EP1937681A1 - 5-oxo-5,8-dihydro-pyrido-pyrimidines comme inhibiteurs de kinase c-fms - Google Patents

5-oxo-5,8-dihydro-pyrido-pyrimidines comme inhibiteurs de kinase c-fms

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Publication number
EP1937681A1
EP1937681A1 EP06803485A EP06803485A EP1937681A1 EP 1937681 A1 EP1937681 A1 EP 1937681A1 EP 06803485 A EP06803485 A EP 06803485A EP 06803485 A EP06803485 A EP 06803485A EP 1937681 A1 EP1937681 A1 EP 1937681A1
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Prior art keywords
oxo
pyrido
pyrimidine
carboxylic acid
dihydro
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German (de)
English (en)
Inventor
Mark R. Player
Hui Huang
Daniel Hutta
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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Publication of EP1937681A1 publication Critical patent/EP1937681A1/fr
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Definitions

  • the invention relates to novel compounds that function as protein tyrosine kinase inhibitors.
  • the family of 5-oxo-5,8-dihydro-pyrido-pyrimidines has exhibited promising pharmaceutical properties in the past; United States Patent 4,556,709, JP 09221424 and DE 19532235 are indicative of recent investigations. More particularly, the invention relates to novel compounds that function as inhibitors of c-fms kinase.
  • c-Fnis is a type III receptor tyrosine kinase selectively expressed on macrophages and their progenitors.
  • Macrophages are a predominant source of tumor necrosis factor (TNF) and interleukin-1 (IL-I) in the destructive pannus of rheumatoid arthritis.
  • TNF and IL-I activate stromal expression of hematopoietic factors including CSF-I.
  • CSF-I recruits monocytes and promotes macrophage survival, functional activation, and in some settings, proliferation.
  • the exclusive receptor for CSF-I is c-fms, and the disclosed invention is a c-fms inhibitor designed to interrupt this cycle.
  • Macrophages are abundant at sites of chronic inflammation where they are are often the most important source of TNF, IL-I, and other cytokines. Moreover, macrophages can be an important source of factors that function in tissue remodeling such as plasminogen activators, matrix metalloproteases, vascular endothelial growth factor, and transforming growth factor - ⁇ . The numbers of macrophages present within target tissues have strongly correlated with disease severity in rheumatoid arthritis (Ann Rheum Dis 53 (1994) pp 39-44), immune nephritis (Kidney Int 54 (1998) pp 143-151), and graft rejection (Transpl Int 7 Suppl 1 (1994) pp 577-579).
  • Macrophage numbers are also elevated in atherosclerotic plaque (Arch Pathol Lab Med 109 (1985) pp 445-449), adipose tissue in obesity (J Clin Invest 112 (2003) ppl796-1898), diabetic nephropathy (Kidney Int 65 (2004) pp 116-128), cardiac hypertrophy (Hypertension 25 (1999) ppl32-138), and in many solid tumors (Trends in Immunology 23 (2002) pp 549-555), particularly breast cancer (J. Experimental Medicine 193 (2001) pp 727-739), where they are thought to contribute to disease progression. Modulation of macrophage function through inhibition of c-fms thus is expected to be useful in treating inflammatory mediated diseases and conditions.
  • Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: rheumatoid arthritis, graft rejection, atherosclerosis, obesity, diabetic nephropathy, cardiac hypertrophy and solid tumor diseases, especially breast cancer, in a subject in need of such treatment.
  • the invention addresses the current need for selective and potent protein tyrosine kinase inhibitors by providing potent inhibitors of c-fms kinase.
  • the invention is also directed to a method of treating or ameliorating a c-fms kinase mediated disorder in a subject in need thereof comprising administering to the subject an effective amount of at least one compound of Formula I.
  • A is absent or alkyl
  • R 200 is halogen, alkoxy optionally substituted with -CH(OH)-CH 2 -NR 203 R 204 , alkyl optionally substituted with R 201 , heterocyclyl optionally substituted with one alkyl and optionally substituted with one R 202 , amino, alkylamino, dialkylamino, -C(O)(CH 2 ) n NR 203 R 204 ,heteroaryl, or -R 300 -R 400 ; wherein n is 0, 1, 2, 3, or 4;
  • R 201 is hydroxyl, methyl, halogen, -CF 3 , amino, alkylamino, dialkylamino or methoxy;
  • R 202 is alkyl, -C(O)-CH 3 , -CH 2 -C(O)-CH 3 , -C(O)(CH 2 ) n NR 203 R 204 , or -CON-alkyl-NR 203 R 204 ; wherein n is 0, 1, 2, 3, or 4;
  • R a , R c and R d are independently hydrogen or alkyl;
  • R 300 is alkyl;
  • R 405 and R 406 are independently hydrogen, alkyl, or R 405 and R 406 may be taken together to form a ring selected from the following:
  • R a , R c and R d are independently hydrogen or alkyl
  • Z is CO 2 H, CO 2 alkyl, or CONR 1 R 2 ; wherein R 1 is hydrogen or alkyl; and R 2 is hydrogen, alkyl, cycloalkyl, or alkoxy.
  • An example of the present invention is a compound of Formula I or a form thereof, wherein:
  • W is N or CH
  • A is absent or alkyl
  • Y is a ring selected from cycloalkyl, bicycloalkyl, aryl, alkylaryl, cycloalkylaryl, arylcycloalkyl, or heteroaryl provided that Y is not thiazole;
  • R 200 is halogen, alkoxy optionally substituted with -CH(OH)-CH 2 -NR 203 R 204 , alkyl optionally substituted with R 201 , heterocyclyl optionally substituted with one alkyl and optionally substituted with one R 202 , dialkylamino, -C(O)(CH 2 ) n NR 203 R 204 , heteroaryl, or -R 300 -R 400 ; wherein n is 0, 1, 2, 3, or 4;
  • R 201 is hydroxyl, methyl, halogen, -CF 3 , dialkylamino or methoxy;
  • R 202 is alkyl, -C(O)-CH 3 , -CH 2 -C(O)-CH 3 , -C(O)(CH 2 ) n NR 203 R 204 , or -CON-alkyl-NR 203 R 204 ; wherein n is 0, 1, 2, 3, or 4;
  • R 203 and R 204 are independently hydrogen, alkyl, or R 203 and R 204 may be taken together to form a ring selected from the following:
  • R a , R c and R d are independently hydrogen or alkyl;
  • R 300 is alkyl;
  • R 400 is -NR 403 R 404 , -SO 2 NR 405 R 406 , oxazolidinonyl wherein said oxazolidinonyl is optionally substituted with one or two R 401 , piperazinyl wherein said piperazinyl is optionally substituted with R 202 or pyrrolidinonyl wherein said pyrrolidinonyl is optionally substituted with one or two R 401 ; wherein R 401 is methyl, -C(O)-CH 3 , or -CH 2 -C(O)-CH 3 ; wherein R 403 and R 404 are independently hydrogen, alkyl, or R 403 and R 404 may be taken together to form a ring selected from the following:
  • R a , R c and R d are independently hydrogen or alkyl
  • R 405 an idd RR 440066 aarree iinnddeeppeennddeennttllyy hhyyddrrooggeenn,, aallkkyyll,, or R 405 and R 406 may be taken together to form a ring selected from the following: wherein R a , R c and R d are independently hydrogen or alkyl; and
  • Z is CO 2 H, CO 2 alkyl, or CONR 1 R 2 ; wherein R 1 is hydrogen or alkyl; and R 2 is hydrogen, alkyl, cycloalkyl, or alkoxy.
