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NZ712194B2 - 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
NZ712194B2
NZ712194B2 NZ712194A NZ71219412A NZ712194B2 NZ 712194 B2 NZ712194 B2 NZ 712194B2 NZ 712194 A NZ712194 A NZ 712194A NZ 71219412 A NZ71219412 A NZ 71219412A NZ 712194 B2 NZ712194 B2 NZ 712194B2
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fluorophenyl
dioxo
lcms
cancer
amide
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NZ712194A
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NZ712194A (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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Publication of NZ712194B2 publication Critical patent/NZ712194B2/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
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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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • 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
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    • 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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    • 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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    • 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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    • 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
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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
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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

The disclosure relates to uracil derivative compounds of the general Formula I, wherein the variables are as defined in the specification. The preferred compound is 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide. The compounds are AXL and c-MET inhibitors. Pharmaceutical compositions comprising these compounds may be useful in the treatment of cancer. yl]-amide. The compounds are AXL and c-MET inhibitors. Pharmaceutical compositions comprising these 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 tyrosine kinases AXL and c-MET. The compounds are suitable for treatment ofAXL or c- MET-mediated disorders such as , and the development of resistance to cancer therapies.
Receptor ne 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 sion or activation of RTKs has been implicated in the pathogenesis of various human cancers, linked with cell transformation, tumor ion and asis. These observations 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 tyrosine kinase (RTK) family originally identified as a orming gene expressed in cells from patients with chronic myelogenous leukemia (O'Bryan et. al Mol. Cell Biol. 1991, 11, 5016) or chronic myeloproliferative disorder (Janssen et. al Oncogene, 1991, 6, 2113). AXL activation occurs by g of its cognate protein ligand, growth arrest specific 6 (Gas6), homotypic dimerization h its extracellular domain or cross-talk via the interleukin (IL)-15 receptor or HER2. AXL signaling stimulates cellular responses, including activation ofphosphoinositide 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, ing invasion, ion, survival signaling, angiogenesis, ance to chemotherapeutic and targeted drugs, cell transformation, and eration, represent undesirable 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 receptors play pivotal roles in innate immunity by inhibiting inflammation in macrophages and dendritic cells (Sharif et al, J. Exp. Med. 2006, 203, 1891; n 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 ci. 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 sion ofAXL has been reported in a variety of human cancers (Crosier et al, Leuk. Lymphoma. 1995, 18, 443; er et al, Leukemia, 1996, 10, 781; Ito et al, Thyroid. 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 veness and metastasis in lung cancer (Shieh et al, Neoplasia. 2005, 7, 1058), prostate cancer (Shiozawa et al, sia. 2010, 12, 116), breast cancer (Zhang et al, Cancer Res. 2008, 68, 1905), esophageal cancer (Hector et al, Cancer Biol. Ther. 2010, 10, 1009), ovarian cancer (Rankin et al, Cancer Res. 2010, 70, 7570), atic 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 carcinoma (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 ated with late stage and poor overall survival in many of those human cancers (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 ancy in human, by promoting cancer cell ion 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; uru 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 y gland to lymph nodes and several major organs and increases overall survival (Gjerdrum 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 gastrointestinal 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 ensitivity of astrocytoma cells in response to herapy ent (Keating et al, Mol. Cancer Ther. 2010, 9, 1298).
These data indicate 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 transform and confer invasive and metastatic properties to non-tumorigenic cells (Sattler et. al, Current gy Rep., 2007, 9, 102). The nic potential is a result of spontaneous dimerization and constitutive activation of T. Aberrant expression ofHGF and c-MET is associated with the development and poor prognosis of a wide range of solid tumors, including breast, prostate, thyroid, lung, stomach, colorectal, pancreatic, , ovarian, and uterine carcinoma, malignant , uveal melanoma, and osteo-and soft-tissue sarcoma (Jaing et. al Critical Rev. Oncol/Hematol., 2005, 53, ). Gastric tumors with an amplification of the ET 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 studies have shown that increased and dysregulated c-MET tion leads to a wide range of biological ses 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, ultraviolet 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 Oncology Rep., 2007, 9, 102; Fan et. al, Mol. Cell Biol., 2001, 21, 4968). Based upon these data, HGF may e mutagenicity following DNA , allowing 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, IressaTM the resistance of , TykerbTM) HER2 positive breast cancer to trastuzumab er 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 ation with an EGFR inhibitor overcame MET-mediated resistance to EGFR inhibitors [Agarwal et. al, Br. J. Cancer, 2009, 100, 941; itner- Hoffman et. al, Mol. Cancer Ther., 2008, 7, 3499, Tang et. al, Br. J. , 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 invention provides a compound of Formula I a. T3 x/“YO R1b / NWME Rd \IY o o R161 Rb N Formula I or a pharmaceutically acceptable salt form thereof, n 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 ty, and may be used to treat AXL-, or c-MET- mediated disorders or conditions.
The present invention fiarther provides a pharmaceutical composition comprising at least one compound of the present invention together with at least one pharmaceutically acceptable carrier, diluent, or excipient therefor.
In another aspect, the present invention provides a method of ng 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 present ion.
The present invention fiarther provides a method of treating a proliferative er in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the t invention.
DETAILED DESCRIPTION OF THE INVENTION I. Definitions As used herein, the following terms have the gs ed 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.
“Alkoxycarbonyl” refers to an all<yl-O-C(=O)- group.
"Alkyl" or “alkyl group” refers to a branched or unbranched saturated hydrocarbon chain. Examples include, but are not limited to, methyl, ethyl, yl, n-butyl, n-pentyl, n-hexyl, yl, 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” indicates 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- 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.
“Alkenyl” refers to an alkyl group containing the requisite number of carbon atoms as bed herein for ”, and which contains at least one double bond. Representative examples of alkenyl groups include, but are not limited to ethenyl, allyl, isopropenyl, and 2- methyl- 1 nyl. ituted alkenyl” 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 tuents include, but are not limited to, n, (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, 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, )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.
“Alkynyl” refers to an alkyl group ning the requisite number of carbon atoms as described herein for “alkyl”, and which contains at least one triple bond. Representative examples of alkenyl groups include, but are not limited to ethynyl, propargyl, and l- and 2- butynyl.
“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 en atom is a ituent”. Representative substituents include, but are not d to, halogen, (Cl-Cg)alkyl, (C1-C8)alkoxy, (C1-C8)alkoxy(C1- C4)alkyl, carboxyl, formyl, (C1-C6)acyl, halo(C1-C4)alkyl, halo(C1-C4)alkoxy, hydroxyl, nitro, cyano, amino, trifluoromethyl, mono- or -C6)alkylamino, oxo, (C6-C10)aryl, (C5- C9)heteroaryl, )alkoxycarbonyl, 0)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 alkyl-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 ” refers to a CN group.
“Cycloalkyl” refers to a omatic, 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. es include, but are not limited to cyclopropyl, cyclobutyl, entyl, cyclohexyl, cycloheptyl, and norbomyl.
“Cycloalkoxyalkyl” refers to a cycloalkyl-O-alkyl- group.
“Cycloalkylalkyl” refers to a cycloalkyl-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, including bridged, spiro, and/or fused ring systems, 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- tetrahydronaphthalenyl, 6,7,8,9-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., ), 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 “substituent”. Representative substituents include, but are not limited to, n, (C1-C8)alkyl, )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-(Cl-C6)alkylamino, oxo, (C6-C10)aryl, (C5- C9)heteroaryl, )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 aryl-alkyl- group.
“Arylalkoxy” refers to an aryl-alkyl-O- group.
“Arylalkoxyalkyl” refers to an aryl-alkyl-O-alkyl- group. xy” 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 bridged, spiro, and/or fused, and which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfilr.
Examples e, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, dyl, piperazinyl, indolinyl, isoindolinyl, linyl, thiomorpholinyl, rpholinyl, homopiperidyl, homopiperazinyl, rpholinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, 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 dinyl ached). 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, respectively.
“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 “substituent”. Representative substituents include, but are not d to, halogen, (C1-C8)alkyl, (Cl-Cg)alkoxy, (C1- 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-(Cl-C6)alkylamino, oxo, (C6- C10)aryl, (C5-C9)heteroaryl, (C1-C6)alkoxycarbonyl, 0)cycloalkyl, (C3- C10)cycloalkyloxy, (Cg-C10)cycloalkyl(C1-C6)alkoxy, (C2-C9)heterocyclyl, (C2- C9)heterocyclyloxy, (C2-C9)heterocyclyl(C1-C4)alkoxy, )alkoxycarbonyl(C1-C4)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylsulf1nyl, (C1-C6)alkylsulfonyl, mono- and di-(Cl- C6)alkylaminocarbonyl, (C1-C6)acylthio, and (C1-C6)acyloxy.
"Heterocyclylalkoxyalkyl" refers to a heterocylylalkyl-O-alkyl- group.
“Heterocyclylcarbonyl” refers to a cyclyl-(C=O)- group.
“Heteroaryl” or oaryl 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 , 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, olyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or 5-pyrimidinyl, lyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, thienyl, nyl, 3- thienyl, tetrazolyl, lyl, thiadiazolyl, triazinyl, lyl, nyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, naphthyridinyl, pteridinyl, phthalazinyl, purinyl, alloxazinyl, benzimidazolyl, benzofuranyl, benzofilrazanyl, 2H-l-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, cinnolinyl, furopyridinyl, indolinyl, indolizinyl, 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 .0*2,7*]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 -tetrahydro- l H-benzo [b] azepinyl, 5 -tetrahydro-benzo [e] [ l ,3 ] diazepin-3 -onyl, 3 ,4-dihydro-2H-benzo [b] [l ,4]dioxepinyl, 3 ydro-2H-benzo[f] [ l ,4]oxazepin-5 -onyl, 6,7,8,9-tetrahydro-5 -thiaaza-benzocycloheptenyl, 5,5-dioxo-6,7,8,9-tetrahydrothia nzocycloheptenyl, 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 e ring systems substituted on ring carbons with one or more —OH or C=O onal 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 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, (Cl-Cg)alkyl, (C1-C8)alkoxy, )alkoxy(C1- C4)alkyl, carboxyl, formyl, (C1-C6)acyl, 1-C4)alkyl, 1-C4)alkoxy, hydroxyl, nitro, cyano, amino, trifluoromethyl, mono- or di-(C1-C6)alkylamino, oxo, 0)aryl, (C5- C9)heteroaryl, (C1-C6)alkoxycarbonyl, o)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.
“Heteroarylalkyl” 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 ens of which have been substituted with halogen atoms, which may be the same or different. Representative omethyl 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 tuting the nitrogen may be the same or ent.
“Carboxy3, “ , carboxyl”, xy 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 sufficiently robust to be isolated to a useful degree of purity from a reaction mixture. The present invention is directed only to chemically stable compounds.
“Pharmaceutical composition” refers to a composition suitable for administration in l or veterinary use.
When lists of alternative substituents include members which, owing to valency requirements, chemical stability, or other reasons, cannot be used to substitute a particular group, the list is intended to be read in t to include those members of the list that are suitable for substituting the particular group. aceutically acceptable” refers to logically ble 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 compound, or a pharmaceutically acceptable salt thereof, sufficient to inhibit, halt, or cause an improvement in a disorder or condition being treated in a ular subject or subject population. For example in a human or other mammal, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular disease and t being treated.
It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts, and is described below.
“Subject” refers to a member of the class Mammalia. Examples als include, t limitation, humans, 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 shment of several symptoms of a disorder or te ation of a disorder.
“Administering” refers to the method of contacting a compound 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, subcutaneously, parentally, intramuscularly, , systemically, and via tion.
