl optionally tuted by 1-6 R119 5-15 membered -l66-
NZ624945A 2011-11-14 2012-11-14 Uracil derivatives as axl and c-met kinase inhibitors NZ624945B2 (en)

Priority Applications (1)

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US201161559312P 2011-11-14 2011-11-14
US61/559,312 2011-11-14
PCT/US2012/065019 WO2013074633A1 (en) 2011-11-14 2012-11-14 Uracil derivatives as axl and c-met kinase inhibitors

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NZ624945B2 true NZ624945B2 (en) 2016-01-06

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