  • Examples of the present invention include those compounds of Formula I or a form thereof wherein one or more of the following limitations are present:
  • W is N or CH
  • A is absent
  • R 101 is hydrogen, hydroxyl, methyl, halogen, -CF 3 , or methoxy
  • R 200 is halogen, C (1-4) alkoxy optionally substituted with -CH(OH)-CH 2 -NR 203 R 204 ,
  • C(i- 4 )alkyl optionally substituted with R 201 , heterocyclyl optionally substituted with one C( 1-4 )alkyl and optionally substituted with one R 202 , dialkylamino, -C(O)(CH 2 ) n NR 203 R 204 , heteroaryl, or -R 300 -R 400 ; wherein n is 0, 1, 2, 3, or 4;
  • R 201 is hydroxyl, methyl, halogen, -CF 3 , dialkylamino or methoxy;
  • R 202 is alkyl, -C(O)-CH 3 , -CH 2 -C(O)-CH 3 , -C(O)(CH 2 ) n NR 203 R 204 , -C(O)N(CH 2 )nNR 203 R 204 ; wherein n is 0, 1, 2, 3, or 4;
  • R 203 and R 204 are independently hydrogen, C( 1-4 )alkyl, or R 203 and R 204 may be taken together to form a ring selected from the following:
  • R 400 is -NR 403 R 404 , -SO 2 NR 405 R 406 , oxazolidinonyl wherein said oxazolidinonyl is optionally substituted with one or two R 401 , piperazinyl wherein said piperazinyl is
  • R >a , R and j R Tj d are independently hydrogen or alkyl
  • R 405 and R 406 are independently hydrogen, C (1-4) alkyl, or R 405 and R 406 may be taken together to form a ring selected from the following:
  • R a , R c and R d are independently hydrogen or alkyl
  • Z is CO 2 alkyl, or CONR 1 R 2 ; wherein R 1 is hydrogen or C( 1-4) alkyl; and R 2 is hydrogen, C( 1-4 )alkyl, cycloalkyl, or C( 1-4 )alkoxy.
  • W is N
  • A is absent
  • Y is a ring selected from cycloalkyl or arylcycloalkyl
  • R 101 is hydrogen;
  • R 200 is -R 300 -R 400 ;
  • W is N; A is absent;
  • R 200 is piperazine optionally substituted with one or two methyl substituents, piperidine optionally substituted with one or two methyl substituents, morpholine or _ R 3oo_ R 4 Q O wherein R 3oo is methy i or ethyl J1n( J R 4oo ig p i perazine optionally substituted with one or two methyl substituents; and
  • Z is CO 2 alkyl, or CONR 1 R 2 ; wherein R 1 is hydrogen or C( 1-4 )alkyl; and R 2 is hydrogen, C(i -4 )alkyl, or cycloalkyl.
  • Examples of the present invention include those compounds of Formula I or a form thereof wherein one or more of the following limitations are present:
  • W is N; A is absent;
  • Y is a ring selected from cyclohexyl, cyclopentyl, bicyclo[2.2.1]heptyl, indanyl, phenyl or
  • R 101 is hydrogen, hydroxyl, methyl, halogen, -CF 3 , or methoxy
  • R 200 is heterocyclyl (preferably tetrahydrofuranyl, pyrrolidinyl, piperidinyl, 4-methyl piperazin-1-yl, piperazinyl, morpholinyl, or thiomorpholino), dialkylamino, -R 300 -R 400 , or C (1-4) alkyl wherein said C( 1-4 )alkyl is optionally substituted with one or both substituents selected from hydroxyl and dialkylamino;
  • R 400 is -NR 403 R 404 , -SO 2 NR 405 R 406 , oxazolidinonyl wherein said oxazolidinonyl is optionally substituted with one or two R 401 , piperazinyl wherein said piperazinyl is optionally substituted with R 202 or pyrrolidinonyl wherein said pyrrolidinonyl is optionally substituted with one or two R 401 ; wherein R 401 is methyl, -C(O)-CH 3 , or -CH 2 -C(O)-CH 3 ; wherein R 403 and R 404 are independently hydrogen, C( 1-4) alkyl, or R 403 and R 404 may be taken together to form a ring selected from the following:
  • R 405 and R 405 are independently hydrogen, C (1-4) alkyl, or R 405 and R 406 may be taken together to form a ring selected from the following:
  • R a , R c and R d are independently hydrogen or alkyl
  • Examples of the present invention include those compounds of Formula I or a form thereof wherein one or more of the following limitations are present:
  • W is N or CH
  • A is absent or alkyl
  • Y is a ring selected from indan-5-yl, phenyl, cyclohexyl, cyclopentyl, bicyclo[2.2.1]heptyl or adamantan-2-yl;
  • R 101 is hydrogen or hydroxyl
  • R 200 is fluorine, alkoxy substituted with -CH(OH)-CH 2 -N(CH 3 ) 2 , alkyl optionally substituted with R 201 , morpholinyl, piperazinyl optionally substituted with R 202 , 3, 5 -dimethyl piperazinyl, piperidinyl, piperidinyl substituted with -C(O)-alkyl-N(CH 3 ) 2 , -C(O)-alkyl-piperazinyl (optionally substituted on piperazinyl with alkyl), dimethylamino, -C(O)N(CH 3 ) 2 , heteroaryl, or -R 300 -R 400 ;
  • R 201 is hydroxyl or dimethylamino
  • R 202 is -CH 3
  • R 300 is alkyl
  • R 400 is -N(CH 3 J 2 , morpholinyl, -SO 2 NR 405 R 406 , piperazinyl optionally substituted with R 202 or oxazolidinonyl;
  • R 405 and R 406 are independently hydrogen, alkyl, or R 405 and R 406 may be taken together to
  • Z is CO 2 alkyl, or CONR 1 R 2 ; wherein R 1 is hydrogen or alkyl; and R 2 is hydrogen, alkyl, cycloalkyl, or alkoxy.
  • An example of the present invention includes compounds of Formula I or a form thereof wherein:
  • Y is a ring selected from cycloalkyl, bicycloalkyl, phenyl, alkylaryl, cycloalkylaryl, arylcycloalkyl, or heteroaryl provided that Y is not thiazole;
  • R 101 is hydrogen, hydroxyl, methyl, halogen, -CF 3 , or methoxy
  • C( 1-4 )alkyl optionally substituted with R
  • heterocyclyl optionally substituted with one C( !4 )alkyl and optionally substituted with one R 202 , dialkylamino, -C(O)(CH 2 ) n NR 203 R 204 , heteroaryl, or -R 300 -R 400 ; wherein n is 0, 1, 2, 3, or 4;
  • R 202 is alkyl, -C(O)-CH 3 , -CH 2 -C(O)-CH 3 , -C(O)(CH 2 ) n NR 203 R 204 , -C(O)N(CH 2 ) n NR 203 R 204 ; wherein n is 0, 1, 2, 3, or 4;
  • R 203 and R 204 are independently hydrogen, C (1-4) alkyl, or R 203 and R 204 may be taken together to form a ring selected from the following: wherein R a , R c and R d are independently hydrogen or alkyl; R 300 is C (1-4) alkyl; and
  • R a , R c and R d are independently hydrogen or alkyl
  • R 405 and R 406 are independently hydrogen, C (1-4 )alkyl, or R 405 and R 406 may be taken together to form a ring selected from the following:
  • Examples of the present invention include those compounds of Formula I or a form thereof selected from, but not limited to, the following:
  • the compounds of the present invention are further useful as markers for the c-fms receptor.