II. Compounds The present invention provides a compound of Formula I or a salt form thereof, R /N 0 R10 I3 XI Y R1b / | NWNxE Rd \ Y O 0 R3 R13 Rb N) 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 cyclyl optionally substituted by l-6 R19, 5-15 membered heteroaryl optionally substituted by 1-6 R19, —C(=O)R20, OR2°, —C(=O)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 substituted by , C2_6alkenyl optionally l-6 R119, C2_6alkynyl optionally substituted by l-6 R , C6_11aryl optionally substituted by l-6 R119, ycloalkyl optionally substituted by 1-6 R119, 3-15 ed heterocyclyl optionally substituted by 1-6 R119, 5-15 membered aryl optionally substituted by l-6 R119, halogen, —CN, —C(=O)R110, — C(=O)OR110,—C(=O)NR112R113,—NC, —N02, —NR112R113, —NR114C(=O)R110, _ NR114C(=O)OR1“, —NR114C(=O)NR112R113, _NR114S(:O)2R111’ _ (=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 ally 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 C1_6alkyl 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 ally substituted by l-6 R39, 3-15 membered heterocyclyl optionally substituted by l-6 R39, 5-15 membered heteroaryl optionally substituted by 1-6 R39, halogen, —CN, —C(=O)R3°, —C(=O)OR3°, — R32R33, —N02, —NR32R33, —NR34C(=0)R3°, —NR34C(=O)OR31, — NR34C(=O)NR32R33, —NR34S(=O)2R31,—NR34S(=O)2NR32R33, —0R3°, =0, — OC(=O)R3°, —OC(=O)NR32R33, )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, ryl 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 membered heteroaryl ally 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 ed heterocyclyl optionally substituted by 1-6 R59, and 5-15 membered aryl 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 heterocyclyl optionally substituted by 1-6 R69 or a 5-15 membered heteroaryl optionally 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 tuted by 1-6 R79, C2_6alkynyl optionally substituted by 1-6 R79, C6_11aryl optionally substituted by 1-6 R79, C3_11cycloalkyl optionally substituted by 1-6 R79, 3-15 membered cyclyl optionally substituted by 1-6 R79, 5-15 membered heteroaryl optionally substituted by 1-6 R79, halogen, —CN, —C(=O)R7°, OR7°, — C(=O)NR72R73, —N02, —NR72R73, —NR74C(=O)R7°, —NR74C(=O)OR71, — NR74C(=O)NR72R73, —NR74S(=O)2R71,—NR74S(=O)2NR72R73, —0R7°, =o, — OC(=O)R7°, —OC(=O)NR72R73, —S(=O)nR7°, and —S(=O)2NR72R73; R70, R71, R72, R73, and R74 at each occurrence is independently chosen from H, C1- 6alkyl and C1_6-haloalkyl; R79 at each occurrence is independently chosen from C1_6alkyl, aloalkyl, benzyl, halogen, —CN, —C(=O)(C1_6alkyl), —C(=O)O(C1_6alkyl), —C(=O)N(C1_ 6alkyl)2, —C(=O)OH, —C(=O)NH2, 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, C2_6alkynyl optionally substituted by 1-6 R129, C6_11aryl optionally substituted by 1-6 R129, C3_11cycloalkyl optionally substituted by 1-6 R129, 3-15 ed heterocyclyl optionally substituted by 1-6 R129 and 5-15 membered heteroaryl optionally tuted 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, er with the nitrogen atom to which they are attached, a 3-15 ed cyclyl optionally substituted by 1-6 R149 or a 5-15 ed heteroaryl optionally substituted by 1-6 R149; R119 at each occurrence is independently chosen from C1_6alkyl optionally substituted by 1-6 R159, C2_6alkenyl optionally substituted by 1-6 R159, C2- 6alkynyl optionally substituted by 1-6 R substituted by , C6_11aryl optionally 1-6 R159, C3_11cycloalkyl optionally tuted by 1-6 R159, 3-15 membered heterocyclyl optionally tuted by 1-6 R159 5 -15 membered heteroaryl optionally substituted 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 C1_6-haloalkyl; R129, R139, R149, and R159 at each ence is independently chosen from C1- 6alkyl, aloalkyl, 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 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 ally tuted by 1-6 R19, C2_6alkynyl optionally substituted by 1-6 R19, phenyl optionally substituted by 1-5 R19, C3_6cycloalkyl optionally substituted by 1-6 R19, 3-6 membered 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 substituted by 1-6 R19, kenyl optionally substituted by 1-6 R19, kynyl 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 C3_6cycloalkyl optionally substituted by 1—3 R19.
In one embodiment, E is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl, kynyl ally tuted 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 substituted by halogen, and cyclohexyl.
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 ally substituted by fluoro, and cyclohexyl.
In one embodiment, E is chosen from C1_6alkyl optionally 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- 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 substituted by 1-6 R19, C2_6alkynyl optionally substituted by 1-6 R19, C6_11aryl ally substituted by 1-6 R19, C3_11cycloalkyl ally substituted by l- 6 R19, and 3-15 membered heterocyclyl optionally substituted by 1-6 R19.
In one embodiment, 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, phenyl optionally substituted by 1-3 R19, C3_6cycloalkyl optionally substituted by 1-3 R19, and 3-6 ed heterocyclyl optionally substituted by 1-3 R19.
In one embodiment, G is chosen from H, C1_6alkyl optionally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 halogen, kynyl, phenyl optionally substituted by 1-3 n, C3_6cycloalkyl, and 3-6 ed heterocyclyl.
In one embodiment, G is chosen from H, C1_6alkyl ally substituted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 halogen, C2_6alkynyl, phenyl ally substituted by 1-3 halogen, 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, kyl 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, cloalkyl, 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 fluoro.
In one embodiment, G is C3_6alkynyl.
In one embodiment, G is phenyl optionally substituted by fluoro.
In one embodment, G is ophenyl.
In one embodiment, G is cloalkyl.
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 embodiment, 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)—, —CHOH—, —CH2—, or —NH—.
In one embodiment, D is —O—, —S—, —C(=O)—, —CHOH—, or —CH2—.
In one embodiment, D is —O—, —C(=O)—, —CHOH—, or —CH2—.
In one embodiment, D is —O—, —C(=O)—, —CHOH—, or —CH2—.
In one embodiment, D is —O—.
In one embodiment, D is —.
In one embodiment, D is —CHOH—.
In one embodiment, D is —CH2—.
In one ment, 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 membered heterocyclyl optionally substituted by l-6 R119, 5-15 membered heteroaryl optionally tuted by 1-6 R119, halogen, —CN, —C(=0)R“°, —C(=O)NR“2R“3, —N02,—NR112R113, —NR“4C(=0)R“°, — NR114C(=O)OR111, C(:O)NR1 12R113, S(=O)2R111, —OR110, —S(=O)2R110, and —S =0 ZNRmRm; or any of Ra and Rb, Ra and Rd, and Rb and RC can, er with the atoms linking them, form a C6_11aryl ally substituted by l-6 R , C3_1lcycloalkyl optionally substituted by 1-6 R119, 3-15 membered heterocyclyl ally substituted by l-6 R119 or a 5-15 membered heteroaryl optionally substituted by l-6 R119.
In one ment, 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 optionally substituted by 1-6 R119, —CN, and —OR110; or Ra and Rb can, together with the atoms linking them, form a 5-6 membered cyclyl optionally substituted by 1-6 R119.
In one embodiment, 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, together with the atoms linking them, form a 5-6 ed heterocyclyl.
In one ment, Ra is chosen from H, —CN, and —OC1_6alkyl; Rb is chosen from H, C1_6alkyl optionally 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 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 ered 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 ally 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, henyl, —OC1_ -O-C1_6alkyl; RC is H; and Rd is chosen from H and —OC1_6alkyl; or Ra and Rb O O < E er 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_ 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 ally substituted by linyl, —OH, —OC1_6alkyl, —OCH2phenyl, —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 alkyl; 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 embodiment, Ra is chosen from H and —OC1_3alkyl; Rb is chosen from H and —OC1_3alkyl; 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 .
In one embodiment, R4 is H.
In one embodiment, R4 is C1_3alkyl.
In one embodiment, R4 is methyl.
In one embodiment, 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 ment, Rla, Rlb, R10, and Rld are independently chosen from H, C1- 6alkyl ally substituted by l-6 R119 substituted by l-6 R119 , cloalkyl optionally , halogen, —NR112R113, and —OR110.
In one embodiment, Rla, Rlb, R10, and Rld are ndently 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, loalkyl, 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 —OC1_3alkyl.
In one ment, Rla, Rlb, R10, and Rld are independently 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 alkyl.
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, halogen, R113, and —OR110.
In one embodiment, Rla and Rlb are ndently chosen from H, C1_6alkyl, C1- 6haloalkyl, C3_6cycloalkyl, halogen, and alkyl; and R10 and Rld are independently chosen from H, C1_6alkyl, halogen, —N(C1_6alkyl)2, and —OC1_6alkyl.
In one embodiment, Rla and Rlb are independently 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, —N(C1_3alkyl)2, and —OC1_3alkyl.
In one embodiment, Rla and Rlb are independently chosen from H, C1_3alkyl, C1_ lkyl, cyclopropyl, halogen, and —OC1_3alkyl; and R10 and Rld are independently chosen from H, C1_3alkyl, n, —N(C1_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 ment, 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 embodiment, 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 tuted by 1-6 R39, C3- 11cycloalkyl optionally substituted by 1-6 R39, 3-15 membered heterocyclyl optionally substituted by 1-6 R39, 5-15 membered aryl optionally substituted by 1-6 R39, halogen, —CN, 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 optionally tuted by 1-6 R39, C3_6cycloalkyl optionally substituted by 1-6 R39, 3-6 membered cyclyl optionally substituted by 1-6 R39, 5-6 membered heteroaryl ally 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 ndently chosen from C1_6alkyl, phenyl optionally substituted by 1-3 halogen, C3_6cycloalkyl, 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 ally substituted by 1-3 halogen, C3_6cycloalkyl, 5-6 membered heterocyclyl, -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, pyrrolidinyl, — C(=O)morpholinyl, —N(C1_6alkyl)2, —OH, —OC1_6alkyl, —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 independently 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, kyl, lolkyl, phenyl, benzyl, C5_6cycloalkyl, 5-6 membered cyclyl, and 5-6 ed heteroaryl; or R32 and R33 may form, together with the nitrogen atom to which they are attached, a 5-6 membered heterocyclyl 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, kyl, C1_6halolkyl, phenyl, benzyl, C5_6cycloalkyl, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl.
In one embodiment, R20, R30, R31, R34, R22, R23, R32 and R33 at each occurrence 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 ndently 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 ence is independently chosen from C1_6alkyl, C1_6-haloalkyl, benzyl, and halogen.
In one ment, 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 ment, R110, R111, R112, R113, and R114 at each occurrence is independently chosen from H and C1_6alkyl optionally substituted by 1-3 R129.
In one embod1ment, R- 110 111 112 113 R R R and R114 - at each occurrence 1s , , , , independently chosen from H and C1_3alkyl optionally substituted by 1-3 R129.
In one embodiment, 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 ally substituted by —OC1_3alkyl.
In one ment, R110, R111, R112, R113, and R114 at each occurrence 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 ally substituted by 1-6 R159, 3-15 membered heterocyclyl optionally 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 tuted by 1-3 R159, and halogen.
In one embodiment, R at each ence is independently chosen from C1- 6alkyl, C1_6haloalkyl, 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 ed 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 .
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 ence is H.
In one embodiment, R129, R139, R149, and R159 at each occurrence is independently chosen from C1_6alkyl, C1_6-haloalkyl, benzyl, and halogen.
In one embodiment, R129, R139, R149, and R159 at each occurrence is independently chosen from C1_6alkyl and halogen.
In one embodiment, R129, R139, R149, and R159 at each occurrence is halogen.
In one embodiment, R129, R139, R149, and R159 at each ence is C1_6alkyl.
In one embodiment, n at each occurrence is 0 or 2.
In one embodiment, n at each occurrence is 0.
In one embodiment, n at each occurrence is 2.
The present ion also provides compounds of Formula II R2 T3 XI/NYO | NWME Rd \ Y o 0 R81 R1 Rb N/J Formula II wherein: Ra is H, alkyl, halo, cyano, hydroxyl, amino, alkylamino, dialkylamino Where the alkyl groups of dialkylamino may be the same or different, oyl, lcarbamoyl, 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, mino, 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, omethyl, 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 koxyalkyl, or A and B together with the oxygen atoms to which they are ed 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 tituted; G is H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, alkyl or cycloalkyl, cycloalkylalkyl, alkenyl or l, where alkyl, alkenyl or cycloalkyl may be substituted by one, two or three groups selected from the group consisting of alkanoyl, cycloalkyl, l, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl, aryl, tuted 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 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, , 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 pharmaceutically acceptable salt f.
A preferred embodiment of the present invention provides compounds of Formula 11 wherein W is CH.
Another preferred embodiment of the present invention provides compounds of a 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 wherein: A and B are, independently, H, alkyl, alkoxyalkyl, cycloalkyl, cycloalkoxyalkyl, heterocyclylalkyl, heterocyclylalkoxyalkyl, arylalkyl or koxyalkyl, 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 heteroarylalkyl may be substituted or unsubstituted; G is H, aryl, substituted aryl, aryl, 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, alkoxycarbonyl, 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, 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.
Another preferred embodiment of the present invention provides compounds of Formula 111 wherein A and B are, independently, alkyl, heterocyclylalkyl or heterocyclylalkoxyalkyl.
Another preferred ment of the present invention provides compounds of Formula 111 wherein A and B are, independently, alkyl. r preferred embodiment of the present invention provides compounds of Formula 111 wherein D is O, S or NH.
Another red embodiment of the present invention provides compounds of Formula 111 wherein D is 0.
Another preferred embodiment of the present invention provides compounds of Formula 111 wherein R1 and R2 are, independently, halo, alkoxy, alkyl or H.
Another preferred ment of the present ion provides compounds of Formula 111 wherein R1 and R2 are, ndently, halo or alkoxy. r preferred embodiment of the t invention provides compounds of Formula 111 wherein R1 and R2 are, independently, methoxy or fluoro.
Another preferred embodiment of the present invention provides compounds of Formula 111 wherein X is N or CH.
Another preferred embodiment of the present ion provides compounds of Formula 111 wherein X is CH. r preferred embodiment of the present invention provides compounds of a 111 wherein G is alkyl where alkyl may be substituted by one, two or three groups ed 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 different, and heterocycyclylcarbonyl.
Another preferred embodiment of the present invention provides compounds of Formula 111 wherein E is aryl, tuted aryl or cycloalkyl.
Another preferred embodiment of the present invention es compounds of Formula 111 wherein E is tuted aryl.
Another preferred embodiment of the present invention provides compounds 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, tuted aryl, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, where the alkyl groups of dialkylamino may be the same or different, heteroaryl, carboxyl, oxo, oyl, alkylcarbamoyl, lcarbamoyl, where the alkyl groups of dialkylcarbamoyl may be the same or different, and cycyclylcarbonyl; and E is aryl, substituted aryl or cycloalkyl.
In other preferred ments, the present invention provides any of the compounds as described in the Examples.
The present invention provides salts of the AXL and c-MET inhibitory compounds described herein. Preferably, 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 orus, as well as the salts derived from c acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted ic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Such salts thus include, but are not limited to, sulfate, lfate, bisulfate, e, bisulf1te, nitrate, phosphate, monohydrogenphosphate, ogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoracetate, propionate, ate, isobutyrate, oxalate, te, succinate, suberate, sebacate, fumarate, mandelate, benzoate, benzoate, methylbenzoate, dinitrobenzoate, phthalate, esulfonate, toluenesulfonate, phenylacetate, citrate, lactate, ascorbate, 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 desired 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 conventional 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. es of metals used as cations include, but are not d to, , ium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-l,2-diamine), N—methylglucamine, and procaine; see, for e, Berge et al., supra., 1977.
The base addition salts of acidic compounds may be prepared by contacting 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 equivalent to their respective free acid for purposes 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 ion that have l groups, which may exist as entgegen or zusammen mations, 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 tuted at more than one carbon atom, in which case all geometric forms thereof, both cis and trans, and es thereof, are within the scope of the present invention. All of these forms, including (R), (S), epimers, reomers, cis, trans, syn, anti, (E), (Z), tautomers, and mixtures thereof, are contemplated in the compounds of the present invention.
The compounds to be used in the present invention can exist in unsolvated forms as well as ed forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
III. Pharmaceutical Compositions The present invention further 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 ceutical composition may contain two or more compounds of the present invention (i.e., two or more nds of the present invention may be used together in the pharmaceutical composition). Preferably, the pharmaceutical composition ns a therapeutically ive amount of at least one compound of the t invention. In another embodiment, these compositions are useful in the ent of an AXL- or c- MET- mediated er or condition. The compounds of the invention can also be combined in a pharmaceutical ition that also comprises compounds that are useful for the treatment of cancer or another AXL- or c-MET- mediated er.
A nd of the present invention can be formulated as a pharmaceutical composition in the form of a syrup, an , a suspension, a powder, a granule, a tablet, a capsule, a lozenge, a troche, an aqueous solution, a cream, an nt, a lotion, a gel, an emulsion, etc. Preferably, a compound of the present invention will cause a decrease in symptoms or a disease indicia associated with an AXL or c-MET- mediated disorder as measured quantitatively or qualitatively.
For preparing a pharmaceutical composition from a compound of the present invention, pharmaceutically acceptable carriers can be either solid or . Solid form ations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In s, the carrier is a finely d solid which is in a mixture with the finely d active component (i.e., compound of the present invention). In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets contain from 1% to 95% (w/w) of the active compound (i.e., compound of the present ion). In another embodiment, the active compound ranges from 5% to 70% (w/w). Suitable carriers are magnesium carbonate, ium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term ration" is intended to include the ation of the active compound with encapsulating material as a r providing a capsule in which the active component with or without other rs, is surrounded by a carrier, which is thus in association with it.
Similarly, cachets and lozenges 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 homogeneously 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 include solutions, suspensions, and emulsions, for example, water or water/propylene glycol ons. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
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 material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well- known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include 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 preferably in unit dosage form. In such form the ation is subdivided into unit doses containing riate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing te ties of ation, such as ed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or e itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose ation 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 ent. The composition can, if desired, also contain other compatible therapeutic agents.
Pharmaceutically acceptable carriers are determined in part by the particular composition being administered, as well as by the ular method used to administer the composition. Accordingly, there is a wide variety of suitable ations of pharmaceutical compositions of the present invention (see, e.g., Remington: The Science and Practice ofPharmacy, 20th ed., Gennaro et al. Eds., Lippincott Williams and Wilkins, 2000).
A compound of the present invention, alone or in combination with other suitable ents, can be made into aerosol formulations (i.e., they can be "nebulized") to be administered via inhalation. Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
Formulations suitable for parenteral administration, such as, for example, by intravenous, intramuscular, intradermal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, s, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended ent, and aqueous and nonaqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In the practice of this invention, compositions 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 ners, such as es and vials. Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
The dose administered to a subject, in the t of the present invention, should be ent to effect a beneficial therapeutic response in the subject over time. The dose will be determined by the efficacy of the ular 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, , and extent of any adverse side-effects that accompany the administration of a particular compound in a particular subject. In determining the effective amount of the nd to be stered in the treatment or prophylaxis 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 s are known to those of skill in the art.
For administration, nds of the present invention can be administered at a rate determined by s that can e, but are not limited to, the LD50 of the compound, the pharmacokinetic profile of the compound, contraindicated drugs, and the side-effects of the compound at various trations, as applied to the mass and overall health of the subject. Administration can be accomplished via single or divided doses.
IV. Methods of Treatment In another aspect, the present invention es 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 of a nd of the present invention or a pharmaceutically acceptable salt form thereof. In another aspect, the t invention provides a compound of the t invention or a pharmaceutically acceptable salt form f for use in treating a subject suffering from an AXL or c-MET- mediated disorder or condition. Preferably, the compound of the present ion 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 pharmaceutically acceptable salt form thereof for use in treating a subject suffering from an AXL- or c-MET- mediated disorder or condition. In another embodiment, the AXL- or c-MET- mediated condition or disorder is cancer. In another embodiment, the AXL- or c-MET-mediated disorder or condition is the development of resistance to cancer therapies. In another embodiment, the AXL or c- MET- mediated condition is selected from chronic myelogenous leukemia, chronic myeloproliferative disorder, lung cancer, prostate , esophageal cancer, n cancer, pancreatic cancer, gastric cancer, liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breast cancer, acute myeloid leukemia, colorectal cancer, uterine , malignant glioma, uveal melanoma, osteosarcoma and soft tissue sarcoma.
The AXL- or c-MET- mediated disorder or ion can be treated prophylactically, y, and chronically using compounds of the present invention, 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 compound of the t invention.
In another embodiment, the present ion provides a method of treating a proliferative disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the t invention or a pharmaceutically able salt form thereof. In another aspect, the t invention provides a compound of the present invention or a pharmaceutically acceptable salt form thereof for use in treating a proliferative disorder in a subject in need thereof. Preferably, the compound of the t invention or a pharmaceutically acceptable salt form thereof is administered to the subject in a pharmaceutical composition comprising a pharmaceutically able 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, c myeloproliferative disorder, lung cancer, prostate cancer, esophageal cancer, ovarian cancer, pancreatic , c cancer, liver cancer, d cancer, renal cell carcinoma, glioblastoma, breast cancer, acute myeloid leukemia, ctal cancer, uterine cancer, malignant glioma, uveal melanoma, osteosarcoma and soft tissue a.
The erative disorder can be treated lactically, 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 compound of the present invention.
In therapeutic applications, the compounds of the present invention can be ed and administered in a wide variety of oral and eral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, utaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by inhalation, for example, intranasally. onally, the compounds of the present invention can be administered 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 ing upon the requirements of the subject, the severity of the condition 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 compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be d and administered in portions during the day, if desired.
V. Chemistry Unless otherwise 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 al 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 Esquire 2000 Mass Spec with the Agilent 1100 HPLC equipped with an Agilent Eclipse , 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 t 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 ative HPLC was performed on a Gilson GX-28l ed 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.
The compounds of the present invention 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 methods 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 skilled in the art of c synthesis.
The reactions are performed in solvents appropriate to the reagents, and materials employed are le for the transformations being effected. Also, in the description of the synthetic methods below, it is to be tood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and workup procedures are chosen to be conditions standard for that on 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 es only and that various modifications or changes in light thereof will be suggested to persons d 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 d 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 limited to, texts such as “Encyclopedia of ts for Organic sis” 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, er, 2005 and references therein.
The es 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 . / W Scheme 1 In Scheme 1, W and X are as defined herein. T is Br, Cl or I. D’ is OH, SH, NH2, or yl. 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 d , or are synthetic precursors thereto. Y is N, CH or C, Where C may be substituted 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 described in the literature from properly substituted arylamines and Meldrum’s acid in the presence of trimethyl orthoformate (Bioorg. Medchem. Lett., 1997, 7, 789, WO9813350, US20080004273). Alternatively properly substituted quinolines can be synthesized from substituted henones by methods described in the literature (for example J. Med. Chem. 2005, 48, 1359; EP1153920; WO201145084). 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 bed in J. Med. Chem. 2005, 48, 1359A 4- (aminophenoxy)quinoline derivative may be produced by reacting a nitrophenol derivative with the 4-chloroquinoline derivative in a suitable solvent, for example, benzene, to synthesize a 4-(nitrophenoxy)-quinoline tive or a corresponding quinazoline derivative and then reacting the 4-(nitrophenoxy)quinoline derivative in a suitable t, for example, N,N—dimethyl formamide, ethanol or ethyl acetate in the presence of a catalyst, for example, palladium hydroxide-carbon or palladium-carbon, under a hydrogen atmosphere. The nitro group can also be reduced with zinc or iron. Alternatively, the 4- phenoxy)quinoline tive can be produced by reacting an aminophenol derivative with the 4-chloroquinoline derivative in a suitable solvent, for example, dimethyl sulfoxide or N,N—dimethyl formamide, in the presence of a base, for example, sodium hydride or potassium t-butoxide. The 4-(aminophenoxy)-quinazoline derivative can be ed 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 er catalyst, for example, tetra-n-butylammonium de.