  • Compounds of formula (I) when used as markers are for example radio-labeled by for example, substituting at least one hydrogen atom with a tritium atom. Other labeling techniques known in the arts can also be used.
  • form means, in reference to compounds of the present invention, such may exist as, without limitation, a salt, stereoisomer, tautomer, crystalline, polymorph, amorphous, solvate, hydrate, ester, prodrug or metabolite form.
  • the present invention encompasses all such compound forms and mixtures thereof.
  • Certain compounds of Formula (I) may exist in various stereoisomer ⁇ or tautomeric forms and mixtures thereof.
  • the invention encompasses all such compounds, including active compounds in the form of essentially pure enantiomers, racemic mixtures and tautomers.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • the invention includes compounds of various isomers and mixtures thereof.
  • the term "isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. Such substances have the same number and kind of atoms but differ in structure. The structural difference may be in constitution (geometric isomers) or in an ability to rotate the plane of polarized light (stereoisomers).
  • racemate or “racemic mixture” means an equimolar mixture of two enantiomeric species, wherein each of the isolated species rotates the plane of polarized light in the opposite direction such that the mixture is devoid of optical activity.
  • the invention is considered to include the tautomeric forms of all compounds of Formula I.
  • the invention is considered to include pure enantiomers, racemic mixtures, as well as mixtures of enantiomers having 0.001% to 99.99% enantiomeric excess.
  • some of the compounds represented by Formula I may be prodrugs, Le., derivatives of a drug that possess superior delivery capabilities and therapeutic value as compared to the active drug. Prodrugs are transformed into active drugs by in vivo enzymatic or chemical processes.
  • the two distinct mirror image versions of the chiral molecule are also known as levo (left-handed), abbreviated L, or dextro (right handed), abbreviated D, depending on which way they rotate polarized light.
  • L left-handed
  • D dextro
  • R and S represent the configuration of groups around a stereogenic carbon atom(s).
  • an example of an enantiomerically enriched form isolated from a racemic mixture includes a levorotatory enantiomer, wherein the mixture is substantially free of the dextrorotatory isomer.
  • substantially free means the dextrorotatory isomer may, in a range, comprise less than 25% of the mixture, less than 10 %, less than 5 %, less than 2 % or less than 1 % of the mixture according to the formula:
  • Gaometric isomer means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or . to a bridged bicyclic system.
  • Substituent atoms (other than hydrogen) on each side of a carbon-carbon double bond may be in an E or Z configuration. In the “E” configuration, the substituents are on opposite sides in relationship to the carbon- carbon double bond. In the "Z" configuration, the substituents are oriented on the same side in relationship to the carbon- carbon double bond.
  • Substituent atoms (other than hydrogen) attached to a ring system may be in a cis or trans configuration.
  • the substituents are on the same side in relationship to the plane of the ring; in the "trans” configuration, the substituents are on opposite sides in relationship to the plane of the ring.
  • Compounds having a mixture of "cis” and “trans” species are designated "cis/trans”.
  • compounds of the present invention may have at least one crystalline, polymorph or amorphous form.
  • the plurality of such forms are included in the scope of the invention.
  • some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents (e.g., organic esters such as ethanolate and the like). The plurality of such solvates are also intended to be encompassed within the scope of this invention.
  • Bond lines drawn into a ring system from a substituent variable indicate that the substituent may be attached to any of the substitutable ring atoms.
  • alkyl refers to both linear and branched chain radicals of up to 8 carbon atoms, unless otherwise indicated, and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl.
  • C( X-y )alkyl refers to an alkyl chain of length not less than x carbons and not more than y carbons. For example, the term refers to both linear and branched chain radicals of up to 4 carbon atoms.
  • Alkyl radicals or linking groups may be attached to a core molecule via a terminal carbon atom or via a carbon atom within the chain. Similarly, substituent variables may be attached to an alkyl linking group when allowed by available valences.
  • amino means an amine group of the formula: -NH 2 .
  • alkylamino or dialkylamino refers to an amino with one or two alkyl substituents, respectively, wherein the amino group is the point of attachment to the rest of the molecule.
  • aryl refers to monocyclic or bicyclic aromatic ring systems containing from 6 to 12 carbons in the ring. Alkyl substituents may optionally be present on the ring. Examples include benzene, biphenyl, naphthalene (also referred toas naphthalenyl), azulenyl, anthracenyl and the like. Aryl radicals may be attached to a core molecule and further substituted on any atom when allowed by available valences.
  • aromatic refers to a cycloalkylic hydrocarbon ring system having an unsaturated, conjugated ⁇ electron system.
  • aralkyl refers to a C 1-6 alkyl group containing an aryl substituent, in which the point of attachment is the alkyl group. Examples include benzyl, phenylethyl or 2-naphthylmethyl. It is possible that both the alkyl and aryl portion may be substituted, and in that case, it is intended that the alkyl group is closer to the core ring structure.
  • alkylaryl refers to a C 1-6 alkyl group containing an aryl substituent, in which the point of attachment is the aryl group. It is possible that both the alkyl and aryl portion may be substituted, and in that case, it is intended that the aryl group is closer to the core ring structure.
  • alkoxy refers to a saturated branched or straight chain monovalent hydrocarbon alcohol radical derived by the removal of the hydrogen atom from the hydroxide oxygen substituent on a parent alkane, as in the formula: -O-C 1-8 alkyl. Examples include methoxy, ethoxy, propoxy, isopropoxy and butoxy.
  • Q x- y )alkoxy refers to an alkoxy chain of length not less than x carbons and not more than y carbons.
  • Q 1-4 )alkoxy refers to both linear and branched alkoxy chain radicals of up to 4 carbon atoms.
  • An alkoxy radical may be attached to a -core molecule and further substituted when allowed by available valences.
  • arylcycloalkyl refers to a C 8-10 fused bicyclic ring system comprising an aryl group and a cycloalkyl group in which the point of attachment is the aryl group, as in a benzofused C 3-14 cycloalkyl ring system defined below. Examples include, but are not limited to lH-indenyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl and the like.
  • cycloalkyl refers to a saturated or partially unsaturated ring composed of from 3 to 14 carbon atoms. Up to four alkyl substituents may optionally be present on the ring.
  • the term also includes a C 3 . 8 cycloalkyl, C 3-10 cycloalkyl, Cs ⁇ cycloaLkyl, C 5-8 cycloalkyl, C 5-12 cycloalkyl, C 8-1 ocycloalkyl, C 9-13 cycloalkyl, C 3-14 cycloalkyl or benzofused C 3-14 cycloalkyl ring system.