An example of the synthesis of 2,4-dioxo-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 2 ONCQ HN EIOJKELN N O 2—Aminomethylene—malonate 2—[3-(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 ropylethylamine, 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.
Starting with a 2-aminomethylene malonate and reacting with any appropriate aryl, aryl 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 oxo-l ,2,3,4-tetrahydro-pyrimidine- -carboxylic acid esters. ng with an N—substituted 2-aminomethylene 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 ,2,3,4- 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 I wR NH —> HO N’ 2 ”A, NAG Scheme 3 a. alkyl halide 80 0C. b. lN LiOH, tetrahydrofuran, , K2C03, dimethylformamide, methanol, 65 0C, or 4N HCl in aqueous e, 80 0C.
H 1 Ii] I? K 0 EtOZC COZEt a,b Y c, d N o 1/ 2 I T R HO H2N (5(ng \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 aqueous e, 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 / hexanes. D. IN LiOH, methanol, 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 sized as outlined in Scheme 5. The synthesis of N1 4-fluorophenyl is delineated for Example 91. The sequential reaction of 4-fluoroaniline with ethyl nate then diethyl ethoxymethylenemalonate produces l-ethyl(4-fluoro- phenyl)-2,4-dioxo-l ,2,3,4-tetrahydro-pyrimidinecarboxylic acid ethyl ester and 3-ethyll- (4-fluoro-phenyl)-2,4-dioxo- l ,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid ethyl ester.
The l-(4-fluorophenyl) isomer is y 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 synthesized under acid conditions, then coupled to (6,7-dimethoxyquinolinyloxy)fluorophenylamine to produce the N1 aryl amide e 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 ophenyl 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- ]triazinecarboxylic acid ethyl ester. Alkylation under conditions described for 2,4-dioxo-1,2,3,4-tetrahydro-pyrimidinecarboxylic acid esters produced N2-substituted 4-(4-fluorophenyl)-3 ,5-dioxo-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 alkylated to produce 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 ions to e 3,5-dioxo-2,3,4,5-tetrahydro- [1,2,4]triazinecarboxylic acids. ng aniline intermediates with these acids may be achieved using known rd 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 t.
Examples General 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 e 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 uorophenyl)-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). 3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid ethyl ester (3.50 g, 11.6 mmol), ium carbonate (3.22 g, 23.3 mmol) and cyclopropylmethyl bromide (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 , 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 lithium ide (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, dissolved 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 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 precipitated, additional water (~ 10 mL) was added and the t 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-tetrahydropyrimidine-5 -carboxylic 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 diluted 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 solution was made acidic with concentrated HCl and the white solid collected to give 125 mg (40%) of uorophenyl)(3-methoxy-propyl)-2,4-dioxo-1,2,3 ,4- ydropyrimidinecarboxylic acid as a white solid. LCMS m/z = 323 (M + 1); 1H NMR (DMSO) 5: 12.6 (s, 1H), 8.7 (s, 1H), .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 uorophenyl)-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid.
LCMS m/z = 251 (M + 1);1H NMR (DMSO) 5: 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-A11y1—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), .41 (m, 4H), 5.89-5.99 (m, 1H), 5.24-5.35 (m, 2H), 4.53 (m, 2H). 1-(3 ,3 r0a11y1)—3 -(4-flu0r0phcny1)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 - carboxylic acid. LCMS m/z = 327 (M + 1); 1H NMR (DMSO) 5: 12.6 (s, 1H), 8.8 (s, 1H), .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)isobuty1—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 -carb0xy1ic 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 nzyloxyethyl)—3-(4-fluorophenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrirnidine- oxylic 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- tetrahydropyrirnidinecarboxylic 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 ,4-tetrahydro- 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- 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- tetrahydropyrirnidinecarboxylic 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- tetrahydropyrirnidinecarboxylic acid; hydrochloride. LCMS rn/z = 398 (M + 1). 3 hexylethyl-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; hloride. 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) 8:12.63 (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), 2.29-2.40 (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 uoro-pheny1)(2-rnorpholiny1—2-oxo-ethy1)-2,4-dioxo-1,2,3 ,4- tetrahydro-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 ,4-tetrahydr0- 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- pyrimidinecarb0xylic 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 rahydro-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 uoropheny1)-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 hy1)- 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 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 atmosphere 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 product was tographed 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 on was d at rt for 12 h, diluted with EtOAc (25mL), then washed with 1N , water and brine and then dried over MgSO4. The product was llized 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 similar to those for Example 1.
Example 2.
OH: .. . 3 -(4-F1uorophcny1)mcthy1—2,4-di0x0- 1 ,2,3 ,4-tctrahydropyrimidinc-5 -carb0xy1ic acid [4-(6,7-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 ,4-tctrahydropyrimidinc-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), .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\ FO 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), 7.34-7.38 (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 ylic 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), 7.34-7.46 (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. @110? 3 u0r0phcny1)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). e 9. m“; . 06 . o o 1-A11y1—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 - carboxylic acid 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), .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 -(4-F1u0r0phcny1)— 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).
Example 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), 7.30-7.34 (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\ aW510FO O N O F F 1-(3 ,3 -Difluor0-a11y1)-3 -(4-flu0r0pheny1)—2,4-di0xo- 1 ,2,3 rahydropyrimidine-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 = , 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. @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, 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), .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 3-(4-F1u0r0phcny1)-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). e 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).
Example 19. 0Q F o o 1 -(2-Benzyloxyethy1)(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 [4-(6,7-dimethoxyquino1iny10xy)—3-flu0r0pheny1]—arnide. mp (HC1 salt): 208-10 0C; LCMS m/z = 618 (M + 1); 1H NMR (DMSO) 8 (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);1HNMR(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), 7.39-7.42 (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 ,4-tctrahydr0pyrimidinc-5 xy1ic 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), .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. a”1&0 3 -Cyc10hexylethy1—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), 7.99,8.03 (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), .98 (m, 8H), 2.32 (m, 3H), 1.80 (m, 2H), 1.62 , 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 O 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—3-(4-flu0r0phcny1)-2,4-di0x0-1 ,2,3 ,4-tctrahydr0pyrimidinc-5 -carb0xy1ic 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 [4-(6,7-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), 1.74-1.83 (m, 1H), .27, 0.54-0.57 (m, 1H), 0.43-0.46 (m, 1H).
Example 30.
MOFo o N O 3 -(4-F1uor0pheny1)-2,4-di0x0(tetrahydr0pyrany1)- 1 ,2,3 ,4-tetrahydr0pyrimidine-5 - carboxylic 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), .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.
/O N\ QMOFo o 1-Ethy1(4-flu0r0pheny1)-2,4-di0x0-1 ,2,3 ,4-tetrahydr0pyrimidine-5 -carb0xy1ic acid [5 - (6,7-dimeth0xyquino1iny10xy)-pyridiny1]-amide was sized 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 (m,2H), .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\ \ / QfigFo o 3 -(4-F1uor0pheny1)is0pr0py1-2,4-diox0-1 ,2,3 ,4-tetrahydropyrimidinecarb0xy1ic 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), .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 e 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 -(4-Fluor0phenyl)—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 0M0 o /o N H PhOPh — >< —» | NHZ —> CH(OMe)3 \o O MeO o /oo \ /O N Zn/NH4CI \ POCI3 / —> / l 8/ —> N02 O 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 collected 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 diphenyl 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 d 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 ophenol (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 Na2S04, and trated to afford 4-(5,7-dimethoxyquinolinyloxy)phenylamine as an te 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), 6.65-6.63 (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). e 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- dimethoxyquinolinyloxy)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 N,N-dimethylformamide (10.3 mL) at rt and stirred for 30 min under an atmosphere of en. 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 trated, 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 rahydropyrimidinecarboxylic acid [4-(7-benzyloxymethoxyquinolinyloxy)fluorophenyl]-amide was synthesized using 4-(7-benzyloxymethoxyquinolinyloxy)fluorophenylamine and 3-(4- fluorophenyl)ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-carboxylic 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 ,4-tetrahydropyrimidinecarboxylic 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 (10:40:50, palladium hydroxide:carbon black:Water, 0.1 g, 0.07 mmol) in N,N—dimethylformamide (10 mL) was hydrogenated on a Parr apparatus under an atmosphere of hydrogen 40 psi for 12 h. The solvent was d and the t 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), .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.
Example 42 (0.100 g, 0.178 mmol), methanesulfonic acid holinyl-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 precipitated 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 example 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). e 45 OK/Nwom 1-Ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid {3- 4-[6-methoxy(2-morpholinyl-ethoxy)-quinolinyloxy]phenyl} -amide.
Example 45 was synthesized by the procedure for example 43 using example 42 and 4-(2- ethyl)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 example 42. mp = 205-7 0C; LCMS m/z = 575 (M +1);1HNMR(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 sized by the procedure for example 43 using e 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), .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.
OH: .. . 1-Ethyl(4-fluorophenyl)-2,4-dioxo-1 ,2,3 rahydropyrimidine-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 mixture 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 , 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.
G”$10Fo o N O 3 -(4-Fluorophenyl)(2-hydroxyethyl)-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine carboxylic acid [4-(6,7-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 acetate (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 apparatus 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 trated and the t 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”$10F0 O N O H\OH 3 -(4-Flu0r0phenyl)(3-hydroxypr0pyl)-2,4-di0xo- 1 ,2,3 ,4-tetrahydropyrimidine carboxylic acid [4-(6,7-dimethoxyquinolinyloxy)flu0r0phenyl]—amide. Example 50 was synthesized using example 13 by the ure 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 -(4-Flu0r0phenyl)(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 e 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.
Q“610Fo o N O KLOH 3 -(4-Flu0r0phenyl)(3-hydroxypr0pyl)-2,4-di0xo- 1 ,2,3 ,4-tetrahydropyrimidine carboxylic acid [4-(6,7-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). e 53 0Q F o o OH 3 -(4-Fluor0phenyl)(2-hydr0xyethyl)-2,4-di0x0-1 ,2,3 rahydr0pyrimidine-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 1-((S)-2,3-Dihydroxypropyl)—3-(4-fluorophenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine- -carboxylic acid 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 stirred overnight. The solution was diluted 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 NMR(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), .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. 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 rahydropyrimidine-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 stirring at rt 4-(4- aminophenoxy)methoxyquinolinecarbonitrile (0.05 g, 0.2 mmol) was added. The reaction was d 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 4-bromo-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 d 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 quenched with satd. NH4Cl on and extracted three times with CHzClz and the combined organics 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), butylphosphine (0.54 mL, 10% solution), m 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- phenyl)-(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)methyl-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 stirring 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) 5:10.92 (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), .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 N O /\ 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 purified by Gilson prep. HPLC to give a white solid (33 mg, 42%), mp 293-295 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), .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 mixture of ro- 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 crystallization from a mixture of CHzClz, MeOH, ether, and hexane to e romonitrophenoxy)-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), potassium 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 on mixture was diluted with CHzClz and filtered over a pad of celite, washed with CHzClz. 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 mixture 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 geneous mixture was filtered over celite, washed with CHzClz and the filtrate was separated into two phases. The aqueous phase was extracted two times with CHzClz and the ed organics was washed with brine, dried (Na2S04), filtered, and evaporated to yield a crude t. 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 ,4-tetrahydropyrimidine-5 -carboxylic 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 rahydropyrimidine-5 -carboxylic 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-pyrimidinecarboxylic 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 analogous 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), .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), .82 (m, 2H), 0.62-0.69 (m, 2H).
The following examples were synthesized using the procedures for Example 1. e 61.
/O N\ \O / 3 -(4-Fluoro-phenyl)-2,4-dioxopropynyl-1 ,2,3 ,4-tetrahydro-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; 6.15:6; 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. 1:131“; 6.15:1? 3 -(4-F1u0ro-pheny1)-2,4-di0x0(2-pyraz01—1-y1-ethy1)-1 ,2,3 ,4-tetrahydro-pyrimidine-5 - ylic 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 xy1ic 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).