  • Examples include 1,1 -dimethyl cyclobutyl, 1,2,3- trimethylcyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, lH-indenyl, indanyl, 9 ⁇ -fluorenyl, 1,2,3,4- tetrahydro-naphthalenyl, acenaphthenyl, bicyclo[2.2.1]heptenyl and the like.
  • C 3-14 cycloalkyl radicals may be attached to a core molecule and further substituted on any atom when allowed by available valences.
  • cycloalkylaryl refers to a C 8-10 fused bicyclic ring system comprising an aryl group and a cycloalkyl group in which the point of attachment is the cycloalkyl group, as in a benzofused C 3-14 cycloalkyl ring system defined above, such as lH-indenyl, indanyl, 1,2,3,4-tetrahydro-naphthalenyl and the like.
  • bicycloalkyl refers to a saturated or partially unsaturated fused ring pair composed of from 8 to 10 carbon atoms. Up to four alkyl substituents may optionally be present on the ring. Examples include adamantyl, bicyclo[2.2.1]heptenyl, decahydronaphthalenyl and 1,2,3,4 tetrahydropentalenyl and the like.
  • hetero used as a prefix for a ring system refers to the replacement of at least one ring carbon atom with one or more heteroatoms independently selected from N, S, or O.
  • Examples include rings wherein 1, 2, 3 or 4 ring members are a nitrogen atom; or, 0, 1, 2 or 3 ring members are nitrogen atoms and 1 member is an oxygen or sulfur atom.
  • up to two adjacent ring members may be heteroatoms; wherein one heteroatom is nitrogen and the other is one heteroatom selected from N, S or O.
  • heterocyclyl refers to a nonaromatic (i.e. saturated or partially unsaturated) ring composed of from 3 to 7 carbon atoms and at least one heteroatom selected from N, O or S. Alkyl substituents and/or carbonyl substituents may optionally be present on the ring.
  • Examples include tetrahydrofuranyl, dihydropyranyl, piperidinyl, 2,5- dimethypiperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 2H-pyrrole, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, imidazolinyl (also referred to as 4,5-dihydro-lH-imidazolyl), 1,3-dioxolanyl, tetrazolinyl, tetrazolidinyl, 1,4- dioxanyl, 1,4-dithianyl, azetidinyl, azepanyl, hexahydro-l,4-diazepinyl, hexahydro-1,4- oxazepanyl, tetrahydro-thien
  • heteroaryl refers to 5- to 7-membered mono- or 8- to 10-membered bicyclic aromatic ring systems, any ring of which may consist of from one to four heteroatoms selected from N, O, S, S(O) or SO 2 where the nitrogen and sulfur atoms can exist in any allowed oxidation state.
  • Examples include benzoimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, thiazolyl, thienyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, indolizinyl, indolyl, azaindolyl, isoindolyl, benzofuranyl, indazolyl, azaindazolyl, benzoisoxazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalzin
  • heteroatom refers to a nitrogen atom, an oxygen atom or a sulfur atom wherein the nitrogen and sulfur atoms can exist in any allowed oxidation states.
  • sulfonyl refers to the group -S(O) 2 R 2 , where R z is hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl.
  • substituted refers to a core molecule on which one or more hydrogen atoms have been replaced with one or more functional radical moieties.
  • the number that is allowed by available valences limits the amount of substituents. Substitution is not limited to the core molecule, but may also occur on a substituent radical, whereby the substituent radical becomes a linking group.
  • the compounds of Formula I represent novel potent inhibitors of protein tyrosine kinases, such as c-fms, and may be useful in the prevention and treatment of disorders resulting from actions of these kinases.
  • the invention also provides methods of inhibiting a protein tyrosine kinase comprising contacting the protein tyrosine kinase with an effective inhibitory amount of at least one of the compounds of Formula I.
  • a preferred tyrosine kinase is c-fms.
  • at least one of the compounds of Formula I is combined with a known tyrosine kinase inhibitor.
  • the protein tyrosine kinases inhibited by the compounds of Formula I are located in cells, in a mammal or in vitro. In the case of mammals, which includes humans, a therapeutically effective amount of a pharmaceutically acceptable form of at least one of the compounds of Formula I is administered.
  • the invention further provides methods of treating cancer in mammals, including humans, by administration of a therapeutically effective amount of a pharmaceutically acceptable composition of least one compound of Formula I.
  • exemplary cancers include, but are not limited to, ovarian cancer, uterine cancer, breast cancer, colon cancer, stomach cancer, hairy cell leukemia and non-small lung carcinoma.
  • an effective amount of at least one compound of Formula I is administered in combination with an effective amount of a chemotherapeutic agent.
  • the invention also provides methods of treating cardiovascular and inflammatory diseases in mammals, including humans, by administration of a therapeutically effective amount of a pharmaceutically acceptable form of at least one of the compounds of Formula I.
  • diseases that may be effectively treated include atherosclerosis, cardiac hypertrophy, glomerulonephritis, rheumatoid arthritis, psoriasis, diabetes, tumor related angiogenesis, restenosis, schizophrenia and Alzheimer's dementia.
  • the compounds of the invention may be administered in an effective amount within the dosage range of about 0.5 mg to about 10 g, preferably between about 0.5 mg to about 5 g, in single or divided daily doses.
  • a preferred dosage is 5 mg/kg, delivered orally.
  • the dosage administered will be affected by factors such as the route of administration, the health, weight and age of the recipient, the frequency of the treatment and the presence of concurrent and unrelated treatments.
  • the compounds of Formula I may be formulated into pharmaceutical compositions comprising any known pharmaceutically acceptable carriers.
  • exemplary carriers include, but are not limited to, any suitable solvents, dispersion media, coatings, antibacterial and antifungal agents and isotonic agents.
  • exemplary excipients that may also be components of the formulation include fillers, binders, disintegrating agents and lubricants.
  • the pharmaceutically-acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts which are formed from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecylsulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate, nitrate, oxalate, pivalate, propionate, succinate, sulfate and tartrate.
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts and salts with amino acids such as arginine. Also, the basic nitrogen-containing groups may be quaternized with, for example, alkyl halides.
  • compositions of the invention may be administered by any means that accomplish their intended purpose. Examples include administration by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or ocular routes. Alternatively or concurrently, administration may be by the oral route.
  • suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, acidic solutions, alkaline solutions, dextrose-water solutions, isotonic carbohydrate solutions and cyclodextrin inclusion complexes.
  • the compounds of Formula I can be prepared by methods known to those who are skilled in the art.
  • the following reaction schemes are only meant to represent examples of the invention and are in no way meant to limit the invention.
  • the resulting carboxylic ester 1-6 was converted to the carboxylic acid 1-7 via basic hydrolysis. Decarboxylation to give 1-8 occured when the carboxylic acid was heated in DMSO in the presence of sodium cyanide (Tet Lett 35 (1994) pp 8303-8306). The carboxylic acid 1-7 was reacted with an amine under normal coupling conditions to form the corresponding amide 1-9.