Example 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), 3.81-3.77 (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), 7.47-7.34 (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)(2-m0rph01iny1—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), .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- dinecarboxy1ic 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; 1-(2-F1u0r0-ethy1)(4-flu0ro-pheny1)—2,4-di0x0- 1 ,2,3 ,4-tetrahydro-pyrimidine-5 - carboxylic acid [4-(6,7-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. :44: 401,9 [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 / O [5-[4-(6,7-Dimeth0xyquinolinyloxy)fluorophenylcarbamoyl]—3-(4-flu0rophenyl)- 2,4-di0x0-3,4-dihydr0-2H-pyrimidinyl]-acetic acid. e 70 was hydrolyzed using trifiaoroacetic acid in dichloromethane at room ature 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 [4-(6,7-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 rahydr0- 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), 4.17-4.09 (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).
Example 74. /o N\ . 1%: N O 3 -(4-F1u0r0-phcny1)-2,4-di0x0(tctrahydro-pyrany1mcthy1)- 1 ,2,3 rahydr0- pyrimidinecarboxy1ic acid [4-(6,7-dimcth0xy-quin01iny10xy)—3-fluor0-phcny1]— amide. mp 185-187 0C; LCMS m/z = 645 (M + 1); 1H NMR (DMSO) 5: 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- pyrimidinecarboxy1ic acid [4-(6,7-dimcth0xy-quin01iny10xy)—3-fluor0-phcny1]— amide. mp 8 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. 9384100 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 ,4-tetrahydro-pyrirnidine-5 -carb0xylic acid [4-(6,7-dirneth0xy-quino1iny10xy)—3-flu0r0-phenyl]—arnide. mp 4 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), 7.47-7.33 (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 rahydr0- 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 [4-(6,7-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 - ylic 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 189-192 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- 0xy1ic 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\ 0.DmigiflF I N O /N1§J:§/ 1-(1-Dimethylcarbamoyloxo-propyl)(4-fluoro-phenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydro- pyrimidinecarboxylic 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. -Dimethoxyquinolinyloxy)fluoro-phenylamine. A mixture of o- 4-nitrophenol (0.644 g, 4.10 mmol) and 60% sodium hydride (0.215 g, 5.60 mmol) in dimethylformamide (20 mL) was d 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 ioning 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 dichloromethane).
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% palladium on carbon (0.05 g) for 4 h.
The on 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), 7.03-6.96 (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 ,4-tctrahydro-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 0 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), 7.43-7.34 (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 -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), 6.03-5.93 (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). e 89. /o N\ 080 . 0 F ”*61 M O 3-(4-Flu0r0-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, 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(4-fluoro-phenyl)-2,4-dioxo- 1 ,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid [4- (6,7-dimethoxy-quinolinyloxy)fluoro-phenyl]-amide. To a on of 4- fluoroaniline (1.0 g, 9.01 mmol) in THF (20 mL) at 0 0C, was slowly added ethyl nate (0.70 g, 10.0 mmol). After stirring 30 min. at 0 0C, the solution was warmed to rt and the solvent was removed 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 solvent 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 ed 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 yzed with 1N LiOH in MeOH and THF at 65 0C. The acid was coupled with 4-(6,7-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\ on O O . 1%“; Ill 0 1,3-Dimethyl-2,4-dioxo-1,2,3 ,4-tetrahydropyrimidinecarboxylic acid [4-(6,7- oxy-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 slurred 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 organics 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 coupled 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). es 92-98 intermediate acids were synthesized as in Scheme 2 and bed in Example 92 and coupled using methods described for e 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 isopr0py1—2,4-diox0-1,2,3,4-tctrahydr0-pyrimidinccarb0xy1ic acid [4-(6,7- dimcthoxy-quino1iny10xy)flu0r0-phcny1]—amidc. mp 113-116 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 Hz),7.41 (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), 6.03-5.03 (m, 2H), 5,31-5.27 (m, 1H), 5.27-5.25 (m, 1H), 5.20-5.17 (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”$1“O O 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\ F H N 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 8 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), , 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. /o\0mN\ 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 solvent 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 removed 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, 1H),11.18 (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). e 100. 1:131“; £11305) l-2,4-dioxophenyl-1,2,3 ,4-tetrahydro-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 isocyanate (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 filtered. 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 d in ethyl acetate. The cs were washed with 1M citric acid solution, water and brine. The solvent was d under vacuum and the residue was d by tography 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 intermediate 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).
Example 102.
O o 000 F ”kw NH/go 3 uoro-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 \ Br N\ lg \O / /O N\ a, b \O / c, d + F \o / O O O O F HO O Br CHO 0 F N N KN 0 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 (0.757 g, 3.73 mmol) in THF (10 mL) was added dropwise over 5 min. After stirring 30 min. at -78 0C, saturated um chloride solution (1 mL) was added. The t was removed under reduced pressure. The residue was dissolved in ethyl e and washed with water. After the solvent was removed under vacuum, the e 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 d under vacuum, ethyl acetate and saturated sodium bicarbonate solution was added until slightly basic. The organics were separated, the solvent removed under vacuum and the e purified by chromatography with 0-5% MeOH in dichloromethane 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. luoro-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 romethane (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 solvent 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), 7.45-7.32 (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. 4-(4-fluorophenyl)oxothioxo-2,3 ,4,5-tetrahydro-[1,2,4]triazinecarboxylic acid ethyl ester. A mixture of 2-oxo-malonic acid l 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 ethanol 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- necarboxylic 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 ed 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 ylic acid ethyl ester. 4-(4-Fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4- triazinecarboxylic 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 concentrated, 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 e 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 magnesium sulfate, 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] necarboxylic 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 ,2,4]triazine 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 concentrated. 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 concentrated. 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 oxo-2,3,4,5-tetrahydro-[1,2,4]triazine ylic acid Method B Step a. 4-(4-Fluoro-phenyl)methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine ylic acid. To a e of 2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine 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 methylene 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 tography (hexane: EtOAc 60:40) to yield 34 mg (10%). LCMS = 294 (M + 1).
Step b. luorophenyl)methyl-3 ,5-dioxo-2,3 ,4,5 -tetrahydro- [1 ,2,4]triazine carboxylic acid. 4-(4-fiuorophenyl)methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine- oxylic acid ethyl ester (30 mg, 0.1 mmol) was dissolved in THF-MeOH (1 :1, 2 mL) and 1M of m hydroxide (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 ed organics were washed with water and brine, dried (MgSO4) and evaporated 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 residue ved in EtOAc and washed with saturated NaHC03 solution 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 -tetrahydro-[1,2,4]triazinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)fluoro-phenyl]—amide TFA salt. The product was d 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 -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 = 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 synthesized from 4-(2,3-dihydro[1,4]dioxino[2,3-g]quinolin yloxy)fluorophenylamine; hloride (synthesized using the procedure 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 hydro- 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\ / NH | 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 (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 108. a” o oN/Q/F N.NA luorophcnyl)(2-hydroxycthyl)-3 ,5-dioxo-2,3 ,4,5 -tctrahydro- [1 ,2,4]triazinc carboxylic acid [4-(6,7-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), 7.41-7.39 (m and s, 4H), 6.89 (d, 1H, J = 5.4 Hz), 4.11 (m, 2H), 4.02 (2s, 6H), 3.77 (m, 2H). e 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), 7.45-7.37 (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 ro(7-methoxy-quinolinyloxy)-phenylamine; hydrochloride.
Step a. A mixture of 4-chloromethoxyquinoline (1.0 g mg, 5 mmol), (3-fluoro hydroxyphenyl)-carbamic acid t-butyl ester (1.88 mg, 8.26 mmol) and 4- dimethylaminopyridine (1010 mg, 8.26 mmol) in methylformamide (25 mL) was d at 145 0C for 5h. The e 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 d and the mixture was triturated with ether and dried to 368 mg (20%, two steps) of 3-fluoro(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- triazinecarboxylic 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.
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 potassium carbonate (10 mg, 0.07 mmol) in N,N—dimethylformamide (1 mL) was stirred at rt 18h. The e was filtered, solvent was removed and the t 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 [4-(6,7- 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 ated with DCM ted 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 potassium carbonate (44.4 mg, 0.321 mmol) in N,N—dimethylformamide (3 mL) was stirred at rt 18h.
The mixture was d and the solvent was removed. The t 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. ”1:05\ / o /9 o o 2-Mcthyl(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. ite 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).
Example 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), .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. 4-(1 ,5 hyl-1H-pyrazol-3 -ylmcthyl)—2-mcthyl-3 ,5 -dioxo-2,3 ,4,5 -tctrahydro- [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), 7.66-7.57 (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 etrahydro- [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 4-Cyanorncthylrncthyl-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), 7.67-7.58 (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 = .
Example 124. @319\ / o o f/ 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.
HCQ\ / 4-Cyclopropylmethylrnethyl-3 ,5-di0X0-2,3 ,4,5 -tetrahydro-[1 ,2,4]triazinecarboxylic 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)- 3-flu0r0-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), .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\ \ / o o ? “MNH | N\TAO 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. ”m\ / o o y NJJYtkNH | N\ “1‘80 4-(2,2-Dirncthylpropyl)rncthyl-3 , 5 -di0X0-2,3 ,4,5 -tctrahydro-[1 riazinc carboxylic 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 -carboxylic acid [4-([1,3]dioxolo[4,5-g]quinolinyloxy)fluoro-phenyl]-amide, TFA salt. This compound was synthesized from 3-(4-fluorophenyl)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- ihydro-[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 yloxy)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- 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), 7.45-7.36 (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). e 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— 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. (6,7-Dimethoxyquinolin yl)-(4-nitrophenyl)amine (0.425 g, 1.31 mmol), palladium hydroxide (0.0844 g, 0.601 mmol) and potassium carbonate (0.542 g, 3.92 mmol) in methanol (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 d 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 ); LCMS m/z = 556 (M + H); 1H NMR d6) 5: 10.85 (s, 1H), 8.85 (s, 1H), 8.65 (s, 1H), 8.25 (d, 1H, J = , 7.70 (d, 2H, J = 8.8Hz), 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. /o N\ o”wNO.o o 3 -(4-Fluorophenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid 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 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 , 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), 0.81-0.91 (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 stirred at rt for 8 h. The product was extracted with m 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 = ), 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\ \ / 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 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 uoro-phenyl)isopropyl-2,4-dioxo-1,2,3 ,4-tetrahydro-pyrimidine-5 -carboxylic acid [4-(6,7-dimethoxy-quinolinylsulfanyl)-phenyl]-amide. This compound was synthesized 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), 4.72-4.81 (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 + 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. imethoxyquinolinyl)-methyl-(4-nitrophenyl)amine (0.30 g, 0.88 mmol), potassium carbonate (1.3 g, 9.4 mmol) and palladium hydroxide (1.00 g, 7.12 mmol) was enated in a mixture of ethanol (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 ,4-tetrahydropyrimidine-5 - carboxylic acid ,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 e 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.
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 t. The solid was triturated 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 4-(6,7-dimethoxyquinazolinyloxy)-phenylamine and 3-(4- henyl)isopropyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid by the ure for example 134. mp = 238-241 0C; LCMS m/z = 572 (M + 1); 1H NMR )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 -carboxylic 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 = 238-241 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 00 HkfiiN MeO NK 0 Step a. A solution of 4-chloro-6,7-dimethoxyquinoline (0.4 g, 2 mmol) , 3-methoxy nitrophenol (0.30 g, 1.8 mmol) and 4-dimethylaminopyridine (0.011 g, 0.089 mmol) in chlorobenzene (5 mL) was d 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 sized 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 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), .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). e 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 here of nitrogen . Then solid 4-bromo-6,7-dimethoxyquinoline (0.30 g, 1.1 mmol) was added and the reaction stirred at 100 0C for 30 h. The mixture was concentrated, dissolved in EtOAc (~75 mL), and washed 1x with 1N Na2C03, water and NaCl solution, then dried over MgSO4. The product was chromatographed on silica gel (5% MeOH/DCM) to give 4-(6,7-dimethoxyquinolinyloxy)-2,3-difluoro-phenylamine 0.066 g (18%). LCMS m/z = 333 (M + 1). 1H C13) 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. 1-Methyl(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 (CDC13)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 e 1. mp = 2 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.