  • the amide 1-9 could also be prepared directly from the ester 1-6 when the amine R 1 -NH 2 was ammonia, or an alkylamine ⁇
  • the synthesis was further extended to include the preparation of 5,8-dihydro- pyrido[2,3-d]pyrimidines with a carbonitrile functional group at the C 6 position.
  • the method of preparation was identical with that used for preparing the esters (Scheme I) except that suitably 3 -substituted aminopropionitriles 2-1 were used in the first step (Scheme II).
  • R is heterocyclyl, alkoxy or dialkylamino
  • anilines of the form R - phenyl-NH 2 were prepared using SNAr reactions as shown in Scheme V (A) followed by hydrogenation converting the nitro group to the amino group.
  • the phenyl portion of the compounds depicted in Scheme V may be optionally substituted with R 101 .
  • R 300 is alkyl
  • anilines of the form R 400 -alkyl-phenyl-NH 2 were prepared using SN 2 reactions as shown in Scheme V (B) followed by hydrogenation converting the nitro group to the amino group.
  • R 200 is -C(O)(CH 2 ) n NR 203 R 204
  • anilines where R 200 is piperidinyl substituted with -C(O)-alkyl- NR 203 R 204 may be obtained according to Scheme V (D and E).
  • Ketones of formula 5-1 can be converted to a vinyl triflate of formula 5-2 by treatment with a non-nucleophilic base such as LDA and then trapping of the resulting enolate with a triflating reagent such as trifluoromethanesulfonic anhydride or preferably N-phenyltrifluoromethanesulfonimide.
  • a triflating reagent such as trifluoromethanesulfonic anhydride or preferably N-phenyltrifluoromethanesulfonimide.
  • Tetrabutylammonium bromide 200 mg was added to a mixture of 5-aminoindan (5 g, 37.6 mmol), ethyl 3-chloropropionate (4.7 mL, 37.6 mmol) and potassium carbonate (5.2 g, 37.6 mmol). The mixture was stirred at 100 °C for 16 hours. After cooling to room temperature (rt), the mixture was extracted into ethyl acetate (EtOAc), washed with water, brine and then dried with sodium sulfate (Na 2 SO 4 ).
  • EtOAc ethyl acetate
  • Potassium carbonate (1.9 g, 14.2 mmol) was added to a mixture of l-fluoro-4- nitrobenzene (1 g, 7.1 mmol) and 1-methyl-piperazine (0.94 mL, 8.5 mmol) in methyl sulfoxide (DMSO, 5 mL). The mixture was stirred at 80 °C for 3 hours. After cooling down, the residue was extracted into EtOAc. The organic layer was washed with water, brine and then dried with Na 2 SO 4 . Removal of the solvent in vacuo yielded an orange solid. The solid was dissolved in 25 mL of methanol and palladium on carbon (10% Pd/C, 50 mg) was added slowly. The system was sealed and blanketed with hydrogen.
  • the plate was developed in NH 4 OH/MeOH/CH 2 Cl 2 (1:9:90, v/v).
  • 8-Indan-5-yl-2- [4-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6- carboxylic acid ethyl ester (Cpd 1) was obtained as a yellow solid (8.6 mg, 61%).
  • Potassium carbonate (1.3 g, 9.6 mmol) was added to a mixture of 4-nitrophenol (1.11 g, 8 mmol) and epibromohydrin (1.37 mL, 16 mmol) The mixture was stirred at 100 0 C for 18 hours. After cooling down, the residue was extracted into EtOAc. The organic layer was washed with water, brine and then dried with Na 2 SO 4 . Removal of the solvent in vacuo gave an orange residue, which was purified chromatographically on silica eluting with EtOAc/ hexanes (1:10, v/v). The product was obtained as a yellow solid (0.8 g, 51%).
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from l-(4-amino-phenoxy)-3-dimethylamino-propan-2-ol (18 mg, 0.083 mmol) and 8- indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example l(e) above, 34 mg, 0.083 mmol).
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 4-morpholin-4-yl-phenylamine (6.5 mg, 0.036 mmol) and 8-indan-5-yl-2- methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example l(e) above, 15 mg, 0.036 mmol).
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 4-dimethylaminoaniline (5 ⁇ L, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5- oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example l(e) above, 15 mg, 0.036 mmol).
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 3-dimethylaminoaniline dihydrochloride (7.6 mg, 0.036 mmol) and 8-indan-5-yl-2- methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-cai"boxylic acid ethyl ester (from Example l(e) above, 15 mg, 0.036 mmol) at the presence of triethylamine (11 ⁇ L, 0.072 mmol).
  • Example 7 Using the procedure outlined in Example 7 the title compound was prepared from 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo-5,8- dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 2 ⁇ c), 5 mg). 4.3 mg of 2-[4-(3-dimethylamino-2-hydroxy-propoxy)-phenylamino]-8-indan-5-yl-5-oxo- 5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide was obtained as a yellow solid.
  • the title compound was prepared from ethyl 4-chloro-2-methylthio-5- pyrimidinecarboxylate (3.7 g, 15.8 mmol) and 3-phenylamino-propionitrile (2.3 g, 15.8 mmol) according to the procedure outlined in Example 1 (B).
  • the product was purified chromatographically (silica, EtOAc/ hexanes 1:20-1:2, v/v). A white solid was obtained (3.5 g, 65%).
  • the title compound was prepared from 4-[(2-cyano-ethyl)- ⁇ henyl-amino]-2- methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (0.78 g, 2.27 mmol) according to the procedure outlined in Example 1 (C).
  • the product was purified chromatographically (silica, EtOAc/ hexanes 1:1-1:0, v/v). A yellow solid was obtained (0.39 g, 58%).
  • 1 H NMR 300MHz, CDCl 3 ) indicated that the presence of both enol and keto forms in a 1:1 ratio.
  • the title compound was prepared from 2-methylsulfanyl-5-oxo-8-phenyl-5,6,7,8- tetrahydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (0.83 g, 2.8 mmol) according to the procedure outlined in Example 1 (D).
  • the product was purified chromatographically (silica, EtOAc/ hexanes (1:5-1:2.5, v/v) and obtained as a white solid (0.73 g, 89%).
  • Example 13 (D) the title compound was prepared from 4-(4-methyl-piperazin-l-yl)-phenylamine (32 mg, 0.16 mmol) and 2- methanesulfonyl-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrate (Example 13 (D) above, 50 mg, 0.15 mmol).
  • the product was obtained as a yellow solid (17.1 mg).
  • Example 7 Using the procedure outlined in Example 7, the title compound was prepared from 2-(4-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 4 above, 4.9 mg, 0.010 mmol). 2-(4-Dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid amide was obtained as a yellow solid (3.8 mg, 83%).
  • Example 7 Using the procedure outlined in Example 7 the title compound was prepared from 2-(3-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 5 above, 3.3 mg, 0.007 mmol). 2-(3-Dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid amide was obtained as a yellow solid (2.7 mg, 88%).
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from (3-amino-phenyl)-methanol (3.2 mg, 0.026 mmol) and 8-indan-5-yl-2- methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example l(e) above, 10 mg, 0.026 mmol).
  • Example 23 (b) Using the procedure outlined in Example 23 (a and c), the title compound was prepared from 3-morpholin-4-ylmethyl-phenylamine (5 mg) and 8-indan-5-yl-2- methaiiesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (from Example 23 (b), 7 mg). Purification by preparative HPLC (32 mL/ min, 5-100% H 2 O/ MeCN (0.01 % TFA, v/v) gradient over 10 min) gave the title compound as a white solid (3.9 mg, 35%).
  • Example 23 (c) Using the procedure outlined in Example 23 (c), the title compound was prepared from 2-amino-5-(4-methyl-piperazin-l-yl)-phenol (5 mg, prepared using the procedure outlined in Example 1 (F) from l-fluoro-2-hydroxy-4-nitrobenzene and 1-methyl- piperazine)and 8-indan-5-yl-2-methanesulfonyl-5-oxo ⁇ 5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid amide (from Example 23 (b), 7 mg).
  • Example 1 Using the procedures outlined in Example 1 (C and D), the title compound was prepared from 6-chloro-4-[(2-ethoxycarbonyl-ethyl)-indan-5-yl-amino]-nicotinic acid ethyl ester (1.6 g, 4 mmol). A white solid was obtained (500 mg, 34%).
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 4-(2-morpholin-4-yl-ethyl)-phenylamine (49 mg, 0.24 mmol) and 8-indan-5-yl-2- methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-cai"boxylic acid ethyl ester (from Example l(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a yellow solid (60 mg, 46%).
  • Example 7 Using the procedure outlined in Example 7 the title compound was prepared from 8-indan-5-yl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.037 mmol). A yellow solid was obtained (15.8 mg, 84%).
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from (4S)-4-(4-amino-benzyl)-l,3-oxazolidin-2-one (46 mg, 0.24 mmol) and 8-indan-5-yl- 2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example l(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a white solid (56 mg, 44%).
  • Example 28 Using the procedure outlined in Example 28 the title compound was prepared from (4,S)-8-indan-5-yl-5-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.038 mmol). A white solid was obtained (17.3 mg, 89%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example 29 Using the procedure outlined in Example 29 the title compound was prepared from (45)-8-indan-5-yl-5-oxo-2-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.038 mmol). A white solid was obtained (13.5 mg, 68 %) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 2-(4-amino-phenyl)-ethanesulfonic acid isopropylamide (58 mg, 0.24 mmol) and 8- indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example l(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a white solid (50 mg, 36%).
  • Example 28 Using the procedure outlined in Example 28 the title compound was prepared from 8-indan-5-yl-2-[4-(2-isopropylsulfamoyl-ethyl)-phenylamino]-5-oxo-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.034 mmol). A yellow solid was obtained (13.9 mg, 70%).
  • Example 29 Using the procedure outlined in Example 29 the title compound was prepared from 8-indan-5-yl-2-[4-(2-isopropylsulfamoyl-ethyl)-phenylamino]-5-oxo-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (15 mg, 0.026 mmol). A yellow solid was obtained (7.5 mg, 50%).
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamine (65 mg, 0.24 mmol) and 8-indan-5- yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-cai'boxylic acid ethyl ester (from Example l(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a white solid (42 mg, 29%).
  • Example 28 Using the procedure outlined in Example 28 the title compound was prepared from 8-indan-5-yl-2- ⁇ 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino ⁇ -5-oxo-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (12 mg, 0.020 mmol). A yellow solid was obtained (6.4 mg, 54%).
  • Example 35 (B), 12 mg, 0.020 mmol).
  • a yellow solid was obtained (7.6 mg, 63%).
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 3-(4-methyl-piperazin-l-yl)-phenylamine (50 mg, 0.27 mmol) and 8-indan-5-yl-2- methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example l(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a yellow solid (60 mg, 46%).
  • Example 7 Using the procedure outlined in Example 7 the title compound was prepared from 8-indan-5-yl-2-[3-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester ( from B above, 20 mg, 0.038 mmol). A yellow solid was obtained (8.3 mg, 44%).
  • Example 28 Using the procedure outlined in Example 28 the title compound was prepared from 8-indan-5-yl-2-[3-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 37(B) above, 15 mg, 0.028 mmol). A yellow solid was obtained (8.8 mg, 62%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example 29 Using the procedure outlined in Example 29 the title compound was prepared from 8-indan-5-yl-2-[3-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydiO-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 37(B) above, 15 mg, 0.028 mmol). A yellow solid was obtained (8.6 mg, 59%) after a preparative HPLC (32 mIV min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example 28 Using the procedure outlined in Example 28 the title compound was prepared from 8-indan-5-yl-5-oxo-2-(4-piperazin-l-yl-phenylamino)-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 40(B) above, 20 mg, 0.039 mmol). A yellow solid was obtained (TFA salt, 12.2 mg, 51%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example 29 Using the procedure outlined in Example 29 the title compound was prepared from 8-indan-5-yl-5-oxo-2-(4-piperazin-l-yl-phenylamino)-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 40(B) above, 20 mg, 0.039 mmol). A yellow solid was obtained (TFA salt, 4.4 mg, 22%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 4-(3,5-dimethyl-piperazin-l-yl)-phenylamine (from the previous step, 27 mg, 0.13 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6- carboxylic acid ethyl ester (from Example l(e) above, 50 mg, 0.12 mmol). A yellow solid was obtained (40 mg, 62 %) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example 7 Using the procedure outlined in Example 7 the title compound was prepared from 2-[4-(3,5-dimethyl-piperazin-l-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from B above, 15 mg, 0.028 mmol). The title compound was obtained as a TFA salt after a preparative HPLC (32 mL/ min 5- 100% MeCN/ H 2 O gradient over 10 min) purification (10.5 mg, 60%).
  • Example 28 Using the procedure outlined in Example 28 the title compound was prepared from 2-[4-(3,5-dimethyl-piperazin-l-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 43(B) above, 15 mg, 0.028 mmol). A yellow solid was obtained (TFA salt, 9.6 mg, 54%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example 29 Using the procedure outlined in Example 29, the title compound was prepared from 2-[4-(3,5-dimethyl-piperazin-l-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 43(B) above, 10 mg, 0.018 mmol). A yellow solid was obtained (TFA salt, 5.2mg, 44%) after a preparative HPLC (32 niL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 4-[2-(4-methyl-piperazin-l-yl)-ethyl]-phenylamine (53 mg, 0.24 mmol) and 8-indan- 5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-dJpyrimidine-6-cai-boxylic acid ethyl ester (from Example l(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a yellow solid (70 mg, 53%).
  • Example 7 Using the procedure outlined in Example 7 the title compound was prepared from 8-indan-5-yl-2- ⁇ 4-[2-(4-methyl-piperazin- 1 -yl)-ethyl] -phenylamino ⁇ -5-oxo-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.036 mmol). A yellow solid was obtained (5.8 mg, 30%).