Step a. 4-(6,7-Dimethoxy-quinolinyloxy)methylphenylamine was synthesized using the ure 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 nd 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- dimethoxy-quinolinyloxy)methyl-phenyl]-amide. This nd 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 = 240-242 0C; LCMS m/z = 543 (M + 1); 1H NMR(CDC13) 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.
O O 0/ MeO 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), 7.32-7.26 (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-Ethyl(4-fluoro-phenyl)-2,4-dioxo- l ,2,3 rahydro-pyrimidine-5 -carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)methoxy-phenyl]-amide. This nd 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 procedure 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), .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 ure for example 1. mp = 257-259 —124— 0C; LCMS m/z = 591 (M + 1); 1H NMR 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 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- phenyl]-amide. This compound was synthesized using [5-(6,7-dimethoxyquinolinyloxy) methylphenyl]dimethylamine and uorophenyl)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), .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 -Dimethoxy-quinolinyloxy)isopropyl-phenylamine was sized using the procedure 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 compound 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 0C;LCMS 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 0C;LCMS m/z = 613 (M + 1); 1H NMR (CDC13)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/ -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 -Dimethoxy-quinolinyloxy)-2,3-dimethyl-phenylamine and 1- ethyl(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidinecarboxylic acid using the procedure for e 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), 7.46-7.42 (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 synthesized 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) .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 compound 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 ure for example 1. mp = 2 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 uoro-phenyl)isopropyl-2,4-dioxo-1 ,2,3 ,4-tetrahydro-pyrimidinecarboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)trifluoromethyl- phenyl]-amide. This compound was synthesized 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), .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 procedure for example 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 [4-(6,7-dimethoxy-quinolinyloxy)-3,5-dimethyl-phenyl]-amide. This nd 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 using the procedure 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. 4-(6,7-Dimethoxy-quinolinyloxy)methyl-phenylamine was sized 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 -Dimethoxy-quinolinyloxy)methyl-phenylamine and 3-(4- fluorophenyl)isopropyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5 -carboxylic acid using the ure for example 1. mp = 238-240 0C;LCMS m/z = 585 (M + 1); 1H NMR (DMSO-d6) 5: 10.92 (s, 1H), 8.65 (s, 1H), 8.44 (d, 1H, J = 6 Hz), 7.73-7.67 (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 synthesized 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 O 0 MeO HJHI/LLN 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), .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- dioxo-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), .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 sized 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), 7.33-7.37 (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. 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)trifluoromethyl-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxy-quinolin- 4-yloxy)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 [4-(6,7-dimethoxy-quinolinyloxy)methoxy-phenyl]-amide. This compound was synthesized using 4-(6,7-dimethoxy-quinolin- 4-yloxy)methoxy-phenylamineand 2- ethyl(4-fluoro-phenyl)- oxo-2,3,4,5-tetrahydro- 1,2,4-triazinecarboxylic acid using the ure 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 ro(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— .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 ed 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 supplement enzymatic buffer, and 1x enzymatic . A 2x concentration of ne kinase (TK) substrate-biotin/ATP mixture made in assay buffer was added to plates at 10 uL/well using the Multidrop Combi (Thermo Fisher Scientific, Waltham, MA). The final trations were 0.3 uM TK substrate-biotin, and 1.3 uM ATP. nds (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 diluted 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 ed 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 performed in 384-well FluotracTM 200 HiBase microplates using the HTRF KinEASETM assay described above for AXL except that the assay volume was reduced to half. Enzyme concentration was 8 ng/mL of recombinant human baculovirus-expressed cMET while the substrate concentrations were 0.1 uM and 0.02 uM for the biotinylated e and ATP, tively. Instead of the Multidrop Combi, the —134— BioRAPTR® FRD microfiuidic workstation (Beckman Coulter, Brea, CA) was utilized for t 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) equation 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 ed. The values for bottom and top were fixed at 0 and 100, respectively.
Results Biological data for Example compounds is presented in the following Table 1.
Unless otherwise specified in Table l, IC50 nanomolar value ranges designated as A, B, or C indicate the ing : IC50 < 10 nM A; IC50 10 nM to 100 nM B; and IC50 101 nM to 1,000 nM C;.
“NT” denotes not tested.
Unless otherwise specified, all values are an average of two or more inations.
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- C-MET IC50 EXamPk m m nM 11112222222222333333333344444444456789012345678901234567890123456789012345678 AAAAABABBABAAABAAAAABAAAAAAAAABBBBABCBBBBBBC MBABBABBBBABAABBBBBAACBBABBBABBBBCMMBCBBBBABC C-MET IC50 Example L w: nM 80000888800999 234567009012 ABAABBAAAAAAAAABAAAAAAAAABBAABAAAABAAC MAAABABBBCBBCAAABBABAABABBBMMBBBCBBBBABBBCBBM C-MET IC50 Example AXL IC50 nM 98 03003030303 118 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 provides 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 a I or a salt thereof having an AXL IC50 of less than 100 nM. In one ment, the invention provides a compound of Formula 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.
In one embodiment, the invention provides the exemplified compounds of a I or salts thereof having AXL IC50s of less than 100 nM. In one embodiment, the invention es the exemplified compounds of Formula I or salts f 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 Formula I or a salt thereof 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 provides the exemplified compounds of Formula I or salts thereof having c-Met IC50s of less than 1 uM. In one ment, the invention es 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 ified nds of Formula I or salts thereof 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 a I or a salt thereof having AXL and c-Met IC50s of less than 100 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 10 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 1 uM. In one embodiment, the ion 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— Additional preferred Embodiments of the present invention e: 1. A nd of the formula R2 T3 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 lamino may be the same or ent, 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, 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, mino, 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 OL; Where A, B, J and L, are, independently, H, alkyl, alkoxyalkyl, cycloalkyl, lkoxyalkyl, 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, , 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, lkylalkyl, alkenyl or alkynyl, where alkyl, alkenyl or lkyl may be substituted by one, two or three groups selected from the group consisting of alkanoyl, cycloalkyl, alkenyl, l, 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 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 tuted 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 lamino may be the same or ent, or cyclyl; and R3 is H, or alkyl; or a pharmaceutically 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 preferred Embodiment l of the formula A_O R1 8—0 N wherein: A and B are, independently, H, alkyl, alkoxyalkyl, lkyl, lkoxyalkyl, 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, tuted alkyl, l, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, substituted aryl, heteroaryl, heterocyclyl, substituted heteroaryl, or heteroarylalkyl, where the heteroaryl group of heteroarylalkyl may be substituted or tituted; G is H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, alkyl or cycloalkyl, cycloalkylalkyl, alkenyl or alkynyl, where alkyl, alkenyl or lkyl 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, arbamoyl, 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 ent; 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 ment 4 wherein D is O. 9. A compound according to preferred Embodiment 4 wherein R1 and R2 are, independently, halo, alkoxy, alkyl or H.
. A compound ing to preferred Embodiment 4 n R1 and R2 are, independently, halo or alkoxy. 11. A compound according 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 preferred Embodiment 4 wherein G is alkyl where alkyl may be substituted by one, two or three groups selected from the group consisting of alkanoyl, lkyl, alkenyl, alkynyl, halo, hydroxyl, alkoxy, alkoxycarbonyl, heterocyclyl, aryl, substituted aryl, aryloxy, arylalkoxy, amino, alkylamino, dialkylamino, -l44- where the alkyl groups of dialkylamino may be the same or ent, heteroaryl, carboxyl, oxo, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, where the alkyl groups of dialkylcarbamoyl may be the same or different, and heterocycyclylcarbonyl.
. A compound ing to preferred Embodiment 4 wherein E is aryl, substituted aryl or cycloalkyl. 16. A compound 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 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, mino, 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; and E is aryl, tuted aryl or cycloalkyl. l 8. A compound which is l-Ethyl(4-fluorophenyl)-2,4-dioxo- l ,2,3 ,4-tetrahydropyrimidine-5 - carboxylicacid 7-dimethoxyquinolinyloxy)fluorophenyl]amide; 3 -(4-Fluorophenyl)- l -methyl-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 carboxylic acid 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- -carboxylic acid [4-(6,7-dimethoxyquinolinyloxy)fluorophenyl]-amide; -l45(4-F1u0r0phcnyl)—1-isobuty1—2,4-di0xo-1 ,2,3 rahydr0pyrirnidinc-5 - carboxylic acid [4-(6,7-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 -(4-F1uorophcnyl)(2-isopr0p0xycthyl)—2,4-dioxo-1 ,2,3 rahydr0pyrimidinc- 5 -carb0xy1ic acid [4-(6,7-dirncthoxyquinolinyloxy)fluor0phcny1]—arnidc; 1-(3 -Bcnzy10xypr0pyl)(4-fluor0phcnyl)-2,4-dioxo-1,2,3 ,4- tctrahydropyrimidinc-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 y1—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 ,4-tctrahydr0pyrirnidinc-5 -carb0xy1ic acid [4- (6,7-dimcthoxyquinolinyloxy)flu0r0phcny1]—arnidc; 3 -(4-F1uorophcnyl)rncthy1—2,4-di0x0-1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 - ylic acid [4-(6,7-dimcthoxyquino1iny10xy)—phcnyl]-arnidc; 1 nzyloxycthyl)(4-flu0ro-phcnyl)-2,4-di0x0- 1 ,2,3 ,4-tctrahydropyrimidinc- -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) hcnyl]—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 10xypr0pyl)(4-fluor0phcnyl)-2,4-dioxo-1,2,3 ,4- tctrahydropyrirnidinc-S -carb0xy1ic 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- tctrahydropyrirnidinc-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 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—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 xy1ic 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 ,4-tctrahydr0pyrirnidinc-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-tctrahydr0pyrimidinc- xylic 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 ylic acid [4-(6,7-dicthoxyquino1iny10xy)flu0r0-phcny1] -arnidc; 3 -(4-F1uorophcny1)isopr0py1—2,4-dioxo- 1 ,2,3 ,4-tctrahydropyrirnidinc carboxylic acid [4-(5,7-dimcthoxyquinoliny10xy)phcnyl]-arnidc; 1-Ethy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 xy1ic acid [4-(5,7-dimcthoxyquino1iny10xy)—phcnyl]-arnidc; 1-Ethy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 rahydr0pyrirnidinc-5 -carb0xy1ic acid [4-(7-bcnzyloxyrncth0xyquino1iny10xy)—3-fluor0phcny1]—arnidc; 3 -(4-F1uorophcny1)isopr0py1—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 ,4-tctrahydr0pyrirnidinc-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-Ethy1—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 uorophcny1)isopr0py1—2,4-dioxo- 1 ,2,3 ,4-tctrahydropyrirnidinc carboxylic acid [3-fluoro(7-hydr0xyrncthoxyquino1iny10xy)-phcnyl]-arnidc; 3 uorophcny1)isopr0py1—2,4-dioxo- 1 ,2,3 ,4-tctrahydropyrirnidinc carboxylic 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 ,4-tctrahydropyrirnidinccarb0xy1ic acid [4-(6,7-dirncthoxyquinolinyloxy)fluor0phcny1]—arnidc; 3 -(4-F1uorophcnyl)(3 -hydroxypr0pyl)-2,4-di0xo- 1 ,2,3 rahydropyrimidinc- -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 uor0phenyl)—1-(2-hydr0xyethy1)-2,4-di0x0-1 ,2,3 ,4-tetrahydr0pyrimidine-5 - carboxylic acid 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 - carboxylic acid [4-(6-cyanometh0xy-quino1inyloxy)-phenyl]-amide; 3 0ro-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 rahydr0-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 -(4-F1u0r0-pheny1)isopr0py1—2,4-di0xo-1 ,2,3 ,4-tetrahydr0-pyrimidine carboxylic 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 rahydr0- 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 -(4-flu0ro-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 ,7-Dimeth0xy-quinolinyloxy)fluor0-pheny1carbamoyl](4-flu0r0- phenyl)-2,4-di0X0-3 ,4-dihydr0-2H-pyrimidiny1]-acetic acid tert-butyl ester; [5 -[4-(6,7-Dimethoxyquinoliny10xy)flu0r0phenylcarbamoy1]—3 -(4- fluorophenyl)-2,4-dioxo-3 ,4-dihydr0-2H-pyrimidiny1]-acetic acid; 3 -(4-F1uor0-phenyl)oxaz01ylmethy1-2,4-di0x0-1 ,2,3 rahydr0-pyrimidinecarb0xy1ic acid [4-(6,7-dimethoxy-quinolinyloxy)flu0r0-phenyl]-amide; 3 -(4-F1u0r0-phenyl)-2,4-di0x0(tetrahydro-fi1rany1methyl)- 1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xy1ic acid [4-(6,7-dimethoxy-quinolinyloxy)flu0r0-pheny1]— amide; 3 -(4-F1u0r0-phenyl)-2,4-di0x0- 1 ahydro-pyrany1methy1)- 1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xy1ic 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- dinecarb0xy1ic 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 u0r0-phenyl)[2-(4-fluor0-pheny1)—ethy1]-2,4-diox0-1 ,2,3 ,4-tetrahydr0- pyrimidinecarb0xy1ic acid 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 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 -(4-flu0rophenyl)-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 xy1ic acid [4- (6,7-dimethoxy-quinolinyloxy)fluoro-pheny1]-amide; 3 uor0-phenyl)methy1-2,4-di0x0-1 ,2,3 ,4-tetrahydr0-pyrimidine-5 - carboxylic acid [4-(6,7-dimethoxy-quino1iny10xy)fluoro-phenyl]-amide; 1-Ethy1—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 -(4-F1uor0-phenyl)-2,4-di0x0-1 ,2,3 ,4-tetrahydr0pyrimidine-5 -carb0xylic acid [4- (6,7-dimethoxy-quinolinyloxy)-3 ,5-difluor0-pheny1]—amide; 1-Ethy1—3-(4-flu0ro-pheny1)—2,4-di0x0- 1 ,2,3 rahydr0-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 yc10propy1rncthy1—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 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- imcthoxy-quinolinyloxy)fluoro-phcny1]—arnidc; 2,4-Di0X0-1 ,2,3 ,4-tctrahydro-pyrirnidinccarb0xy1ic acid [4-(6,7-dirncthoxy- quinolinyloxy)flu0ro-phcnyl]-arnidc; 1-Ethy1—2,4-di0X0phcny1—1,2,3 ,4-tctrahydr0-pyrirnidinc-5 -carb0xy1ic acid [4- (6,7-dimcthoxy-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 u0ro-phcnyl)-2,4-diox0pr0py1—1 ,2,3 ,4-tctrahydro-pyrirnidinc-5 - carboxylic acid [4-(6,7-dimcthoxy-quino1inccarb0nyl)flu0ro-phcny1]—arnidc; 4-(4-Fluoro-phcnyl)isopropyl-3 ,5 -di0X0-2,3 ,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 ylic 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 ylic 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; 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 -2,3 ,4,5 -tetrahydr0-[1,2,4]triazine carboxylic acid [5-(6,7-dimethoxy-quino1iny10xy)-pyridiny1]-amide; luorophenyl)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 (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] ne 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- dimethoxy-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 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 -Dimethy1-1H-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 ylic 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; 4-Cyanomethy1methy1-3 ,5-dioxo-2, 3 ,4,5 -tetrahydr0- [1 ,2,4]triazine carboxylic acid [4-(6,7-dimethoxy-quino1iny10xy)fluor0-pheny1]-amide; 4-Ethy1methy1-3 ,5-diox0-2,3 ,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; 4-Cyclopropylmcthyl-Z-rncthy1—3 X0-2,3 ,4,5 -tctrahydro-[1 riazinc carboxylic acid [4-(6,7-dirncthoxy-quinolinyloxy)flu0r0-phcny1]—arnidc; 2-Mcthy1—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 -tctrahydr0-[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 n01iny10xy)fluoro-phcnyl] c; 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 -g]quin01iny10xy)-3 -flu0r0-phcny1]—arnidc; , 4] 2-Cyclopr0pylmcthyl(4-fluorophcnyl)—3 X0-2,3 ,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 uor0phcnyl)—1-isopr0py1—2,4-diox0-1 ,2,3 ,4-tctrahydr0pyrirnidinc-5 - carboxylic acid [4-(6,7-dimcthoxyquino1iny1amino)-phcny1]-arnidc; luoro-phcnyl)isopropyl-3 ,5 -di0X0-2,3 ,4,5 -tctrahydr0-[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 -(4-F1u0r0-phcny1)isopr0py1—2,4-di0xo-1 ,2,3 ,4-tctrahydr0-pyrirnidinc-5 - carboxylic 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-Ethy1—3-(4-flu0rophcnyl)-2,4-di0xo- 1 ,2,3 ,4-tctrahydro-pyrirnidinc-5 -carb0xy1ic acid ,7-dimcthoxy-quinoliny1)-rncthylarnin0]-phcny1}-arnidc; 3 u0r0-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 xy1ic 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; y1—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-Ethy1—3-(4-flu0ro-phcny1)—2,4-di0x0- 1 ,2,3 ,4-tctrahydr0-pyrimidinc-5 -carb0xy1ic acid [4-(6,7-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 uor0-phcnyl)-2,4-di0x0-1 ,2,3 ,4-tctrahydro-pyrirnidinc-5 -carb0xy1ic acid [4- (6,7-dirncthoxy-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-Ethy1—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 [4-(6,7-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 - 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 uoro-phenyl)- l -isopropyl-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 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 xylic acid [4-(6,7-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)-3,5-dimethyl-phenyl]-amide; 3 -(4-Fluoro-phenyl)- l -isopropyl-2,4-dioxo-l ,2,3 rahydro-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 ,5-dioxo-2,3 ,4,5-tetrahydro- l ,2,4-triazine- 6- carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)isopropyl-phenyl]-amide; or 4-(4-Fluoro-phenyl)isopropyl-3 ,5 -dioxo-2,3 ,4,5 hydro-l ,2,4-triazine- 6- carboxylic acid [4-(6,7-dimethoxy-quinolinyloxy)methoxy-phenyl]-amide; or a ceutically 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 subject a eutically effective amount of a compound according to any one of preferred Embodiments l to 18.
. A method ing to preferred ment 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 er is selected from chronic myelogenous ia, c roliferative disorder, lung cancer, prostate cancer, esophageal cancer, ovarian , pancreatic , gastric cancer, liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breast cancer, acute myeloid leukemia, 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 c myelogenous leukemia, chronic myeloproliferative disorder, lung cancer, prostate , esophageal cancer, ovarian cancer, pancreatic cancer, gastric cancer, liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breast cancer, acute myeloid leukemia, colorectal cancer, e cancer, malignant , uveal melanoma, osteosarcoma and soft tissue sarcoma. 26. A method of treating a proliferative disorder in a t in need thereof, sing administering to the subject a therapeutically effective amount of a compound according 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 preferred Embodiment 26 wherein the proliferative disorder is cancer. 29. A compound according to preferred Embodiment 27 wherein the proliferative disorder is cancer.
. A method ing to preferred Embodiment 26 wherein the proliferative disorder is ed from chronic myelogenous leukemia, chronic myeloproliferative disorder, lung cancer, prostate cancer, esophageal , ovarian cancer, pancreatic - l 5 7- cancer, c cancer, liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breast cancer, acute d leukemia, ctal cancer, uterine cancer, malignant glioma, uveal melanoma, osteosarcoma and soft tissue sarcoma. 3 l. A compound according to preferred ment 29 n the proliferative disorder is selected from chronic myelogenous leukemia, chronic myeloproliferative disorder, lung cancer, prostate cancer, esophageal cancer, ovarian cancer, atic cancer, gastric , liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breast cancer, acute myeloid leukemia, colorectal cancer, uterine cancer, malignant glioma, uveal melanoma, osteosarcoma and soft tissue sarcoma. 32. A pharmaceutical composition sing a compound according to any one of preferred Embodiments l to 18 and a pharmaceutically acceptable 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) Formula I wherein: 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 cloalkyl 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, 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 C(—O) CHOH , , , , CH2 NH or , NC1_6alkyl—; W is CH or N; 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, together with the atoms g them, form a 3-6 membered heterocyclyl optionally substituted by 1-6 R119; Rla, Rlb, R10, and Rld are independently chosen from H, C1_6alkyl ally 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 kyl; R19 at each occurrence is independently chosen from C1_6alkyl optionally substituted 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 optionally substituted by 1-6 R39, halogen, —CN, —C(=O)OR3°, —C(=O)NR32R33, —NR32R33, —0R3°, and =0; R30, R32 and R33 at each ence is ndently chosen from H, C1_6alkyl, C1- kyl, 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 attached, a 5-6 membered heterocyclyl or a 5-6 membered heteroaryl; R39 at each occurrence is independently chosen from C1_6alkyl, loalkyl, and benzyl; R110, R112, and R113 at each occurrence is independently chosen from H and C1- 6alkyl optionally 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 halogen; R129 and R159 at each occurrence is ndently chosen from C1_6alkyl, C1_6- haloalkyl, , and halogen; and n at each occurrence is independently chosen from 0, l, and 2. 34. A compound according to preferred Embodiment 33, n 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. 34. A compound according to preferred ment 33, n 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 cyclohexyl.
. A compound according to preferred Embodiment 33, wherein E is chosen from C1_ 6alkyl optionally substituted by R19, phenyl, and p-fluorophenyl. 36. A compound according to preferred ment 33, wherein E is p-fluorophenyl. 37. A compound according to any of preferred Embodiments 33-36, wherein G is chosen from H, kyl optionally tuted by 1-3 R19, C2_6alkenyl optionally substituted by 1-3 halogen, C2_6alkynyl, 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 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. 39. A compound ing to any of preferred Embodiments 33-36, n 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. - l 60- 40. A nd 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 ments 33-42, n Y is N. 44. A compound ing to any of preferred Embodiments 33-42, wherein Y is CH. 45. A compound according to any of preferred Embodiments 33-42, n Y is C- Rld. 46. A compound according to any of preferred Embodiments 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—, —C(=O)—, —CHOH—, or —CH2—. 49. A compound according to any of preferred ments 33-46, wherein D is —O—. 50. A compound according to any of preferred Embodiments 33-49, wherein W is CH. 51. A compound according to any of preferred 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 —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. 53. 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 ered heterocyclyl, —OH, —OC1_6alkyl, —OCH2phenyl, —OC1_6alkyl- alkyl; RC is chosen from H and —OC1_6alkyl; and Rd is chosen from H and —OC1_ ; or Ra and Rb can, together with the atoms linking them, form a 5-6 membered cyclyl. 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 tuted 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 ing 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- 57. A compound according to any of preferred Embodiments 33-50, wherein RC and Rd <0 [0 O O are H, and Ra and Rb are alkyl; 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, C3_6cycloalkyl, halogen, —NH2, —NHC1_6alkylz, —N(C1_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 nd ing to any of preferred Embodiments 33-59, wherein Rla, Rlb, R10, and Rld are independently chosen from H and n. 64. A nd 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, n, and —OC1_3alkyl. 65. A compound according to any of preferred Embodiments 33-59, wherein Rla, R10, and Rld are H and Rlb is chosen from H, halogen, and —OC1_3alkyl. 66. A nd according to any of preferred Embodiments 33-59, wherein Rla, R10, and Rld are H and Rlb is fluoro. 67. A nd according to any of preferred Embodiments 33-66, wherein R19 at each occurrence is independently chosen from C1_6alkyl, 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, OC1_6alkyl, — C(=O)N(C1_6alkyl)2, —C(=O)pyrrolidinyl, —C(=O)morpholinyl, —N(C1_6alkyl)2, —OH, — lkyl, —Obenzyl, and =0. 68. A compound according to any of preferred Embodiments 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 compound ing to any of preferred ments 33-69, wherein R110, R112, and R113 at each occurrence is independently chosen from H and C1_6alkyl. 71. A compound ing to any of preferred Embodiments 33-70, wherein R at each occurrence is ndently 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 according to any of preferred Embodiments 33-72, wherein R129 and R159 at each occurrence is independently chosen from C1_6alkyl and halogen. 74. A compound according to any of preferred ments 33-73, wherein n at each occurrence is 2. 75. A compound according to preferred Embodiment 33, wherein E is p-fluorophenyl; G is C1_4alkyl optionally substituted by ropyl, —OH, or -OC1_3alkyl; X, Y, and W are CH; R3, R0, Rd, Rlb and R10 are H; D is —O—; Ra and Rb are —OCH3 or er form or ; and Rla is fluoro.
THE

Claims (38)

CLAIMS :
1. A pharmaceutical composition, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, R3 N O R X R N N 1b E Rd Y O O Ra R W 1a Rb N Formula I wherein: E and G are independently chosen from H, C 1-6alkyl optionally substituted by 1 -6 R19 , C 19 6-11 aryl optionally substituted by 1 -6 R , and 5 -15 membered heteroaryl ally substituted by 1 -6 R 19 ; X is C -R4; Y is C -R1d ; R3 is H or C 1-6alkyl; D is –O–, –S–, –SO –, or –SO 2–; W is CH or N; Ra, R b, R c, R d, R1a , R 1b , R 1c , R 1d , and R4 are ind ependently chosen from H, C 1- 6alkyl optionally substituted by 1 -6 R 119 , halogen, –CN, –NC, –OR 110 , and – NO 2; or any of R a and R b, R a and R d, and R b and R c can, together with the atoms linking them, form a C 119 6-11 aryl ally substituted by 1 -6 R or a 5-15 membered heteroaryl ally substituted by 1 -6 R 119 ; R19 at each occurrence is ndently chosen from C 1-6alkyl, C 2-6alkenyl, C 2- 6alkynyl, C 6-11 aryl, C 3-11 cycloalkyl, 3 -15 membered heterocyclyl, 5 -15 membered heteroaryl, halogen, –CN, and =O; R110 is chosen from H, C 1-6alkyl, C 6-11 aryl, C 3-11 cycloalkyl, 3 -15 membered heterocyclyl, and 5 -15 membered heteroaryl; and R119 at each occurrence is independently chosen from C 1-6alkyl, C 2-6alkenyl, C 2- 6alkynyl, C 6-11 aryl, C 3-11 cycloalkyl, 3 -15 ed cyclyl, 5 -15 membered heteroaryl, halogen, –CN, –NC, –NO 2, and =O, and a pharmaceutically acceptable ent..
2. The pharmaceutical ition according to Claim 1, wherein E and G are independently chosen from H, C 1-6alkyl ally substitut ed by 1 -6 R 19 , phenyl optionally substituted by 1 -5 R 19 , and 5 -6 membered heteroaryl optionally substituted by 1-3 R 19 .
3. The pharmaceutical composition ing to any one of Claims 1 -2, or a pharmaceutically acceptable salt thereof, wherein E is chose n from H, C 1-6alkyl optionally substituted by 1 -3 R 19 , and phenyl optionally substituted by halogen.
4. The ceutical composition according to any one of Claims 1 -3, or a pharmaceutically acceptable salt thereof, wherein W is CH .
5. The pharmaceutic al ition according to any one of Claims 1 -4, or a pharmaceutically acceptable salt thereof, wherein R a, R b, R c, and R d are independently chosen from H, C 1-6alkyl optionally substituted by 1 -6 R 119 , and –OR 110 .
6. The pharmaceutical composition accor ding to any one of Claims 1 -5, or a pharmaceutically acceptable salt thereof, wherein R 110 is chosen from H and C 1-6alkyl.
7. The pharmaceutical composition according to Claim 1, wherein the compound of Formula (I), or pharmaceutically acceptable salt th ereof, is 3 -(4 -fluorophenyl) isopropyl -2,4 -dioxo -1,2,3,4 -tetrahydropyrimidine carboxylic acid [4 -(6,7 - oxyquinolin yloxy) fluorophenyl] -amide having the structure
8. The pharmaceutical composition accordi ng to Claim 7, wherein the composition comprises from about 0.1 mg to about 1,000 mg of 3 -(4 -fluorophenyl) isopropyl -2,4 - dioxo -1,2,3,4 hydropyrimidine carboxylic acid [4 -(6,7 -dimethoxyquinolin yloxy) fluorophenyl] -amide, or a pharmaceutically acceptable salt f.
9. The pharmaceutical composition according to Claim 8, wherein the composition ses from about 1 mg to about 1,000 mg of 3 -(4 -fluorophenyl) isopropyl -2,4 - dioxo -1,2,3,4 -tetrahydropyrimidine carboxylic acid [4 -(6,7 -dimeth oxyquinolin yloxy) fluorophenyl] -amide, or a pharmaceutically acceptable salt thereof.
10. The pharmaceutical composition according to Claim 0, wherein the ition comprises from about 1 mg to about 500 mg of 3 -(4 -fluorophenyl) isopropyl -2,4 -dio xo - 1,2,3,4 hydropyrimidine carboxylic acid [4 -(6,7 -dimethoxyquinolin yloxy) fluorophenyl] -amide, or a pharmaceutically able salt thereof.
11. The pharmaceutical composition according to Claim 10, wherein the composition comprises from ab out 1 mg to about 100 mg of 3 -(4 -fluorophenyl) isopropyl -2,4 -dioxo - 1,2,3,4 -tetrahydropyrimidine carboxylic acid [4 -(6,7 -dimethoxyquinolin yloxy) fluorophenyl] -amide, or a pharmaceutically acceptable salt thereof.
12. The pharmaceutical composition according to Claim 7, wherein the composition comprises from about 1% to about 95% (w/w) of 3 -(4 ophenyl) isopropyl -2,4 - dioxo -1,2,3,4 -tetrahydropyrimidine carboxylic acid [4 -(6,7 -dimethoxyquinolin yloxy) fluorophenyl] -amide, or a ceutic ally acceptable salt f.
13. The pharmaceutical composition according to Claim 12, wherein the ition comprises from about 10% to about 80% (w/w) of 3 -(4 -fluorophenyl) isopropyl -2,4 - dioxo -1,2,3,4 -tetrahydropyrimidine carboxylic acid [4 -(6,7 -dimethoxyquinolin yloxy) fluorophenyl] -amide, or a pharmaceutically able salt thereof.
14. The pharmaceutical composition according to Claim 13, wherein the composition ses from about 20% to about 70% (w/w) of 3 -(4 -fluorophenyl) isoprop yl -2,4 - dioxo -1,2,3,4 -tetrahydropyrimidine carboxylic acid [4 -(6,7 -dimethoxyquinolin yloxy) fluorophenyl] -amide, or a pharmaceutically acceptable salt thereof.
15. The pharmaceutical composition according to Claim 14, wherein the composition comprise s from about 30% to about 60% (w/w) of 3 -(4 -fluorophenyl) isopropyl -2,4 - dioxo -1,2,3,4 -tetrahydropyrimidine carboxylic acid [4 -(6,7 -dimethoxyquinolin yloxy) fluorophenyl] -amide, or a pharmaceutically acceptable salt thereof.
16. The pharmaceutical composition according to Claim 15, wherein the composition ses from about 40% to about 50% (w/w) of 3 -(4 -fluorophenyl) isopropyl -2,4 - dioxo -1,2,3,4 -tetrahydropyrimidine carboxylic acid [4 -(6,7 -dimethoxyquinolin yloxy) fluorophenyl] , or a ceutically acceptable salt thereof.
17. A pharmaceutical composition, comprising a therapeutically effective amount of a compound which is 3 -(4 -fluorophenyl) isopropyl -2,4 -dioxo -1,2,3,4 - tetrahydropyrimidine carboxylic acid [4 -(6,7 hoxyquin olin yloxy) fluorophenyl] -amide having the structure or a pharmaceutically acceptable salt thereof, and another therapeutic agent.
18. Use of a compound which is 3 -(4 -fluorophenyl) isopropyl -2,4 -dioxo -1,2,3,4 - te trahydropyrimidine carboxylic acid [4 -(6,7 -dimethoxyquinolin yloxy) phenyl] -amide having the structure or a pharmaceutically acceptable salt thereof, for preparing a medicament for contacting a cell, wherein the medicament is formulated for ting AXL, c -met, or AXL and c -met.
19. A use according to Claim 18, wherein the medicament is formulated for inhibiting AXL.
20. A use ing to Claim 18, wherein the medicament is formulated for inhibiting c-met.
21. A use ing to Claim 18, wherein the medicament is formulated for inhibiting AXL and c -met.
22. Use of a compound which is 3 -(4 -fluorophenyl) isopropyl -2,4 -dioxo -1,2,3,4 - tetrahydropyrimidine boxylic acid [4 -(6,7 -dimethoxyquinolin xy) fluorophenyl] -amide having the structure or a pharmaceutically acceptable salt thereof, for preparing a medicament for ng an AXL or c -met -mediated disorder or condition.
23. A use ing to Claim 22, n said ment comprises about 0.001 mg/kg to about 100 mg/kg of said 3 -(4 -fluorophenyl) isopropyl -2,4 -dioxo -1,2,3,4 - tetrahydropyrimidine carboxylic acid [4 -(6,7 -dimethoxyquinolin yloxy) fluorophenyl] -amide, or a pharmaceutically acceptab le salt thereof.
24. A use according to Claim 23, wherein said medicament comprises about 0.1 mg/kg to about 10 mg/kg of said 3 -(4 -fluorophenyl) isopropyl -2,4 -dioxo -1,2,3,4 - tetrahydropyrimidine carboxylic acid [4 -(6,7 -dimethoxyquinolin yloxy) flu orophenyl] -amide, or a pharmaceutically acceptable salt thereof.
25. A use according to Claim 24, n said medicament comprises about 0.5 mg/kg to about 5 mg/kg of said 3 -(4 -fluorophenyl) isopropyl -2,4 -dioxo -1,2,3,4 - tetrahydropyrimidine boxylic acid [4 -(6,7 -dimethoxyquinolin yloxy) fluorophenyl] -amide, or a pharmaceutically acceptable salt thereof.
26. A use according to Claim 25, wherein said medicament comprises about 1 mg/kg to about 2 mg/kg of said 3 -(4 -fluorophenyl) isopropyl -2,4 -dio xo -1,2,3,4 - tetrahydropyrimidine carboxylic acid [4 -(6,7 -dimethoxyquinolin yloxy) fluorophenyl] -amide, or a pharmaceutically acceptable salt thereof.
27. A use according to any one of Claims 22 -26, n said medicament is formulated for administr ation on a daily basis.
28. A use according to any one of Claims 22 -27, wherein said disorder or condition is chronic myeloproliferative disorder.
29. A use according to any one of Claims 22 -27, wherein said disorder or ion is cancer.
30. A us e ing to Claim 29, wherein said cancer is resistant to at least one cancer therapy.
31. A use according to any one of Claims 29 -30, wherein said cancer is selected from chronic enous leukemia, lung cancer, non -small cell lung cancer, prostate cancer, esophageal cancer, ovarian cancer, atic cancer, gastric cancer, liver cancer, thyroid cancer, renal cell carcinoma, glioblastoma, breast , acute myeloid ia, colorectal cancer, uterine cancer, malignant glioma, melanoma, uveal mel anoma, osteosarcoma, and soft tissue sarcoma.
32. A use according to Claim 31, wherein said cancer is selected from non -small cell lung cancer, breast cancer, pancreatic cancer, ctal cancer, melanoma, and glioblastoma.
33. A use according to Clai m 32, wherein said cancer is non -small cell lung cancer.
34. A use according to Claim 32, wherein said cancer is breast cancer.
35. A use according to Claim 32, wherein said cancer is pancreatic cancer.
36. A use according to Claim 32, wherein said c ancer is colorectal cancer.
37. A use according to Claim 32, wherein said cancer is melanoma.
38. A use ing to Claim 32, wherein said cancer is glioblastoma.
NZ712194A 2011-11-14 2012-11-14 Uracil derivatives as axl and c-met kinase inhibitors NZ712194B2 (en)

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