  • Example 28 Using the procedure outlined in Example 28 the title compound was prepared from 8-indan-5-yl-2- ⁇ 4- [2-(4-methyl-piperazin- 1 -yl)-ethyl] -phenylamino ⁇ -5-oxo-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 46(B) above, 20 mg, 0.036 mmol). A yellow solid was obtained (5.1 mg, 26%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example 29 Using the procedure outlined in Example 29 the title compound was prepared from 8-indan-5-yl-2- ⁇ 4-[2-(4-methyl-piperazin-l-yl)-ethyl]-phenylamino ⁇ -5-oxo-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 46(B) above, 20 mg, 0.036 mmol). A yellow solid was obtained (7.1 mg, 36%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 4-(4-amino-phenyl)-piperidine-l-carboxylic acid terf-butyl ester (from the previous step, 66 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example l(e), 100 mg, 0.24 mmol). A yellow solid was obtained (75 mg, 51 %) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example 7 Using the procedure outlined in Example 7 the title compound was prepared from 8-indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (27 mg, 0.053 mmol). A yellow solid was obtained as a TFA salt after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification (24 mg, 76 %).
  • Example 28 Using the procedure outlined in Example 28 the title compound was prepared from 8-indan-5-yl-5-oxo-2-(4-piperidin-4 ⁇ yl ⁇ phenylamino)-5,8-dihydro-pyrido[2,3- d]pyrimidine ⁇ 6-carboxylic acid ethyl ester (from Example 48(C) above, 20 mg, 0.039 mmol). A yellow solid was obtained (TFA salt, 8.9 mg, 37%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example 29 Using the procedure outlined in Example 29 the title compound was prepared from 8 ⁇ indan-5-yl-5-oxo-2-(4-piperidin-4-yl-phenylamino)-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 48(C) above, 20 mg, 0.039 mmol). A yellow solid was obtained (TFA salt, 7.3 mg, 30%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 4-(3-amino-phenyl)-piperazine-l-carboxylic acid terf-butyl ester (from the previous step, 54 mg, 0.19 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example l(e) above, 80 mg, 0.19 mmol). A yellow solid was obtained (60 mg, 62 %) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example 7 Using the procedure outlined in Example 7 the title compound was prepared from 8-indan-5-yl-5-oxo-2-(3-piperazin-l-yl-phenylamino)-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step, 20 mg, 0.038 mmol). The title compound was obtained as a TFA salt after a preparative HPLC (32 mL/ min 5- 100% MeCN/ H 2 O gradient over 10 min) purification (6.9 mg, 30%).
  • Example 28 Using the procedure outlined in Example 28 the title compound was prepared from 8-indan-5 -yl-5 -oxo-2-(3 -piperazin- 1 -yl-phenylamino)-5 , 8-dihydro-pyrido [2,3 - d]pyrimidine-6-carboxylic acid ethyl ester (from Example 52(B) above, 20 mg, 0.039 mmol). A yellow solid was obtained (TFA salt, 13.2 mg, 56%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example 29 Using the procedure outlined in Example 29 the title compound was prepared from 8-indan-5-yl-5-oxo-2-(3-piperazin-l-yl-phenylamino) ⁇ 5,8-dmydro-pyrido ⁇ 2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 52(B) above, 20 mg, 0.039 mmol). A yellow solid was obtained (TFA salt, 8.5 mg, 35%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 3-(3,5-dimethyl-piperazin-l-yl)-phenylamine (from the previous step, 52 mg, 0.25 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6- carboxylic acid ethyl ester (from Example l(e) above, 100 mg, 0.24 mmol). A yellow solid was obtained (67 mg, 52 %) after a preparative HPLC (32 niL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example 7 Using the procedure outlined in Example 7 the title compound was prepared from 2- [3 -(3 ,5 -dimethyl-piperazin- 1 -yl)-phenylamino] - 8 -indan-5-yl-5-oxo-5 , 8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step, 15 mg, 0.028 mmol). The title compound was obtained as a TFA salt after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification (10.8 mg, 62%).
  • Example 28 Using the procedure outlined in Example 28 the title compound was prepared from 2-[3-(3,5-dimethyl-piperazin-l-yl)-phenylamino]-8-indan-5-yl-5-oxo-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 55(B), 15 mg, 0.028 mmol). A yellow solid was obtained (TFA salt, 5.3 mg, 30%) after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification.
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 4-(2-rnorpholin-4-yl-ethyl)- ⁇ henylamine (from Example 27(A), 54 mg, 0.26 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d] ⁇ yrimidine-6- carboxylic acid ethyl ester (from Example 17(e) above, 100 mg, 0.26 mmol). The title compound was obtained as a white solid (77 mg, 59%).
  • Example 7 Using the procedure outlined in Example 7 the title compound was prepared from 8-cyclohexyl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step, 20 mg, 0.039 mmol). The title compound was obtained as yellow solid after a preparative HPLC (32 niL/ min 5- 100% MeCN/ H 2 O gradient over 10 min) purification (10.7 mg, 56%).
  • Example 28 Using the procedure outlined in Example 28 the title compound was prepared from 8 -cyclohexyl-2- [4-(2-morpholin-4 ⁇ yl-ethyl)-phenyl amino] -5 -oxo-5 , 8-dihydro- ⁇ yrido [2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 57(A), 20 mg, 0.039 mmol). The title compound was obtained as yellow solid after a preparative HPLC (32 niL/ min 5- 100% MeCN/ H 2 O gradient over 10 min) purification (13.4 mg, 70%).
  • Example 29 Using the procedure outlined in Example 29, the title compound was prepared from 8-cyclohexyl-2-[4-(2-morpholin-4-yl-ethyl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 57(A), 20 mg, 0.039 mmol). The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5- 100% MeCN/ H 2 O gradient over 10 min) purification (11.9 mg, 60%).
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 4-(4-methyl-piperazin-l-yl)- ⁇ henylamine (50 mg, 0.26 mmol) and 8-cyclohexyl-2- methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e), 100 mg, 0.26 mmol). The title compound was obtained as a yellow solid (80 mg, 63%).
  • Example 7 Using the procedure outlined in Example 7 the title compound was prepared from 8-cyclohexyl-2-[4-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step, 20 mg, 0.040 mmol). The title compound was obtained as yellow solid after a preparative HPLC (32 niL/ min 5- 100% MeCN/ H 2 O gradient over 10 min) purification (9.9 mg, 54%).
  • Example 28 Using the procedure outlined in Example 28 the title compound was prepared from 8-cyclohexyl-2-[4-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 60(A), 20 mg, 0.040 mmol). The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5- 100% MeCN/ H 2 O gradient over 10 min) purification (9.0 mg, 47%).
  • Example 29 Using the procedure outlined in Example 29 the title compound was prepared from 8-cyclohexyl-2-[4-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 60(A), 20 mg, 0.040 mmol). The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5- 100% MeCN/ H 2 O gradient over 10 min) purification (8.3 mg, 42%).
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 3 -(4-methyl-piperazin- l-yl)-phenylamine (from Example 37(A), 55 mg, 0.29 mmol) and 8-cyclohexyl-2-methanesulf onyl-5 -oxo-5 , 8-dihydro-pyrido [2, 3-d]pyrimidine-6- carboxylic acid ethyl ester (from Example 17(e), 100 mg, 0.26 mmol). The title compound was obtained as a yellow solid (72 mg, 56%).
  • Example 7 Using the procedure outlined in Example 7 the title compound was prepared from 8-cyclohexyl-2-[3-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step, 20 mg, 0.040 mmol). The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5- 100% MeCN/ H 2 O gradient over 10 min) purification (2.3 mg, 12%).
  • Example 29 Using the procedure outlined in Example 29 the title compound was prepared from 8-cyclohexyl-2-[3-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 63(A), 20 mg, 0.040 mmol). The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5- 100% MeCN/ H 2 O gradient over 10 min) purification (7.5 mg, 38%).
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 2-(4-amino-phenyl)-ethanesulfonic acid isopropylamide (from Example 33(B), 68 mg, 0.28 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e), 100 mg, 0.26 mmol). The title compound was obtained as a yellow solid (50 mg, 35%).
  • Example 7 Using the procedure outlined in Example 7 the title compound was prepared from 8-cyclohexyl-2- ⁇ 4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamino ⁇ -5-oxo-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step, 20 mg, 0.035 mmol). The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification (9.2 mg, 49%).
  • Example l(g) Using the procedure outlined in Example l(g) the title compound was prepared from 4-[l-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenylamine (from Example 70(B)), 73 mg, 0.28 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e), 100 mg, 0.26 mmol). The title compound was obtained as a white solid (40 mg, 25%).
  • Example 7 Using the procedure outlined in Example 7 the title compound was prepared from 8-cyclohexyl-2- ⁇ 4- [ 1 -(2-dimethylamino-acetyl)-piperidin-4-yl] -phenylamino ⁇ -5-oxo-5,8- dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from the previous step, 20 mg, 0.036 mmol). The title compound was obtained as yellow solid after a preparative HPLC (32 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) purification (16 mg, 84%).
  • reaction mixture was concentrated and purified by preparative HPLC (30 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) and lyophilized to provide 24 mg (80%) of 2- ⁇ 4- [ 1 -(2-Dimethylamino-acetyl)-piperidin-4-yl] -phenylamino ⁇ -8-indan-5-yl-5- oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester.
  • reaction mixture was concentrated and purified by preparative HPLC (30 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) and lyophilized to provide 16.5 mg of 2- ⁇ 3-[l-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenylamino ⁇ -8-indan-5-yl-5- oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester.
  • reaction mixture was concentrated and purified by preparative HPLC (30 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) and lyophilized to provide 16.5 mg of 2- ⁇ 3-[l-(2-Dimethylamino-acetyl)-piperidin-4-yl]-phenylamino ⁇ -8-indan-5-yl-5- oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester.
  • reaction mixture was concentrated and purified by preparative HPLC (30 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) and lyophilized to provide 20 mg of 8-Indan-5-yl-2-[4-(4-methyl-piperazin-l-ylmethyl)-phenylamino]-5-oxo-5,8-dihydro- pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester.
  • reaction mixture was concentrated and purified by preparative HPLC (30 mL/ min 5-100% MeCN/ H 2 O gradient over 10 min) and lyophilized to provide 66 mg of 2-(4- Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3- d] ⁇ yrimidine-6-carboxylic acid ethyl ester.
  • reaction mixture was concentrated and purified by preparative HPLC (30 rnL/ min 5-100% MeCN/ H 2 O gradient over 10 min) and lyophilized to provide 56 mg of 2-(3- Dimethylaminomethyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester.
  • Bicyclo[2.2.1]hept-2-ylamine (2.0 g, 18.0 mmol) and 4-chloro-2-methylsulfanyl- pyrimidine-5-carboxylic acid ethyl ester (2.45 g, 18.0 mmol) were combined neat and K 2 CO 3 (3.72 g, 27.0 mmol) and a catalytic amount of tetrabutylammonium iodide (ca. 2 mg) was added. The mixture was heated at 80 0 C overnight. The resulting mixture was then partitioned between water and DCM.
  • Recrystallization from /-PrOH provided 0.51 g of 8-bicyclo[2.2.1]hept-2-yl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3- d]pyrimidine-6-carboxylic acid ethyl ester.
  • reaction mixture was concentrated and purified by preparative HPLC (C- 18 column, 32 mL/ min 5-100% MeCN/ H 2 O gradient over 15 min) and lyophilized to provide 11.4 mg of 8-bicyclo[2.2.1]hept-2-yl-2- [4-(4-methyl-piperazin-l-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6- carboxylic acid ethyl ester.

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Abstract

L'invention concerne le besoin actuel d'inhibiteurs sélectifs et puissants de la protéine tyrosine kinase qui consiste à fournir des inhibiteurs puissants de kinase C-FMS. L'invention concerne les nouveaux composés de la formule I; ou un solvate, un hydrate, un tautomère ou un sel pharmaceutiquement acceptable de ceux-ci. W, A, Y, Z, R101 et R200 sont précisés dans le descriptif.
EP06803485A 2005-09-14 2006-09-13 5-oxo-5,8-dihydro-pyrido-pyrimidines comme inhibiteurs de kinase c-fms Withdrawn EP1937681A1 (fr)

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TW200800983A (en) 2005-09-14 2008-01-01 Janssen Pharmaceutica Nv 5-oxo-5,8-dihydro-pyrido-pyrimidines as inhibitors of C-FMS kinase
US7642270B2 (en) 2005-09-14 2010-01-05 Janssen Pharmaceutica N.V. 5-oxo-5,8-dihydro-pyrido-pyrimidine as inhibitors of c-fms kinase
WO2008055013A2 (fr) * 2006-10-31 2008-05-08 Janssen Pharmaceutica N.V. 5-oxo-5,8-dihydro-pyrido-pyrimidines comme inhibiteurs de la kinase c-fms
EP2201010B1 (fr) 2007-09-14 2013-11-06 Vertex Pharmaceuticals Incorporated Modulateurs du régulateur de la conductance transmembranaire de la mucoviscidose
GB0919274D0 (en) * 2009-11-03 2009-12-16 Univ The Glasgow Plasma generation apparatus and use of plasma generation apparatus
FR2955109B1 (fr) * 2010-01-08 2012-09-07 Sanofi Aventis Derives de 5-oxo-5,8-dihydro-pyrido[2, 3-d]pyrimidine, leur preparation et leur application en therapeutique
KR101939682B1 (ko) * 2011-05-27 2019-01-17 바이엘 인텔렉쳐 프로퍼티 게엠베하 Ｎ-｛3,4-디플루오로-2-〔(2-플루오로-4-요오도페닐)아미노〕-6-메톡시페닐｝-1-[2,3-디하이드록시프로필]사이클로프로판설폰아미드의 키랄 합성
CN103435608A (zh) * 2013-08-22 2013-12-11 中国药科大学 吡啶并嘧啶类plk1抑制剂及其用途
US10954216B2 (en) 2016-12-27 2021-03-23 Riken BMP-signal-inhibiting compound
CN111848613B (zh) * 2020-08-11 2021-09-24 山东大学 一种二芳基嘧啶骈吡啶酮类衍生物及其制备方法与应用
WO2023125812A1 (fr) * 2021-12-31 2023-07-06 上海海雁医药科技有限公司 Dérivé de pyrimidone substitué, composition pharmaceutique et utilisation médicale de celui-ci

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IL117923A (en) * 1995-05-03 2000-06-01 Warner Lambert Co Anti-cancer pharmaceutical compositions containing polysubstituted pyrido¬2,3-d¾pyrimidine derivatives and certain such novel compounds
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